10188109|a|<g>Transforming growth factor-beta</g> <g>TGF-beta</g> and <g>tumor necrosis factor-alpha</g> <g>TNF-alpha</g> are two polypeptide mediators which are believed to play a role in the evolution of <d>idiopathic pulmonary fibrosis</d> IPF. We have evaluated the effect of these two substances on the expression of receptors for collagen c<g>C1q</g>-R and globular g<g>C1q</g>-R domains of <g>C1q</g> and on type I collagen in human lung fibroblasts. Two fibroblast subpopulations differing in <g>C1q</g> receptor expression were obtained by culturing human lung explants in medium containing fresh human serum and heated plasma-derived serum and separating them based on <g>C1q</g> binding [Narayanan, Lurton and Raghu: Am J Resp Cell Mol Biol. 1998; 17:84]. The cells, referred to as HH and NL cells, respectively, were exposed to <g>TGF-beta</g> and <g>TNF-alpha</g> in serum-free conditions. The levels of mRNA were assessed by in situ hybridization and Northern analysis, and protein levels compared after SDS-polyacrylamide gel electrophoresis and Western blotting. NL cells exposed to <g>TGF-beta</g> and <g>TNF-alpha</g> contained 1.4 and 1.6 times as much c<g>C1q</g>-R mRNA, respectively, whereas in HH cells c<g>C1q</g>-R mRNA increased 2.0- and 2.4-fold. The g<g>C1q</g>-R mRNA levels increased to a lesser extent in both cells. These increases were not reflected in protein levels of C<g>C1q</g>-R and g<g>C1q</g>-R, which were similar to or less than controls. Both <g>TGF-beta</g> and <g>TNF-alpha</g> also increased procollagen [I] mRNA levels in both cells. Overall, <g>TNF-alpha</g> caused a greater increase and the degree of response by HH fibroblasts to both <g>TGF-beta</g> and <g>TNF-alpha</g> was higher than NL cells. These results indicated that <g>TGF-beta</g> and <g>TNF-alpha</g> upregulate the mRNA levels for c<g>C1q</g>-R and collagen and that they do not affect g<g>C1q</g>-R mRNA levels significantly. They also indicated different subsets of human lung fibroblasts respond differently to inflammatory mediators.
10188109|a|<g>Transforming growth factor-beta</g> <g>TGF-beta</g> and <g>tumor necrosis factor-alpha</g> <g>TNF-alpha</g> are two polypeptide mediators which are believed to play a role in the evolution of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. We have evaluated the effect of these two substances on the expression of receptors for collagen c<g>C1q</g>-R and globular g<g>C1q</g>-R domains of <g>C1q</g> and on type I collagen in human lung fibroblasts. Two fibroblast subpopulations differing in <g>C1q</g> receptor expression were obtained by culturing human lung explants in medium containing fresh human serum and heated plasma-derived serum and separating them based on <g>C1q</g> binding [Narayanan, Lurton and Raghu: Am J Resp Cell Mol Biol. 1998; 17:84]. The cells, referred to as HH and NL cells, respectively, were exposed to <g>TGF-beta</g> and <g>TNF-alpha</g> in serum-free conditions. The levels of mRNA were assessed by in situ hybridization and Northern analysis, and protein levels compared after SDS-polyacrylamide gel electrophoresis and Western blotting. NL cells exposed to <g>TGF-beta</g> and <g>TNF-alpha</g> contained 1.4 and 1.6 times as much c<g>C1q</g>-R mRNA, respectively, whereas in HH cells c<g>C1q</g>-R mRNA increased 2.0- and 2.4-fold. The g<g>C1q</g>-R mRNA levels increased to a lesser extent in both cells. These increases were not reflected in protein levels of C<g>C1q</g>-R and g<g>C1q</g>-R, which were similar to or less than controls. Both <g>TGF-beta</g> and <g>TNF-alpha</g> also increased procollagen [I] mRNA levels in both cells. Overall, <g>TNF-alpha</g> caused a greater increase and the degree of response by HH fibroblasts to both <g>TGF-beta</g> and <g>TNF-alpha</g> was higher than NL cells. These results indicated that <g>TGF-beta</g> and <g>TNF-alpha</g> upregulate the mRNA levels for c<g>C1q</g>-R and collagen and that they do not affect g<g>C1q</g>-R mRNA levels significantly. They also indicated different subsets of human lung fibroblasts respond differently to inflammatory mediators.
10337028|a|The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for <d>lymphocytic alveolitis</d> in interstitial lung disease ILD, alphaE expression on CD4+ and CD8+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid BALF of patients with idiopathic pulmonary fibrosis IPF; n = 18, hypersensitivity pneumonitis HP; n = 20 and sarcoidosis n = 44 in comparison with healthy controls n = 15. In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar CD8+ T cells consistently co-expressed alphaE. Absolute alveolar CD8+alphaE+ cell numbers/ml were up to 30-fold increased in HP patients. Proportions of alphaE-bearing CD4+ cells in BALF were significantly elevated in IPF 74.0 +/- 2.7% and HP 70.0 +/- 2.4% compared with normals 30.0 +/- 1.8% mean +/- s.e.m.; P < 0.01. In sarcoidosis, the alphaE expression on BALF CD4+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I 14.3 +/- 1.5%, but increased proportions in stages II 50.0 +/- 3.8% and III 64.0 +/- 4.8%. Correlations between common markers of T cell activation or BALF transforming growth factor-beta TGF-beta  bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar CD8+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar CD4+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung.
10337028|a|The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for <d>lymphocytic alveolitis</d> in <d>interstitial lung disease</d> ILD, alphaE expression on CD4+ and CD8+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid BALF of patients with idiopathic pulmonary fibrosis IPF; n = 18, hypersensitivity pneumonitis HP; n = 20 and sarcoidosis n = 44 in comparison with healthy controls n = 15. In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar CD8+ T cells consistently co-expressed alphaE. Absolute alveolar CD8+alphaE+ cell numbers/ml were up to 30-fold increased in HP patients. Proportions of alphaE-bearing CD4+ cells in BALF were significantly elevated in IPF 74.0 +/- 2.7% and HP 70.0 +/- 2.4% compared with normals 30.0 +/- 1.8% mean +/- s.e.m.; P < 0.01. In sarcoidosis, the alphaE expression on BALF CD4+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I 14.3 +/- 1.5%, but increased proportions in stages II 50.0 +/- 3.8% and III 64.0 +/- 4.8%. Correlations between common markers of T cell activation or BALF transforming growth factor-beta TGF-beta  bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar CD8+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar CD4+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung.
10337028|a|The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for <d>lymphocytic alveolitis</d> in <d>interstitial lung disease</d> <d>ILD</d>, alphaE expression on CD4+ and CD8+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid BALF of patients with idiopathic pulmonary fibrosis IPF; n = 18, hypersensitivity pneumonitis HP; n = 20 and sarcoidosis n = 44 in comparison with healthy controls n = 15. In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar CD8+ T cells consistently co-expressed alphaE. Absolute alveolar CD8+alphaE+ cell numbers/ml were up to 30-fold increased in HP patients. Proportions of alphaE-bearing CD4+ cells in BALF were significantly elevated in IPF 74.0 +/- 2.7% and HP 70.0 +/- 2.4% compared with normals 30.0 +/- 1.8% mean +/- s.e.m.; P < 0.01. In sarcoidosis, the alphaE expression on BALF CD4+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I 14.3 +/- 1.5%, but increased proportions in stages II 50.0 +/- 3.8% and III 64.0 +/- 4.8%. Correlations between common markers of T cell activation or BALF transforming growth factor-beta TGF-beta  bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar CD8+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar CD4+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung.
10337028|a|The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for <d>lymphocytic alveolitis</d> in <d>interstitial lung disease</d> <d>ILD</d>, alphaE expression on <g>CD4</g>+ and <g>CD8</g>+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid BALF of patients with <d>idiopathic pulmonary fibrosis</d> IPF; n = 18, hypersensitivity pneumonitis HP; n = 20 and sarcoidosis n = 44 in comparison with healthy controls n = 15. In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar <g>CD8</g>+ T cells consistently co-expressed alphaE. Absolute alveolar <g>CD8</g>+alphaE+ cell numbers/ml were up to 30-fold increased in HP patients. Proportions of alphaE-bearing <g>CD4</g>+ cells in BALF were significantly elevated in IPF 74.0 +/- 2.7% and HP 70.0 +/- 2.4% compared with normals 30.0 +/- 1.8% mean +/- s.e.m.; P < 0.01. In sarcoidosis, the alphaE expression on BALF <g>CD4</g>+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I 14.3 +/- 1.5%, but increased proportions in stages II 50.0 +/- 3.8% and III 64.0 +/- 4.8%. Correlations between common markers of T cell activation or BALF transforming growth factor-beta TGF-beta  bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar <g>CD8</g>+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar <g>CD4</g>+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung.
10337028|a|The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for <d>lymphocytic alveolitis</d> in <d>interstitial lung disease</d> <d>ILD</d>, alphaE expression on <g>CD4</g>+ and <g>CD8</g>+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid BALF of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>; n = 18, hypersensitivity pneumonitis HP; n = 20 and sarcoidosis n = 44 in comparison with healthy controls n = 15. In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar <g>CD8</g>+ T cells consistently co-expressed alphaE. Absolute alveolar <g>CD8</g>+alphaE+ cell numbers/ml were up to 30-fold increased in HP patients. Proportions of alphaE-bearing <g>CD4</g>+ cells in BALF were significantly elevated in <d>IPF</d> 74.0 +/- 2.7% and HP 70.0 +/- 2.4% compared with normals 30.0 +/- 1.8% mean +/- s.e.m.; P < 0.01. In sarcoidosis, the alphaE expression on BALF <g>CD4</g>+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I 14.3 +/- 1.5%, but increased proportions in stages II 50.0 +/- 3.8% and III 64.0 +/- 4.8%. Correlations between common markers of T cell activation or BALF transforming growth factor-beta TGF-beta  bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar <g>CD8</g>+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar <g>CD4</g>+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung.
10337028|a|The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for <d>lymphocytic alveolitis</d> in <d>interstitial lung disease</d> <d>ILD</d>, alphaE expression on <g>CD4</g>+ and <g>CD8</g>+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid BALF of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>; n = 18, <d>hypersensitivity pneumonitis</d> HP; n = 20 and sarcoidosis n = 44 in comparison with healthy controls n = 15. In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar <g>CD8</g>+ T cells consistently co-expressed alphaE. Absolute alveolar <g>CD8</g>+alphaE+ cell numbers/ml were up to 30-fold increased in HP patients. Proportions of alphaE-bearing <g>CD4</g>+ cells in BALF were significantly elevated in <d>IPF</d> 74.0 +/- 2.7% and HP 70.0 +/- 2.4% compared with normals 30.0 +/- 1.8% mean +/- s.e.m.; P < 0.01. In sarcoidosis, the alphaE expression on BALF <g>CD4</g>+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I 14.3 +/- 1.5%, but increased proportions in stages II 50.0 +/- 3.8% and III 64.0 +/- 4.8%. Correlations between common markers of T cell activation or BALF transforming growth factor-beta TGF-beta  bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar <g>CD8</g>+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar <g>CD4</g>+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung.
10337028|a|The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for <d>lymphocytic alveolitis</d> in <d>interstitial lung disease</d> <d>ILD</d>, alphaE expression on <g>CD4</g>+ and <g>CD8</g>+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid BALF of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>; n = 18, <d>hypersensitivity pneumonitis</d> <d>HP</d>; n = 20 and sarcoidosis n = 44 in comparison with healthy controls n = 15. In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar <g>CD8</g>+ T cells consistently co-expressed alphaE. Absolute alveolar <g>CD8</g>+alphaE+ cell numbers/ml were up to 30-fold increased in <d>HP</d> patients. Proportions of alphaE-bearing <g>CD4</g>+ cells in BALF were significantly elevated in <d>IPF</d> 74.0 +/- 2.7% and <d>HP</d> 70.0 +/- 2.4% compared with normals 30.0 +/- 1.8% mean +/- s.e.m.; P < 0.01. In sarcoidosis, the alphaE expression on BALF <g>CD4</g>+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I 14.3 +/- 1.5%, but increased proportions in stages II 50.0 +/- 3.8% and III 64.0 +/- 4.8%. Correlations between common markers of T cell activation or BALF transforming growth factor-beta TGF-beta  bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar <g>CD8</g>+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar <g>CD4</g>+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung.
10337028|a|The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for <d>lymphocytic alveolitis</d> in <d>interstitial lung disease</d> <d>ILD</d>, alphaE expression on <g>CD4</g>+ and <g>CD8</g>+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid BALF of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>; n = 18, <d>hypersensitivity pneumonitis</d> <d>HP</d>; n = 20 and <d>sarcoidosis</d> n = 44 in comparison with healthy controls n = 15. In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar <g>CD8</g>+ T cells consistently co-expressed alphaE. Absolute alveolar <g>CD8</g>+alphaE+ cell numbers/ml were up to 30-fold increased in <d>HP</d> patients. Proportions of alphaE-bearing <g>CD4</g>+ cells in BALF were significantly elevated in <d>IPF</d> 74.0 +/- 2.7% and <d>HP</d> 70.0 +/- 2.4% compared with normals 30.0 +/- 1.8% mean +/- s.e.m.; P < 0.01. In <d>sarcoidosis</d>, the alphaE expression on BALF <g>CD4</g>+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I 14.3 +/- 1.5%, but increased proportions in stages II 50.0 +/- 3.8% and III 64.0 +/- 4.8%. Correlations between common markers of T cell activation or BALF transforming growth factor-beta TGF-beta  bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar <g>CD8</g>+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar <g>CD4</g>+ lymphocytes in <d>sarcoidosis</d> are related to the diverse manifestations of the sarcoid inflammatory process in the lung.
10931794|a|Interstitial pulmonary <d>fibrosis</d> IPF is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases. The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for this lack of useful treatments is that few of the molecular mechanisms of disease have been defined sufficiently to design appropriate targets for therapy. Our laboratory has focused on the molecular mechanisms through which three selected peptide growth factors could play a role in the development of IPF. Hundreds of growth factors and cytokines could be involved in the complex disease process. We are studying platelet-derived growth factor because it is the most potent mesenchymal cell mitogen yet described, transforming growth factor beta because it is a powerful inducer of extracellular matrix scar tissue components by mesenchymal cells, and tumor necrosis factor alpha because it is a pleiotropic cytokine that we and others have shown is essential for the development of IPF in animal models. This review describes some of the evidence from studies in humans, in animal models, and in vitro, that supports the growth factor hypothesis. The use of modern molecular and transgenic technologies could elucidate those targets that will allow effective therapeutic approaches.
10931794|a|Interstitial pulmonary <d>fibrosis</d> <d>IPF</d> is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases. The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for this lack of useful treatments is that few of the molecular mechanisms of disease have been defined sufficiently to design appropriate targets for therapy. Our laboratory has focused on the molecular mechanisms through which three selected peptide growth factors could play a role in the development of <d>IPF</d>. Hundreds of growth factors and cytokines could be involved in the complex disease process. We are studying platelet-derived growth factor because it is the most potent mesenchymal cell mitogen yet described, transforming growth factor beta because it is a powerful inducer of extracellular matrix scar tissue components by mesenchymal cells, and tumor necrosis factor alpha because it is a pleiotropic cytokine that we and others have shown is essential for the development of <d>IPF</d> in animal models. This review describes some of the evidence from studies in humans, in animal models, and in vitro, that supports the growth factor hypothesis. The use of modern molecular and transgenic technologies could elucidate those targets that will allow effective therapeutic approaches.
11306432|a|It has been reported that transforming growth factor TGF-beta, which plays an integral role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF, suppresses proliferation of alveolar epithelial cells in vitro. Although hyperplastic lesions of alveolar lining epithelial cells ALECs are characteristic pathologic features of IPF, the mechanism of their involvement in the pathogenesis has not yet been extensively studied. On the assumption that the hyperplastic ALECs have escaped from the growth-inhibitory effects of TGF-beta, we searched for mutations in the microsatellite of the TGF-beta receptor type II T beta RII gene. To detect a deletion in the polyadenine tract in exon 3 of the T beta RII gene, cells were isolated by microdissection from lung sections of IPF patients, and DNA was extracted from these cells and amplified by high-fidelity polymerase chain reaction. A total of 121 sites of hyperplastic ALECs from 11 IPF patients were analyzed, and a one-base-pair deletion was detected in nine sites from five patients. The mutation was also detected in smooth muscle-like cells of the thickened pulmonary artery. In some tissue areas where the deletion was detected, low T beta RII expression was confirmed by immunohistochemical staining. These data suggest that microsatellite instability in the T beta RII gene occurred in some lesions of hyperplastic ALECs in IPF, although at a low incidence, and that this genetic disorder might play a partial role in the pathologic changes of IPF.
11306432|a|It has been reported that transforming growth factor TGF-beta, which plays an integral role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, suppresses proliferation of alveolar epithelial cells in vitro. Although hyperplastic lesions of alveolar lining epithelial cells ALECs are characteristic pathologic features of <d>IPF</d>, the mechanism of their involvement in the pathogenesis has not yet been extensively studied. On the assumption that the hyperplastic ALECs have escaped from the growth-inhibitory effects of TGF-beta, we searched for mutations in the microsatellite of the TGF-beta receptor type II T beta RII gene. To detect a deletion in the polyadenine tract in exon 3 of the T beta RII gene, cells were isolated by microdissection from lung sections of <d>IPF</d> patients, and DNA was extracted from these cells and amplified by high-fidelity polymerase chain reaction. A total of 121 sites of hyperplastic ALECs from 11 <d>IPF</d> patients were analyzed, and a one-base-pair deletion was detected in nine sites from five patients. The mutation was also detected in smooth muscle-like cells of the thickened pulmonary artery. In some tissue areas where the deletion was detected, low T beta RII expression was confirmed by immunohistochemical staining. These data suggest that microsatellite instability in the T beta RII gene occurred in some lesions of hyperplastic ALECs in <d>IPF</d>, although at a low incidence, and that this genetic disorder might play a partial role in the pathologic changes of <d>IPF</d>.
11306432|a|It has been reported that transforming growth factor TGF-beta, which plays an integral role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, suppresses proliferation of alveolar epithelial cells in vitro. Although <d>hyperplastic lesions</d> of alveolar lining epithelial cells ALECs are characteristic pathologic features of <d>IPF</d>, the mechanism of their involvement in the pathogenesis has not yet been extensively studied. On the assumption that the hyperplastic ALECs have escaped from the growth-inhibitory effects of TGF-beta, we searched for mutations in the microsatellite of the TGF-beta receptor type II T beta RII gene. To detect a deletion in the polyadenine tract in exon 3 of the T beta RII gene, cells were isolated by microdissection from lung sections of <d>IPF</d> patients, and DNA was extracted from these cells and amplified by high-fidelity polymerase chain reaction. A total of 121 sites of hyperplastic ALECs from 11 <d>IPF</d> patients were analyzed, and a one-base-pair deletion was detected in nine sites from five patients. The mutation was also detected in smooth muscle-like cells of the thickened pulmonary artery. In some tissue areas where the deletion was detected, low T beta RII expression was confirmed by immunohistochemical staining. These data suggest that microsatellite instability in the T beta RII gene occurred in some lesions of hyperplastic ALECs in <d>IPF</d>, although at a low incidence, and that this genetic disorder might play a partial role in the pathologic changes of <d>IPF</d>.
11306432|a|It has been reported that transforming growth factor TGF-beta, which plays an integral role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, suppresses proliferation of alveolar epithelial cells in vitro. Although <d>hyperplastic lesions</d> of alveolar lining epithelial cells ALECs are characteristic pathologic features of <d>IPF</d>, the mechanism of their involvement in the pathogenesis has not yet been extensively studied. On the assumption that the hyperplastic ALECs have escaped from the growth-inhibitory effects of TGF-beta, we searched for mutations in the microsatellite of the TGF-beta receptor type II <g>T beta RII</g> gene. To detect a deletion in the polyadenine tract in exon 3 of the <g>T beta RII</g> gene, cells were isolated by microdissection from lung sections of <d>IPF</d> patients, and DNA was extracted from these cells and amplified by high-fidelity polymerase chain reaction. A total of 121 sites of hyperplastic ALECs from 11 <d>IPF</d> patients were analyzed, and a one-base-pair deletion was detected in nine sites from five patients. The mutation was also detected in smooth muscle-like cells of the thickened pulmonary artery. In some tissue areas where the deletion was detected, low <g>T beta RII</g> expression was confirmed by immunohistochemical staining. These data suggest that microsatellite instability in the <g>T beta RII</g> gene occurred in some lesions of hyperplastic ALECs in <d>IPF</d>, although at a low incidence, and that this <d>genetic disorder</d> might play a partial role in the pathologic changes of <d>IPF</d>.
11350829|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic lung disorder characterized by fibroblast proliferation and extracellular matrix accumulation. However, studies on fibroblast growth rate and collagen synthesis have given contradictory results. Here we analyzed fibroblast growth rate by a formazan-based chromogenic assay; fibroblast apoptosis by in situ end labeling ISEL and propidium iodide staining; percent of alpha-smooth muscle actin alpha-SMA positive cells by fluorescence-activated cell sorter; and alpha1-I collagen, transforming growth factor TGF-beta1, collagenase-1, gelatinases A and B, and tissue inhibitor of metalloproteinase TIMP-1, -2, -3, and -4 expression by reverse transcriptase/polymerase chain reaction in fibroblasts derived from IPF and control lungs. Growth rate was significantly lower in IPF fibroblasts compared with controls 13.3 +/- 38.5% versus 294.6 +/- 57%, P < 0.0001 at 13 d. Conversely, a significantly higher percentage of apoptotic cells was observed in IPF-derived fibroblasts ISEL: 31.9 +/- 7.0% versus 15.5 +/- 7.6% from controls; P < 0.008. alpha-SMA analysis revealed a significantly higher percentage of myofibroblasts in IPF samples 62.8 +/- 25.2% versus 14.8 +/- 11.7% from controls; P < 0.01. IPF fibroblasts were characterized by an increase in pro-alpha1-I collagen, TGF-beta1, gelatinase B, and all TIMPs' gene expression, whereas collagenase-1 and gelatinase A expression showed no differences. These results suggest that fibroblasts from IPF exhibit a profibrotic secretory phenotype, with lower growth rate and increased spontaneous apoptosis.
11350829|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic lung disorder characterized by fibroblast proliferation and extracellular matrix accumulation. However, studies on fibroblast growth rate and collagen synthesis have given contradictory results. Here we analyzed fibroblast growth rate by a formazan-based chromogenic assay; fibroblast apoptosis by in situ end labeling ISEL and propidium iodide staining; percent of alpha-smooth muscle actin alpha-SMA positive cells by fluorescence-activated cell sorter; and alpha1-I collagen, transforming growth factor TGF-beta1, collagenase-1, gelatinases A and B, and tissue inhibitor of metalloproteinase TIMP-1, -2, -3, and -4 expression by reverse transcriptase/polymerase chain reaction in fibroblasts derived from <d>IPF</d> and control lungs. Growth rate was significantly lower in <d>IPF</d> fibroblasts compared with controls 13.3 +/- 38.5% versus 294.6 +/- 57%, P < 0.0001 at 13 d. Conversely, a significantly higher percentage of apoptotic cells was observed in <d>IPF</d>-derived fibroblasts ISEL: 31.9 +/- 7.0% versus 15.5 +/- 7.6% from controls; P < 0.008. alpha-SMA analysis revealed a significantly higher percentage of myofibroblasts in <d>IPF</d> samples 62.8 +/- 25.2% versus 14.8 +/- 11.7% from controls; P < 0.01. <d>IPF</d> fibroblasts were characterized by an increase in pro-alpha1-I collagen, TGF-beta1, gelatinase B, and all TIMPs' gene expression, whereas collagenase-1 and gelatinase A expression showed no differences. These results suggest that fibroblasts from <d>IPF</d> exhibit a profibrotic secretory phenotype, with lower growth rate and increased spontaneous apoptosis.
11350829|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic lung disorder</d> characterized by fibroblast proliferation and extracellular matrix accumulation. However, studies on fibroblast growth rate and collagen synthesis have given contradictory results. Here we analyzed fibroblast growth rate by a formazan-based chromogenic assay; fibroblast apoptosis by in situ end labeling ISEL and propidium iodide staining; percent of alpha-smooth muscle actin alpha-SMA positive cells by fluorescence-activated cell sorter; and alpha1-I collagen, transforming growth factor TGF-beta1, collagenase-1, gelatinases A and B, and tissue inhibitor of metalloproteinase TIMP-1, -2, -3, and -4 expression by reverse transcriptase/polymerase chain reaction in fibroblasts derived from <d>IPF</d> and control lungs. Growth rate was significantly lower in <d>IPF</d> fibroblasts compared with controls 13.3 +/- 38.5% versus 294.6 +/- 57%, P < 0.0001 at 13 d. Conversely, a significantly higher percentage of apoptotic cells was observed in <d>IPF</d>-derived fibroblasts ISEL: 31.9 +/- 7.0% versus 15.5 +/- 7.6% from controls; P < 0.008. alpha-SMA analysis revealed a significantly higher percentage of myofibroblasts in <d>IPF</d> samples 62.8 +/- 25.2% versus 14.8 +/- 11.7% from controls; P < 0.01. <d>IPF</d> fibroblasts were characterized by an increase in pro-alpha1-I collagen, TGF-beta1, gelatinase B, and all TIMPs' gene expression, whereas collagenase-1 and gelatinase A expression showed no differences. These results suggest that fibroblasts from <d>IPF</d> exhibit a profibrotic secretory phenotype, with lower growth rate and increased spontaneous apoptosis.
11394717|a|Inhalation of numerous fibrogenic agents causes <d>interstitial pulmonary fibrosis</d> IPF in humans and in a number of animal models. Several of these models provide evidence that certain peptide growth factors GF are playing a role in the disease process. Transforming growth factor beta 1 <g>TGF-beta1</g> is a potent inducer of extracellular matrix production by mesenchymal cells, and we have shown that this peptide is produced in the lung after asbestos exposure. We used in situ hybridization to demonstrate that the mRNA for <g>TGF-beta1</g> is rapidly expressed post-exposure at sites of initial asbestos-induced lung injury in both rats and mice. The <g>TGF-beta1</g> is expressed by bronchiolar-alveolar epithelial cells as well as by mesenchymal cells and lung macrophages in exposed animals. Normal rats and mice express little <g>TGF-beta1</g>, as we have demonstrated previously for PDGF-A and -B, TGF-alpha, and <g>TNF-alpha</g>. <g>TGF-beta1</g> expression is accompanied by collagen and fibronectin production in asbestos-exposed animals. Most interesting, <g>TGF-beta1</g> expression is largely absent in the lungs of <g>TNF-alpha</g> receptor knockout mice that fail to develop asbestos-induced IPE We have shown previously that the mRNAs and cognate peptides of PDGF-A and -B and TGF-alpha, but not <g>TNF-alpha</g>, are reduced in the fibrosis-resistant knockout mice. In this article, we show that <g>TGF-beta1</g> is included in this group of cytokines, supporting the postulate that <g>TNF-alpha</g> is necessary for the expression of other, more downstream growth factors, and the consequent development of idiopathic pulmonary fibrosis IPF.
11394717|a|Inhalation of numerous fibrogenic agents causes <d>interstitial pulmonary fibrosis</d> <d>IPF</d> in humans and in a number of animal models. Several of these models provide evidence that certain peptide growth factors GF are playing a role in the disease process. Transforming growth factor beta 1 <g>TGF-beta1</g> is a potent inducer of extracellular matrix production by mesenchymal cells, and we have shown that this peptide is produced in the lung after asbestos exposure. We used in situ hybridization to demonstrate that the mRNA for <g>TGF-beta1</g> is rapidly expressed post-exposure at sites of initial asbestos-induced lung injury in both rats and mice. The <g>TGF-beta1</g> is expressed by bronchiolar-alveolar epithelial cells as well as by mesenchymal cells and lung macrophages in exposed animals. Normal rats and mice express little <g>TGF-beta1</g>, as we have demonstrated previously for PDGF-A and -B, TGF-alpha, and <g>TNF-alpha</g>. <g>TGF-beta1</g> expression is accompanied by collagen and fibronectin production in asbestos-exposed animals. Most interesting, <g>TGF-beta1</g> expression is largely absent in the lungs of <g>TNF-alpha</g> receptor knockout mice that fail to develop asbestos-induced IPE We have shown previously that the mRNAs and cognate peptides of PDGF-A and -B and TGF-alpha, but not <g>TNF-alpha</g>, are reduced in the fibrosis-resistant knockout mice. In this article, we show that <g>TGF-beta1</g> is included in this group of cytokines, supporting the postulate that <g>TNF-alpha</g> is necessary for the expression of other, more downstream growth factors, and the consequent development of idiopathic pulmonary fibrosis <d>IPF</d>.
11394717|a|Inhalation of numerous fibrogenic agents causes <d>interstitial pulmonary fibrosis</d> <d>IPF</d> in humans and in a number of animal models. Several of these models provide evidence that certain peptide growth factors GF are playing a role in the disease process. <g>Transforming growth factor beta 1</g> <g>TGF-beta1</g> is a potent inducer of extracellular matrix production by mesenchymal cells, and we have shown that this peptide is produced in the lung after asbestos exposure. We used in situ hybridization to demonstrate that the mRNA for <g>TGF-beta1</g> is rapidly expressed post-exposure at sites of initial asbestos-induced <d>lung injury</d> in both rats and mice. The <g>TGF-beta1</g> is expressed by bronchiolar-alveolar epithelial cells as well as by mesenchymal cells and lung macrophages in exposed animals. Normal rats and mice express little <g>TGF-beta1</g>, as we have demonstrated previously for PDGF-A and -B, TGF-alpha, and <g>TNF-alpha</g>. <g>TGF-beta1</g> expression is accompanied by collagen and fibronectin production in asbestos-exposed animals. Most interesting, <g>TGF-beta1</g> expression is largely absent in the lungs of <g>TNF-alpha</g> receptor knockout mice that fail to develop asbestos-induced IPE We have shown previously that the mRNAs and cognate peptides of PDGF-A and -B and TGF-alpha, but not <g>TNF-alpha</g>, are reduced in the fibrosis-resistant knockout mice. In this article, we show that <g>TGF-beta1</g> is included in this group of cytokines, supporting the postulate that <g>TNF-alpha</g> is necessary for the expression of other, more downstream growth factors, and the consequent development of idiopathic pulmonary fibrosis <d>IPF</d>.
11394717|a|Inhalation of numerous fibrogenic agents causes <d>interstitial pulmonary <d>fibrosis</d></d> <d>IPF</d> in humans and in a number of animal models. Several of these models provide evidence that certain peptide growth factors GF are playing a role in the disease process. <g>Transforming growth factor beta 1</g> <g>TGF-beta1</g> is a potent inducer of extracellular matrix production by mesenchymal cells, and we have shown that this peptide is produced in the lung after asbestos exposure. We used in situ hybridization to demonstrate that the mRNA for <g>TGF-beta1</g> is rapidly expressed post-exposure at sites of initial asbestos-induced <d>lung injury</d> in both rats and mice. The <g>TGF-beta1</g> is expressed by bronchiolar-alveolar epithelial cells as well as by mesenchymal cells and lung macrophages in exposed animals. Normal rats and mice express little <g>TGF-beta1</g>, as we have demonstrated previously for <g>PDGF-A and -B</g>, <g>TGF-alpha</g>, and <g>TNF-alpha</g>. <g>TGF-beta1</g> expression is accompanied by collagen and <g>fibronectin</g> production in asbestos-exposed animals. Most interesting, <g>TGF-beta1</g> expression is largely absent in the lungs of <g>TNF-alpha</g> receptor knockout mice that fail to develop asbestos-induced IPE We have shown previously that the mRNAs and cognate peptides of <g>PDGF-A and -B</g> and <g>TGF-alpha</g>, but not <g>TNF-alpha</g>, are reduced in the <d>fibrosis</d>-resistant knockout mice. In this article, we show that <g>TGF-beta1</g> is included in this group of cytokines, supporting the postulate that <g>TNF-alpha</g> is necessary for the expression of other, more downstream growth factors, and the consequent development of idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>.
11463599|a|Insulin-like growth factor-1 IGF-1 is a highly mitogenic polypeptide detectable in human lung. Using competitive reverse transcriptase/polymerase chain reaction RT-PCR, expression of four IGF-1 transcripts was examined in bronchoalveolar lavage cells BALC from normal subjects, <d>idiopathic pulmonary fibrosis</d> IPF, stage I/II no fibrosis, and stage III/IV confirmed fibrosis pulmonary sarcoidosis patients, and fibroblast strains isolated from normal and IPF lungs. Transcripts studied were Class 1 and Class 2 exons 1 or 2, respectively with IGF-1Eb or IGF-1Ea exons 5 or 6, respectively. Total IGF-1 expression was downregulated in BALC of both patients with IPF p < 0.01 and patients with sarcoidosis p < 0.04 compared with healthy subjects. In contrast, both constitutive p < 0.003 and transforming growth factor-beta TGF-beta- induced p < 0.02 IGF-1 expression was higher in fibrotic, compared with normal, fibroblasts. These changes were associated with differential expression of IGF-1 splice variants. Healthy subjects and sarcoidosis patients without fibrosis showed similar expression of Class 1/Class 2 and IGF-1Ea/IGF-1Eb. However, patients with fibrosis demonstrated discordant, increased relative abundance of Class 1 transcripts p < 0.01. In parallel, all fibrosis patients failed to express Class 2, IGF-1Eb forms and sarcoidosis patients with fibrosis did not express the Class 1, IGF-1Eb variant either. Fibrotic fibroblasts expressed higher constitutive levels of Class 1, IGF-1Ea transcripts compared with normal fibroblasts. Class 2, IGF-1Eb forms were moderately expressed by fibroblasts only after stimulation with TGF-beta, which also further increased levels of Class 1, IGF-1Ea transcripts. Our findings suggest that transition from a healthy to a fibrotic phenotype occurs in association with a changing pattern of IGF-1 mRNA heterogeneity and leads us to hypothesize a potential role for specific IGF-1 variants in fibrogenesis.
11463599|a|Insulin-like growth factor-1 IGF-1 is a highly mitogenic polypeptide detectable in human lung. Using competitive reverse transcriptase/polymerase chain reaction RT-PCR, expression of four IGF-1 transcripts was examined in bronchoalveolar lavage cells BALC from normal subjects, <d>idiopathic pulmonary fibrosis</d> IPF, stage I/II no fibrosis, and stage III/IV confirmed fibrosis <d>pulmonary sarcoidosis</d> patients, and fibroblast strains isolated from normal and IPF lungs. Transcripts studied were Class 1 and Class 2 exons 1 or 2, respectively with IGF-1Eb or IGF-1Ea exons 5 or 6, respectively. Total IGF-1 expression was downregulated in BALC of both patients with IPF p < 0.01 and patients with sarcoidosis p < 0.04 compared with healthy subjects. In contrast, both constitutive p < 0.003 and transforming growth factor-beta TGF-beta- induced p < 0.02 IGF-1 expression was higher in fibrotic, compared with normal, fibroblasts. These changes were associated with differential expression of IGF-1 splice variants. Healthy subjects and sarcoidosis patients without fibrosis showed similar expression of Class 1/Class 2 and IGF-1Ea/IGF-1Eb. However, patients with fibrosis demonstrated discordant, increased relative abundance of Class 1 transcripts p < 0.01. In parallel, all fibrosis patients failed to express Class 2, IGF-1Eb forms and sarcoidosis patients with fibrosis did not express the Class 1, IGF-1Eb variant either. Fibrotic fibroblasts expressed higher constitutive levels of Class 1, IGF-1Ea transcripts compared with normal fibroblasts. Class 2, IGF-1Eb forms were moderately expressed by fibroblasts only after stimulation with TGF-beta, which also further increased levels of Class 1, IGF-1Ea transcripts. Our findings suggest that transition from a healthy to a fibrotic phenotype occurs in association with a changing pattern of IGF-1 mRNA heterogeneity and leads us to hypothesize a potential role for specific IGF-1 variants in fibrogenesis.
11463599|a|<g>Insulin-like growth factor-1</g> <g>IGF-1</g> is a highly mitogenic polypeptide detectable in human lung. Using competitive reverse transcriptase/polymerase chain reaction RT-PCR, expression of four <g>IGF-1</g> transcripts was examined in bronchoalveolar lavage cells BALC from normal subjects, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, stage I/II no fibrosis, and stage III/IV confirmed fibrosis <d>pulmonary sarcoidosis</d> patients, and fibroblast strains isolated from normal and <d>IPF</d> lungs. Transcripts studied were Class 1 and Class 2 exons 1 or 2, respectively with <g>IGF-1</g>Eb or <g>IGF-1</g>Ea exons 5 or 6, respectively. Total <g>IGF-1</g> expression was downregulated in BALC of both patients with <d>IPF</d> p < 0.01 and patients with sarcoidosis p < 0.04 compared with healthy subjects. In contrast, both constitutive p < 0.003 and transforming growth factor-beta TGF-beta- induced p < 0.02 <g>IGF-1</g> expression was higher in fibrotic, compared with normal, fibroblasts. These changes were associated with differential expression of <g>IGF-1</g> splice variants. Healthy subjects and sarcoidosis patients without fibrosis showed similar expression of Class 1/Class 2 and <g>IGF-1</g>Ea/<g>IGF-1</g>Eb. However, patients with fibrosis demonstrated discordant, increased relative abundance of Class 1 transcripts p < 0.01. In parallel, all fibrosis patients failed to express Class 2, <g>IGF-1</g>Eb forms and sarcoidosis patients with fibrosis did not express the Class 1, <g>IGF-1</g>Eb variant either. Fibrotic fibroblasts expressed higher constitutive levels of Class 1, <g>IGF-1</g>Ea transcripts compared with normal fibroblasts. Class 2, <g>IGF-1</g>Eb forms were moderately expressed by fibroblasts only after stimulation with TGF-beta, which also further increased levels of Class 1, <g>IGF-1</g>Ea transcripts. Our findings suggest that transition from a healthy to a fibrotic phenotype occurs in association with a changing pattern of <g>IGF-1</g> mRNA heterogeneity and leads us to hypothesize a potential role for specific <g>IGF-1</g> variants in fibrogenesis.
11463599|a|<g>Insulin-like growth factor-1</g> <g>IGF-1</g> is a highly mitogenic polypeptide detectable in human lung. Using competitive reverse transcriptase/polymerase chain reaction RT-PCR, expression of four <g>IGF-1</g> transcripts was examined in bronchoalveolar lavage cells BALC from normal subjects, <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, stage I/II no <d>fibrosis</d>, and stage III/IV confirmed <d>fibrosis</d> <d>pulmonary sarcoidosis</d> patients, and fibroblast strains isolated from normal and <d>IPF</d> lungs. Transcripts studied were Class 1 and Class 2 exons 1 or 2, respectively with <g>IGF-1</g>Eb or <g>IGF-1</g>Ea exons 5 or 6, respectively. Total <g>IGF-1</g> expression was downregulated in BALC of both patients with <d>IPF</d> p < 0.01 and patients with sarcoidosis p < 0.04 compared with healthy subjects. In contrast, both constitutive p < 0.003 and transforming growth factor-beta TGF-beta- induced p < 0.02 <g>IGF-1</g> expression was higher in fibrotic, compared with normal, fibroblasts. These changes were associated with differential expression of <g>IGF-1</g> splice variants. Healthy subjects and sarcoidosis patients without <d>fibrosis</d> showed similar expression of Class 1/Class 2 and <g>IGF-1</g>Ea/<g>IGF-1</g>Eb. However, patients with <d>fibrosis</d> demonstrated discordant, increased relative abundance of Class 1 transcripts p < 0.01. In parallel, all <d>fibrosis</d> patients failed to express Class 2, <g>IGF-1</g>Eb forms and sarcoidosis patients with <d>fibrosis</d> did not express the Class 1, <g>IGF-1</g>Eb variant either. Fibrotic fibroblasts expressed higher constitutive levels of Class 1, <g>IGF-1</g>Ea transcripts compared with normal fibroblasts. Class 2, <g>IGF-1</g>Eb forms were moderately expressed by fibroblasts only after stimulation with TGF-beta, which also further increased levels of Class 1, <g>IGF-1</g>Ea transcripts. Our findings suggest that transition from a healthy to a fibrotic phenotype occurs in association with a changing pattern of <g>IGF-1</g> mRNA heterogeneity and leads us to hypothesize a potential role for specific <g>IGF-1</g> variants in fibrogenesis.
11463599|a|<g>Insulin-like growth factor-1</g> <g>IGF-1</g> is a highly mitogenic polypeptide detectable in human lung. Using competitive reverse transcriptase/polymerase chain reaction RT-PCR, expression of four <g>IGF-1</g> transcripts was examined in bronchoalveolar lavage cells BALC from normal subjects, <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, stage I/II no <d>fibrosis</d>, and stage III/IV confirmed <d>fibrosis</d> <d>pulmonary <d>sarcoidosis</d></d> patients, and fibroblast strains isolated from normal and <d>IPF</d> lungs. Transcripts studied were Class 1 and Class 2 exons 1 or 2, respectively with <g>IGF-1</g>Eb or <g>IGF-1</g>Ea exons 5 or 6, respectively. Total <g>IGF-1</g> expression was downregulated in BALC of both patients with <d>IPF</d> p < 0.01 and patients with <d>sarcoidosis</d> p < 0.04 compared with healthy subjects. In contrast, both constitutive p < 0.003 and transforming growth factor-beta TGF-beta- induced p < 0.02 <g>IGF-1</g> expression was higher in fibrotic, compared with normal, fibroblasts. These changes were associated with differential expression of <g>IGF-1</g> splice variants. Healthy subjects and <d>sarcoidosis</d> patients without <d>fibrosis</d> showed similar expression of Class 1/Class 2 and <g>IGF-1</g>Ea/<g>IGF-1</g>Eb. However, patients with <d>fibrosis</d> demonstrated discordant, increased relative abundance of Class 1 transcripts p < 0.01. In parallel, all <d>fibrosis</d> patients failed to express Class 2, <g>IGF-1</g>Eb forms and <d>sarcoidosis</d> patients with <d>fibrosis</d> did not express the Class 1, <g>IGF-1</g>Eb variant either. Fibrotic fibroblasts expressed higher constitutive levels of Class 1, <g>IGF-1</g>Ea transcripts compared with normal fibroblasts. Class 2, <g>IGF-1</g>Eb forms were moderately expressed by fibroblasts only after stimulation with TGF-beta, which also further increased levels of Class 1, <g>IGF-1</g>Ea transcripts. Our findings suggest that transition from a healthy to a fibrotic phenotype occurs in association with a changing pattern of <g>IGF-1</g> mRNA heterogeneity and leads us to hypothesize a potential role for specific <g>IGF-1</g> variants in fibrogenesis.
11491168|a|Connective tissue growth factor CTGF is a growth and chemotactic factor for fibroblasts encoded by an immediate early gene that is transcriptionally activated by transforming growth factor-beta. Previous studies have shown that both CTGF messenger ribonuclear acid mRNA and protein are expressed in renal fibrosis and bleomycin-induced pulmonary fibrosis in mice. The aim of the present study was to investigate the localization of CTGF protein and its mRNA expression in the fibrotic lung tissue of patients with idiopathic pulmonary fibrosis <d>IPF</d>. Using human fibrotic lung tissue obtained from eight autopsy cases and four biopsy cases with <d>IPF</d>, immunohistochemical staining, in situ hybridization, and reverse transcription-polymerase chain reaction RT-PCR were performed. The cellular immunoreactivity for CTGF was markedly increased in the lung tissue of patients with <d>IPF</d>, compared to normal lungs. The immunolocalization of CTGF was confined predominantly to proliferating type II alveolar epithelial cells and activated fibroblasts. In the normal lung, type II alveolar epithelial cells stained for CTGF were sparsely distributed. CTGF mRNA was localized in proliferating type II alveolar epithelial cells and activated fibroblasts in the interstitium of fibrotic lung tissues. RT-PCR analysis showed that CTGF mRNA was expressed at a higher level in fibrotic lungs than in normal lungs. In both an autocrine and a paracrine manner, type II alveolar epithelial cells and activated fibroblasts may play a critical role in pulmonary fibrosis by producing <g>connective tissue growth factor</g> which modulates fibroblast proliferation and extracellular matrix production.
11491168|a|<g>Connective tissue growth factor</g> <g>CTGF</g> is a growth and chemotactic factor for fibroblasts encoded by an immediate early gene that is transcriptionally activated by transforming growth factor-beta. Previous studies have shown that both <g>CTGF</g> messenger ribonuclear acid mRNA and protein are expressed in renal <d>fibrosis</d> and bleomycin-induced pulmonary <d>fibrosis</d> in mice. The aim of the present study was to investigate the localization of <g>CTGF</g> protein and its mRNA expression in the fibrotic lung tissue of patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. Using human fibrotic lung tissue obtained from eight autopsy cases and four biopsy cases with <d>IPF</d>, immunohistochemical staining, in situ hybridization, and reverse transcription-polymerase chain reaction RT-PCR were performed. The cellular immunoreactivity for <g>CTGF</g> was markedly increased in the lung tissue of patients with <d>IPF</d>, compared to normal lungs. The immunolocalization of <g>CTGF</g> was confined predominantly to proliferating type II alveolar epithelial cells and activated fibroblasts. In the normal lung, type II alveolar epithelial cells stained for <g>CTGF</g> were sparsely distributed. <g>CTGF</g> mRNA was localized in proliferating type II alveolar epithelial cells and activated fibroblasts in the interstitium of fibrotic lung tissues. RT-PCR analysis showed that <g>CTGF</g> mRNA was expressed at a higher level in fibrotic lungs than in normal lungs. In both an autocrine and a paracrine manner, type II alveolar epithelial cells and activated fibroblasts may play a critical role in pulmonary <d>fibrosis</d> by producing <g>connective tissue growth factor</g> which modulates fibroblast proliferation and extracellular matrix production.
11502094|a|The <d>bronchiolar-alveolar epithelium</d> BAE is a primary target site for inhaled agents that cause lung injury. These cells, consequently, release a broad range of mediators that influence other cell populations, including interstitial lung fibroblasts that are central to the development of interstitial pulmonary fibrosis IPF. A number of peptide growth factors GF have been postulated to be essential in the pathogenesis of IPF. We demonstrate here that primary populations of mouse BAE and mesenchymal cells, maintained in culture, synthesize four potent GF. These are platelet-derived growth factor isoforms PDGF A and B, transforming growth factor beta-1 <g>TGF-beta1</g>, and tumor necrosis factor alpha <g>TNF-alpha</g>. A mouse lung epithelial cell isolation technique pioneered in this laboratory has been used to purify the BAE cells to greater than 85% 80 +/- 5.6% alveolar type II and 9 +/- 2.3% Clara cells in culture. Northern analysis, RNase protection assay, and immunocytochemistry ICC were used to establish mRNA and protein expression of the GF over time in the cultured BAE and mesenchymal cells. We show for the first time in these primary mouse lung cells that treatment of both cell types with <g>TNF-alpha</g> upregulates expression of <g>TGF-beta1</g>. The four GF are produced by both epithelial and mesenchymal cells but with different temporal patterns. <g>TGF-beta1</g> is expressed constitutively by BAE and mesenchymal cells, whereas <g>TNF-alpha</g> expression wanes over time. The findings by ICC were consistent with levels of mRNA expression in both cell types. As genetically defined and altered mouse strains are becoming increasingly valuable for modeling lung disease, studying the gene expression patterns of target cells from these animals in vitro would be useful in sorting out the complex responses by individual cell types of the lung and the interactions among the multitude of mediators that are released during lung cell injury.
11502094|a|The <d>bronchiolar-alveolar epithelium</d> <d>BAE</d> is a primary target site for inhaled agents that cause lung injury. These cells, consequently, release a broad range of mediators that influence other cell populations, including interstitial lung fibroblasts that are central to the development of interstitial pulmonary fibrosis IPF. A number of peptide growth factors GF have been postulated to be essential in the pathogenesis of IPF. We demonstrate here that primary populations of mouse <d>BAE</d> and mesenchymal cells, maintained in culture, synthesize four potent GF. These are platelet-derived growth factor isoforms PDGF A and B, transforming growth factor beta-1 <g>TGF-beta1</g>, and tumor necrosis factor alpha <g>TNF-alpha</g>. A mouse lung epithelial cell isolation technique pioneered in this laboratory has been used to purify the <d>BAE</d> cells to greater than 85% 80 +/- 5.6% alveolar type II and 9 +/- 2.3% Clara cells in culture. Northern analysis, RNase protection assay, and immunocytochemistry ICC were used to establish mRNA and protein expression of the GF over time in the cultured <d>BAE</d> and mesenchymal cells. We show for the first time in these primary mouse lung cells that treatment of both cell types with <g>TNF-alpha</g> upregulates expression of <g>TGF-beta1</g>. The four GF are produced by both epithelial and mesenchymal cells but with different temporal patterns. <g>TGF-beta1</g> is expressed constitutively by <d>BAE</d> and mesenchymal cells, whereas <g>TNF-alpha</g> expression wanes over time. The findings by ICC were consistent with levels of mRNA expression in both cell types. As genetically defined and altered mouse strains are becoming increasingly valuable for modeling lung disease, studying the gene expression patterns of target cells from these animals in vitro would be useful in sorting out the complex responses by individual cell types of the lung and the interactions among the multitude of mediators that are released during lung cell injury.
11502094|a|The <d>bronchiolar-alveolar epithelium</d> <d>BAE</d> is a primary target site for inhaled agents that cause <d>lung injury</d>. These cells, consequently, release a broad range of mediators that influence other cell populations, including interstitial lung fibroblasts that are central to the development of interstitial pulmonary fibrosis IPF. A number of peptide growth factors GF have been postulated to be essential in the pathogenesis of IPF. We demonstrate here that primary populations of mouse <d>BAE</d> and mesenchymal cells, maintained in culture, synthesize four potent GF. These are platelet-derived growth factor isoforms PDGF A and B, transforming growth factor beta-1 <g>TGF-beta1</g>, and tumor necrosis factor alpha <g>TNF-alpha</g>. A mouse lung epithelial cell isolation technique pioneered in this laboratory has been used to purify the <d>BAE</d> cells to greater than 85% 80 +/- 5.6% alveolar type II and 9 +/- 2.3% Clara cells in culture. Northern analysis, RNase protection assay, and immunocytochemistry ICC were used to establish mRNA and protein expression of the GF over time in the cultured <d>BAE</d> and mesenchymal cells. We show for the first time in these primary mouse lung cells that treatment of both cell types with <g>TNF-alpha</g> upregulates expression of <g>TGF-beta1</g>. The four GF are produced by both epithelial and mesenchymal cells but with different temporal patterns. <g>TGF-beta1</g> is expressed constitutively by <d>BAE</d> and mesenchymal cells, whereas <g>TNF-alpha</g> expression wanes over time. The findings by ICC were consistent with levels of mRNA expression in both cell types. As genetically defined and altered mouse strains are becoming increasingly valuable for modeling lung disease, studying the gene expression patterns of target cells from these animals in vitro would be useful in sorting out the complex responses by individual cell types of the lung and the interactions among the multitude of mediators that are released during lung cell injury.
11502094|a|The <d>bronchiolar-alveolar epithelium</d> <d>BAE</d> is a primary target site for inhaled agents that cause <d>lung injury</d>. These cells, consequently, release a broad range of mediators that influence other cell populations, including interstitial lung fibroblasts that are central to the development of <d>interstitial pulmonary fibrosis</d> IPF. A number of peptide growth factors GF have been postulated to be essential in the pathogenesis of IPF. We demonstrate here that primary populations of mouse <d>BAE</d> and mesenchymal cells, maintained in culture, synthesize four potent GF. These are platelet-derived growth factor isoforms PDGF A and B, transforming growth factor beta-1 <g>TGF-beta1</g>, and tumor necrosis factor alpha <g>TNF-alpha</g>. A mouse lung epithelial cell isolation technique pioneered in this laboratory has been used to purify the <d>BAE</d> cells to greater than 85% 80 +/- 5.6% alveolar type II and 9 +/- 2.3% Clara cells in culture. Northern analysis, RNase protection assay, and immunocytochemistry ICC were used to establish mRNA and protein expression of the GF over time in the cultured <d>BAE</d> and mesenchymal cells. We show for the first time in these primary mouse lung cells that treatment of both cell types with <g>TNF-alpha</g> upregulates expression of <g>TGF-beta1</g>. The four GF are produced by both epithelial and mesenchymal cells but with different temporal patterns. <g>TGF-beta1</g> is expressed constitutively by <d>BAE</d> and mesenchymal cells, whereas <g>TNF-alpha</g> expression wanes over time. The findings by ICC were consistent with levels of mRNA expression in both cell types. As genetically defined and altered mouse strains are becoming increasingly valuable for modeling lung disease, studying the gene expression patterns of target cells from these animals in vitro would be useful in sorting out the complex responses by individual cell types of the lung and the interactions among the multitude of mediators that are released during lung cell injury.
11502094|a|The <d>bronchiolar-alveolar epithelium</d> <d>BAE</d> is a primary target site for inhaled agents that cause <d>lung injury</d>. These cells, consequently, release a broad range of mediators that influence other cell populations, including interstitial lung fibroblasts that are central to the development of <d>interstitial pulmonary fibrosis</d> <d>IPF</d>. A number of peptide growth factors GF have been postulated to be essential in the pathogenesis of <d>IPF</d>. We demonstrate here that primary populations of mouse <d>BAE</d> and mesenchymal cells, maintained in culture, synthesize four potent GF. These are platelet-derived growth factor isoforms PDGF A and B, transforming growth factor beta-1 <g>TGF-beta1</g>, and tumor necrosis factor alpha <g>TNF-alpha</g>. A mouse lung epithelial cell isolation technique pioneered in this laboratory has been used to purify the <d>BAE</d> cells to greater than 85% 80 +/- 5.6% alveolar type II and 9 +/- 2.3% Clara cells in culture. Northern analysis, RNase protection assay, and immunocytochemistry ICC were used to establish mRNA and protein expression of the GF over time in the cultured <d>BAE</d> and mesenchymal cells. We show for the first time in these primary mouse lung cells that treatment of both cell types with <g>TNF-alpha</g> upregulates expression of <g>TGF-beta1</g>. The four GF are produced by both epithelial and mesenchymal cells but with different temporal patterns. <g>TGF-beta1</g> is expressed constitutively by <d>BAE</d> and mesenchymal cells, whereas <g>TNF-alpha</g> expression wanes over time. The findings by ICC were consistent with levels of mRNA expression in both cell types. As genetically defined and altered mouse strains are becoming increasingly valuable for modeling lung disease, studying the gene expression patterns of target cells from these animals in vitro would be useful in sorting out the complex responses by individual cell types of the lung and the interactions among the multitude of mediators that are released during lung cell injury.
11502094|a|The <d>bronchiolar-alveolar epithelium</d> <d>BAE</d> is a primary target site for inhaled agents that cause <d>lung injury</d>. These cells, consequently, release a broad range of mediators that influence other cell populations, including interstitial lung fibroblasts that are central to the development of <d>interstitial pulmonary fibrosis</d> <d>IPF</d>. A number of peptide growth factors GF have been postulated to be essential in the pathogenesis of <d>IPF</d>. We demonstrate here that primary populations of mouse <d>BAE</d> and mesenchymal cells, maintained in culture, synthesize four potent GF. These are <g>platelet-derived growth factor isoforms PDGF A and B</g>, <g>transforming growth factor beta-1</g> <g>TGF-beta1</g>, and <g>tumor necrosis factor alpha</g> <g>TNF-alpha</g>. A mouse lung epithelial cell isolation technique pioneered in this laboratory has been used to purify the <d>BAE</d> cells to greater than 85% 80 +/- 5.6% alveolar type II and 9 +/- 2.3% Clara cells in culture. Northern analysis, RNase protection assay, and immunocytochemistry ICC were used to establish mRNA and protein expression of the GF over time in the cultured <d>BAE</d> and mesenchymal cells. We show for the first time in these primary mouse lung cells that treatment of both cell types with <g>TNF-alpha</g> upregulates expression of <g>TGF-beta1</g>. The four GF are produced by both epithelial and mesenchymal cells but with different temporal patterns. <g>TGF-beta1</g> is expressed constitutively by <d>BAE</d> and mesenchymal cells, whereas <g>TNF-alpha</g> expression wanes over time. The findings by ICC were consistent with levels of mRNA expression in both cell types. As genetically defined and altered mouse strains are becoming increasingly valuable for modeling <d>lung disease</d>, studying the gene expression patterns of target cells from these animals in vitro would be useful in sorting out the complex responses by individual cell types of the lung and the interactions among the multitude of mediators that are released during lung cell injury.
11713352|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is characterised by subpleural fibrosis that progresses to involve all areas of the lung. The expression of transforming growth factor-beta1 <g>TGF-beta 1</g>, a potent regulator of connective tissue synthesis, is increased in lung sections of patients with IPF. <g>TGF-beta 1</g> is generally released in a biologically latent form L-<g>TGF-beta 1</g>. Before being biologically active, TGF-beta must be converted to its active form and interact with both TGF-beta receptors type I and II T beta R-I and T beta R-II. TGF-beta latency binding protein 1 LTBP-1, which facilitates the release and activation of L-<g>TGF-beta 1</g>, is also important in the biology of <g>TGF-beta 1</g>. METHODS: Open lung biopsy samples from patients with IPF and normal controls were examined to localise T beta R-I, T beta R-II, and LTBP-1. Alveolar macrophages AM and bronchoalveolar lavage BAL fluid were examined using the CCL-64 bioassay to determine if TGF-beta is present in its active form in the lungs of patients with IPF. RESULTS: Immunoreactive L-<g>TGF-beta 1</g> was present in all lung cells of patients with IPF except for fibroblasts in the subepithelial regions of honeycomb cysts. LTBP-1 was detected primarily in AM and epithelial cells lining honeycomb cysts in areas of advanced IPF. In normal lungs LTBP-1 immunoreactivity was observed in a few AM. AM from the upper and lower lobes of patients with IPF secreted 1.6 0.6 fmol and 4.1 1.9 fmol active TGF-beta, respectively, while AM from the lower lobes of control patients secreted no active TGF-beta p< or =0.01 for TGF-beta in the conditioned media from AM obtained from the lower lobes of IPF patients v normal controls. The difference in percentage active TGF-beta secreted by AM from the lower lobes of patients with IPF and the lower lobes of control patients was significant p< or =0.01, but the difference between the total TGF-beta secreted from these lobes was not significant. The difference in active TGF-beta in conditioned media of AM from the upper and lower lobes of patients with IPF was also not statistically significant. BAL fluid from the upper and lower lobes of patients with IPF contained 0.7 0.2 fmol and 2.9 1.2 fmol active TGF-beta, respectively p< or =0.03. The percentage of active TGF-beta in the upper and lower lobes was 17.6 1.0% and 78.4 1.6%, respectively p< or =0.03. In contrast, BAL fluid from control patients contained small amounts of L-TGF-beta. Using immunostaining, both T beta R-I and T beta R-II were present on all cells of normal lungs but T beta R-I was markedly reduced in most cells in areas of honeycomb cysts except for interstitial myofibroblasts in lungs of patients with IPF. <g>TGF-beta 1</g> inhibits epithelial cell proliferation and a lack of T beta R-I expression by epithelial cells lining honeycomb cysts would facilitate repair of the alveoli by epithelial cell proliferation. However, the presence of both T beta Rs on fibroblasts is likely to result in a response to <g>TGF-beta 1</g> for synthesis of connective tissue proteins. Our findings show that biologically active <g>TGF-beta 1</g> is only present in the lungs of patients with IPF. In addition, the effects of <g>TGF-beta 1</g> on cells may be further regulated by the expression of T beta Rs. CONCLUSION: Activation of L-<g>TGF-beta 1</g> and the differential expression of T beta Rs may be important in the pathogenesis of remodelling and fibrosis in IPF.
11713352|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterised by subpleural fibrosis that progresses to involve all areas of the lung. The expression of transforming growth factor-beta1 <g>TGF-beta 1</g>, a potent regulator of connective tissue synthesis, is increased in lung sections of patients with <d>IPF</d>. <g>TGF-beta 1</g> is generally released in a biologically latent form L-<g>TGF-beta 1</g>. Before being biologically active, TGF-beta must be converted to its active form and interact with both TGF-beta receptors type I and II T beta R-I and T beta R-II. TGF-beta latency binding protein 1 LTBP-1, which facilitates the release and activation of L-<g>TGF-beta 1</g>, is also important in the biology of <g>TGF-beta 1</g>. METHODS: Open lung biopsy samples from patients with <d>IPF</d> and normal controls were examined to localise T beta R-I, T beta R-II, and LTBP-1. Alveolar macrophages AM and bronchoalveolar lavage BAL fluid were examined using the CCL-64 bioassay to determine if TGF-beta is present in its active form in the lungs of patients with <d>IPF</d>. RESULTS: Immunoreactive L-<g>TGF-beta 1</g> was present in all lung cells of patients with <d>IPF</d> except for fibroblasts in the subepithelial regions of honeycomb cysts. LTBP-1 was detected primarily in AM and epithelial cells lining honeycomb cysts in areas of advanced <d>IPF</d>. In normal lungs LTBP-1 immunoreactivity was observed in a few AM. AM from the upper and lower lobes of patients with <d>IPF</d> secreted 1.6 0.6 fmol and 4.1 1.9 fmol active TGF-beta, respectively, while AM from the lower lobes of control patients secreted no active TGF-beta p< or =0.01 for TGF-beta in the conditioned media from AM obtained from the lower lobes of <d>IPF</d> patients v normal controls. The difference in percentage active TGF-beta secreted by AM from the lower lobes of patients with <d>IPF</d> and the lower lobes of control patients was significant p< or =0.01, but the difference between the total TGF-beta secreted from these lobes was not significant. The difference in active TGF-beta in conditioned media of AM from the upper and lower lobes of patients with <d>IPF</d> was also not statistically significant. BAL fluid from the upper and lower lobes of patients with <d>IPF</d> contained 0.7 0.2 fmol and 2.9 1.2 fmol active TGF-beta, respectively p< or =0.03. The percentage of active TGF-beta in the upper and lower lobes was 17.6 1.0% and 78.4 1.6%, respectively p< or =0.03. In contrast, BAL fluid from control patients contained small amounts of L-TGF-beta. Using immunostaining, both T beta R-I and T beta R-II were present on all cells of normal lungs but T beta R-I was markedly reduced in most cells in areas of honeycomb cysts except for interstitial myofibroblasts in lungs of patients with <d>IPF</d>. <g>TGF-beta 1</g> inhibits epithelial cell proliferation and a lack of T beta R-I expression by epithelial cells lining honeycomb cysts would facilitate repair of the alveoli by epithelial cell proliferation. However, the presence of both T beta Rs on fibroblasts is likely to result in a response to <g>TGF-beta 1</g> for synthesis of connective tissue proteins. Our findings show that biologically active <g>TGF-beta 1</g> is only present in the lungs of patients with <d>IPF</d>. In addition, the effects of <g>TGF-beta 1</g> on cells may be further regulated by the expression of T beta Rs. CONCLUSION: Activation of L-<g>TGF-beta 1</g> and the differential expression of T beta Rs may be important in the pathogenesis of remodelling and fibrosis in <d>IPF</d>.
11713352|a|BACKGROUND: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is characterised by subpleural <d>fibrosis</d> that progresses to involve all areas of the lung. The expression of transforming growth factor-beta1 <g>TGF-beta 1</g>, a potent regulator of connective tissue synthesis, is increased in lung sections of patients with <d>IPF</d>. <g>TGF-beta 1</g> is generally released in a biologically latent form L-<g>TGF-beta 1</g>. Before being biologically active, TGF-beta must be converted to its active form and interact with both TGF-beta receptors type I and II T beta R-I and T beta R-II. TGF-beta latency binding protein 1 LTBP-1, which facilitates the release and activation of L-<g>TGF-beta 1</g>, is also important in the biology of <g>TGF-beta 1</g>. METHODS: Open lung biopsy samples from patients with <d>IPF</d> and normal controls were examined to localise T beta R-I, T beta R-II, and LTBP-1. Alveolar macrophages AM and bronchoalveolar lavage BAL fluid were examined using the CCL-64 bioassay to determine if TGF-beta is present in its active form in the lungs of patients with <d>IPF</d>. RESULTS: Immunoreactive L-<g>TGF-beta 1</g> was present in all lung cells of patients with <d>IPF</d> except for fibroblasts in the subepithelial regions of honeycomb cysts. LTBP-1 was detected primarily in AM and epithelial cells lining honeycomb cysts in areas of advanced <d>IPF</d>. In normal lungs LTBP-1 immunoreactivity was observed in a few AM. AM from the upper and lower lobes of patients with <d>IPF</d> secreted 1.6 0.6 fmol and 4.1 1.9 fmol active TGF-beta, respectively, while AM from the lower lobes of control patients secreted no active TGF-beta p< or =0.01 for TGF-beta in the conditioned media from AM obtained from the lower lobes of <d>IPF</d> patients v normal controls. The difference in percentage active TGF-beta secreted by AM from the lower lobes of patients with <d>IPF</d> and the lower lobes of control patients was significant p< or =0.01, but the difference between the total TGF-beta secreted from these lobes was not significant. The difference in active TGF-beta in conditioned media of AM from the upper and lower lobes of patients with <d>IPF</d> was also not statistically significant. BAL fluid from the upper and lower lobes of patients with <d>IPF</d> contained 0.7 0.2 fmol and 2.9 1.2 fmol active TGF-beta, respectively p< or =0.03. The percentage of active TGF-beta in the upper and lower lobes was 17.6 1.0% and 78.4 1.6%, respectively p< or =0.03. In contrast, BAL fluid from control patients contained small amounts of L-TGF-beta. Using immunostaining, both T beta R-I and T beta R-II were present on all cells of normal lungs but T beta R-I was markedly reduced in most cells in areas of honeycomb cysts except for interstitial myofibroblasts in lungs of patients with <d>IPF</d>. <g>TGF-beta 1</g> inhibits epithelial cell proliferation and a lack of T beta R-I expression by epithelial cells lining honeycomb cysts would facilitate repair of the alveoli by epithelial cell proliferation. However, the presence of both T beta Rs on fibroblasts is likely to result in a response to <g>TGF-beta 1</g> for synthesis of connective tissue proteins. Our findings show that biologically active <g>TGF-beta 1</g> is only present in the lungs of patients with <d>IPF</d>. In addition, the effects of <g>TGF-beta 1</g> on cells may be further regulated by the expression of T beta Rs. CONCLUSION: Activation of L-<g>TGF-beta 1</g> and the differential expression of T beta Rs may be important in the pathogenesis of remodelling and <d>fibrosis</d> in <d>IPF</d>.
11776068|a|OBJECTIVE: To identify the role of cytokines involved in the development of <d>lung fibrosis</d> in patients with idiopathic-pulmonary fibrosis IPF. METHODS: Proteins and gene expression of platelet-derived growth factor PDGF-A and -B, insulin-like growth factor 1 <g>IGF-1</g>, and transforming growth factor beta <g>TGF-beta</g> were measured in alveolar macrophages and open lung biopsies from patients with IPF using immunohistochemistry IHC and in situ hybridization ISH. RESULTS: In specimens of bronchoalveolar lavage fluid BALF, PDGF-A, PDGF-B, <g>IGF-1</g>, <g>TGF-beta</g> were localized in alveolar macrophages. Evaluation of open lung biopsies from patients with IPF showed that <g>IGF-1</g> was prominently present in pulmonary vessel walls in fibrotic lesions. PDGF and <g>TGF-beta</g> proteins were localized to hyperplastic bronchio-alveolar epithelial cells, alveolar macrophages, fibroblasts, vascular smooth muscle and endothelial cells. Our in situ hybridization results were consistent with that of immunohistochemistry except that PDGF-A and <g>TGF-beta</g> mRNA transcripts were not detected in bronchoalveolar epithelial cells. CONCLUSION: These observations suggest that 1 alveolar macrophages play key roles not only in inflammation but also in the fibrotic process by releasing PDGF, <g>IGF-1</g> and <g>TGF-beta</g>; 2 <g>IGF-1</g> could be responsible for angiogenesis in IPF; 3 PDGF, <g>TGF-beta</g> are associated with fibroplasia and the deposition of extracellular matrix, as well as vessel remodeling and epithelial cell repopularization.
11776068|a|OBJECTIVE: To identify the role of cytokines involved in the development of <d>lung fibrosis</d> in patients with <d>idiopathic-pulmonary fibrosis</d> IPF. METHODS: Proteins and gene expression of platelet-derived growth factor PDGF-A and -B, insulin-like growth factor 1 <g>IGF-1</g>, and transforming growth factor beta <g>TGF-beta</g> were measured in alveolar macrophages and open lung biopsies from patients with IPF using immunohistochemistry IHC and in situ hybridization ISH. RESULTS: In specimens of bronchoalveolar lavage fluid BALF, PDGF-A, PDGF-B, <g>IGF-1</g>, <g>TGF-beta</g> were localized in alveolar macrophages. Evaluation of open lung biopsies from patients with IPF showed that <g>IGF-1</g> was prominently present in pulmonary vessel walls in fibrotic lesions. PDGF and <g>TGF-beta</g> proteins were localized to hyperplastic bronchio-alveolar epithelial cells, alveolar macrophages, fibroblasts, vascular smooth muscle and endothelial cells. Our in situ hybridization results were consistent with that of immunohistochemistry except that PDGF-A and <g>TGF-beta</g> mRNA transcripts were not detected in bronchoalveolar epithelial cells. CONCLUSION: These observations suggest that 1 alveolar macrophages play key roles not only in inflammation but also in the fibrotic process by releasing PDGF, <g>IGF-1</g> and <g>TGF-beta</g>; 2 <g>IGF-1</g> could be responsible for angiogenesis in IPF; 3 PDGF, <g>TGF-beta</g> are associated with fibroplasia and the deposition of extracellular matrix, as well as vessel remodeling and epithelial cell repopularization.
11776068|a|OBJECTIVE: To identify the role of cytokines involved in the development of <d>lung fibrosis</d> in patients with <d>idiopathic-pulmonary fibrosis</d> <d>IPF</d>. METHODS: Proteins and gene expression of platelet-derived growth factor PDGF-A and -B, insulin-like growth factor 1 <g>IGF-1</g>, and transforming growth factor beta <g>TGF-beta</g> were measured in alveolar macrophages and open lung biopsies from patients with <d>IPF</d> using immunohistochemistry IHC and in situ hybridization ISH. RESULTS: In specimens of bronchoalveolar lavage fluid BALF, PDGF-A, PDGF-B, <g>IGF-1</g>, <g>TGF-beta</g> were localized in alveolar macrophages. Evaluation of open lung biopsies from patients with <d>IPF</d> showed that <g>IGF-1</g> was prominently present in pulmonary vessel walls in fibrotic lesions. PDGF and <g>TGF-beta</g> proteins were localized to hyperplastic bronchio-alveolar epithelial cells, alveolar macrophages, fibroblasts, vascular smooth muscle and endothelial cells. Our in situ hybridization results were consistent with that of immunohistochemistry except that PDGF-A and <g>TGF-beta</g> mRNA transcripts were not detected in bronchoalveolar epithelial cells. CONCLUSION: These observations suggest that 1 alveolar macrophages play key roles not only in inflammation but also in the fibrotic process by releasing PDGF, <g>IGF-1</g> and <g>TGF-beta</g>; 2 <g>IGF-1</g> could be responsible for angiogenesis in <d>IPF</d>; 3 PDGF, <g>TGF-beta</g> are associated with fibroplasia and the deposition of extracellular matrix, as well as vessel remodeling and epithelial cell repopularization.
11776068|a|OBJECTIVE: To identify the role of cytokines involved in the development of <d>lung fibrosis</d> in patients with <d>idiopathic-pulmonary fibrosis</d> <d>IPF</d>. METHODS: Proteins and gene expression of platelet-derived growth factor <g>PDGF-A</g> and -B, insulin-like growth factor 1 <g>IGF-1</g>, and <g>transforming growth factor beta</g> <g>TGF-beta</g> were measured in alveolar macrophages and open lung biopsies from patients with <d>IPF</d> using immunohistochemistry IHC and in situ hybridization ISH. RESULTS: In specimens of bronchoalveolar lavage fluid BALF, <g>PDGF-A</g>, <g>PDGF-B</g>, <g>IGF-1</g>, <g>TGF-beta</g> were localized in alveolar macrophages. Evaluation of open lung biopsies from patients with <d>IPF</d> showed that <g>IGF-1</g> was prominently present in pulmonary vessel walls in <d>fibrotic lesions</d>. PDGF and <g>TGF-beta</g> proteins were localized to hyperplastic bronchio-alveolar epithelial cells, alveolar macrophages, fibroblasts, vascular smooth muscle and endothelial cells. Our in situ hybridization results were consistent with that of immunohistochemistry except that <g>PDGF-A</g> and <g>TGF-beta</g> mRNA transcripts were not detected in bronchoalveolar epithelial cells. CONCLUSION: These observations suggest that 1 alveolar macrophages play key roles not only in inflammation but also in the fibrotic process by releasing PDGF, <g>IGF-1</g> and <g>TGF-beta</g>; 2 <g>IGF-1</g> could be responsible for angiogenesis in <d>IPF</d>; 3 PDGF, <g>TGF-beta</g> are associated with fibroplasia and the deposition of extracellular matrix, as well as vessel remodeling and epithelial cell repopularization.
11776068|a|OBJECTIVE: To identify the role of cytokines involved in the development of <d>lung fibrosis</d> in patients with <d>idiopathic-pulmonary fibrosis</d> <d>IPF</d>. METHODS: Proteins and gene expression of platelet-derived growth factor <g>PDGF-A</g> and -B, insulin-like growth factor 1 <g>IGF-1</g>, and <g>transforming growth factor beta</g> <g>TGF-beta</g> were measured in alveolar macrophages and open lung biopsies from patients with <d>IPF</d> using immunohistochemistry IHC and in situ hybridization ISH. RESULTS: In specimens of bronchoalveolar lavage fluid BALF, <g>PDGF-A</g>, <g>PDGF-B</g>, <g>IGF-1</g>, <g>TGF-beta</g> were localized in alveolar macrophages. Evaluation of open lung biopsies from patients with <d>IPF</d> showed that <g>IGF-1</g> was prominently present in pulmonary vessel walls in <d>fibrotic lesions</d>. PDGF and <g>TGF-beta</g> proteins were localized to hyperplastic bronchio-alveolar epithelial cells, alveolar macrophages, fibroblasts, vascular smooth muscle and endothelial cells. Our in situ hybridization results were consistent with that of immunohistochemistry except that <g>PDGF-A</g> and <g>TGF-beta</g> mRNA transcripts were not detected in bronchoalveolar epithelial cells. CONCLUSION: These observations suggest that 1 alveolar macrophages play key roles not only in <d>inflammation</d> but also in the fibrotic process by releasing PDGF, <g>IGF-1</g> and <g>TGF-beta</g>; 2 <g>IGF-1</g> could be responsible for angiogenesis in <d>IPF</d>; 3 PDGF, <g>TGF-beta</g> are associated with fibroplasia and the deposition of extracellular matrix, as well as vessel remodeling and epithelial cell repopularization.
11776068|a|OBJECTIVE: To identify the role of cytokines involved in the development of <d>lung fibrosis</d> in patients with <d>idiopathic-pulmonary fibrosis</d> <d>IPF</d>. METHODS: Proteins and gene expression of platelet-derived growth factor <g>PDGF-A</g> and -B, insulin-like growth factor 1 <g>IGF-1</g>, and <g>transforming growth factor beta</g> <g>TGF-beta</g> were measured in alveolar macrophages and open lung biopsies from patients with <d>IPF</d> using immunohistochemistry IHC and in situ hybridization ISH. RESULTS: In specimens of bronchoalveolar lavage fluid BALF, <g>PDGF-A</g>, <g>PDGF-B</g>, <g>IGF-1</g>, <g>TGF-beta</g> were localized in alveolar macrophages. Evaluation of open lung biopsies from patients with <d>IPF</d> showed that <g>IGF-1</g> was prominently present in pulmonary vessel walls in <d>fibrotic lesions</d>. PDGF and <g>TGF-beta</g> proteins were localized to hyperplastic bronchio-alveolar epithelial cells, alveolar macrophages, fibroblasts, vascular smooth muscle and endothelial cells. Our in situ hybridization results were consistent with that of immunohistochemistry except that <g>PDGF-A</g> and <g>TGF-beta</g> mRNA transcripts were not detected in bronchoalveolar epithelial cells. CONCLUSION: These observations suggest that 1 alveolar macrophages play key roles not only in <d>inflammation</d> but also in the fibrotic process by releasing PDGF, <g>IGF-1</g> and <g>TGF-beta</g>; 2 <g>IGF-1</g> could be responsible for angiogenesis in <d>IPF</d>; 3 PDGF, <g>TGF-beta</g> are associated with <d>fibroplasia</d> and the deposition of extracellular matrix, as well as vessel remodeling and epithelial cell repopularization.
11812353|a|OBJECTIVE: To investigate the protein and gene expression in bronchoalveolar lavage cells and open lung biopsies from patients with <d>IPF</d>. METHODS: The immunohistochemical methods were used to analyze the expression of PDGF, TGF-beta in bronchoalveolar lavage cells of patients with <d>IPF</d>. For open lung biopsies, both immunohistochemistry and in situ hybridization were used. RESULTS: In specimens of bronchoalveolar lavage fluid, PDGF-AA, PDGF-BB, TGF-beta were localized to alveolar macrophages in patients with <d>IPF</d>. Though there were no differences between <d>IPF</d> and sarcoidosis in terms of the staining intensity 2.5 - 3.0 or number of positive cells 81% - 90%, the number of such cells were less in the control 0 - 1.7, 25% - 32% respectively. Evaluation of open lung biopsies from patients with <d>IPF</d> showed that PDGF, TGF-beta proteins were localized to hyperplastic bronchio-alveolar epithelial cells 2.4 - 3.7, in control 0, alveolar macrophages 2.9 - 3.7, in control 0.8 - 1.3, fibroblasts 3.0 - 3.6, in control 2.7 - 2.8, vascular smooth muscle cells, vascular endothelial cells, and fibroblast-like cells surrounding pulmonary vessels 2.7 - 4.0, in control 2.1 - 2.9. In situ hybridization results were consistent with that of immunohistochemistry except that PDGF and TGF-beta mRNA transcripts were not detected in bronchio-alveolar epithelial cells. In control lungs, however, both ISH and IHC revealed that PDGF and TGF-beta were only present in the pleura and in fibroblast-like cells surrounding pulmonary vessels. CONCLUSIONS: PDGF and TGF-beta, which interplay with pulmonary mesenchymal cells, are involved in fibroplasia and deposition of extracellular matrix as well as angiogenesis and epithelial cell repopularization.
11812353|a|OBJECTIVE: To investigate the protein and gene expression in broncho<d>alveolar</d> lavage cells and open lung biopsies from patients with <d>IPF</d>. METHODS: The immunohistochemical methods were used to analyze the expression of PDGF, <g>TGF-beta</g> in broncho<d>alveolar</d> lavage cells of patients with <d>IPF</d>. For open lung biopsies, both immunohistochemistry and in situ hybridization were used. RESULTS: In specimens of broncho<d>alveolar</d> lavage fluid, PDGF-AA, PDGF-BB, <g>TGF-beta</g> were localized to <d>alveolar</d> macrophages in patients with <d>IPF</d>. Though there were no differences between <d>IPF</d> and sarcoidosis in terms of the staining intensity 2.5 - 3.0 or number of positive cells 81% - 90%, the number of such cells were less in the control 0 - 1.7, 25% - 32% respectively. Evaluation of open lung biopsies from patients with <d>IPF</d> showed that PDGF, <g>TGF-beta</g> proteins were localized to hyperplastic bronchio-<d>alveolar</d> epithelial cells 2.4 - 3.7, in control 0, <d>alveolar</d> macrophages 2.9 - 3.7, in control 0.8 - 1.3, fibroblasts 3.0 - 3.6, in control 2.7 - 2.8, vascular smooth muscle cells, vascular endothelial cells, and fibroblast-like cells surrounding pulmonary vessels 2.7 - 4.0, in control 2.1 - 2.9. In situ hybridization results were consistent with that of immunohistochemistry except that PDGF and <g>TGF-beta</g> mRNA transcripts were not detected in bronchio-<d>alveolar</d> epithelial cells. In control lungs, however, both ISH and IHC revealed that PDGF and <g>TGF-beta</g> were only present in the pleura and in fibroblast-like cells surrounding pulmonary vessels. CONCLUSIONS: PDGF and <g>TGF-beta</g>, which interplay with pulmonary mesenchymal cells, are involved in fibroplasia and deposition of extracellular matrix as well as angiogenesis and epithelial cell repopularization.
11812353|a|OBJECTIVE: To investigate the protein and gene expression in broncho<d>alveolar</d> lavage cells and open lung biopsies from patients with <d>IPF</d>. METHODS: The immunohistochemical methods were used to analyze the expression of PDGF, <g>TGF-beta</g> in broncho<d>alveolar</d> lavage cells of patients with <d>IPF</d>. For open lung biopsies, both immunohistochemistry and in situ hybridization were used. RESULTS: In specimens of broncho<d>alveolar</d> lavage fluid, PDGF-AA, PDGF-BB, <g>TGF-beta</g> were localized to <d>alveolar</d> macrophages in patients with <d>IPF</d>. Though there were no differences between <d>IPF</d> and <d>sarcoidosis</d> in terms of the staining intensity 2.5 - 3.0 or number of positive cells 81% - 90%, the number of such cells were less in the control 0 - 1.7, 25% - 32% respectively. Evaluation of open lung biopsies from patients with <d>IPF</d> showed that PDGF, <g>TGF-beta</g> proteins were localized to hyperplastic bronchio-<d>alveolar</d> epithelial cells 2.4 - 3.7, in control 0, <d>alveolar</d> macrophages 2.9 - 3.7, in control 0.8 - 1.3, fibroblasts 3.0 - 3.6, in control 2.7 - 2.8, vascular smooth muscle cells, vascular endothelial cells, and fibroblast-like cells surrounding pulmonary vessels 2.7 - 4.0, in control 2.1 - 2.9. In situ hybridization results were consistent with that of immunohistochemistry except that PDGF and <g>TGF-beta</g> mRNA transcripts were not detected in bronchio-<d>alveolar</d> epithelial cells. In control lungs, however, both ISH and IHC revealed that PDGF and <g>TGF-beta</g> were only present in the pleura and in fibroblast-like cells surrounding pulmonary vessels. CONCLUSIONS: PDGF and <g>TGF-beta</g>, which interplay with pulmonary mesenchymal cells, are involved in fibroplasia and deposition of extracellular matrix as well as angiogenesis and epithelial cell repopularization.
11812353|a|OBJECTIVE: To investigate the protein and gene expression in broncho<d>alveolar</d> lavage cells and open lung biopsies from patients with <d>IPF</d>. METHODS: The immunohistochemical methods were used to analyze the expression of PDGF, <g>TGF-beta</g> in broncho<d>alveolar</d> lavage cells of patients with <d>IPF</d>. For open lung biopsies, both immunohistochemistry and in situ hybridization were used. RESULTS: In specimens of broncho<d>alveolar</d> lavage fluid, PDGF-AA, PDGF-BB, <g>TGF-beta</g> were localized to <d>alveolar</d> macrophages in patients with <d>IPF</d>. Though there were no differences between <d>IPF</d> and <d>sarcoidosis</d> in terms of the staining intensity 2.5 - 3.0 or number of positive cells 81% - 90%, the number of such cells were less in the control 0 - 1.7, 25% - 32% respectively. Evaluation of open lung biopsies from patients with <d>IPF</d> showed that PDGF, <g>TGF-beta</g> proteins were localized to hyperplastic bronchio-<d>alveolar</d> epithelial cells 2.4 - 3.7, in control 0, <d>alveolar</d> macrophages 2.9 - 3.7, in control 0.8 - 1.3, fibroblasts 3.0 - 3.6, in control 2.7 - 2.8, vascular smooth muscle cells, vascular endothelial cells, and fibroblast-like cells surrounding pulmonary vessels 2.7 - 4.0, in control 2.1 - 2.9. In situ hybridization results were consistent with that of immunohistochemistry except that PDGF and <g>TGF-beta</g> mRNA transcripts were not detected in bronchio-<d>alveolar</d> epithelial cells. In control lungs, however, both ISH and IHC revealed that PDGF and <g>TGF-beta</g> were only present in the pleura and in fibroblast-like cells surrounding pulmonary vessels. CONCLUSIONS: PDGF and <g>TGF-beta</g>, which interplay with pulmonary mesenchymal cells, are involved in <d>fibroplasia</d> and deposition of extracellular matrix as well as angiogenesis and epithelial cell repopularization.
12055267|a|<g>Transforming growth factor-beta 1</g> <g>TGF-beta 1</g> has important roles in lung <d>fibrosis</d> and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary <d>fibrosis</d>. In this study, we show that TGF-beta1 induces apoptosis of primary cultured bronchiolar epithelial cells via caspase-3 activation and down-regulation of cyclin-dependent kinase inhibitor p21. Concentrations of <g>TGF-beta 1</g> that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or rFas ligand-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble Fas ligand in the bronchoalveolar lavage fluid BALF from patients with idiopathic pulmonary <d>fibrosis</d> IPF also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-beta Ab. Otherwise, BALF from patients with hypersensitivity pneumonitis HP could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble Fas ligand. The concentrations of <g>TGF-beta 1</g> in BALF from patients with IPF were significantly higher compared with those in BALF from patients with HP or controls. Furthermore, coincubation with the low concentration of <g>TGF-beta 1</g> and HP BALF created proapoptotic effects comparable with the IPF BALF. In vivo, the administration of <g>TGF-beta 1</g> could enhance Fas-mediated epithelial cell apoptosis and lung injury via caspase-3 activation in mice. Our results demonstrate a novel role of <g>TGF-beta 1</g> in the pathophysiology of pulmonary <d>fibrosis</d> as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
12055267|a|<g>Transforming growth factor-beta 1</g> <g>TGF-beta 1</g> has important roles in lung <d>fibrosis</d> and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary <d>fibrosis</d>. In this study, we show that <g>TGF-beta1</g> induces apoptosis of primary cultured bronchiolar epithelial cells via <g>caspase-3</g> activation and down-regulation of cyclin-dependent kinase inhibitor <g>p21</g>. Concentrations of <g>TGF-beta 1</g> that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or r<g>Fas ligand</g>-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble <g>Fas ligand</g> in the bronchoalveolar lavage fluid BALF from patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-beta Ab. Otherwise, BALF from patients with hypersensitivity pneumonitis HP could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble <g>Fas ligand</g>. The concentrations of <g>TGF-beta 1</g> in BALF from patients with <d>IPF</d> were significantly higher compared with those in BALF from patients with HP or controls. Furthermore, coincubation with the low concentration of <g>TGF-beta 1</g> and HP BALF created proapoptotic effects comparable with the <d>IPF</d> BALF. In vivo, the administration of <g>TGF-beta 1</g> could enhance Fas-mediated epithelial cell apoptosis and lung injury via <g>caspase-3</g> activation in mice. Our results demonstrate a novel role of <g>TGF-beta 1</g> in the pathophysiology of pulmonary <d>fibrosis</d> as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
12055267|a|<g>Transforming growth factor-beta 1</g> <g>TGF-beta 1</g> has important roles in lung <d>fibrosis</d> and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary <d>fibrosis</d>. In this study, we show that <g>TGF-beta1</g> induces apoptosis of primary cultured bronchiolar epithelial cells via <g>caspase-3</g> activation and down-regulation of cyclin-dependent kinase inhibitor <g>p21</g>. Concentrations of <g>TGF-beta 1</g> that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or r<g>Fas ligand</g>-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble <g>Fas ligand</g> in the bronchoalveolar lavage fluid BALF from patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-beta Ab. Otherwise, BALF from patients with <d>hypersensitivity pneumonitis</d> HP could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble <g>Fas ligand</g>. The concentrations of <g>TGF-beta 1</g> in BALF from patients with <d>IPF</d> were significantly higher compared with those in BALF from patients with HP or controls. Furthermore, coincubation with the low concentration of <g>TGF-beta 1</g> and HP BALF created proapoptotic effects comparable with the <d>IPF</d> BALF. In vivo, the administration of <g>TGF-beta 1</g> could enhance Fas-mediated epithelial cell apoptosis and lung injury via <g>caspase-3</g> activation in mice. Our results demonstrate a novel role of <g>TGF-beta 1</g> in the pathophysiology of pulmonary <d>fibrosis</d> as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
12055267|a|<g>Transforming growth factor-beta 1</g> <g>TGF-beta 1</g> has important roles in lung <d>fibrosis</d> and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary <d>fibrosis</d>. In this study, we show that <g>TGF-beta1</g> induces apoptosis of primary cultured bronchiolar epithelial cells via <g>caspase-3</g> activation and down-regulation of cyclin-dependent kinase inhibitor <g>p21</g>. Concentrations of <g>TGF-beta 1</g> that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or r<g>Fas ligand</g>-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble <g>Fas ligand</g> in the bronchoalveolar lavage fluid BALF from patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-beta Ab. Otherwise, BALF from patients with <d>hypersensitivity pneumonitis</d> <d>HP</d> could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble <g>Fas ligand</g>. The concentrations of <g>TGF-beta 1</g> in BALF from patients with <d>IPF</d> were significantly higher compared with those in BALF from patients with <d>HP</d> or controls. Furthermore, coincubation with the low concentration of <g>TGF-beta 1</g> and <d>HP</d> BALF created proapoptotic effects comparable with the <d>IPF</d> BALF. In vivo, the administration of <g>TGF-beta 1</g> could enhance Fas-mediated epithelial cell apoptosis and lung injury via <g>caspase-3</g> activation in mice. Our results demonstrate a novel role of <g>TGF-beta 1</g> in the pathophysiology of pulmonary <d>fibrosis</d> as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
12055267|a|<g>Transforming growth factor-beta 1</g> <g>TGF-beta 1</g> has important roles in lung <d>fibrosis</d> and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary <d>fibrosis</d>. In this study, we show that <g>TGF-beta1</g> induces apoptosis of primary cultured bronchiolar epithelial cells via <g>caspase-3</g> activation and down-regulation of cyclin-dependent kinase inhibitor <g>p21</g>. Concentrations of <g>TGF-beta 1</g> that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or r<g>Fas ligand</g>-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble <g>Fas ligand</g> in the bronchoalveolar lavage fluid BALF from patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-beta Ab. Otherwise, BALF from patients with <d>hypersensitivity pneumonitis</d> <d>HP</d> could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble <g>Fas ligand</g>. The concentrations of <g>TGF-beta 1</g> in BALF from patients with <d>IPF</d> were significantly higher compared with those in BALF from patients with <d>HP</d> or controls. Furthermore, coincubation with the low concentration of <g>TGF-beta 1</g> and <d>HP</d> BALF created proapoptotic effects comparable with the <d>IPF</d> BALF. In vivo, the administration of <g>TGF-beta 1</g> could enhance Fas-mediated epithelial cell apoptosis and <d>lung injury</d> via <g>caspase-3</g> activation in mice. Our results demonstrate a novel role of <g>TGF-beta 1</g> in the pathophysiology of pulmonary <d>fibrosis</d> as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
12243323|a|The lysosomal enzymes N-acetylglucosaminidase N-ACGA and <g>beta-galactosidase</g> beta-gal are involved in cellular collagen metabolism and may, therefore, be markers of fibrosis in idiopathic interstitial pneumonias, such as <d>idiopathic pulmonary fibrosis</d> IPF. N-ACGA and beta-gal were analyzed in the bronchoalveolar lavage fluid BALF of patients with the histologic pattern of usual interstitial pneumonia UIP, n=10 and controls n=9. Cellular distribution in BALF as well as the concentration of TGF-beta a well-known mediator of fibroblast matrix deposition were correlated to the enzyme activities in both groups of patients. We found that both, N-ACGA UIP: 25.2 nmol/l s +/- 3.4; controls: 73 nmol/l s +/- 1.3 and beta-gal UIP: 4.7 nmol/l s +/- 0.5; controls: 2.4 nmol/l s +/- 0.3 were elevated significantly in BALF of patients with IPF compared to that of control patients P<0.003. This increase was paralleled by an increase in neutrophils IPF: 17.9% +/- 21.8; controls: 5.4% +/- 6.3; P=0.03 and eosinophils IPF: 2.0% +/- 1.5; controls: 0.2% +/- 0.45; P=0.002 in BALF fluid. In addition, N-ACGA activity correlated closely with lung function FVC, TLC, and DLCO, transforming growth factor-beta TGF-beta in BALF r=0.77, P=0.008 and activated lymphocytes r=0.66, P=0.0021. Our findings suggest that measurement of lysosomal enzymes such as N-ACGA may represent a useful indicator of fibrotic activity in IPF.
12243323|a|The lysosomal enzymes N-acetylglucosaminidase N-ACGA and <g><g>beta-gal</g>actosidase</g> <g>beta-gal</g> are involved in cellular collagen metabolism and may, therefore, be markers of <d>fibrosis</d> in idiopathic interstitial pneumonias, such as <d>idiopathic pulmonary <d>fibrosis</d></d> IPF. N-ACGA and <g>beta-gal</g> were analyzed in the bronchoalveolar lavage fluid BALF of patients with the histologic pattern of usual interstitial pneumonia UIP, n=10 and controls n=9. Cellular distribution in BALF as well as the concentration of TGF-beta a well-known mediator of fibroblast matrix deposition were correlated to the enzyme activities in both groups of patients. We found that both, N-ACGA UIP: 25.2 nmol/l s +/- 3.4; controls: 73 nmol/l s +/- 1.3 and <g>beta-gal</g> UIP: 4.7 nmol/l s +/- 0.5; controls: 2.4 nmol/l s +/- 0.3 were elevated significantly in BALF of patients with IPF compared to that of control patients P<0.003. This increase was paralleled by an increase in neutrophils IPF: 17.9% +/- 21.8; controls: 5.4% +/- 6.3; P=0.03 and eosinophils IPF: 2.0% +/- 1.5; controls: 0.2% +/- 0.45; P=0.002 in BALF fluid. In addition, N-ACGA activity correlated closely with lung function FVC, TLC, and DLCO, transforming growth factor-beta TGF-beta in BALF r=0.77, P=0.008 and activated lymphocytes r=0.66, P=0.0021. Our findings suggest that measurement of lysosomal enzymes such as N-ACGA may represent a useful indicator of fibrotic activity in IPF.
12243323|a|The lysosomal enzymes N-acetylglucosaminidase N-ACGA and <g><g>beta-gal</g>actosidase</g> <g>beta-gal</g> are involved in cellular collagen metabolism and may, therefore, be markers of <d>fibrosis</d> in <d>idiopathic interstitial pneumonias</d>, such as <d>idiopathic pulmonary <d>fibrosis</d></d> IPF. N-ACGA and <g>beta-gal</g> were analyzed in the bronchoalveolar lavage fluid BALF of patients with the histologic pattern of usual interstitial pneumonia UIP, n=10 and controls n=9. Cellular distribution in BALF as well as the concentration of TGF-beta a well-known mediator of fibroblast matrix deposition were correlated to the enzyme activities in both groups of patients. We found that both, N-ACGA UIP: 25.2 nmol/l s +/- 3.4; controls: 73 nmol/l s +/- 1.3 and <g>beta-gal</g> UIP: 4.7 nmol/l s +/- 0.5; controls: 2.4 nmol/l s +/- 0.3 were elevated significantly in BALF of patients with IPF compared to that of control patients P<0.003. This increase was paralleled by an increase in neutrophils IPF: 17.9% +/- 21.8; controls: 5.4% +/- 6.3; P=0.03 and eosinophils IPF: 2.0% +/- 1.5; controls: 0.2% +/- 0.45; P=0.002 in BALF fluid. In addition, N-ACGA activity correlated closely with lung function FVC, TLC, and DLCO, transforming growth factor-beta TGF-beta in BALF r=0.77, P=0.008 and activated lymphocytes r=0.66, P=0.0021. Our findings suggest that measurement of lysosomal enzymes such as N-ACGA may represent a useful indicator of fibrotic activity in IPF.
12243323|a|The lysosomal enzymes N-acetylglucosaminidase N-ACGA and <g><g>beta-gal</g>actosidase</g> <g>beta-gal</g> are involved in cellular collagen metabolism and may, therefore, be markers of <d>fibrosis</d> in <d>idiopathic interstitial pneumonias</d>, such as <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. N-ACGA and <g>beta-gal</g> were analyzed in the bronchoalveolar lavage fluid BALF of patients with the histologic pattern of usual interstitial pneumonia UIP, n=10 and controls n=9. Cellular distribution in BALF as well as the concentration of TGF-beta a well-known mediator of fibroblast matrix deposition were correlated to the enzyme activities in both groups of patients. We found that both, N-ACGA UIP: 25.2 nmol/l s +/- 3.4; controls: 73 nmol/l s +/- 1.3 and <g>beta-gal</g> UIP: 4.7 nmol/l s +/- 0.5; controls: 2.4 nmol/l s +/- 0.3 were elevated significantly in BALF of patients with <d>IPF</d> compared to that of control patients P<0.003. This increase was paralleled by an increase in neutrophils <d>IPF</d>: 17.9% +/- 21.8; controls: 5.4% +/- 6.3; P=0.03 and eosinophils <d>IPF</d>: 2.0% +/- 1.5; controls: 0.2% +/- 0.45; P=0.002 in BALF fluid. In addition, N-ACGA activity correlated closely with lung function FVC, TLC, and DLCO, transforming growth factor-beta TGF-beta in BALF r=0.77, P=0.008 and activated lymphocytes r=0.66, P=0.0021. Our findings suggest that measurement of lysosomal enzymes such as N-ACGA may represent a useful indicator of fibrotic activity in <d>IPF</d>.
12243323|a|The lysosomal enzymes N-acetylglucosaminidase N-ACGA and <g><g>beta-gal</g>actosidase</g> <g>beta-gal</g> are involved in cellular collagen metabolism and may, therefore, be markers of <d>fibrosis</d> in <d>idiopathic interstitial pneumonias</d>, such as <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. N-ACGA and <g>beta-gal</g> were analyzed in the bronchoalveolar lavage fluid BALF of patients with the histologic pattern of <d>usual interstitial pneumonia</d> UIP, n=10 and controls n=9. Cellular distribution in BALF as well as the concentration of TGF-beta a well-known mediator of fibroblast matrix deposition were correlated to the enzyme activities in both groups of patients. We found that both, N-ACGA UIP: 25.2 nmol/l s +/- 3.4; controls: 73 nmol/l s +/- 1.3 and <g>beta-gal</g> UIP: 4.7 nmol/l s +/- 0.5; controls: 2.4 nmol/l s +/- 0.3 were elevated significantly in BALF of patients with <d>IPF</d> compared to that of control patients P<0.003. This increase was paralleled by an increase in neutrophils <d>IPF</d>: 17.9% +/- 21.8; controls: 5.4% +/- 6.3; P=0.03 and eosinophils <d>IPF</d>: 2.0% +/- 1.5; controls: 0.2% +/- 0.45; P=0.002 in BALF fluid. In addition, N-ACGA activity correlated closely with lung function FVC, TLC, and DLCO, transforming growth factor-beta TGF-beta in BALF r=0.77, P=0.008 and activated lymphocytes r=0.66, P=0.0021. Our findings suggest that measurement of lysosomal enzymes such as N-ACGA may represent a useful indicator of fibrotic activity in <d>IPF</d>.
12243323|a|The lysosomal enzymes N-acetylglucosaminidase N-ACGA and <g><g>beta-gal</g>actosidase</g> <g>beta-gal</g> are involved in cellular collagen metabolism and may, therefore, be markers of <d>fibrosis</d> in <d>idiopathic interstitial pneumonias</d>, such as <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. N-ACGA and <g>beta-gal</g> were analyzed in the bronchoalveolar lavage fluid BALF of patients with the histologic pattern of <d>usual interstitial pneumonia</d> <d>UIP</d>, n=10 and controls n=9. Cellular distribution in BALF as well as the concentration of TGF-beta a well-known mediator of fibroblast matrix deposition were correlated to the enzyme activities in both groups of patients. We found that both, N-ACGA <d>UIP</d>: 25.2 nmol/l s +/- 3.4; controls: 73 nmol/l s +/- 1.3 and <g>beta-gal</g> <d>UIP</d>: 4.7 nmol/l s +/- 0.5; controls: 2.4 nmol/l s +/- 0.3 were elevated significantly in BALF of patients with <d>IPF</d> compared to that of control patients P<0.003. This increase was paralleled by an increase in neutrophils <d>IPF</d>: 17.9% +/- 21.8; controls: 5.4% +/- 6.3; P=0.03 and eosinophils <d>IPF</d>: 2.0% +/- 1.5; controls: 0.2% +/- 0.45; P=0.002 in BALF fluid. In addition, N-ACGA activity correlated closely with lung function FVC, TLC, and DLCO, transforming growth factor-beta TGF-beta in BALF r=0.77, P=0.008 and activated lymphocytes r=0.66, P=0.0021. Our findings suggest that measurement of lysosomal enzymes such as N-ACGA may represent a useful indicator of fibrotic activity in <d>IPF</d>.
12475802|a|Idiopathic pulmonary fibrosis IPF is a lung disease that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with IPF leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that IPF is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including IPF, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic lung disease</d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as IPF. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with IPF.
12475802|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a lung disease that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with IPF leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that IPF is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including IPF, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic lung disease</d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as IPF. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with IPF.
12475802|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lung disease that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including <d>IPF</d>, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic lung disease</d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including <d>IPF</d>, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including <d>IPF</d>, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including <d>IPF</d>, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including <d>IPF</d>, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including <d>IPF</d>, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including <d>IPF</d>, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an <d>immune disorder</d>. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including <d>IPF</d>, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an <d>immune disorder</d>. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as <g>tumor necrosis factor-alpha</g> and <g>interleukin-1beta</g>, have been shown to be exaggerated in several <d>fibrotic lung disorders</d> including <d>IPF</d>, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an <d>immune disorder</d>. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as <g>tumor necrosis factor-alpha</g> and <g>interleukin-1beta</g>, have been shown to be exaggerated in several <d>fibrotic lung disorders</d> including <d>IPF</d>, <d>ARDS</d>, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an <d>immune disorder</d>. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as <g>tumor necrosis factor-alpha</g> and <g>interleukin-1beta</g>, have been shown to be exaggerated in several <d>fibrotic lung disorders</d> including <d>IPF</d>, <d>ARDS</d>, <d>sarcoidosis</d>, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an <d>immune disorder</d>. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as <g>tumor necrosis factor-alpha</g> and <g>interleukin-1beta</g>, have been shown to be exaggerated in several <d>fibrotic lung disorders</d> including <d>IPF</d>, <d>ARDS</d>, <d>sarcoidosis</d>, and <d>bronchopulmonary dysplasia</d>, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an <d>immune disorder</d>. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as <g>tumor necrosis factor-alpha</g> and <g>interleukin-1beta</g>, have been shown to be exaggerated in several <d>fibrotic lung disorders</d> including <d>IPF</d>, <d>ARDS</d>, <d>sarcoidosis</d>, and <d>bronchopulmonary dysplasia</d>, as well as pulmonary manifestations of <d>systemic diseases</d> such as rheumatoid arthritis or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an <d>immune disorder</d>. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as <g>tumor necrosis factor-alpha</g> and <g>interleukin-1beta</g>, have been shown to be exaggerated in several <d>fibrotic lung disorders</d> including <d>IPF</d>, <d>ARDS</d>, <d>sarcoidosis</d>, and <d>bronchopulmonary dysplasia</d>, as well as pulmonary manifestations of <d>systemic diseases</d> such as <d>rheumatoid arthritis</d> or progressive systemic sclerosis scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an <d>immune disorder</d>. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as <g>tumor necrosis factor-alpha</g> and <g>interleukin-1beta</g>, have been shown to be exaggerated in several <d>fibrotic lung disorders</d> including <d>IPF</d>, <d>ARDS</d>, <d>sarcoidosis</d>, and <d>bronchopulmonary dysplasia</d>, as well as pulmonary manifestations of <d>systemic diseases</d> such as <d>rheumatoid arthritis</d> or <d>progressive systemic sclerosis</d> scleroderma. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12475802|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>lung disease</d> that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in <d>inflammation</d>, fibroblast proliferation, excessive extracellular matrix ECM deposition, and remodeling of <d>alveolar gas exchange units</d>. The progressive loss of lung gas exchange units in patients with <d>IPF</d> leads to <d>respiratory failure</d> and eventually to <d>death</d>. While the etiology of this disease is unknown, for many years studies suggested that chronic <d>inflammation</d> was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and <d>fibrosis</d> can occur independently of <d>inflammation</d>, suggesting that <d>IPF</d> is a disease caused by a mesenchymal, rather than an <d>immune disorder</d>. Mesenchymal growth factors, including transforming growth factor TGF-beta, <g>insulin-like growth factor I</g>GF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as <g>tumor necrosis factor-alpha</g> and <g>interleukin-1beta</g>, have been shown to be exaggerated in several <d>fibrotic lung disorders</d> including <d>IPF</d>, <d>ARDS</d>, <d>sarcoidosis</d>, and <d>bronchopulmonary dysplasia</d>, as well as pulmonary manifestations of <d>systemic diseases</d> such as <d>rheumatoid arthritis</d> or <d>progressive systemic sclerosis</d> <d>scleroderma</d>. We argue that <d>inflammation</d> is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in <d>fibrotic <d>lung disease</d></d>s and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as <d>IPF</d>. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with <d>IPF</d>.
12485463|a|Investigators have shown that <d>interstitial pulmonary fibrosis</d> IPF can be induced in rats by overexpressing transforming growth factor beta1 <g>TGF-beta1</g> through a replication-deficient recombinant adenovirus vector instilled into the lungs Sime et al. 1997. We have shown that this vector induces IPF in fibrogenic-resistant tumour necrosis factor alpha-receptor knockout TNF-alphaRKO mice Liu et al. 2001. The object of our studies is to understand how peptide growth factors, such as <g>TGF-beta1</g>, mediate interstitial lung disease ILD. To do so, we must be able to manipulate the dose of the factor and sort out its effects on multiple other mediators in the lung parenchyma. As a step in this complex process, in the studies reported here, we have determined the concentrations of the recombinant adenovirus vector carrying the gene for porcine active <g>TGF-beta1</g> AVTGFbeta1 that have little apparent effect, cause clear induction of disease, or severe disease. The disease largely resolves by 28 days in all cases, thus providing a valuable model to understand the mechanisms of the IPF that is mediated, at least in part, by <g>TGF-beta1</g>. The findings here show that 106 plaque-forming units pfu of AVTGFbeta1, provide essentially a 'no-effect' dose, but even this amount of <g>TGF-beta1</g> causes a significant increase in whole-lung collagen by day 28 after treatment. In contrast, 108 and 109 pfu cause severe IPF in 4 days, whereas 107 and 5 x 107 are intermediate for all parameters studied, i.e. TGF-beta protein, inflammatory cells, cell proliferation, pro-alpha 1I collagen gene expression and whole-lung collagen accumulation, and expression of growth factors such as <g>TGF-beta1</g>, TNF-alpha and PDGF-A and -B. Interestingly enough, <g>TGF-beta1</g>, as a potent blocker of epithelial cell proliferation, appears to suppress airway epithelial cell growth that would be expected during the inflammatory phase of IPF. Thus, this model system helps us to understand some quantitative aspects of <g>TGF-beta1</g> biological activity and allows us to manipulate this potent factor as a mediator of interstitial fibrogenesis.
12485463|a|Investigators have shown that <d>interstitial pulmonary fibrosis</d> <d>IPF</d> can be induced in rats by overexpressing transforming growth factor beta1 <g>TGF-beta1</g> through a replication-deficient recombinant adenovirus vector instilled into the lungs Sime et al. 1997. We have shown that this vector induces <d>IPF</d> in fibrogenic-resistant tumour necrosis factor alpha-receptor knockout TNF-alphaRKO mice Liu et al. 2001. The object of our studies is to understand how peptide growth factors, such as <g>TGF-beta1</g>, mediate interstitial lung disease ILD. To do so, we must be able to manipulate the dose of the factor and sort out its effects on multiple other mediators in the lung parenchyma. As a step in this complex process, in the studies reported here, we have determined the concentrations of the recombinant adenovirus vector carrying the gene for porcine active <g>TGF-beta1</g> AVTGFbeta1 that have little apparent effect, cause clear induction of disease, or severe disease. The disease largely resolves by 28 days in all cases, thus providing a valuable model to understand the mechanisms of the <d>IPF</d> that is mediated, at least in part, by <g>TGF-beta1</g>. The findings here show that 106 plaque-forming units pfu of AVTGFbeta1, provide essentially a 'no-effect' dose, but even this amount of <g>TGF-beta1</g> causes a significant increase in whole-lung collagen by day 28 after treatment. In contrast, 108 and 109 pfu cause severe <d>IPF</d> in 4 days, whereas 107 and 5 x 107 are intermediate for all parameters studied, i.e. TGF-beta protein, inflammatory cells, cell proliferation, pro-alpha 1I collagen gene expression and whole-lung collagen accumulation, and expression of growth factors such as <g>TGF-beta1</g>, TNF-alpha and PDGF-A and -B. Interestingly enough, <g>TGF-beta1</g>, as a potent blocker of epithelial cell proliferation, appears to suppress airway epithelial cell growth that would be expected during the inflammatory phase of <d>IPF</d>. Thus, this model system helps us to understand some quantitative aspects of <g>TGF-beta1</g> biological activity and allows us to manipulate this potent factor as a mediator of interstitial fibrogenesis.
12485463|a|Investigators have shown that <d>interstitial pulmonary fibrosis</d> <d>IPF</d> can be induced in rats by overexpressing <g>transforming growth factor beta1</g> <g>TGF-beta1</g> through a replication-deficient recombinant adenovirus vector instilled into the lungs Sime et al. 1997. We have shown that this vector induces <d>IPF</d> in fibrogenic-resistant <d>tumour</d> necrosis factor alpha-receptor knockout TNF-alphaRKO mice Liu et al. 2001. The object of our studies is to understand how peptide growth factors, such as <g>TGF-beta1</g>, mediate interstitial lung disease ILD. To do so, we must be able to manipulate the dose of the factor and sort out its effects on multiple other mediators in the lung parenchyma. As a step in this complex process, in the studies reported here, we have determined the concentrations of the recombinant adenovirus vector carrying the gene for porcine active <g>TGF-beta1</g> AVTGFbeta1 that have little apparent effect, cause clear induction of disease, or severe disease. The disease largely resolves by 28 days in all cases, thus providing a valuable model to understand the mechanisms of the <d>IPF</d> that is mediated, at least in part, by <g>TGF-beta1</g>. The findings here show that 106 plaque-forming units pfu of AVTGFbeta1, provide essentially a 'no-effect' dose, but even this amount of <g>TGF-beta1</g> causes a significant increase in whole-lung collagen by day 28 after treatment. In contrast, 108 and 109 pfu cause severe <d>IPF</d> in 4 days, whereas 107 and 5 x 107 are intermediate for all parameters studied, i.e. TGF-beta protein, inflammatory cells, cell proliferation, pro-alpha 1I collagen gene expression and whole-lung collagen accumulation, and expression of growth factors such as <g>TGF-beta1</g>, TNF-alpha and PDGF-A and -B. Interestingly enough, <g>TGF-beta1</g>, as a potent blocker of epithelial cell proliferation, appears to suppress airway epithelial cell growth that would be expected during the inflammatory phase of <d>IPF</d>. Thus, this model system helps us to understand some quantitative aspects of <g>TGF-beta1</g> biological activity and allows us to manipulate this potent factor as a mediator of interstitial fibrogenesis.
12485463|a|Investigators have shown that <d>interstitial pulmonary fibrosis</d> <d>IPF</d> can be induced in rats by overexpressing <g>transforming growth factor beta1</g> <g>TGF-beta1</g> through a replication-deficient recombinant adenovirus vector instilled into the lungs Sime et al. 1997. We have shown that this vector induces <d>IPF</d> in fibrogenic-resistant <d>tumour</d> necrosis factor alpha-receptor knockout TNF-alphaRKO mice Liu et al. 2001. The object of our studies is to understand how peptide growth factors, such as <g>TGF-beta1</g>, mediate <d>interstitial lung disease</d> ILD. To do so, we must be able to manipulate the dose of the factor and sort out its effects on multiple other mediators in the lung parenchyma. As a step in this complex process, in the studies reported here, we have determined the concentrations of the recombinant adenovirus vector carrying the gene for porcine active <g>TGF-beta1</g> AVTGFbeta1 that have little apparent effect, cause clear induction of disease, or severe disease. The disease largely resolves by 28 days in all cases, thus providing a valuable model to understand the mechanisms of the <d>IPF</d> that is mediated, at least in part, by <g>TGF-beta1</g>. The findings here show that 106 plaque-forming units pfu of AVTGFbeta1, provide essentially a 'no-effect' dose, but even this amount of <g>TGF-beta1</g> causes a significant increase in whole-lung collagen by day 28 after treatment. In contrast, 108 and 109 pfu cause severe <d>IPF</d> in 4 days, whereas 107 and 5 x 107 are intermediate for all parameters studied, i.e. TGF-beta protein, inflammatory cells, cell proliferation, pro-alpha 1I collagen gene expression and whole-lung collagen accumulation, and expression of growth factors such as <g>TGF-beta1</g>, TNF-alpha and PDGF-A and -B. Interestingly enough, <g>TGF-beta1</g>, as a potent blocker of epithelial cell proliferation, appears to suppress airway epithelial cell growth that would be expected during the inflammatory phase of <d>IPF</d>. Thus, this model system helps us to understand some quantitative aspects of <g>TGF-beta1</g> biological activity and allows us to manipulate this potent factor as a mediator of interstitial fibrogenesis.
12485463|a|Investigators have shown that <d>interstitial pulmonary fibrosis</d> <d>IPF</d> can be induced in rats by overexpressing <g>transforming growth factor beta1</g> <g>TGF-beta1</g> through a replication-deficient recombinant adenovirus vector instilled into the lungs Sime et al. 1997. We have shown that this vector induces <d>IPF</d> in fibrogenic-resistant <d>tumour</d> necrosis factor alpha-receptor knockout TNF-alphaRKO mice Liu et al. 2001. The object of our studies is to understand how peptide growth factors, such as <g>TGF-beta1</g>, mediate <d>interstitial lung disease</d> <d>ILD</d>. To do so, we must be able to manipulate the dose of the factor and sort out its effects on multiple other mediators in the lung parenchyma. As a step in this complex process, in the studies reported here, we have determined the concentrations of the recombinant adenovirus vector carrying the gene for porcine active <g>TGF-beta1</g> AVTGFbeta1 that have little apparent effect, cause clear induction of disease, or severe disease. The disease largely resolves by 28 days in all cases, thus providing a valuable model to understand the mechanisms of the <d>IPF</d> that is mediated, at least in part, by <g>TGF-beta1</g>. The findings here show that 106 plaque-forming units pfu of AVTGFbeta1, provide essentially a 'no-effect' dose, but even this amount of <g>TGF-beta1</g> causes a significant increase in whole-lung collagen by day 28 after treatment. In contrast, 108 and 109 pfu cause severe <d>IPF</d> in 4 days, whereas 107 and 5 x 107 are intermediate for all parameters studied, i.e. TGF-beta protein, inflammatory cells, cell proliferation, pro-alpha 1I collagen gene expression and whole-lung collagen accumulation, and expression of growth factors such as <g>TGF-beta1</g>, TNF-alpha and PDGF-A and -B. Interestingly enough, <g>TGF-beta1</g>, as a potent blocker of epithelial cell proliferation, appears to suppress airway epithelial cell growth that would be expected during the inflammatory phase of <d>IPF</d>. Thus, this model system helps us to understand some quantitative aspects of <g>TGF-beta1</g> biological activity and allows us to manipulate this potent factor as a mediator of interstitial fibrogenesis.
12540741|a|Pharmacological agents currently in use to treat <d>interstitial lung fibrosis</d> are either ineffective or too toxic in humans. This review addresses mechanistically based novel approaches that have the potential to minimize the accumulation of collagen in the lung, a hallmark of lung fibrosis. These approaches include maintaining the intracellular levels of NAD+ and ATP, blocking the biological activities of TGF-beta and integrins, evaluating the effectiveness of PAF-receptor antagonists and NOS inhibitors, and developing a new generation of cysteine pro-drugs with an adequate degree of bioavailability. A critical analysis of each approach as it relates to management of IPF in humans is presented.
12540741|a|Pharmacological agents currently in use to treat <d>interstitial lung fibrosis</d> are either ineffective or too toxic in humans. This review addresses mechanistically based novel approaches that have the potential to minimize the accumulation of collagen in the lung, a <d>hallmark of lung fibrosis</d>. These approaches include maintaining the intracellular levels of NAD+ and ATP, blocking the biological activities of TGF-beta and integrins, evaluating the effectiveness of PAF-receptor antagonists and NOS inhibitors, and developing a new generation of cysteine pro-drugs with an adequate degree of bioavailability. A critical analysis of each approach as it relates to management of IPF in humans is presented.
12540741|a|Pharmacological agents currently in use to treat <d>interstitial lung fibrosis</d> are either ineffective or too toxic in humans. This review addresses mechanistically based novel approaches that have the potential to minimize the accumulation of collagen in the lung, a <d>hallmark of lung fibrosis</d>. These approaches include maintaining the intracellular levels of NAD+ and ATP, blocking the biological activities of TGF-beta and integrins, evaluating the effectiveness of PAF-receptor antagonists and <g>NOS</g> inhibitors, and developing a new generation of cysteine pro-drugs with an adequate degree of bioavailability. A critical analysis of each approach as it relates to management of <d>IPF</d> in humans is presented.
12570673|a|<d>Idiopathic Pulmonary Fibrosis</d> IPF is a chronic interstitial lung disease which results in end-stage fibrosis. The pathogenesis is believed to be related to a dysregulation in cross-talk between inflammatory and structural cells, mediated by various cytokines, chemokines and growth factors, which are responsible for the maintenance of tissue homeostasis and which coordinate the response to injury. The large number of mediators involved and the complexity of their interaction makes it difficult to identify the factors responsible for initiation of fibrogenesis and progression to chronicity. Whether a mediator's presence in fibrotic lung is as a result of tissue injury or if it playsan active role in disease onset and progression has been partly answered by the use of transient and/or permanent transgenic and gene knock-out approaches to over-express single factors at a time. Chemokines such as interleukin-8 IL-8, RANTES, IP-10, MIG or lymphotactin, do not appear to induce fibrosis when over-expressed in rodent lung. Amongst many tested, four cytokines and growth factors have been found to be pro-fibrotic; IL-1beta, which demonstrates marked inflammation, tissue damage and chronic fibrosis, TNF-alpha, which induces inflammation and mild fibrosis, and GM-CSF, which induces moderate inflammation and fibrosis. A common finding with these cytokines are increased lung TGF-beta levels, proportionate to the degree of fibrosis generated, while TGF-beta itself causes minor inflammation but marked progressive chronic fibrosis. A growth factor 'downstream' from the pro-fibrotic effects of TGF-beta, CTGF, is a likely critical mediator. However, over-expression of CTGF produces only mild and reversible fibrosis.
12570673|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a chronic interstitial lung disease which results in end-stage fibrosis. The pathogenesis is believed to be related to a dysregulation in cross-talk between inflammatory and structural cells, mediated by various cytokines, chemokines and growth factors, which are responsible for the maintenance of tissue homeostasis and which coordinate the response to injury. The large number of mediators involved and the complexity of their interaction makes it difficult to identify the factors responsible for initiation of fibrogenesis and progression to chronicity. Whether a mediator's presence in fibrotic lung is as a result of tissue injury or if it playsan active role in disease onset and progression has been partly answered by the use of transient and/or permanent transgenic and gene knock-out approaches to over-express single factors at a time. Chemokines such as interleukin-8 IL-8, RANTES, IP-10, MIG or lymphotactin, do not appear to induce fibrosis when over-expressed in rodent lung. Amongst many tested, four cytokines and growth factors have been found to be pro-fibrotic; IL-1beta, which demonstrates marked inflammation, tissue damage and chronic fibrosis, TNF-alpha, which induces inflammation and mild fibrosis, and GM-CSF, which induces moderate inflammation and fibrosis. A common finding with these cytokines are increased lung TGF-beta levels, proportionate to the degree of fibrosis generated, while TGF-beta itself causes minor inflammation but marked progressive chronic fibrosis. A growth factor 'downstream' from the pro-fibrotic effects of TGF-beta, CTGF, is a likely critical mediator. However, over-expression of CTGF produces only mild and reversible fibrosis.
12570673|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a chronic <d>interstitial lung disease</d> which results in end-stage fibrosis. The pathogenesis is believed to be related to a dysregulation in cross-talk between inflammatory and structural cells, mediated by various cytokines, chemokines and growth factors, which are responsible for the maintenance of tissue homeostasis and which coordinate the response to injury. The large number of mediators involved and the complexity of their interaction makes it difficult to identify the factors responsible for initiation of fibrogenesis and progression to chronicity. Whether a mediator's presence in fibrotic lung is as a result of tissue injury or if it playsan active role in disease onset and progression has been partly answered by the use of transient and/or permanent transgenic and gene knock-out approaches to over-express single factors at a time. Chemokines such as interleukin-8 IL-8, RANTES, IP-10, MIG or lymphotactin, do not appear to induce fibrosis when over-expressed in rodent lung. Amongst many tested, four cytokines and growth factors have been found to be pro-fibrotic; IL-1beta, which demonstrates marked inflammation, tissue damage and chronic fibrosis, TNF-alpha, which induces inflammation and mild fibrosis, and GM-CSF, which induces moderate inflammation and fibrosis. A common finding with these cytokines are increased lung TGF-beta levels, proportionate to the degree of fibrosis generated, while TGF-beta itself causes minor inflammation but marked progressive chronic fibrosis. A growth factor 'downstream' from the pro-fibrotic effects of TGF-beta, CTGF, is a likely critical mediator. However, over-expression of CTGF produces only mild and reversible fibrosis.
12570673|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a chronic <d>interstitial lung disease</d> which results in end-stage <d>fibrosis</d>. The pathogenesis is believed to be related to a dysregulation in cross-talk between inflammatory and structural cells, mediated by various cytokines, chemokines and growth factors, which are responsible for the maintenance of tissue homeostasis and which coordinate the response to injury. The large number of mediators involved and the complexity of their interaction makes it difficult to identify the factors responsible for initiation of fibrogenesis and progression to chronicity. Whether a mediator's presence in fibrotic lung is as a result of tissue injury or if it playsan active role in disease onset and progression has been partly answered by the use of transient and/or permanent transgenic and gene knock-out approaches to over-express single factors at a time. Chemokines such as interleukin-8 IL-8, RANTES, IP-10, MIG or lymphotactin, do not appear to induce <d>fibrosis</d> when over-expressed in rodent lung. Amongst many tested, four cytokines and growth factors have been found to be pro-fibrotic; IL-1beta, which demonstrates marked inflammation, tissue damage and chronic <d>fibrosis</d>, TNF-alpha, which induces inflammation and mild <d>fibrosis</d>, and GM-CSF, which induces moderate inflammation and <d>fibrosis</d>. A common finding with these cytokines are increased lung TGF-beta levels, proportionate to the degree of <d>fibrosis</d> generated, while TGF-beta itself causes minor inflammation but marked progressive chronic <d>fibrosis</d>. A growth factor 'downstream' from the pro-fibrotic effects of TGF-beta, CTGF, is a likely critical mediator. However, over-expression of CTGF produces only mild and reversible <d>fibrosis</d>.
12570673|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a chronic <d>interstitial lung disease</d> which results in end-stage <d>fibrosis</d>. The pathogenesis is believed to be related to a dysregulation in cross-talk between inflammatory and structural cells, mediated by various cytokines, chemokines and growth factors, which are responsible for the maintenance of tissue homeostasis and which coordinate the response to injury. The large number of mediators involved and the complexity of their interaction makes it difficult to identify the factors responsible for initiation of fibrogenesis and progression to chronicity. Whether a mediator's presence in fibrotic lung is as a result of tissue injury or if it playsan active role in disease onset and progression has been partly answered by the use of transient and/or permanent transgenic and gene knock-out approaches to over-express single factors at a time. Chemokines such as <g>interleukin-8</g> <g>IL-8</g>, <g>RANTES</g>, <g>IP-10</g>, <g>MIG</g> or <g>lymphotactin</g>, do not appear to induce <d>fibrosis</d> when over-expressed in rodent lung. Amongst many tested, four cytokines and growth factors have been found to be pro-fibrotic; <g>IL-1beta</g>, which demonstrates marked <d>inflammation</d>, tissue damage and chronic <d>fibrosis</d>, TNF-alpha, which induces <d>inflammation</d> and mild <d>fibrosis</d>, and GM-CSF, which induces moderate <d>inflammation</d> and <d>fibrosis</d>. A common finding with these cytokines are increased lung TGF-beta levels, proportionate to the degree of <d>fibrosis</d> generated, while TGF-beta itself causes minor <d>inflammation</d> but marked progressive chronic <d>fibrosis</d>. A growth factor 'downstream' from the pro-fibrotic effects of TGF-beta, CTGF, is a likely critical mediator. However, over-expression of CTGF produces only mild and reversible <d>fibrosis</d>.
12598227|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive fatal fibrotic lung disease. Transforming growth factor <g>TGF-beta1</g> is present in a biologically active conformation in the epithelial cells lining lesions with advanced IPF. To determine the role of aberrant expression of biologically active <g>TGF-beta1</g> by alveolar epithelial cells AECs, the AECs of explanted normal rat lungs were transfected with the <g>TGF-beta1</g> gene using the retrovirus pMX-L-s223,225-<g>TGF-beta1</g>. In situ hybridization using a digoxigenin-labeled cDNA of the puromycin resistance gene contained in the pMX demonstrated that pMX-L-s233,225-<g>TGF-beta1</g> was selectively transfected into AECs of the explants. Conditioned media overlying explants obtained 7 days after being treated with pMX-L-s223,225-<g>TGF-beta1</g> contained 14.5 +/- 3.15 pg/ml of active <g>TGF-beta1</g>. With the use of Masson's trichrome staining of explant sections obtained 14 days after transfection, there were lesions similar to those in IPF, characterized by type II AEC hyperplasia, interstitial thickening, extensive increase in interstitial and subepithelial collagen, an increase in the number of fibroblasts, and areas resembling fibroblast buds. Collagens I, III, IV, and V and fibronectin were increased in explants treated with pMX-L-s223,225-<g>TGF-beta1</g>. The findings in the current study suggest that IPF may be a disorder of epithelial cells and not inflammatory cells.
12598227|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive fatal fibrotic lung disease. Transforming growth factor <g>TGF-beta1</g> is present in a biologically active conformation in the epithelial cells lining lesions with advanced <d>IPF</d>. To determine the role of aberrant expression of biologically active <g>TGF-beta1</g> by alveolar epithelial cells AECs, the AECs of explanted normal rat lungs were transfected with the <g>TGF-beta1</g> gene using the retrovirus pMX-L-s223,225-<g>TGF-beta1</g>. In situ hybridization using a digoxigenin-labeled cDNA of the puromycin resistance gene contained in the pMX demonstrated that pMX-L-s233,225-<g>TGF-beta1</g> was selectively transfected into AECs of the explants. Conditioned media overlying explants obtained 7 days after being treated with pMX-L-s223,225-<g>TGF-beta1</g> contained 14.5 +/- 3.15 pg/ml of active <g>TGF-beta1</g>. With the use of Masson's trichrome staining of explant sections obtained 14 days after transfection, there were lesions similar to those in <d>IPF</d>, characterized by type II AEC hyperplasia, interstitial thickening, extensive increase in interstitial and subepithelial collagen, an increase in the number of fibroblasts, and areas resembling fibroblast buds. Collagens I, III, IV, and V and fibronectin were increased in explants treated with pMX-L-s223,225-<g>TGF-beta1</g>. The findings in the current study suggest that <d>IPF</d> may be a disorder of epithelial cells and not inflammatory cells.
12598227|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive fatal <d>fibrotic lung disease</d>. Transforming growth factor <g>TGF-beta1</g> is present in a biologically active conformation in the epithelial cells lining lesions with advanced <d>IPF</d>. To determine the role of aberrant expression of biologically active <g>TGF-beta1</g> by alveolar epithelial cells AECs, the AECs of explanted normal rat lungs were transfected with the <g>TGF-beta1</g> gene using the retrovirus pMX-L-s223,225-<g>TGF-beta1</g>. In situ hybridization using a digoxigenin-labeled cDNA of the puromycin resistance gene contained in the pMX demonstrated that pMX-L-s233,225-<g>TGF-beta1</g> was selectively transfected into AECs of the explants. Conditioned media overlying explants obtained 7 days after being treated with pMX-L-s223,225-<g>TGF-beta1</g> contained 14.5 +/- 3.15 pg/ml of active <g>TGF-beta1</g>. With the use of Masson's trichrome staining of explant sections obtained 14 days after transfection, there were lesions similar to those in <d>IPF</d>, characterized by type II AEC hyperplasia, interstitial thickening, extensive increase in interstitial and subepithelial collagen, an increase in the number of fibroblasts, and areas resembling fibroblast buds. Collagens I, III, IV, and V and fibronectin were increased in explants treated with pMX-L-s223,225-<g>TGF-beta1</g>. The findings in the current study suggest that <d>IPF</d> may be a disorder of epithelial cells and not inflammatory cells.
12598227|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive fatal <d>fibrotic lung disease</d>. Transforming growth factor <g>TGF-beta1</g> is present in a biologically active conformation in the epithelial cells lining lesions with advanced <d>IPF</d>. To determine the role of aberrant expression of biologically active <g>TGF-beta1</g> by alveolar epithelial cells AECs, the AECs of explanted normal rat lungs were transfected with the <g>TGF-beta1</g> gene using the retrovirus pMX-L-s223,225-<g>TGF-beta1</g>. In situ hybridization using a digoxigenin-labeled cDNA of the puromycin resistance gene contained in the pMX demonstrated that pMX-L-s233,225-<g>TGF-beta1</g> was selectively transfected into AECs of the explants. Conditioned media overlying explants obtained 7 days after being treated with pMX-L-s223,225-<g>TGF-beta1</g> contained 14.5 +/- 3.15 pg/ml of active <g>TGF-beta1</g>. With the use of Masson's trichrome staining of explant sections obtained 14 days after transfection, there were lesions similar to those in <d>IPF</d>, characterized by <d>type II AEC hyperplasia</d>, interstitial thickening, extensive increase in interstitial and subepithelial collagen, an increase in the number of fibroblasts, and areas resembling fibroblast buds. Collagens I, III, IV, and V and fibronectin were increased in explants treated with pMX-L-s223,225-<g>TGF-beta1</g>. The findings in the current study suggest that <d>IPF</d> may be a disorder of epithelial cells and not inflammatory cells.
12610869|a|It is widely known that patients with idiopathic pulmonary fibrosis IPF are frequently associated with <d>lung cancer</d>. Although a complication with <d>lung cancer</d> is an important prognostic factor for IPF, standard treatments for <d>lung cancer</d> cannot be given because of IPF. Especially, the administration of many anticancer agents is limited by a complication with IPF, which is recognized as a risk factor for the development of fatal lung injury in cancer chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both IPF and <d>lung cancer</d>. It has been assumed that metaplasia in fibrous lesions is pathologically a precancerous lesion, but it is necessary to prove several genetic abnormalities in the process of carcinogenesis in order to clarify that. Currently, several genetic abnormalities in IPF, including in p53, K-ras, FHIT and transforming growth factor TGF-beta 1 type II receptor, have been reported.
12610869|a|It is widely known that patients with <d>idiopathic pulmonary fibrosis</d> IPF are frequently associated with <d>lung cancer</d>. Although a complication with <d>lung cancer</d> is an important prognostic factor for IPF, standard treatments for <d>lung cancer</d> cannot be given because of IPF. Especially, the administration of many anticancer agents is limited by a complication with IPF, which is recognized as a risk factor for the development of fatal lung injury in cancer chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both IPF and <d>lung cancer</d>. It has been assumed that metaplasia in fibrous lesions is pathologically a precancerous lesion, but it is necessary to prove several genetic abnormalities in the process of carcinogenesis in order to clarify that. Currently, several genetic abnormalities in IPF, including in p53, K-ras, FHIT and transforming growth factor TGF-beta 1 type II receptor, have been reported.
12610869|a|It is widely known that patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> are frequently associated with <d>lung cancer</d>. Although a complication with <d>lung cancer</d> is an important prognostic factor for <d>IPF</d>, standard treatments for <d>lung cancer</d> cannot be given because of <d>IPF</d>. Especially, the administration of many anticancer agents is limited by a complication with <d>IPF</d>, which is recognized as a risk factor for the development of fatal lung injury in cancer chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both <d>IPF</d> and <d>lung cancer</d>. It has been assumed that metaplasia in fibrous lesions is pathologically a precancerous lesion, but it is necessary to prove several genetic abnormalities in the process of carcinogenesis in order to clarify that. Currently, several genetic abnormalities in <d>IPF</d>, including in p53, K-ras, FHIT and transforming growth factor TGF-beta 1 type II receptor, have been reported.
12610869|a|It is widely known that patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> are frequently associated with <d>lung cancer</d>. Although a complication with <d>lung cancer</d> is an important prognostic factor for <d>IPF</d>, standard treatments for <d>lung cancer</d> cannot be given because of <d>IPF</d>. Especially, the administration of many anticancer agents is limited by a complication with <d>IPF</d>, which is recognized as a risk factor for the development of <d>fatal lung injury</d> in cancer chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both <d>IPF</d> and <d>lung cancer</d>. It has been assumed that metaplasia in fibrous lesions is pathologically a precancerous lesion, but it is necessary to prove several genetic abnormalities in the process of carcinogenesis in order to clarify that. Currently, several genetic abnormalities in <d>IPF</d>, including in p53, K-ras, FHIT and transforming growth factor TGF-beta 1 type II receptor, have been reported.
12610869|a|It is widely known that patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> are frequently associated with <d>lung <d>cancer</d></d>. Although a complication with <d>lung <d>cancer</d></d> is an important prognostic factor for <d>IPF</d>, standard treatments for <d>lung <d>cancer</d></d> cannot be given because of <d>IPF</d>. Especially, the administration of many anti<d>cancer</d> agents is limited by a complication with <d>IPF</d>, which is recognized as a risk factor for the development of <d>fatal lung injury</d> in <d>cancer</d> chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both <d>IPF</d> and <d>lung <d>cancer</d></d>. It has been assumed that metaplasia in fibrous lesions is pathologically a pre<d>cancer</d>ous lesion, but it is necessary to prove several genetic abnormalities in the process of carcinogenesis in order to clarify that. Currently, several genetic abnormalities in <d>IPF</d>, including in p53, K-ras, FHIT and transforming growth factor TGF-beta 1 type II receptor, have been reported.
12610869|a|It is widely known that patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> are frequently associated with <d>lung <d>cancer</d></d>. Although a complication with <d>lung <d>cancer</d></d> is an important prognostic factor for <d>IPF</d>, standard treatments for <d>lung <d>cancer</d></d> cannot be given because of <d>IPF</d>. Especially, the administration of many anti<d>cancer</d> agents is limited by a complication with <d>IPF</d>, which is recognized as a risk factor for the development of <d>fatal lung injury</d> in <d>cancer</d> chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both <d>IPF</d> and <d>lung <d>cancer</d></d>. It has been assumed that metaplasia in fibrous lesions is pathologically a pre<d>cancer</d>ous lesion, but it is necessary to prove several <d>genetic abnormalities</d> in the process of carcinogenesis in order to clarify that. Currently, several <d>genetic abnormalities</d> in <d>IPF</d>, including in p53, K-ras, FHIT and transforming growth factor TGF-beta 1 type II receptor, have been reported.
12610869|a|It is widely known that patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> are frequently associated with <d>lung <d>cancer</d></d>. Although a complication with <d>lung <d>cancer</d></d> is an important prognostic factor for <d>IPF</d>, standard treatments for <d>lung <d>cancer</d></d> cannot be given because of <d>IPF</d>. Especially, the administration of many anti<d>cancer</d> agents is limited by a complication with <d>IPF</d>, which is recognized as a risk factor for the development of <d>fatal lung injury</d> in <d>cancer</d> chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both <d>IPF</d> and <d>lung <d>cancer</d></d>. It has been assumed that metaplasia in fibrous lesions is pathologically a pre<d>cancer</d>ous lesion, but it is necessary to prove several <d>genetic abnormalities</d> in the process of <d>carcinogenesis</d> in order to clarify that. Currently, several <d>genetic abnormalities</d> in <d>IPF</d>, including in p53, K-ras, FHIT and transforming growth factor TGF-beta 1 type II receptor, have been reported.
12837171|a|OBJECTIVE: To investigate the expression of platelet-derived growth factorPDGF and transforming growth factor-beta TGF-beta in transbronchial lung biopsy TBLB from patients with <d>idiopathic pulmonary fibrosis</d>IPF, and study the potential role of cytokines in the development of IPF. METHODS: The immunohistochemical methods were used to determine the expression of PDGF, TGF-beta in TBLB from patients with IPF. RESULTS: In IPF patients, TGF-beta mainly existed at tiny bronchial epithelial cells, alveolar epithelial type-II cells and alveolar macrophages, showing strong expression compared with controls P<0.01. PDGF mainly existed at fibroblast-like cells surrounding pulmonary vessels, fibroblasts, tiny bronchial epithelial cells, alveolar epithelial type-II cells and alveolar macrophages, showing strong expression compared with controls P<0.01. CONCLUSION: PDGF and TGF-beta, which interact with pulmonary mesenchymal cells, are involved in the formation of pulmonary fibrosis.
12837171|a|OBJECTIVE: To investigate the expression of platelet-derived growth factorPDGF and <g>transforming growth factor-beta</g> <g>TGF-beta</g> in transbronchial lung biopsy TBLB from patients with <d>idiopathic pulmonary fibrosis</d><d>IPF</d>, and study the potential role of cytokines in the development of <d>IPF</d>. METHODS: The immunohistochemical methods were used to determine the expression of PDGF, <g>TGF-beta</g> in TBLB from patients with <d>IPF</d>. RESULTS: In <d>IPF</d> patients, <g>TGF-beta</g> mainly existed at tiny bronchial epithelial cells, alveolar epithelial type-II cells and alveolar macrophages, showing strong expression compared with controls P<0.01. PDGF mainly existed at fibroblast-like cells surrounding pulmonary vessels, fibroblasts, tiny bronchial epithelial cells, alveolar epithelial type-II cells and alveolar macrophages, showing strong expression compared with controls P<0.01. CONCLUSION: PDGF and <g>TGF-beta</g>, which interact with pulmonary mesenchymal cells, are involved in the formation of pulmonary fibrosis.
12837171|a|OBJECTIVE: To investigate the expression of platelet-derived growth factorPDGF and <g>transforming growth factor-beta</g> <g>TGF-beta</g> in transbronchial lung biopsy TBLB from patients with <d>idiopathic <d>pulmonary fibrosis</d></d><d>IPF</d>, and study the potential role of cytokines in the development of <d>IPF</d>. METHODS: The immunohistochemical methods were used to determine the expression of PDGF, <g>TGF-beta</g> in TBLB from patients with <d>IPF</d>. RESULTS: In <d>IPF</d> patients, <g>TGF-beta</g> mainly existed at tiny bronchial epithelial cells, alveolar epithelial type-II cells and alveolar macrophages, showing strong expression compared with controls P<0.01. PDGF mainly existed at fibroblast-like cells surrounding pulmonary vessels, fibroblasts, tiny bronchial epithelial cells, alveolar epithelial type-II cells and alveolar macrophages, showing strong expression compared with controls P<0.01. CONCLUSION: PDGF and <g>TGF-beta</g>, which interact with pulmonary mesenchymal cells, are involved in the formation of <d>pulmonary fibrosis</d>.
12851645|a|Mounting evidence suggests that <g>CCL2</g> <g>MCP-1</g> and its hematopoietic cell receptor <g>CC chemokine receptor 2</g> <g>CCR2</g> are involved in inflammatory disorders of the lung. In animal models of <d>allergic asthma</d>, idiopathic pulmonary fibrosis IPF, and bronchiolitis obliterans syndrome BOS, <g>CCL2</g> expression and protein production are increased and the disease process is attenuated by <g>CCL2</g> immunoneutralization. Mechanisms by which <g>CCL2</g> may be acting include recruitment of regulatory and effector leukocytes; stimulation of histamine or leukotriene release from mast cells or basophils; induction of fibroblast production of transforming growth factor-beta TGF-beta and procollagen; and enhancement of Th2 polarization. Recently, polymorphism for <g>CCL2</g> has been described with increased cytokine-induced release of <g>CCL2</g> by monocytes and increased risk of <d>allergic asthma</d>. These studies identify potentially important roles for <g>CCL2</g> in these lung inflammatory disorders. While <g>CCL2</g> inhibition in patients with acute respiratory distress syndrome ARDS may be hazardous by interfering with defense against bacteremia, future studies are needed to determine if <g>CCL2</g>/<g>CCR2</g> antagonism will offer breakthrough therapy for patients with <d>allergic asthma</d>, IPF, or BOS, and to confirm the hypothesis that <g>CCL2</g> polymorphism places patients at greater risk for these disorders.
12851645|a|Mounting evidence suggests that <g>CCL2</g> <g>MCP-1</g> and its hematopoietic cell receptor <g>CC chemokine receptor 2</g> <g>CCR2</g> are involved in inflammatory disorders of the lung. In animal models of <d>allergic asthma</d>, <d>idiopathic pulmonary fibrosis</d> IPF, and bronchiolitis obliterans syndrome BOS, <g>CCL2</g> expression and protein production are increased and the disease process is attenuated by <g>CCL2</g> immunoneutralization. Mechanisms by which <g>CCL2</g> may be acting include recruitment of regulatory and effector leukocytes; stimulation of histamine or leukotriene release from mast cells or basophils; induction of fibroblast production of transforming growth factor-beta TGF-beta and procollagen; and enhancement of Th2 polarization. Recently, polymorphism for <g>CCL2</g> has been described with increased cytokine-induced release of <g>CCL2</g> by monocytes and increased risk of <d>allergic asthma</d>. These studies identify potentially important roles for <g>CCL2</g> in these lung inflammatory disorders. While <g>CCL2</g> inhibition in patients with acute respiratory distress syndrome ARDS may be hazardous by interfering with defense against bacteremia, future studies are needed to determine if <g>CCL2</g>/<g>CCR2</g> antagonism will offer breakthrough therapy for patients with <d>allergic asthma</d>, IPF, or BOS, and to confirm the hypothesis that <g>CCL2</g> polymorphism places patients at greater risk for these disorders.
12851645|a|Mounting evidence suggests that <g>CCL2</g> <g>MCP-1</g> and its hematopoietic cell receptor <g>CC chemokine receptor 2</g> <g>CCR2</g> are involved in inflammatory disorders of the lung. In animal models of <d>allergic asthma</d>, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, and bronchiolitis obliterans syndrome BOS, <g>CCL2</g> expression and protein production are increased and the disease process is attenuated by <g>CCL2</g> immunoneutralization. Mechanisms by which <g>CCL2</g> may be acting include recruitment of regulatory and effector leukocytes; stimulation of histamine or leukotriene release from mast cells or basophils; induction of fibroblast production of transforming growth factor-beta TGF-beta and procollagen; and enhancement of Th2 polarization. Recently, polymorphism for <g>CCL2</g> has been described with increased cytokine-induced release of <g>CCL2</g> by monocytes and increased risk of <d>allergic asthma</d>. These studies identify potentially important roles for <g>CCL2</g> in these lung inflammatory disorders. While <g>CCL2</g> inhibition in patients with acute respiratory distress syndrome ARDS may be hazardous by interfering with defense against bacteremia, future studies are needed to determine if <g>CCL2</g>/<g>CCR2</g> antagonism will offer breakthrough therapy for patients with <d>allergic asthma</d>, <d>IPF</d>, or BOS, and to confirm the hypothesis that <g>CCL2</g> polymorphism places patients at greater risk for these disorders.
12851645|a|Mounting evidence suggests that <g>CCL2</g> <g>MCP-1</g> and its hematopoietic cell receptor <g>CC chemokine receptor 2</g> <g>CCR2</g> are involved in inflammatory disorders of the lung. In animal models of <d>allergic asthma</d>, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, and <d>bronchiolitis obliterans syndrome</d> BOS, <g>CCL2</g> expression and protein production are increased and the disease process is attenuated by <g>CCL2</g> immunoneutralization. Mechanisms by which <g>CCL2</g> may be acting include recruitment of regulatory and effector leukocytes; stimulation of histamine or leukotriene release from mast cells or basophils; induction of fibroblast production of transforming growth factor-beta TGF-beta and procollagen; and enhancement of Th2 polarization. Recently, polymorphism for <g>CCL2</g> has been described with increased cytokine-induced release of <g>CCL2</g> by monocytes and increased risk of <d>allergic asthma</d>. These studies identify potentially important roles for <g>CCL2</g> in these lung inflammatory disorders. While <g>CCL2</g> inhibition in patients with acute respiratory distress syndrome ARDS may be hazardous by interfering with defense against bacteremia, future studies are needed to determine if <g>CCL2</g>/<g>CCR2</g> antagonism will offer breakthrough therapy for patients with <d>allergic asthma</d>, <d>IPF</d>, or BOS, and to confirm the hypothesis that <g>CCL2</g> polymorphism places patients at greater risk for these disorders.
12851645|a|Mounting evidence suggests that <g>CCL2</g> <g>MCP-1</g> and its hematopoietic cell receptor <g>CC chemokine receptor 2</g> <g>CCR2</g> are involved in inflammatory disorders of the lung. In animal models of <d>allergic asthma</d>, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, and <d>bronchiolitis obliterans syndrome</d> <d>BOS</d>, <g>CCL2</g> expression and protein production are increased and the disease process is attenuated by <g>CCL2</g> immunoneutralization. Mechanisms by which <g>CCL2</g> may be acting include recruitment of regulatory and effector leukocytes; stimulation of histamine or leukotriene release from mast cells or basophils; induction of fibroblast production of transforming growth factor-beta TGF-beta and procollagen; and enhancement of Th2 polarization. Recently, polymorphism for <g>CCL2</g> has been described with increased cytokine-induced release of <g>CCL2</g> by monocytes and increased risk of <d>allergic asthma</d>. These studies identify potentially important roles for <g>CCL2</g> in these lung inflammatory disorders. While <g>CCL2</g> inhibition in patients with acute respiratory distress syndrome ARDS may be hazardous by interfering with defense against bacteremia, future studies are needed to determine if <g>CCL2</g>/<g>CCR2</g> antagonism will offer breakthrough therapy for patients with <d>allergic asthma</d>, <d>IPF</d>, or <d>BOS</d>, and to confirm the hypothesis that <g>CCL2</g> polymorphism places patients at greater risk for these disorders.
12851645|a|Mounting evidence suggests that <g>CCL2</g> <g>MCP-1</g> and its hematopoietic cell receptor <g>CC chemokine receptor 2</g> <g>CCR2</g> are involved in inflammatory disorders of the lung. In animal models of <d>allergic asthma</d>, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, and <d>bronchiolitis obliterans syndrome</d> <d>BOS</d>, <g>CCL2</g> expression and protein production are increased and the disease process is attenuated by <g>CCL2</g> immunoneutralization. Mechanisms by which <g>CCL2</g> may be acting include recruitment of regulatory and effector leukocytes; stimulation of histamine or leukotriene release from mast cells or basophils; induction of fibroblast production of transforming growth factor-beta TGF-beta and procollagen; and enhancement of Th2 polarization. Recently, polymorphism for <g>CCL2</g> has been described with increased cytokine-induced release of <g>CCL2</g> by monocytes and increased risk of <d>allergic asthma</d>. These studies identify potentially important roles for <g>CCL2</g> in these lung inflammatory disorders. While <g>CCL2</g> inhibition in patients with <d>acute respiratory distress syndrome</d> ARDS may be hazardous by interfering with defense against bacteremia, future studies are needed to determine if <g>CCL2</g>/<g>CCR2</g> antagonism will offer breakthrough therapy for patients with <d>allergic asthma</d>, <d>IPF</d>, or <d>BOS</d>, and to confirm the hypothesis that <g>CCL2</g> polymorphism places patients at greater risk for these disorders.
12851645|a|Mounting evidence suggests that <g>CCL2</g> <g>MCP-1</g> and its hematopoietic cell receptor <g>CC chemokine receptor 2</g> <g>CCR2</g> are involved in inflammatory disorders of the lung. In animal models of <d>allergic asthma</d>, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, and <d>bronchiolitis obliterans syndrome</d> <d>BOS</d>, <g>CCL2</g> expression and protein production are increased and the disease process is attenuated by <g>CCL2</g> immunoneutralization. Mechanisms by which <g>CCL2</g> may be acting include recruitment of regulatory and effector leukocytes; stimulation of histamine or leukotriene release from mast cells or basophils; induction of fibroblast production of transforming growth factor-beta TGF-beta and procollagen; and enhancement of Th2 polarization. Recently, polymorphism for <g>CCL2</g> has been described with increased cytokine-induced release of <g>CCL2</g> by monocytes and increased risk of <d>allergic asthma</d>. These studies identify potentially important roles for <g>CCL2</g> in these lung inflammatory disorders. While <g>CCL2</g> inhibition in patients with <d>acute respiratory distress syndrome</d> <d>ARDS</d> may be hazardous by interfering with defense against bacteremia, future studies are needed to determine if <g>CCL2</g>/<g>CCR2</g> antagonism will offer breakthrough therapy for patients with <d>allergic asthma</d>, <d>IPF</d>, or <d>BOS</d>, and to confirm the hypothesis that <g>CCL2</g> polymorphism places patients at greater risk for these disorders.
12851645|a|Mounting evidence suggests that <g>CCL2</g> <g>MCP-1</g> and its hematopoietic cell receptor <g>CC chemokine receptor 2</g> <g>CCR2</g> are involved in inflammatory disorders of the lung. In animal models of <d>allergic asthma</d>, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, and <d>bronchiolitis obliterans syndrome</d> <d>BOS</d>, <g>CCL2</g> expression and protein production are increased and the disease process is attenuated by <g>CCL2</g> immunoneutralization. Mechanisms by which <g>CCL2</g> may be acting include recruitment of regulatory and effector leukocytes; stimulation of histamine or leukotriene release from mast cells or basophils; induction of fibroblast production of transforming growth factor-beta TGF-beta and procollagen; and enhancement of Th2 polarization. Recently, polymorphism for <g>CCL2</g> has been described with increased cytokine-induced release of <g>CCL2</g> by monocytes and increased risk of <d>allergic asthma</d>. These studies identify potentially important roles for <g>CCL2</g> in these lung inflammatory disorders. While <g>CCL2</g> inhibition in patients with <d>acute respiratory distress syndrome</d> <d>ARDS</d> may be hazardous by interfering with defense against <d>bacteremia</d>, future studies are needed to determine if <g>CCL2</g>/<g>CCR2</g> antagonism will offer breakthrough therapy for patients with <d>allergic asthma</d>, <d>IPF</d>, or <d>BOS</d>, and to confirm the hypothesis that <g>CCL2</g> polymorphism places patients at greater risk for these disorders.
12882453|a|Modulation of cytokine expression represents a potentially useful approach for the treatment of <d>idiopathic pulmonary fibrosis</d> IPF. To identify potential targets for such intervention, semi-quantitative reverse transcriptase-polymerase chain reaction was used to compare the expression of messenger ribonucleic acids mRNAs coding for 17 cytokines in lung tissue obtained from patients with IPF at the time of diagnosis and control subjects. Some cytokines were also studied at the protein level by immunohistochemical techniques. mRNAs coding for all of the cytokines evaluated were detected in both control and fibrotic lung samples. Only transforming growth factor TGF-beta and interleukin IL-10 mRNAs were quantitatively increased in lung biopsies from patients with IPF compared with those of controls, results confirmed at the protein level by immunohistochemistry. Although mRNAs for platelet-derived growth factor PDGF-BB and keratinocyte growth factor KGF were expressed in similar amounts in lungs from patients with IPF and controls, localised accumulation of both factors was also observed in IPF. Hyperplastic alveolar epithelial cells were a prominent source of cytokines, where IL-10, PDGF-BB and KGF were present in increased amounts, although increased accumulation in fibroblasts, smooth-muscle cells and matrix components was also observed PDGF-BB, TGF-beta. These results offer new insights into the cytokines produced in the lung in <d>idiopathic pulmonary fibrosis</d> and suggest that modulation of the production of transforming growth factor-beta and interleukin-10 may represent a potentially useful therapeutic strategy for this disabling disease.
12882453|a|Modulation of cytokine expression represents a potentially useful approach for the treatment of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. To identify potential targets for such intervention, semi-quantitative reverse transcriptase-polymerase chain reaction was used to compare the expression of messenger ribonucleic acids mRNAs coding for 17 cytokines in lung tissue obtained from patients with <d>IPF</d> at the time of diagnosis and control subjects. Some cytokines were also studied at the protein level by immunohistochemical techniques. mRNAs coding for all of the cytokines evaluated were detected in both control and fibrotic lung samples. Only transforming growth factor <g>TGF-beta</g> and interleukin <g>IL-10</g> mRNAs were quantitatively increased in lung biopsies from patients with <d>IPF</d> compared with those of controls, results confirmed at the protein level by immunohistochemistry. Although mRNAs for platelet-derived growth factor PDGF-BB and keratinocyte growth factor KGF were expressed in similar amounts in lungs from patients with <d>IPF</d> and controls, localised accumulation of both factors was also observed in <d>IPF</d>. Hyperplastic alveolar epithelial cells were a prominent source of cytokines, where <g>IL-10</g>, PDGF-BB and KGF were present in increased amounts, although increased accumulation in fibroblasts, smooth-muscle cells and matrix components was also observed PDGF-BB, <g>TGF-beta</g>. These results offer new insights into the cytokines produced in the lung in <d>idiopathic pulmonary fibrosis</d> and suggest that modulation of the production of transforming growth factor-beta and interleukin-10 may represent a potentially useful therapeutic strategy for this disabling disease.
12899768|a|OBJECTIVE: To study the distribution, the expression and the significance of TGF-beta1, b-FGF, IL-8, IL-13 and IFN-gamma in different lung tissue compartments in <d>usual interstitial pneumonia</d>/idiopathic pulmonary fibrosis UIP/IPF and nonspecific interstitial pneumonia NSIP. METHODS: Specimens were obtained by open or video-assisted thoracoscopic lung biopsy from patients with UIP n = 5 and NSIP n = 8. Control specimens were obtained by surgical lobectomy from patients with primary lung cancer n = 5. The distribution of these cytokines in lung tissues was observed by semi-quantitative method using immunohistochemical staining. RESULTS: TGF-beta1, IL-8 and b-FGF were localized in alveolar epithelial cells, alveolar macrophages, and the bronchial epithelium. Overall intensity of TGF-beta1, IL-8 and b-FGF expression in UIP was stronger in comparison with NSIP. IL-13 was distributed in alveolar epithelial cells, alveolar macrophages and interstitial mononuclear cells. Its expression in UIP was similar to that in NSIP. IFN-gamma was expressed mainly in interstitial mononuclear cells. Its expression in NSIP was stronger than that in UIP. The ratio of IL-13 to IFN-gamma in UIP 2.18 +/- 0.76 was significantly higher than that in NSIP 0.95 +/- 0.28 or that in the control 0.91 +/- 0.16 P < 0.05, UIP versus NSIP or control, whereas the ratio of IL-13 to IFN-gamma in NSIP was similar to that in the control. In normal lungs, only alveolar macrophages expressed these cytokines. CONCLUSION: The different expression of TGF-beta1, IL-8 and b-FGF in UIP and NSIP and the balance of IL-13/IFN-gamma may be involved in the different pathogenesis in these two diseases.
12899768|a|OBJECTIVE: To study the distribution, the expression and the significance of TGF-beta1, b-FGF, IL-8, IL-13 and IFN-gamma in different lung tissue compartments in <d>usual interstitial pneumonia</d>/idiopathic pulmonary fibrosis UIP/IPF and <d>nonspecific interstitial pneumonia</d> NSIP. METHODS: Specimens were obtained by open or video-assisted thoracoscopic lung biopsy from patients with UIP n = 5 and NSIP n = 8. Control specimens were obtained by surgical lobectomy from patients with primary lung cancer n = 5. The distribution of these cytokines in lung tissues was observed by semi-quantitative method using immunohistochemical staining. RESULTS: TGF-beta1, IL-8 and b-FGF were localized in alveolar epithelial cells, alveolar macrophages, and the bronchial epithelium. Overall intensity of TGF-beta1, IL-8 and b-FGF expression in UIP was stronger in comparison with NSIP. IL-13 was distributed in alveolar epithelial cells, alveolar macrophages and interstitial mononuclear cells. Its expression in UIP was similar to that in NSIP. IFN-gamma was expressed mainly in interstitial mononuclear cells. Its expression in NSIP was stronger than that in UIP. The ratio of IL-13 to IFN-gamma in UIP 2.18 +/- 0.76 was significantly higher than that in NSIP 0.95 +/- 0.28 or that in the control 0.91 +/- 0.16 P < 0.05, UIP versus NSIP or control, whereas the ratio of IL-13 to IFN-gamma in NSIP was similar to that in the control. In normal lungs, only alveolar macrophages expressed these cytokines. CONCLUSION: The different expression of TGF-beta1, IL-8 and b-FGF in UIP and NSIP and the balance of IL-13/IFN-gamma may be involved in the different pathogenesis in these two diseases.
12899768|a|OBJECTIVE: To study the distribution, the expression and the significance of <g>TGF-beta1</g>, <g>b-FGF</g>, <g>IL-8</g>, <g>IL-13</g> and <g>IFN-gamma</g> in different lung tissue compartments in <d>usual interstitial pneumonia</d>/<d>idiopathic pulmonary fibrosis</d> UIP/IPF and <d>nonspecific interstitial pneumonia</d> NSIP. METHODS: Specimens were obtained by open or video-assisted thoracoscopic lung biopsy from patients with UIP n = 5 and NSIP n = 8. Control specimens were obtained by surgical lobectomy from patients with primary lung cancer n = 5. The distribution of these cytokines in lung tissues was observed by semi-quantitative method using immunohistochemical staining. RESULTS: <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> were localized in alveolar epithelial cells, alveolar macrophages, and the bronchial epithelium. Overall intensity of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> expression in UIP was stronger in comparison with NSIP. <g>IL-13</g> was distributed in alveolar epithelial cells, alveolar macrophages and interstitial mononuclear cells. Its expression in UIP was similar to that in NSIP. <g>IFN-gamma</g> was expressed mainly in interstitial mononuclear cells. Its expression in NSIP was stronger than that in UIP. The ratio of <g>IL-13</g> to <g>IFN-gamma</g> in UIP 2.18 +/- 0.76 was significantly higher than that in NSIP 0.95 +/- 0.28 or that in the control 0.91 +/- 0.16 P < 0.05, UIP versus NSIP or control, whereas the ratio of <g>IL-13</g> to <g>IFN-gamma</g> in NSIP was similar to that in the control. In normal lungs, only alveolar macrophages expressed these cytokines. CONCLUSION: The different expression of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> in UIP and NSIP and the balance of <g>IL-13</g>/<g>IFN-gamma</g> may be involved in the different pathogenesis in these two diseases.
12899768|a|OBJECTIVE: To study the distribution, the expression and the significance of <g>TGF-beta1</g>, <g>b-FGF</g>, <g>IL-8</g>, <g>IL-13</g> and <g>IFN-gamma</g> in different lung tissue compartments in <d>usual interstitial pneumonia</d>/<d>idiopathic pulmonary fibrosis</d> <d>UIP</d>/IPF and <d>nonspecific interstitial pneumonia</d> NSIP. METHODS: Specimens were obtained by open or video-assisted thoracoscopic lung biopsy from patients with <d>UIP</d> n = 5 and NSIP n = 8. Control specimens were obtained by surgical lobectomy from patients with primary lung cancer n = 5. The distribution of these cytokines in lung tissues was observed by semi-quantitative method using immunohistochemical staining. RESULTS: <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> were localized in alveolar epithelial cells, alveolar macrophages, and the bronchial epithelium. Overall intensity of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> expression in <d>UIP</d> was stronger in comparison with NSIP. <g>IL-13</g> was distributed in alveolar epithelial cells, alveolar macrophages and interstitial mononuclear cells. Its expression in <d>UIP</d> was similar to that in NSIP. <g>IFN-gamma</g> was expressed mainly in interstitial mononuclear cells. Its expression in NSIP was stronger than that in <d>UIP</d>. The ratio of <g>IL-13</g> to <g>IFN-gamma</g> in <d>UIP</d> 2.18 +/- 0.76 was significantly higher than that in NSIP 0.95 +/- 0.28 or that in the control 0.91 +/- 0.16 P < 0.05, <d>UIP</d> versus NSIP or control, whereas the ratio of <g>IL-13</g> to <g>IFN-gamma</g> in NSIP was similar to that in the control. In normal lungs, only alveolar macrophages expressed these cytokines. CONCLUSION: The different expression of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> in <d>UIP</d> and NSIP and the balance of <g>IL-13</g>/<g>IFN-gamma</g> may be involved in the different pathogenesis in these two diseases.
12899768|a|OBJECTIVE: To study the distribution, the expression and the significance of <g>TGF-beta1</g>, <g>b-FGF</g>, <g>IL-8</g>, <g>IL-13</g> and <g>IFN-gamma</g> in different lung tissue compartments in <d>usual interstitial pneumonia</d>/<d>idiopathic pulmonary fibrosis</d> <d>UIP</d>/<d>IPF</d> and <d>nonspecific interstitial pneumonia</d> NSIP. METHODS: Specimens were obtained by open or video-assisted thoracoscopic lung biopsy from patients with <d>UIP</d> n = 5 and NSIP n = 8. Control specimens were obtained by surgical lobectomy from patients with primary lung cancer n = 5. The distribution of these cytokines in lung tissues was observed by semi-quantitative method using immunohistochemical staining. RESULTS: <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> were localized in alveolar epithelial cells, alveolar macrophages, and the bronchial epithelium. Overall intensity of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> expression in <d>UIP</d> was stronger in comparison with NSIP. <g>IL-13</g> was distributed in alveolar epithelial cells, alveolar macrophages and interstitial mononuclear cells. Its expression in <d>UIP</d> was similar to that in NSIP. <g>IFN-gamma</g> was expressed mainly in interstitial mononuclear cells. Its expression in NSIP was stronger than that in <d>UIP</d>. The ratio of <g>IL-13</g> to <g>IFN-gamma</g> in <d>UIP</d> 2.18 +/- 0.76 was significantly higher than that in NSIP 0.95 +/- 0.28 or that in the control 0.91 +/- 0.16 P < 0.05, <d>UIP</d> versus NSIP or control, whereas the ratio of <g>IL-13</g> to <g>IFN-gamma</g> in NSIP was similar to that in the control. In normal lungs, only alveolar macrophages expressed these cytokines. CONCLUSION: The different expression of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> in <d>UIP</d> and NSIP and the balance of <g>IL-13</g>/<g>IFN-gamma</g> may be involved in the different pathogenesis in these two diseases.
12899768|a|OBJECTIVE: To study the distribution, the expression and the significance of <g>TGF-beta1</g>, <g>b-FGF</g>, <g>IL-8</g>, <g>IL-13</g> and <g>IFN-gamma</g> in different lung tissue compartments in <d>usual interstitial pneumonia</d>/<d>idiopathic pulmonary fibrosis</d> <d>UIP</d>/<d>IPF</d> and <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>. METHODS: Specimens were obtained by open or video-assisted thoracoscopic lung biopsy from patients with <d>UIP</d> n = 5 and <d>NSIP</d> n = 8. Control specimens were obtained by surgical lobectomy from patients with primary lung cancer n = 5. The distribution of these cytokines in lung tissues was observed by semi-quantitative method using immunohistochemical staining. RESULTS: <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> were localized in alveolar epithelial cells, alveolar macrophages, and the bronchial epithelium. Overall intensity of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> expression in <d>UIP</d> was stronger in comparison with <d>NSIP</d>. <g>IL-13</g> was distributed in alveolar epithelial cells, alveolar macrophages and interstitial mononuclear cells. Its expression in <d>UIP</d> was similar to that in <d>NSIP</d>. <g>IFN-gamma</g> was expressed mainly in interstitial mononuclear cells. Its expression in <d>NSIP</d> was stronger than that in <d>UIP</d>. The ratio of <g>IL-13</g> to <g>IFN-gamma</g> in <d>UIP</d> 2.18 +/- 0.76 was significantly higher than that in <d>NSIP</d> 0.95 +/- 0.28 or that in the control 0.91 +/- 0.16 P < 0.05, <d>UIP</d> versus <d>NSIP</d> or control, whereas the ratio of <g>IL-13</g> to <g>IFN-gamma</g> in <d>NSIP</d> was similar to that in the control. In normal lungs, only alveolar macrophages expressed these cytokines. CONCLUSION: The different expression of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> in <d>UIP</d> and <d>NSIP</d> and the balance of <g>IL-13</g>/<g>IFN-gamma</g> may be involved in the different pathogenesis in these two diseases.
12899768|a|OBJECTIVE: To study the distribution, the expression and the significance of <g>TGF-beta1</g>, <g>b-FGF</g>, <g>IL-8</g>, <g>IL-13</g> and <g>IFN-gamma</g> in different lung tissue compartments in <d>usual interstitial pneumonia</d>/<d>idiopathic pulmonary fibrosis</d> <d>UIP</d>/<d>IPF</d> and <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>. METHODS: Specimens were obtained by open or video-assisted thoracoscopic lung biopsy from patients with <d>UIP</d> n = 5 and <d>NSIP</d> n = 8. Control specimens were obtained by surgical lobectomy from patients with primary <d>lung cancer</d> n = 5. The distribution of these cytokines in lung tissues was observed by semi-quantitative method using immunohistochemical staining. RESULTS: <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> were localized in alveolar epithelial cells, alveolar macrophages, and the bronchial epithelium. Overall intensity of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> expression in <d>UIP</d> was stronger in comparison with <d>NSIP</d>. <g>IL-13</g> was distributed in alveolar epithelial cells, alveolar macrophages and interstitial mononuclear cells. Its expression in <d>UIP</d> was similar to that in <d>NSIP</d>. <g>IFN-gamma</g> was expressed mainly in interstitial mononuclear cells. Its expression in <d>NSIP</d> was stronger than that in <d>UIP</d>. The ratio of <g>IL-13</g> to <g>IFN-gamma</g> in <d>UIP</d> 2.18 +/- 0.76 was significantly higher than that in <d>NSIP</d> 0.95 +/- 0.28 or that in the control 0.91 +/- 0.16 P < 0.05, <d>UIP</d> versus <d>NSIP</d> or control, whereas the ratio of <g>IL-13</g> to <g>IFN-gamma</g> in <d>NSIP</d> was similar to that in the control. In normal lungs, only alveolar macrophages expressed these cytokines. CONCLUSION: The different expression of <g>TGF-beta1</g>, <g>IL-8</g> and <g>b-FGF</g> in <d>UIP</d> and <d>NSIP</d> and the balance of <g>IL-13</g>/<g>IFN-gamma</g> may be involved in the different pathogenesis in these two diseases.
12947024|a|Hepatocyte growth factor HGF is a growth factor that protects alveolar epithelial cells from pulmonary fibrosis in various animal models. We compared in vitro HGF production by human lung fibroblasts from patients with <d>idiopathic pulmonary fibrosis</d> IPF, n = 8 and from control subjects n = 6. Basal HGF secretion by IPF fibroblasts was decreased by 50% when compared with control fibroblasts p < 0.05. HGF was secreted mainly in the cleaved mature form, both in IPF and control fibroblasts. HGF messenger RNA levels were reduced in IPF fibroblasts. Prostaglandin PG E2 secretion by IPF fibroblasts was low when compared with control subjects p < 0.05. After the addition of PGE2 10-6 M or dibutyryl cyclic AMP 10-3 M, HGF secretion by IPF fibroblasts reached the level of control subjects. Inhibition of PGE2 synthesis with indomethacin reduced HGF secretion by control fibroblasts but had no effect on IPF fibroblasts. HGF secretion by control fibroblasts was also slightly inhibited by transforming growth factor TGF-beta1 and stimulated by anti-TGF-beta antibody, whereas both agents had no effect on IPF fibroblasts. Our results demonstrate a defect in HGF production by IPF fibroblasts that seems secondary to a defect in PGE2 secretion.
12947024|a|<g>Hepatocyte growth factor</g> <g>HGF</g> is a growth factor that protects alveolar epithelial cells from <d>pulmonary fibrosis</d> in various animal models. We compared in vitro <g>HGF</g> production by human lung fibroblasts from patients with <d>idiopathic <d>pulmonary fibrosis</d></d> IPF, n = 8 and from control subjects n = 6. Basal <g>HGF</g> secretion by IPF fibroblasts was decreased by 50% when compared with control fibroblasts p < 0.05. <g>HGF</g> was secreted mainly in the cleaved mature form, both in IPF and control fibroblasts. <g>HGF</g> messenger RNA levels were reduced in IPF fibroblasts. Prostaglandin PG E2 secretion by IPF fibroblasts was low when compared with control subjects p < 0.05. After the addition of PGE2 10-6 M or dibutyryl cyclic AMP 10-3 M, <g>HGF</g> secretion by IPF fibroblasts reached the level of control subjects. Inhibition of PGE2 synthesis with indomethacin reduced <g>HGF</g> secretion by control fibroblasts but had no effect on IPF fibroblasts. <g>HGF</g> secretion by control fibroblasts was also slightly inhibited by transforming growth factor TGF-beta1 and stimulated by anti-TGF-beta antibody, whereas both agents had no effect on IPF fibroblasts. Our results demonstrate a defect in <g>HGF</g> production by IPF fibroblasts that seems secondary to a defect in PGE2 secretion.
12947024|a|<g>Hepatocyte growth factor</g> <g>HGF</g> is a growth factor that protects alveolar epithelial cells from <d>pulmonary fibrosis</d> in various animal models. We compared in vitro <g>HGF</g> production by human lung fibroblasts from patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, n = 8 and from control subjects n = 6. Basal <g>HGF</g> secretion by <d>IPF</d> fibroblasts was decreased by 50% when compared with control fibroblasts p < 0.05. <g>HGF</g> was secreted mainly in the cleaved mature form, both in <d>IPF</d> and control fibroblasts. <g>HGF</g> messenger RNA levels were reduced in <d>IPF</d> fibroblasts. Prostaglandin PG E2 secretion by <d>IPF</d> fibroblasts was low when compared with control subjects p < 0.05. After the addition of PGE2 10-6 M or dibutyryl cyclic AMP 10-3 M, <g>HGF</g> secretion by <d>IPF</d> fibroblasts reached the level of control subjects. Inhibition of PGE2 synthesis with indomethacin reduced <g>HGF</g> secretion by control fibroblasts but had no effect on <d>IPF</d> fibroblasts. <g>HGF</g> secretion by control fibroblasts was also slightly inhibited by transforming growth factor TGF-beta1 and stimulated by anti-TGF-beta antibody, whereas both agents had no effect on <d>IPF</d> fibroblasts. Our results demonstrate a defect in <g>HGF</g> production by <d>IPF</d> fibroblasts that seems secondary to a defect in PGE2 secretion.
14653626|a|The need for transplantable beta cells with a stable phenotype has given rise to several strategies including the expansion of existing <d>pancreatic islets</d> and/or growth of new ones. In vitro studies of beta cell proliferation on extracellular matrices plus growth factors have highlighted a possible cell expansion technique; however, the technique was accompanied with loss of insulin secretion. Herein we showed that human islet cell proliferation was marked by a decreased expression of specific differentiation markers, particularly insulin, insulin promoting factor-1 IPF-1, and glucokinase. After a 6-day expansion period, we tried to reexpress the beta cell differentiation markers with compounds known for their differentiation and/or insulin-secreting properties. Sodium butyrate was a potent factor of IPF-1, insulin, and glucokinase gene reexpression; it also clearly induced secretion of gastrin, a known neogenic factor. Other compounds, namely TGF-beta, calcitriol, GLP-1, and activin A, efficiently enhanced the glucose sensor machinery, particularly Glut-1 and glucokinase, thus triggering glucose responsiveness. Our results indicate that specific beta cell gene expression may be induced after expansion and dedifferentiation. This rekindles interest in human beta cell expansion. The possible stabilization of specialized genes needed by beta cells to fulfill their role as nutrient sensors and metabolic regulators may also be of interest to ensure graft maintenance and efficiency.
15030461|a|Pro- and anti-fibrotic cytokine gene polymorphisms may affect expression of <d>idiopathic pulmonary fibrosis</d> IPF. The aims of the present case-control study were to examine polymorphisms in the IL-6, transforming growth factor TGF-beta 1, tumour necrosis factor TNF-alpha and interleukin-1 IL-1Ra genes in patients with IPF n = 22 -compared to healthy controls n = 140. Genotyping was performed on DNA extracted from peripheral blood lymphocytes, using polymerase chain reaction - restriction fragment length polymorphism with gene polymorphisms determined according to -published techniques. The following sites were examined: i IL-1Ra*1-5 86 bp variable tandem repeat intron 2, ii IL-6 -174G > C, iii TNF-alpha -308G > A and iv TGF-beta 1 Arg25Pro. The TNF-alpha -308 A allele was over-represented in the IPF pcorr = 0.004 group compared to controls. Risk of IPF was significant for heterozygotes for: i the TNF-alpha -308 A allele A/G odds ratio OR 2.9; 95% confidence interval CI 1.2-7.2; P = 0.02, ii homozygotes A/A OR 13.9; 95%CI 1.2-160; P = 0.04 and iii carriage of the allele A/A + A/G OR 4; 95%CI 1.6-10.2; P = 0.003. The distribution of alleles and genotypes for IL-6, TGF-beta 1 and IL-1Ra between the two groups was not significantly different. This is the third study to independently confirm that there is a significant association of the TNF-alpha -308 A allele with IPF. Further research is needed to assess the utility of cytokine gene polymorphisms as markers of disease -susceptibility.
15030461|a|Pro- and anti-fibrotic cytokine gene polymorphisms may affect expression of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The aims of the present case-control study were to examine polymorphisms in the IL-6, transforming growth factor TGF-beta 1, tumour necrosis factor TNF-alpha and interleukin-1 IL-1Ra genes in patients with <d>IPF</d> n = 22 -compared to healthy controls n = 140. Genotyping was performed on DNA extracted from peripheral blood lymphocytes, using polymerase chain reaction - restriction fragment length polymorphism with gene polymorphisms determined according to -published techniques. The following sites were examined: i IL-1Ra*1-5 86 bp variable tandem repeat intron 2, ii IL-6 -174G > C, iii TNF-alpha -308G > A and iv TGF-beta 1 Arg25Pro. The TNF-alpha -308 A allele was over-represented in the <d>IPF</d> pcorr = 0.004 group compared to controls. Risk of <d>IPF</d> was significant for heterozygotes for: i the TNF-alpha -308 A allele A/G odds ratio OR 2.9; 95% confidence interval CI 1.2-7.2; P = 0.02, ii homozygotes A/A OR 13.9; 95%CI 1.2-160; P = 0.04 and iii carriage of the allele A/A + A/G OR 4; 95%CI 1.6-10.2; P = 0.003. The distribution of alleles and genotypes for IL-6, TGF-beta 1 and IL-1Ra between the two groups was not significantly different. This is the third study to independently confirm that there is a significant association of the TNF-alpha -308 A allele with <d>IPF</d>. Further research is needed to assess the utility of cytokine gene polymorphisms as markers of disease -susceptibility.
15030461|a|Pro- and anti-fibrotic cytokine gene polymorphisms may affect expression of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The aims of the present case-control study were to examine polymorphisms in the <g>IL-6</g>, <g>transforming growth factor TGF-beta 1</g>, <d>tumour</d> necrosis factor TNF-alpha and interleukin-1 IL-1Ra genes in patients with <d>IPF</d> n = 22 -compared to healthy controls n = 140. Genotyping was performed on DNA extracted from peripheral blood lymphocytes, using polymerase chain reaction - restriction fragment length polymorphism with gene polymorphisms determined according to -published techniques. The following sites were examined: i IL-1Ra*1-5 86 bp variable tandem repeat intron 2, ii <g>IL-6</g> -174G > C, iii TNF-alpha -308G > A and iv TGF-beta 1 Arg25Pro. The TNF-alpha -308 A allele was over-represented in the <d>IPF</d> pcorr = 0.004 group compared to controls. Risk of <d>IPF</d> was significant for heterozygotes for: i the TNF-alpha -308 A allele A/G odds ratio OR 2.9; 95% confidence interval CI 1.2-7.2; P = 0.02, ii homozygotes A/A OR 13.9; 95%CI 1.2-160; P = 0.04 and iii carriage of the allele A/A + A/G OR 4; 95%CI 1.6-10.2; P = 0.003. The distribution of alleles and genotypes for <g>IL-6</g>, TGF-beta 1 and IL-1Ra between the two groups was not significantly different. This is the third study to independently confirm that there is a significant association of the TNF-alpha -308 A allele with <d>IPF</d>. Further research is needed to assess the utility of cytokine gene polymorphisms as markers of disease -susceptibility.
15030461|a|Pro- and anti-fibrotic cytokine gene polymorphisms may affect expression of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The aims of the present case-control study were to examine polymorphisms in the <g>IL-6</g>, <g>transforming growth factor TGF-beta 1</g>, <d>tumour</d> <d>necrosis</d> factor TNF-alpha and interleukin-1 IL-1Ra genes in patients with <d>IPF</d> n = 22 -compared to healthy controls n = 140. Genotyping was performed on DNA extracted from peripheral blood lymphocytes, using polymerase chain reaction - restriction fragment length polymorphism with gene polymorphisms determined according to -published techniques. The following sites were examined: i IL-1Ra*1-5 86 bp variable tandem repeat intron 2, ii <g>IL-6</g> -174G > C, iii TNF-alpha -308G > A and iv TGF-beta 1 Arg25Pro. The TNF-alpha -308 A allele was over-represented in the <d>IPF</d> pcorr = 0.004 group compared to controls. Risk of <d>IPF</d> was significant for heterozygotes for: i the TNF-alpha -308 A allele A/G odds ratio OR 2.9; 95% confidence interval CI 1.2-7.2; P = 0.02, ii homozygotes A/A OR 13.9; 95%CI 1.2-160; P = 0.04 and iii carriage of the allele A/A + A/G OR 4; 95%CI 1.6-10.2; P = 0.003. The distribution of alleles and genotypes for <g>IL-6</g>, TGF-beta 1 and IL-1Ra between the two groups was not significantly different. This is the third study to independently confirm that there is a significant association of the TNF-alpha -308 A allele with <d>IPF</d>. Further research is needed to assess the utility of cytokine gene polymorphisms as markers of disease -susceptibility.
15117744|a|<g>Pigment epithelium-derived factor</g> PEDF is a 50-kD protein with angiostatic and neurotrophic activities that regulates vascular development within the eye. PEDF expression was increased in the lungs of patients with <d>idiopathic pulmonary fibrosis</d> IPF based on microarray analyses. Angiogenesis has been implicated in the pathogenesis of fibrotic lung diseases, we therefore hypothesized that regional abnormalities in vascularization occur in IPF as a result of an imbalance between PEDF and vascular endothelial growth factor. We demonstrated that vascular density is regionally decreased in IPF within the fibroblastic foci, and that within these areas PEDF was increased, whereas vascular endothelial growth factor was decreased. PEDF colocalized with the fibrogenic cytokine, transforming growth factor TGF-beta 1, particularly within the fibrotic interstitium and the fibroblastic focus, and prominently within the epithelium directly overlying the fibroblastic focus. This suggested that TGF-beta 1 might regulate PEDF expression. Using 3T3-L1 fibroblasts and human lung fibroblasts, we showed that PEDF was indeed a TGF-beta 1 target gene. Collectively, our findings implicate PEDF as a regulator of pulmonary angiogenesis and an important mediator in IPF.
15117744|a|<g>Pigment epithelium-derived factor</g> <g>PEDF</g> is a 50-kD protein with angiostatic and neurotrophic activities that regulates vascular development within the eye. <g>PEDF</g> expression was increased in the lungs of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> based on microarray analyses. Angiogenesis has been implicated in the pathogenesis of fibrotic lung diseases, we therefore hypothesized that regional abnormalities in vascularization occur in <d>IPF</d> as a result of an imbalance between <g>PEDF</g> and vascular endothelial growth factor. We demonstrated that vascular density is regionally decreased in <d>IPF</d> within the fibroblastic foci, and that within these areas <g>PEDF</g> was increased, whereas vascular endothelial growth factor was decreased. <g>PEDF</g> colocalized with the fibrogenic cytokine, transforming growth factor TGF-beta 1, particularly within the fibrotic interstitium and the fibroblastic focus, and prominently within the epithelium directly overlying the fibroblastic focus. This suggested that TGF-beta 1 might regulate <g>PEDF</g> expression. Using 3T3-L1 fibroblasts and human lung fibroblasts, we showed that <g>PEDF</g> was indeed a TGF-beta 1 target gene. Collectively, our findings implicate <g>PEDF</g> as a regulator of pulmonary angiogenesis and an important mediator in <d>IPF</d>.
15117744|a|<g>Pigment epithelium-derived factor</g> <g>PEDF</g> is a 50-kD protein with angiostatic and neurotrophic activities that regulates vascular development within the eye. <g>PEDF</g> expression was increased in the lungs of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> based on microarray analyses. Angiogenesis has been implicated in the pathogenesis of <d>fibrotic lung diseases</d>, we therefore hypothesized that regional abnormalities in vascularization occur in <d>IPF</d> as a result of an imbalance between <g>PEDF</g> and vascular endothelial growth factor. We demonstrated that vascular density is regionally decreased in <d>IPF</d> within the fibroblastic foci, and that within these areas <g>PEDF</g> was increased, whereas vascular endothelial growth factor was decreased. <g>PEDF</g> colocalized with the fibrogenic cytokine, transforming growth factor TGF-beta 1, particularly within the fibrotic interstitium and the fibroblastic focus, and prominently within the epithelium directly overlying the fibroblastic focus. This suggested that TGF-beta 1 might regulate <g>PEDF</g> expression. Using 3T3-L1 fibroblasts and human lung fibroblasts, we showed that <g>PEDF</g> was indeed a TGF-beta 1 target gene. Collectively, our findings implicate <g>PEDF</g> as a regulator of pulmonary angiogenesis and an important mediator in <d>IPF</d>.
15281432|a|BACKGROUND AND AIM: Fibrosing alveolitis develops in up to 80% of <d>systemic sclerosis</d> patients SSc but progression to end stage fibrosis occurs in about 15% of cases. Mechanisms leading to the process remain mostly unknown. We compared cytokine profiles of broncho-alveolar lavage fluids BAL-f from patients with SSc associated interstitial lung disease SSc-ILD n. 34, idiopathic pulmonary fibrosis IPF n. 13, stage II sarcoidosis n. 14 and 9 controls. METHODS: Interleukin IL 8, monocyte chemoattractant protein 1 MCP-1, gamma-interferon IFN-gamma, IL12, IL18 and IL10 and transforming growth factor-beta TGF-beta were assessed by ELISA in concentrated BAL-f. RESULTS: Levels of IL8 and MCP-1 were significantly elevated in SSc-ILD and in IPF as compared with controls Mann Whitney test p < 0.05, while MCP-1 values were significantly lower in SSc-ILD than in IPF. A significant correlation between neutrophils and IL8 levels p = 0.047, as well as between eosinophils and MCP-1 levels p = 0.004 was also observed. IFN-gamma levels were slightly higher than normal only in sarcoidosis p = 0.06, whereas IL12 levels increased both in sarcoidosis and SSc-ILD p < 0.05. No differences were found in IL18 and TGF-beta levels. Finally, IL10 levels were higher in SSc-ILD and sarcoidosis than in controls and IPF p < 0.05. CONCLUSION: BAL-f cytokine profile differentiates ILD associated with SSc from IPF. The lower expression of MCP-1 and the higher expression of the anti-fibrotic IL12 and the anti-inflammatory IL10, observed both in sarcoidosis and in SSc-ILD, could account for the better prognosis of these ILDs. Further longitudinal studies are required to confirm whether a different cytokine phenotype may be considered predictive of clinical outcome in SSc-ILD.
15281432|a|BACKGROUND AND AIM: <d>Fibrosing alveolitis</d> develops in up to 80% of <d>systemic sclerosis</d> patients SSc but progression to end stage fibrosis occurs in about 15% of cases. Mechanisms leading to the process remain mostly unknown. We compared cytokine profiles of broncho-alveolar lavage fluids BAL-f from patients with SSc associated interstitial lung disease SSc-ILD n. 34, idiopathic pulmonary fibrosis IPF n. 13, stage II sarcoidosis n. 14 and 9 controls. METHODS: Interleukin IL 8, monocyte chemoattractant protein 1 MCP-1, gamma-interferon IFN-gamma, IL12, IL18 and IL10 and transforming growth factor-beta TGF-beta were assessed by ELISA in concentrated BAL-f. RESULTS: Levels of IL8 and MCP-1 were significantly elevated in SSc-ILD and in IPF as compared with controls Mann Whitney test p < 0.05, while MCP-1 values were significantly lower in SSc-ILD than in IPF. A significant correlation between neutrophils and IL8 levels p = 0.047, as well as between eosinophils and MCP-1 levels p = 0.004 was also observed. IFN-gamma levels were slightly higher than normal only in sarcoidosis p = 0.06, whereas IL12 levels increased both in sarcoidosis and SSc-ILD p < 0.05. No differences were found in IL18 and TGF-beta levels. Finally, IL10 levels were higher in SSc-ILD and sarcoidosis than in controls and IPF p < 0.05. CONCLUSION: BAL-f cytokine profile differentiates ILD associated with SSc from IPF. The lower expression of MCP-1 and the higher expression of the anti-fibrotic IL12 and the anti-inflammatory IL10, observed both in sarcoidosis and in SSc-ILD, could account for the better prognosis of these ILDs. Further longitudinal studies are required to confirm whether a different cytokine phenotype may be considered predictive of clinical outcome in SSc-ILD.
15281432|a|BACKGROUND AND AIM: <d>Fibrosing alveolitis</d> develops in up to 80% of <d>systemic sclerosis</d> patients SSc but progression to end stage <d>fibrosis</d> occurs in about 15% of cases. Mechanisms leading to the process remain mostly unknown. We compared cytokine profiles of broncho-alveolar lavage fluids BAL-f from patients with SSc associated interstitial lung disease SSc-ILD n. 34, idiopathic pulmonary <d>fibrosis</d> IPF n. 13, stage II sarcoidosis n. 14 and 9 controls. METHODS: Interleukin IL 8, monocyte chemoattractant protein 1 MCP-1, gamma-interferon IFN-gamma, IL12, IL18 and IL10 and transforming growth factor-beta TGF-beta were assessed by ELISA in concentrated BAL-f. RESULTS: Levels of IL8 and MCP-1 were significantly elevated in SSc-ILD and in IPF as compared with controls Mann Whitney test p < 0.05, while MCP-1 values were significantly lower in SSc-ILD than in IPF. A significant correlation between neutrophils and IL8 levels p = 0.047, as well as between eosinophils and MCP-1 levels p = 0.004 was also observed. IFN-gamma levels were slightly higher than normal only in sarcoidosis p = 0.06, whereas IL12 levels increased both in sarcoidosis and SSc-ILD p < 0.05. No differences were found in IL18 and TGF-beta levels. Finally, IL10 levels were higher in SSc-ILD and sarcoidosis than in controls and IPF p < 0.05. CONCLUSION: BAL-f cytokine profile differentiates ILD associated with SSc from IPF. The lower expression of MCP-1 and the higher expression of the anti-fibrotic IL12 and the anti-inflammatory IL10, observed both in sarcoidosis and in SSc-ILD, could account for the better prognosis of these ILDs. Further longitudinal studies are required to confirm whether a different cytokine phenotype may be considered predictive of clinical outcome in SSc-ILD.
15281432|a|BACKGROUND AND AIM: <d>Fibrosing alveolitis</d> develops in up to 80% of <d>systemic sclerosis</d> patients SSc but progression to end stage <d>fibrosis</d> occurs in about 15% of cases. Mechanisms leading to the process remain mostly unknown. We compared cytokine profiles of broncho-alveolar lavage fluids BAL-f from patients with <d>SSc associated interstitial lung disease</d> SSc-ILD n. 34, idiopathic pulmonary <d>fibrosis</d> IPF n. 13, stage II sarcoidosis n. 14 and 9 controls. METHODS: Interleukin IL 8, monocyte chemoattractant protein 1 MCP-1, gamma-interferon IFN-gamma, IL12, IL18 and IL10 and transforming growth factor-beta TGF-beta were assessed by ELISA in concentrated BAL-f. RESULTS: Levels of IL8 and MCP-1 were significantly elevated in SSc-ILD and in IPF as compared with controls Mann Whitney test p < 0.05, while MCP-1 values were significantly lower in SSc-ILD than in IPF. A significant correlation between neutrophils and IL8 levels p = 0.047, as well as between eosinophils and MCP-1 levels p = 0.004 was also observed. IFN-gamma levels were slightly higher than normal only in sarcoidosis p = 0.06, whereas IL12 levels increased both in sarcoidosis and SSc-ILD p < 0.05. No differences were found in IL18 and TGF-beta levels. Finally, IL10 levels were higher in SSc-ILD and sarcoidosis than in controls and IPF p < 0.05. CONCLUSION: BAL-f cytokine profile differentiates ILD associated with SSc from IPF. The lower expression of MCP-1 and the higher expression of the anti-fibrotic IL12 and the anti-inflammatory IL10, observed both in sarcoidosis and in SSc-ILD, could account for the better prognosis of these ILDs. Further longitudinal studies are required to confirm whether a different cytokine phenotype may be considered predictive of clinical outcome in SSc-ILD.
15281432|a|BACKGROUND AND AIM: <d>Fibrosing alveolitis</d> develops in up to 80% of <d>systemic sclerosis</d> patients SSc but progression to end stage <d>fibrosis</d> occurs in about 15% of cases. Mechanisms leading to the process remain mostly unknown. We compared cytokine profiles of broncho-alveolar lavage fluids BAL-f from patients with <d>SSc associated interstitial lung disease</d> <d>SSc-ILD</d> n. 34, idiopathic pulmonary <d>fibrosis</d> IPF n. 13, stage II sarcoidosis n. 14 and 9 controls. METHODS: Interleukin IL 8, monocyte chemoattractant protein 1 MCP-1, gamma-interferon IFN-gamma, IL12, IL18 and IL10 and transforming growth factor-beta TGF-beta were assessed by ELISA in concentrated BAL-f. RESULTS: Levels of IL8 and MCP-1 were significantly elevated in <d>SSc-ILD</d> and in IPF as compared with controls Mann Whitney test p < 0.05, while MCP-1 values were significantly lower in <d>SSc-ILD</d> than in IPF. A significant correlation between neutrophils and IL8 levels p = 0.047, as well as between eosinophils and MCP-1 levels p = 0.004 was also observed. IFN-gamma levels were slightly higher than normal only in sarcoidosis p = 0.06, whereas IL12 levels increased both in sarcoidosis and <d>SSc-ILD</d> p < 0.05. No differences were found in IL18 and TGF-beta levels. Finally, IL10 levels were higher in <d>SSc-ILD</d> and sarcoidosis than in controls and IPF p < 0.05. CONCLUSION: BAL-f cytokine profile differentiates ILD associated with SSc from IPF. The lower expression of MCP-1 and the higher expression of the anti-fibrotic IL12 and the anti-inflammatory IL10, observed both in sarcoidosis and in <d>SSc-ILD</d>, could account for the better prognosis of these ILDs. Further longitudinal studies are required to confirm whether a different cytokine phenotype may be considered predictive of clinical outcome in <d>SSc-ILD</d>.
15281432|a|BACKGROUND AND AIM: <d>Fibrosing alveolitis</d> develops in up to 80% of <d>systemic sclerosis</d> patients SSc but progression to end stage <d>fibrosis</d> occurs in about 15% of cases. Mechanisms leading to the process remain mostly unknown. We compared cytokine profiles of broncho-alveolar lavage fluids BAL-f from patients with <d>SSc associated interstitial lung disease</d> <d>SSc-ILD</d> n. 34, idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> n. 13, stage II sarcoidosis n. 14 and 9 controls. METHODS: Interleukin IL 8, monocyte chemoattractant protein 1 MCP-1, gamma-interferon IFN-gamma, IL12, IL18 and IL10 and transforming growth factor-beta TGF-beta were assessed by ELISA in concentrated BAL-f. RESULTS: Levels of IL8 and MCP-1 were significantly elevated in <d>SSc-ILD</d> and in <d>IPF</d> as compared with controls Mann Whitney test p < 0.05, while MCP-1 values were significantly lower in <d>SSc-ILD</d> than in <d>IPF</d>. A significant correlation between neutrophils and IL8 levels p = 0.047, as well as between eosinophils and MCP-1 levels p = 0.004 was also observed. IFN-gamma levels were slightly higher than normal only in sarcoidosis p = 0.06, whereas IL12 levels increased both in sarcoidosis and <d>SSc-ILD</d> p < 0.05. No differences were found in IL18 and TGF-beta levels. Finally, IL10 levels were higher in <d>SSc-ILD</d> and sarcoidosis than in controls and <d>IPF</d> p < 0.05. CONCLUSION: BAL-f cytokine profile differentiates ILD associated with SSc from <d>IPF</d>. The lower expression of MCP-1 and the higher expression of the anti-fibrotic IL12 and the anti-inflammatory IL10, observed both in sarcoidosis and in <d>SSc-ILD</d>, could account for the better prognosis of these ILDs. Further longitudinal studies are required to confirm whether a different cytokine phenotype may be considered predictive of clinical outcome in <d>SSc-ILD</d>.
15281432|a|BACKGROUND AND AIM: <d>Fibrosing alveolitis</d> develops in up to 80% of <d>systemic sclerosis</d> patients SSc but progression to end stage <d>fibrosis</d> occurs in about 15% of cases. Mechanisms leading to the process remain mostly unknown. We compared cytokine profiles of broncho-alveolar lavage fluids BAL-f from patients with <d>SSc associated interstitial lung disease</d> <d>SSc-ILD</d> n. 34, idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> n. 13, stage II <d>sarcoidosis</d> n. 14 and 9 controls. METHODS: Interleukin IL 8, monocyte chemoattractant protein 1 MCP-1, gamma-interferon IFN-gamma, IL12, IL18 and IL10 and transforming growth factor-beta TGF-beta were assessed by ELISA in concentrated BAL-f. RESULTS: Levels of IL8 and MCP-1 were significantly elevated in <d>SSc-ILD</d> and in <d>IPF</d> as compared with controls Mann Whitney test p < 0.05, while MCP-1 values were significantly lower in <d>SSc-ILD</d> than in <d>IPF</d>. A significant correlation between neutrophils and IL8 levels p = 0.047, as well as between eosinophils and MCP-1 levels p = 0.004 was also observed. IFN-gamma levels were slightly higher than normal only in <d>sarcoidosis</d> p = 0.06, whereas IL12 levels increased both in <d>sarcoidosis</d> and <d>SSc-ILD</d> p < 0.05. No differences were found in IL18 and TGF-beta levels. Finally, IL10 levels were higher in <d>SSc-ILD</d> and <d>sarcoidosis</d> than in controls and <d>IPF</d> p < 0.05. CONCLUSION: BAL-f cytokine profile differentiates ILD associated with SSc from <d>IPF</d>. The lower expression of MCP-1 and the higher expression of the anti-fibrotic IL12 and the anti-inflammatory IL10, observed both in <d>sarcoidosis</d> and in <d>SSc-ILD</d>, could account for the better prognosis of these ILDs. Further longitudinal studies are required to confirm whether a different cytokine phenotype may be considered predictive of clinical outcome in <d>SSc-ILD</d>.
15281432|a|BACKGROUND AND AIM: <d>Fibrosing alveolitis</d> develops in up to 80% of <d>systemic sclerosis</d> patients SSc but progression to end stage <d>fibrosis</d> occurs in about 15% of cases. Mechanisms leading to the process remain mostly unknown. We compared cytokine profiles of broncho-alveolar lavage fluids BAL-f from patients with <d>SSc associated interstitial lung disease</d> <d>SSc-<d>ILD</d></d> n. 34, idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> n. 13, stage II <d>sarcoidosis</d> n. 14 and 9 controls. METHODS: <g>Interleukin IL 8</g>, <g>monocyte chemoattractant protein 1</g> <g>MCP-1</g>, gamma-interferon <g>IFN-gamma</g>, IL12, <g>IL18</g> and <g>IL10</g> and <g>transforming growth factor-beta</g> <g>TGF-beta</g> were assessed by ELISA in concentrated BAL-f. RESULTS: Levels of <g>IL8</g> and <g>MCP-1</g> were significantly elevated in <d>SSc-<d>ILD</d></d> and in <d>IPF</d> as compared with controls Mann Whitney test p < 0.05, while <g>MCP-1</g> values were significantly lower in <d>SSc-<d>ILD</d></d> than in <d>IPF</d>. A significant correlation between neutrophils and <g>IL8</g> levels p = 0.047, as well as between eosinophils and <g>MCP-1</g> levels p = 0.004 was also observed. <g>IFN-gamma</g> levels were slightly higher than normal only in <d>sarcoidosis</d> p = 0.06, whereas IL12 levels increased both in <d>sarcoidosis</d> and <d>SSc-<d>ILD</d></d> p < 0.05. No differences were found in <g>IL18</g> and <g>TGF-beta</g> levels. Finally, <g>IL10</g> levels were higher in <d>SSc-<d>ILD</d></d> and <d>sarcoidosis</d> than in controls and <d>IPF</d> p < 0.05. CONCLUSION: BAL-f cytokine profile differentiates <d>ILD</d> associated with SSc from <d>IPF</d>. The lower expression of <g>MCP-1</g> and the higher expression of the anti-fibrotic IL12 and the anti-inflammatory <g>IL10</g>, observed both in <d>sarcoidosis</d> and in <d>SSc-<d>ILD</d></d>, could account for the better prognosis of these <d>ILD</d>s. Further longitudinal studies are required to confirm whether a different cytokine phenotype may be considered predictive of clinical outcome in <d>SSc-<d>ILD</d></d>.
15298857|a|<g>Connective tissue growth factor</g> <g>CTGF</g>, a potent profibrotic mediator, acts downstream and in concert with transforming growth factor TGF-beta to drive fibrogenesis. Significant upregulation of <g>CTGF</g> has been reported in <d>fibrogenic diseases</d>, including idiopathic pulmonary fibrosis IPF, and is partly responsible for associated excessive fibroblast proliferation and extracellular matrix deposition, but no effective therapy exists for averting such fibrogeneic events. Simvastatin has reported putative antifibrotic actions in renal fibroblasts; this study explores such actions on human IPF-derived and normal lung fibroblasts and examines associated driving mechanisms. Simvastatin reduces basal <g>CTGF</g> gene and protein expression in all fibroblast lines, overriding TGF-beta induction through inhibition of the cholesterol synthesis pathway. Signaling pathways driving simvastatin's effects on <g>CTGF</g>/TGF-beta interaction were evaluated using transient reporter transfection of a <g>CTGF</g> promoter construct. Inhibition of <g>CTGF</g> promoter activity by simvastatin was most marked at 10 muM concentration, reducing activity by 76.2 and 51.8% over TGF-beta-stimulated cultures in IPF and normal fibroblasts, respectively. We also show that geranylgeranylpyrophosphate GGPP, but not farnesylpyrophosphate, induces <g>CTGF</g> promoter activity following simvastatin inhibition by 55.3 and 31.1% over GGPP-negative cultures in IMR90 and IPF-derived fibroblasts, respectively, implicating small GTPase Rho involvement rather than Ras in these effects. Indeed, the specific Rho inhibitor C3 exotoxin significantly P < 0.05 suppressed TGF-beta-induced <g>CTGF</g> promoter activity in transfected lung fibroblasts, a finding further supported by transfection of dominant-negative and constitutively active RhoA constructs, thus demonstrating that simvastatin through a Rho signaling mechanism in lung fibroblasts can modulate <g>CTGF</g> expression and interaction with TGF-beta.
15298857|a|<g>Connective tissue growth factor</g> <g>CTGF</g>, a potent profibrotic mediator, acts downstream and in concert with transforming growth factor TGF-beta to drive fibrogenesis. Significant upregulation of <g>CTGF</g> has been reported in <d>fibrogenic diseases</d>, including <d>idiopathic pulmonary fibrosis</d> IPF, and is partly responsible for associated excessive fibroblast proliferation and extracellular matrix deposition, but no effective therapy exists for averting such fibrogeneic events. Simvastatin has reported putative antifibrotic actions in renal fibroblasts; this study explores such actions on human IPF-derived and normal lung fibroblasts and examines associated driving mechanisms. Simvastatin reduces basal <g>CTGF</g> gene and protein expression in all fibroblast lines, overriding TGF-beta induction through inhibition of the cholesterol synthesis pathway. Signaling pathways driving simvastatin's effects on <g>CTGF</g>/TGF-beta interaction were evaluated using transient reporter transfection of a <g>CTGF</g> promoter construct. Inhibition of <g>CTGF</g> promoter activity by simvastatin was most marked at 10 muM concentration, reducing activity by 76.2 and 51.8% over TGF-beta-stimulated cultures in IPF and normal fibroblasts, respectively. We also show that geranylgeranylpyrophosphate GGPP, but not farnesylpyrophosphate, induces <g>CTGF</g> promoter activity following simvastatin inhibition by 55.3 and 31.1% over GGPP-negative cultures in IMR90 and IPF-derived fibroblasts, respectively, implicating small GTPase Rho involvement rather than Ras in these effects. Indeed, the specific Rho inhibitor C3 exotoxin significantly P < 0.05 suppressed TGF-beta-induced <g>CTGF</g> promoter activity in transfected lung fibroblasts, a finding further supported by transfection of dominant-negative and constitutively active RhoA constructs, thus demonstrating that simvastatin through a Rho signaling mechanism in lung fibroblasts can modulate <g>CTGF</g> expression and interaction with TGF-beta.
15298857|a|<g>Connective tissue growth factor</g> <g>CTGF</g>, a potent profibrotic mediator, acts downstream and in concert with transforming growth factor TGF-beta to drive fibrogenesis. Significant upregulation of <g>CTGF</g> has been reported in <d>fibrogenic diseases</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, and is partly responsible for associated excessive fibroblast proliferation and extracellular matrix deposition, but no effective therapy exists for averting such fibrogeneic events. Simvastatin has reported putative antifibrotic actions in renal fibroblasts; this study explores such actions on human <d>IPF</d>-derived and normal lung fibroblasts and examines associated driving mechanisms. Simvastatin reduces basal <g>CTGF</g> gene and protein expression in all fibroblast lines, overriding TGF-beta induction through inhibition of the cholesterol synthesis pathway. Signaling pathways driving simvastatin's effects on <g>CTGF</g>/TGF-beta interaction were evaluated using transient reporter transfection of a <g>CTGF</g> promoter construct. Inhibition of <g>CTGF</g> promoter activity by simvastatin was most marked at 10 muM concentration, reducing activity by 76.2 and 51.8% over TGF-beta-stimulated cultures in <d>IPF</d> and normal fibroblasts, respectively. We also show that geranylgeranylpyrophosphate GGPP, but not farnesylpyrophosphate, induces <g>CTGF</g> promoter activity following simvastatin inhibition by 55.3 and 31.1% over GGPP-negative cultures in IMR90 and <d>IPF</d>-derived fibroblasts, respectively, implicating small GTPase Rho involvement rather than Ras in these effects. Indeed, the specific Rho inhibitor C3 exotoxin significantly P < 0.05 suppressed TGF-beta-induced <g>CTGF</g> promoter activity in transfected lung fibroblasts, a finding further supported by transfection of dominant-negative and constitutively active RhoA constructs, thus demonstrating that simvastatin through a Rho signaling mechanism in lung fibroblasts can modulate <g>CTGF</g> expression and interaction with TGF-beta.
15563636|a|<d>Pulmonary fibrosis</d> is characterized by chronic scar formation and deposition of extracellular matrix, resulting in impaired lung function and respiratory failure. Idiopathic pulmonary fibrosis IPF is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta TGF-beta is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases ALK. We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of <g>ALK5</g>, the specific TGF-beta receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for IPF and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-beta receptor activation.
15563636|a|<d>Pulmonary fibrosis</d> is characterized by chronic scar formation and deposition of extracellular matrix, resulting in <d>impaired lung function</d> and respiratory failure. Idiopathic pulmonary fibrosis IPF is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta TGF-beta is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases ALK. We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of <g>ALK5</g>, the specific TGF-beta receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for IPF and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-beta receptor activation.
15563636|a|<d>Pulmonary fibrosis</d> is characterized by chronic scar formation and deposition of extracellular matrix, resulting in <d>impaired lung function</d> and <d>respiratory failure</d>. Idiopathic pulmonary fibrosis IPF is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta TGF-beta is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases ALK. We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of <g>ALK5</g>, the specific TGF-beta receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for IPF and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-beta receptor activation.
15563636|a|<d>Pulmonary fibrosis</d> is characterized by chronic scar formation and deposition of extracellular matrix, resulting in <d>impaired lung function</d> and <d>respiratory failure</d>. <d>Idiopathic pulmonary fibrosis</d> IPF is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta TGF-beta is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases ALK. We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of <g>ALK5</g>, the specific TGF-beta receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for IPF and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-beta receptor activation.
15563636|a|<d>Pulmonary fibrosis</d> is characterized by chronic scar formation and deposition of extracellular matrix, resulting in <d>impaired lung function</d> and <d>respiratory failure</d>. <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta TGF-beta is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of <d>IPF</d>. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases ALK. We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of <g>ALK5</g>, the specific TGF-beta receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for <d>IPF</d> and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-beta receptor activation.
15563636|a|<d>Pulmonary <d>fibrosis</d></d> is characterized by chronic scar formation and deposition of extracellular matrix, resulting in <d>impaired lung function</d> and <d>respiratory failure</d>. <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive <d>fibrosis</d>. Transforming growth factor beta TGF-beta is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of <d>IPF</d>. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases ALK. We have used a gene transfer model of progressive TGF-beta1-induced pulmonary <d>fibrosis</d> in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of <g>ALK5</g>, the specific TGF-beta receptor. We show that the drug inhibits the induction of <d>fibrosis</d> when administered at the time of initiation of fibrogenesis and, most important, blocks progressive <d>fibrosis</d> when administered transiently to animals with established <d>fibrosis</d>. These data show promise of the development of an effective therapeutic intervention for <d>IPF</d> and that inhibition of chronic progressive <d>fibrosis</d> may be achieved by blocking TGF-beta receptor activation.
15563636|a|<d>Pulmonary <d>fibrosis</d></d> is characterized by chronic scar formation and deposition of extracellular matrix, resulting in <d>impaired lung function</d> and <d>respiratory failure</d>. <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive <d>fibrosis</d>. <d>Transforming</d> growth factor beta TGF-beta is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of <d>IPF</d>. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases ALK. We have used a gene transfer model of progressive TGF-beta1-induced pulmonary <d>fibrosis</d> in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of <g>ALK5</g>, the specific TGF-beta receptor. We show that the drug inhibits the induction of <d>fibrosis</d> when administered at the time of initiation of fibrogenesis and, most important, blocks progressive <d>fibrosis</d> when administered transiently to animals with established <d>fibrosis</d>. These data show promise of the development of an effective therapeutic intervention for <d>IPF</d> and that inhibition of chronic progressive <d>fibrosis</d> may be achieved by blocking TGF-beta receptor activation.
15564021|a|A diagnosis of idiopathic <d>pulmonary fibrosis</d> IPF carries a poor prognosis, with our currently available therapies offering little clinical benefit. Unfortunately, recent major advances in our understanding of the clinical and biologic features of this disease have not been matched by similar advances in treatment. This is likely because of the complex cascade of biologic and pathobiologic events that occurs in IPF. The necessary, and desperately needed, next generation of therapies, focused on specific molecular targets thought to play pivotal roles in the development and progression of fibrosis, are under active investigation.
15564021|a|A diagnosis of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> carries a poor prognosis, with our currently available therapies offering little clinical benefit. Unfortunately, recent major advances in our understanding of the clinical and biologic features of this disease have not been matched by similar advances in treatment. This is likely because of the complex cascade of biologic and pathobiologic events that occurs in <d>IPF</d>. The necessary, and desperately needed, next generation of therapies, focused on specific molecular targets thought to play pivotal roles in the development and progression of fibrosis, are under active investigation.
15564021|a|A diagnosis of idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> carries a poor prognosis, with our currently available therapies offering little clinical benefit. Unfortunately, recent major advances in our understanding of the clinical and biologic features of this disease have not been matched by similar advances in treatment. This is likely because of the complex cascade of biologic and pathobiologic events that occurs in <d>IPF</d>. The necessary, and desperately needed, next generation of therapies, focused on specific molecular targets thought to play pivotal roles in the development and progression of <d>fibrosis</d>, are under active investigation.
15677772|a|Simvastatin is best known for its antilipidemic action and use in <d>cardiovascular disease</d> due to its inhibition of 3-hydroxy-3-methylglutaryl CoenzymeA HMG CoA reductase, a key enzyme in the cholesterol synthesis pathway. Inhibition of biological precursors in this pathway also enables pleiotrophic immunomodulatory and anti-inflammatory capabilities, including modulation of growth factor expression. Connective tissue growth factor CTGF and persistent myofibroblast formation are major determinants of the aggressive fibrotic disease, idiopathic pulmonary fibrosis IPF. In this study we used human lung fibroblasts derived from healthy and IPF lungs to examine Simvastatin effects on CTGF gene and protein expression, analyzed by RT-PCR and ELISA, respectively. Simvastatin significantly inhibited P < 0.05 CTGF gene and protein expression, overriding the induction by transforming growth factor-beta1, a known potent inducer of CTGF. Such Simvastatin suppressor action on growth factor interaction was reflected functionally on recognized phenotypes of fibrosis. alpha-smooth muscle actin expression was downregulated and collagen gel contraction reduced by 4.94- and 7.58-fold in IMR90 and HIPF lung fibroblasts, respectively, when preconditioned with 10 microM Simvastatin compared with transforming growth factor-beta1 treatment alone after 24 h. Our data suggest that Simvastatin can modify critical determinants of the profibrogenic machinery responsible for the aggressive clinical profile of IPF, and potentially prevents adverse lung parenchymal remodeling associated with persistent myofibroblast formation.
15677772|a|Simvastatin is best known for its antilipidemic action and use in <d>cardiovascular disease</d> due to its inhibition of <g>3-hydroxy-3-methylglutaryl CoenzymeA HMG CoA reductase</g>, a key enzyme in the cholesterol synthesis pathway. Inhibition of biological precursors in this pathway also enables pleiotrophic immunomodulatory and anti-inflammatory capabilities, including modulation of growth factor expression. <g>Connective tissue growth factor</g> <g>CTGF</g> and persistent myofibroblast formation are major determinants of the aggressive <d>fibrotic disease</d>, idiopathic pulmonary fibrosis IPF. In this study we used human lung fibroblasts derived from healthy and IPF lungs to examine Simvastatin effects on <g>CTGF</g> gene and protein expression, analyzed by RT-PCR and ELISA, respectively. Simvastatin significantly inhibited P < 0.05 <g>CTGF</g> gene and protein expression, overriding the induction by transforming growth factor-beta1, a known potent inducer of <g>CTGF</g>. Such Simvastatin suppressor action on growth factor interaction was reflected functionally on recognized phenotypes of fibrosis. alpha-smooth muscle actin expression was downregulated and collagen gel contraction reduced by 4.94- and 7.58-fold in IMR90 and HIPF lung fibroblasts, respectively, when preconditioned with 10 microM Simvastatin compared with transforming growth factor-beta1 treatment alone after 24 h. Our data suggest that Simvastatin can modify critical determinants of the profibrogenic machinery responsible for the aggressive clinical profile of IPF, and potentially prevents adverse lung parenchymal remodeling associated with persistent myofibroblast formation.
15677772|a|Simvastatin is best known for its antilipidemic action and use in <d>cardiovascular disease</d> due to its inhibition of <g>3-hydroxy-3-methylglutaryl CoenzymeA HMG CoA reductase</g>, a key enzyme in the cholesterol synthesis pathway. Inhibition of biological precursors in this pathway also enables pleiotrophic immunomodulatory and anti-inflammatory capabilities, including modulation of growth factor expression. <g>Connective tissue growth factor</g> <g>CTGF</g> and persistent myofibroblast formation are major determinants of the aggressive <d>fibrotic disease</d>, <d>idiopathic pulmonary fibrosis</d> IPF. In this study we used human lung fibroblasts derived from healthy and IPF lungs to examine Simvastatin effects on <g>CTGF</g> gene and protein expression, analyzed by RT-PCR and ELISA, respectively. Simvastatin significantly inhibited P < 0.05 <g>CTGF</g> gene and protein expression, overriding the induction by transforming growth factor-beta1, a known potent inducer of <g>CTGF</g>. Such Simvastatin suppressor action on growth factor interaction was reflected functionally on recognized phenotypes of fibrosis. alpha-smooth muscle actin expression was downregulated and collagen gel contraction reduced by 4.94- and 7.58-fold in IMR90 and HIPF lung fibroblasts, respectively, when preconditioned with 10 microM Simvastatin compared with transforming growth factor-beta1 treatment alone after 24 h. Our data suggest that Simvastatin can modify critical determinants of the profibrogenic machinery responsible for the aggressive clinical profile of IPF, and potentially prevents adverse lung parenchymal remodeling associated with persistent myofibroblast formation.
15677772|a|Simvastatin is best known for its antilipidemic action and use in <d>cardiovascular disease</d> due to its inhibition of <g>3-hydroxy-3-methylglutaryl CoenzymeA HMG CoA reductase</g>, a key enzyme in the cholesterol synthesis pathway. Inhibition of biological precursors in this pathway also enables pleiotrophic immunomodulatory and anti-inflammatory capabilities, including modulation of growth factor expression. <g>Connective tissue growth factor</g> <g>CTGF</g> and persistent myofibroblast formation are major determinants of the aggressive <d>fibrotic disease</d>, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. In this study we used human lung fibroblasts derived from healthy and <d>IPF</d> lungs to examine Simvastatin effects on <g>CTGF</g> gene and protein expression, analyzed by RT-PCR and ELISA, respectively. Simvastatin significantly inhibited P < 0.05 <g>CTGF</g> gene and protein expression, overriding the induction by transforming growth factor-beta1, a known potent inducer of <g>CTGF</g>. Such Simvastatin suppressor action on growth factor interaction was reflected functionally on recognized phenotypes of fibrosis. alpha-smooth muscle actin expression was downregulated and collagen gel contraction reduced by 4.94- and 7.58-fold in IMR90 and H<d>IPF</d> lung fibroblasts, respectively, when preconditioned with 10 microM Simvastatin compared with transforming growth factor-beta1 treatment alone after 24 h. Our data suggest that Simvastatin can modify critical determinants of the profibrogenic machinery responsible for the aggressive clinical profile of <d>IPF</d>, and potentially prevents adverse lung parenchymal remodeling associated with persistent myofibroblast formation.
15677772|a|Simvastatin is best known for its antilipidemic action and use in <d>cardiovascular disease</d> due to its inhibition of <g>3-hydroxy-3-methylglutaryl CoenzymeA HMG CoA reductase</g>, a key enzyme in the cholesterol synthesis pathway. Inhibition of biological precursors in this pathway also enables pleiotrophic immunomodulatory and anti-inflammatory capabilities, including modulation of growth factor expression. <g>Connective tissue growth factor</g> <g>CTGF</g> and persistent myofibroblast formation are major determinants of the aggressive <d>fibrotic disease</d>, <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. In this study we used human lung fibroblasts derived from healthy and <d>IPF</d> lungs to examine Simvastatin effects on <g>CTGF</g> gene and protein expression, analyzed by RT-PCR and ELISA, respectively. Simvastatin significantly inhibited P < 0.05 <g>CTGF</g> gene and protein expression, overriding the induction by <g>transforming growth factor-beta1</g>, a known potent inducer of <g>CTGF</g>. Such Simvastatin suppressor action on growth factor interaction was reflected functionally on recognized phenotypes of <d>fibrosis</d>. alpha-smooth muscle actin expression was downregulated and collagen gel contraction reduced by 4.94- and 7.58-fold in IMR90 and H<d>IPF</d> lung fibroblasts, respectively, when preconditioned with 10 microM Simvastatin compared with <g>transforming growth factor-beta1</g> treatment alone after 24 h. Our data suggest that Simvastatin can modify critical determinants of the profibrogenic machinery responsible for the aggressive clinical profile of <d>IPF</d>, and potentially prevents adverse lung parenchymal remodeling associated with persistent myofibroblast formation.
15681824|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a fibrotic disease of unknown etiology that results in significant morbidity and mortality. The pathogenesis of IPF is not completely understood. Because recent studies have implicated insulin-like growth factor-I IGF-I in the pathogenesis of fibrosis, we examined the expression and function of insulin-like growth factor binding proteins IGFBP-3 and -5 in IPF. IGFBP-3 and -5 levels were increased in vivo in IPF lung tissues and in vitro in fibroblasts cultured from IPF lung. The IGFBPs secreted by IPF fibroblasts are functionally active and can bind IGF-I, and IGFBPs secreted by primary fibroblasts bind extracellular matrix components. Our results also suggest that IGFBPs may be involved in the initiation and/or perpetuation of fibrosis by virtue of their ability to induce the production of extracellular matrix components such as collagen type I and fibronectin in normal primary adult lung fibroblasts. Although transforming growth factor-beta increased IGFBP-3 production by primary fibroblasts in a time-dependent manner, IGFBP-5 levels were not increased by transforming growth factor-beta. Taken together, our results suggest that IGFBPs play an important role in the development of fibrosis in IPF.
15681824|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fibrotic disease of unknown etiology that results in significant morbidity and mortality. The pathogenesis of <d>IPF</d> is not completely understood. Because recent studies have implicated insulin-like growth factor-I IGF-I in the pathogenesis of fibrosis, we examined the expression and function of insulin-like growth factor binding proteins IGFBP-3 and -5 in <d>IPF</d>. IGFBP-3 and -5 levels were increased in vivo in <d>IPF</d> lung tissues and in vitro in fibroblasts cultured from <d>IPF</d> lung. The IGFBPs secreted by <d>IPF</d> fibroblasts are functionally active and can bind IGF-I, and IGFBPs secreted by primary fibroblasts bind extracellular matrix components. Our results also suggest that IGFBPs may be involved in the initiation and/or perpetuation of fibrosis by virtue of their ability to induce the production of extracellular matrix components such as collagen type I and fibronectin in normal primary adult lung fibroblasts. Although transforming growth factor-beta increased IGFBP-3 production by primary fibroblasts in a time-dependent manner, IGFBP-5 levels were not increased by transforming growth factor-beta. Taken together, our results suggest that IGFBPs play an important role in the development of fibrosis in <d>IPF</d>.
15681824|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>fibrotic disease</d> of unknown etiology that results in significant morbidity and mortality. The pathogenesis of <d>IPF</d> is not completely understood. Because recent studies have implicated insulin-like growth factor-I IGF-I in the pathogenesis of fibrosis, we examined the expression and function of insulin-like growth factor binding proteins IGFBP-3 and -5 in <d>IPF</d>. IGFBP-3 and -5 levels were increased in vivo in <d>IPF</d> lung tissues and in vitro in fibroblasts cultured from <d>IPF</d> lung. The IGFBPs secreted by <d>IPF</d> fibroblasts are functionally active and can bind IGF-I, and IGFBPs secreted by primary fibroblasts bind extracellular matrix components. Our results also suggest that IGFBPs may be involved in the initiation and/or perpetuation of fibrosis by virtue of their ability to induce the production of extracellular matrix components such as collagen type I and fibronectin in normal primary adult lung fibroblasts. Although transforming growth factor-beta increased IGFBP-3 production by primary fibroblasts in a time-dependent manner, IGFBP-5 levels were not increased by transforming growth factor-beta. Taken together, our results suggest that IGFBPs play an important role in the development of fibrosis in <d>IPF</d>.
15681824|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>fibrotic disease</d> of unknown etiology that results in significant morbidity and mortality. The pathogenesis of <d>IPF</d> is not completely understood. Because recent studies have implicated <g>insulin-like growth factor-I</g> <g>IGF-I</g> in the pathogenesis of <d>fibrosis</d>, we examined the expression and function of insulin-like growth factor binding proteins IGFBP-3 and -5 in <d>IPF</d>. IGFBP-3 and -5 levels were increased in vivo in <d>IPF</d> lung tissues and in vitro in fibroblasts cultured from <d>IPF</d> lung. The IGFBPs secreted by <d>IPF</d> fibroblasts are functionally active and can bind <g>IGF-I</g>, and IGFBPs secreted by primary fibroblasts bind extracellular matrix components. Our results also suggest that IGFBPs may be involved in the initiation and/or perpetuation of <d>fibrosis</d> by virtue of their ability to induce the production of extracellular matrix components such as collagen type I and fibronectin in normal primary adult lung fibroblasts. Although transforming growth factor-beta increased IGFBP-3 production by primary fibroblasts in a time-dependent manner, IGFBP-5 levels were not increased by transforming growth factor-beta. Taken together, our results suggest that IGFBPs play an important role in the development of <d>fibrosis</d> in <d>IPF</d>.
15734789|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive, fibrotic lung disease of unknown etiology. A viral pathogenesis in IPF has been suggested since >95% of IPF patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine whether pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine gamma-herpesvirus 68 MHV68. Because IPF patients have a T helper type 2 Th2 pulmonary phenotype, we used IFN-gammaR-/-, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-gammaR-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in IPF, increased transforming growth factor-beta expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also present in chronically infected IFN-gammaR-/- mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial IPF. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus pulmonary infection in IFN-gammaR-/- mice causes progressive <d>pulmonary fibrosis</d> and many of the pathological features seen in IPF.
15734789|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, fibrotic lung disease of unknown etiology. A viral pathogenesis in <d>IPF</d> has been suggested since >95% of <d>IPF</d> patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine whether pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine gamma-herpesvirus 68 MHV68. Because <d>IPF</d> patients have a T helper type 2 Th2 pulmonary phenotype, we used IFN-gammaR-/-, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-gammaR-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in <d>IPF</d>, increased transforming growth factor-beta expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also present in chronically infected IFN-gammaR-/- mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial <d>IPF</d>. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus pulmonary infection in IFN-gammaR-/- mice causes progressive <d>pulmonary fibrosis</d> and many of the pathological features seen in <d>IPF</d>.
15734789|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, <d>fibrotic lung disease</d> of unknown etiology. A viral pathogenesis in <d>IPF</d> has been suggested since >95% of <d>IPF</d> patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine whether pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine gamma-herpesvirus 68 MHV68. Because <d>IPF</d> patients have a T helper type 2 Th2 pulmonary phenotype, we used IFN-gammaR-/-, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-gammaR-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in <d>IPF</d>, increased transforming growth factor-beta expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also present in chronically infected IFN-gammaR-/- mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial <d>IPF</d>. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus pulmonary infection in IFN-gammaR-/- mice causes progressive <d>pulmonary fibrosis</d> and many of the pathological features seen in <d>IPF</d>.
15734789|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, <d>fibrotic lung disease</d> of unknown etiology. A viral pathogenesis in <d>IPF</d> has been suggested since >95% of <d>IPF</d> patients have evidence of chronic <d>pulmonary infection</d> with one or more herpesviruses. To determine whether <d>pulmonary infection</d> with herpesvirus can cause lung fibrosis, we infected mice with the murine gamma-herpesvirus 68 MHV68. Because <d>IPF</d> patients have a T helper type 2 Th2 pulmonary phenotype, we used IFN-gammaR-/-, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-gammaR-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in <d>IPF</d>, increased transforming growth factor-beta expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also present in chronically infected IFN-gammaR-/- mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial <d>IPF</d>. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus <d>pulmonary infection</d> in IFN-gammaR-/- mice causes progressive <d>pulmonary fibrosis</d> and many of the pathological features seen in <d>IPF</d>.
15734789|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive, <d>fibrotic lung disease</d> of unknown etiology. A viral pathogenesis in <d>IPF</d> has been suggested since >95% of <d>IPF</d> patients have evidence of chronic <d>pulmonary infection</d> with one or more herpesviruses. To determine whether <d>pulmonary infection</d> with herpesvirus can cause lung <d>fibrosis</d>, we infected mice with the murine gamma-herpesvirus 68 MHV68. Because <d>IPF</d> patients have a T helper type 2 Th2 pulmonary phenotype, we used IFN-gammaR-/-, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-gammaR-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in <d>IPF</d>, increased transforming growth factor-beta expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also present in chronically infected IFN-gammaR-/- mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial <d>IPF</d>. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus <d>pulmonary infection</d> in IFN-gammaR-/- mice causes progressive <d>pulmonary <d>fibrosis</d></d> and many of the pathological features seen in <d>IPF</d>.
15734789|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive, <d>fibrotic lung disease</d> of unknown etiology. A viral pathogenesis in <d>IPF</d> has been suggested since >95% of <d>IPF</d> patients have evidence of chronic <d>pulmonary infection</d> with one or more herpesviruses. To determine whether <d>pulmonary infection</d> with herpesvirus can cause lung <d>fibrosis</d>, we infected mice with the murine gamma-herpesvirus 68 MHV68. Because <d>IPF</d> patients have a T helper type 2 Th2 pulmonary phenotype, we used <g>IFN-gammaR</g>-/-, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of <g>IFN-gammaR</g>-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in <d>IPF</d>, increased transforming growth factor-beta expression, myofibroblast transformation, production of Th2 cytokines, <d>hyperplasia</d> of type II cells, and increased expression of matrix metalloproteinase-7, were also present in chronically infected <g>IFN-gammaR</g>-/- mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial <d>IPF</d>. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus <d>pulmonary infection</d> in <g>IFN-gammaR</g>-/- mice causes progressive <d>pulmonary <d>fibrosis</d></d> and many of the pathological features seen in <d>IPF</d>.
15734789|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive, <d>fibrotic lung disease</d> of unknown etiology. A viral pathogenesis in <d>IPF</d> has been suggested since >95% of <d>IPF</d> patients have evidence of chronic <d>pulmonary infection</d> with one or more herpesviruses. To determine whether <d>pulmonary infection</d> with herpesvirus can cause lung <d>fibrosis</d>, we infected mice with the murine gamma-herpesvirus 68 MHV68. Because <d>IPF</d> patients have a T helper type 2 Th2 pulmonary phenotype, we used <g>IFN-gammaR</g>-/-, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of <g>IFN-gammaR</g>-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in <d>IPF</d>, increased transforming growth factor-beta expression, myofibroblast transformation, production of Th2 cytokines, <d>hyperplasia</d> of type II cells, and increased expression of <g>matrix metalloproteinase-7</g>, were also present in chronically infected <g>IFN-gammaR</g>-/- mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial <d>IPF</d>. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with <d>extensive alveolar remodeling</d>. In summary, chronic herpesvirus <d>pulmonary infection</d> in <g>IFN-gammaR</g>-/- mice causes progressive <d>pulmonary <d>fibrosis</d></d> and many of the pathological features seen in <d>IPF</d>.
15855634|a|The hallmark of <d>idiopathic pulmonary fibrosis</d> IPF is the myofibroblast, the cellular origin of which in the lung is unknown. We hypothesized that alveolar epithelial cells AECs may serve as a source of myofibroblasts through epithelial-mesenchymal transition EMT. Effects of chronic exposure to transforming growth factor TGF-beta1 on the phenotype of isolated rat AECs in primary culture and a rat type II cell line RLE-6TN were evaluated. Additionally, tissue samples from patients with IPF were evaluated for cells co-expressing epithelial thyroid transcription factor TTF-1 and pro-surfactant protein-B pro-SP-B, and mesenchymal alpha-smooth muscle actin alpha-SMA markers. RLE-6TN cells exposed to TGF-beta1 for 6 days demonstrated increased expression of mesenchymal cell markers and a fibroblast-like morphology, an effect augmented by tumor necrosis factor-alpha TNF-alpha. Exposure of rat AECs to TGF-beta1 100 pmol/L resulted in increased expression of alpha-SMA, type I collagen, vimentin, and desmin, with concurrent transition to a fibroblast-like morphology and decreased expression of TTF-1, aquaporin-5 AQP5, zonula occludens-1 ZO-1, and cytokeratins. Cells co-expressing epithelial markers and alpha-SMA were abundant in lung tissue from IPF patients. These results suggest that AECs undergo EMT when chronically exposed to TGF-beta1, raising the possibility that epithelial cells may serve as a novel source of myofibroblasts in IPF.
15855634|a|The hallmark of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> is the myofibroblast, the cellular origin of which in the lung is unknown. We hypothesized that alveolar epithelial cells AECs may serve as a source of myofibroblasts through epithelial-mesenchymal transition EMT. Effects of chronic exposure to transforming growth factor TGF-beta1 on the phenotype of isolated rat AECs in primary culture and a rat type II cell line RLE-6TN were evaluated. Additionally, tissue samples from patients with <d>IPF</d> were evaluated for cells co-expressing epithelial thyroid transcription factor TTF-1 and pro-surfactant protein-B pro-SP-B, and mesenchymal alpha-smooth muscle actin alpha-SMA markers. RLE-6TN cells exposed to TGF-beta1 for 6 days demonstrated increased expression of mesenchymal cell markers and a fibroblast-like morphology, an effect augmented by tumor necrosis factor-alpha TNF-alpha. Exposure of rat AECs to TGF-beta1 100 pmol/L resulted in increased expression of alpha-SMA, type I collagen, vimentin, and desmin, with concurrent transition to a fibroblast-like morphology and decreased expression of TTF-1, aquaporin-5 AQP5, zonula occludens-1 ZO-1, and cytokeratins. Cells co-expressing epithelial markers and alpha-SMA were abundant in lung tissue from <d>IPF</d> patients. These results suggest that AECs undergo EMT when chronically exposed to TGF-beta1, raising the possibility that epithelial cells may serve as a novel source of myofibroblasts in <d>IPF</d>.
15857893|a|Cell-cell signaling roles for reactive oxygen species ROS generated in response to growth factors/cytokines in nonphagocytic cells are not well defined. In this study, we show that fibroblasts isolated from lungs of patients with <d>idiopathic pulmonary fibrosis</d> IPF generate extracellular hydrogen peroxide H2O2 in response to the multifunctional cytokine, transforming growth factor-beta1 TGF-beta1. In contrast, TGF-beta1 stimulation of small airway epithelial cells SAECs does not result in detectable levels of extracellular H2O2. IPF fibroblasts independently stimulated with TGF-beta1 induce loss of viability and death of overlying SAECs when cocultured in a compartmentalized Transwell system. These effects on SAECs are inhibited by the addition of catalase to the coculture system or by the selective enzymatic blockade of H2O2 production by IPF fibroblasts. IPF fibroblasts heterogeneously express alpha-smooth muscle actin stress fibers, a marker of myofibroblast differentiation. Cellular localization of H2O2 by a fluorescent-labeling strategy demonstrated that extracellular secretion of H2O2 is specific to the myofibroblast phenotype. Thus, myofibroblast secretion of H2O2 functions as a diffusible death signal for lung epithelial cells. This novel mechanism for intercellular ROS signaling may be important in physiological/pathophysiological processes characterized by regenerating epithelial cells and activated myofibroblasts.
15857893|a|Cell-cell signaling roles for reactive oxygen species ROS generated in response to growth factors/cytokines in nonphagocytic cells are not well defined. In this study, we show that fibroblasts isolated from lungs of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> generate extracellular hydrogen peroxide H2O2 in response to the multifunctional cytokine, transforming growth factor-beta1 TGF-beta1. In contrast, TGF-beta1 stimulation of small airway epithelial cells SAECs does not result in detectable levels of extracellular H2O2. <d>IPF</d> fibroblasts independently stimulated with TGF-beta1 induce loss of viability and death of overlying SAECs when cocultured in a compartmentalized Transwell system. These effects on SAECs are inhibited by the addition of catalase to the coculture system or by the selective enzymatic blockade of H2O2 production by <d>IPF</d> fibroblasts. <d>IPF</d> fibroblasts heterogeneously express alpha-smooth muscle actin stress fibers, a marker of myofibroblast differentiation. Cellular localization of H2O2 by a fluorescent-labeling strategy demonstrated that extracellular secretion of H2O2 is specific to the myofibroblast phenotype. Thus, myofibroblast secretion of H2O2 functions as a diffusible death signal for lung epithelial cells. This novel mechanism for intercellular ROS signaling may be important in physiological/pathophysiological processes characterized by regenerating epithelial cells and activated myofibroblasts.
15946381|a|BACKGROUND: Fibroblastic foci are characteristic features in lung parenchyma of patients with <d>idiopathic pulmonary fibrosis</d> IPF. They comprise aggregates of mesenchymal cells which underlie sites of unresolved epithelial injury and are associated with progression of fibrosis. However, the cellular origins of these mesenchymal phenotypes remain unclear. We examined whether the potent fibrogenic cytokine <g>TGF-beta1</g> could induce epithelial mesenchymal transition EMT in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of <g>TGF-beta1</g>-mediated EMT. METHODS: A549 cells were examined for evidence of EMT after treatment with <g>TGF-beta1</g>. EMT was assessed by: morphology under phase-contrast microscopy; Western analysis of cell lysates for expression of mesenchymal phenotypic markers including fibronectin EDA Fn-EDA, and expression of epithelial phenotypic markers including E-cadherin E-cad. Markers of fibrogenesis, including collagens and connective tissue growth factor CTGF were also evaluated by measuring mRNA level using RT-PCR, and protein by immunofluorescence or Western blotting. Signaling pathways for EMT were characterized by Western analysis of cell lysates using monoclonal antibodies to detect phosphorylated Erk1/2 and Smad2 after <g>TGF-beta1</g> treatment in the presence or absence of MEK inhibitors. The role of Smad2 in <g>TGF-beta1</g>-mediated EMT was investigated using siRNA. RESULTS: The data showed that <g>TGF-beta1</g>, but not TNF-alpha or IL-1beta, induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner. The process of EMT was accompanied by morphological alteration and expression of the fibroblast phenotypic markers Fn-EDA and vimentin, concomitant with a downregulation of the epithelial phenotype marker E-cad. Furthermore, cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF. MMP-2 expression was also evidenced. <g>TGF-beta1</g>-induced EMT occurred through phosphorylation of Smad2 and was inhibited by Smad2 gene silencing; MEK inhibitors failed to attenuate either EMT-associated Smad2 phosphorylation or the observed phenotypic changes. CONCLUSION: Our study shows that <g>TGF-beta1</g> induces A549 alveolar epithelial cells to undergo EMT via Smad2 activation. Our data support the concept of EMT in lung epithelial cells, and suggest the need for further studies to investigate the phenomenon.
15946381|a|BACKGROUND: Fibroblastic foci are characteristic features in lung parenchyma of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. They comprise aggregates of mesenchymal cells which underlie sites of unresolved epithelial injury and are associated with progression of fibrosis. However, the cellular origins of these mesenchymal phenotypes remain unclear. We examined whether the potent fibrogenic cytokine <g>TGF-beta1</g> could induce epithelial mesenchymal transition EMT in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of <g>TGF-beta1</g>-mediated EMT. METHODS: A549 cells were examined for evidence of EMT after treatment with <g>TGF-beta1</g>. EMT was assessed by: morphology under phase-contrast microscopy; Western analysis of cell lysates for expression of mesenchymal phenotypic markers including fibronectin EDA Fn-EDA, and expression of epithelial phenotypic markers including E-cadherin E-cad. Markers of fibrogenesis, including collagens and connective tissue growth factor CTGF were also evaluated by measuring mRNA level using RT-PCR, and protein by immunofluorescence or Western blotting. Signaling pathways for EMT were characterized by Western analysis of cell lysates using monoclonal antibodies to detect phosphorylated Erk1/2 and Smad2 after <g>TGF-beta1</g> treatment in the presence or absence of MEK inhibitors. The role of Smad2 in <g>TGF-beta1</g>-mediated EMT was investigated using siRNA. RESULTS: The data showed that <g>TGF-beta1</g>, but not TNF-alpha or IL-1beta, induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner. The process of EMT was accompanied by morphological alteration and expression of the fibroblast phenotypic markers Fn-EDA and vimentin, concomitant with a downregulation of the epithelial phenotype marker E-cad. Furthermore, cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF. MMP-2 expression was also evidenced. <g>TGF-beta1</g>-induced EMT occurred through phosphorylation of Smad2 and was inhibited by Smad2 gene silencing; MEK inhibitors failed to attenuate either EMT-associated Smad2 phosphorylation or the observed phenotypic changes. CONCLUSION: Our study shows that <g>TGF-beta1</g> induces A549 alveolar epithelial cells to undergo EMT via Smad2 activation. Our data support the concept of EMT in lung epithelial cells, and suggest the need for further studies to investigate the phenomenon.
15946381|a|BACKGROUND: Fibroblastic foci are characteristic features in lung parenchyma of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. They comprise aggregates of mesenchymal cells which underlie sites of unresolved <d>epithelial injury</d> and are associated with progression of fibrosis. However, the cellular origins of these mesenchymal phenotypes remain unclear. We examined whether the potent fibrogenic cytokine <g>TGF-beta1</g> could induce epithelial mesenchymal transition EMT in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of <g>TGF-beta1</g>-mediated EMT. METHODS: A549 cells were examined for evidence of EMT after treatment with <g>TGF-beta1</g>. EMT was assessed by: morphology under phase-contrast microscopy; Western analysis of cell lysates for expression of mesenchymal phenotypic markers including fibronectin EDA Fn-EDA, and expression of epithelial phenotypic markers including E-cadherin E-cad. Markers of fibrogenesis, including collagens and connective tissue growth factor CTGF were also evaluated by measuring mRNA level using RT-PCR, and protein by immunofluorescence or Western blotting. Signaling pathways for EMT were characterized by Western analysis of cell lysates using monoclonal antibodies to detect phosphorylated Erk1/2 and Smad2 after <g>TGF-beta1</g> treatment in the presence or absence of MEK inhibitors. The role of Smad2 in <g>TGF-beta1</g>-mediated EMT was investigated using siRNA. RESULTS: The data showed that <g>TGF-beta1</g>, but not TNF-alpha or IL-1beta, induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner. The process of EMT was accompanied by morphological alteration and expression of the fibroblast phenotypic markers Fn-EDA and vimentin, concomitant with a downregulation of the epithelial phenotype marker E-cad. Furthermore, cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF. MMP-2 expression was also evidenced. <g>TGF-beta1</g>-induced EMT occurred through phosphorylation of Smad2 and was inhibited by Smad2 gene silencing; MEK inhibitors failed to attenuate either EMT-associated Smad2 phosphorylation or the observed phenotypic changes. CONCLUSION: Our study shows that <g>TGF-beta1</g> induces A549 alveolar epithelial cells to undergo EMT via Smad2 activation. Our data support the concept of EMT in lung epithelial cells, and suggest the need for further studies to investigate the phenomenon.
15946381|a|BACKGROUND: Fibroblastic foci are characteristic features in lung parenchyma of patients with <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. They comprise aggregates of mesenchymal cells which underlie sites of unresolved <d>epithelial injury</d> and are associated with progression of <d>fibrosis</d>. However, the cellular origins of these mesenchymal phenotypes remain unclear. We examined whether the potent fibrogenic cytokine <g>TGF-beta1</g> could induce epithelial mesenchymal transition EMT in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of <g>TGF-beta1</g>-mediated EMT. METHODS: A549 cells were examined for evidence of EMT after treatment with <g>TGF-beta1</g>. EMT was assessed by: morphology under phase-contrast microscopy; Western analysis of cell lysates for expression of mesenchymal phenotypic markers including fibronectin EDA Fn-EDA, and expression of epithelial phenotypic markers including E-cadherin E-cad. Markers of fibrogenesis, including collagens and connective tissue growth factor CTGF were also evaluated by measuring mRNA level using RT-PCR, and protein by immunofluorescence or Western blotting. Signaling pathways for EMT were characterized by Western analysis of cell lysates using monoclonal antibodies to detect phosphorylated Erk1/2 and Smad2 after <g>TGF-beta1</g> treatment in the presence or absence of MEK inhibitors. The role of Smad2 in <g>TGF-beta1</g>-mediated EMT was investigated using siRNA. RESULTS: The data showed that <g>TGF-beta1</g>, but not TNF-alpha or IL-1beta, induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner. The process of EMT was accompanied by morphological alteration and expression of the fibroblast phenotypic markers Fn-EDA and vimentin, concomitant with a downregulation of the epithelial phenotype marker E-cad. Furthermore, cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF. MMP-2 expression was also evidenced. <g>TGF-beta1</g>-induced EMT occurred through phosphorylation of Smad2 and was inhibited by Smad2 gene silencing; MEK inhibitors failed to attenuate either EMT-associated Smad2 phosphorylation or the observed phenotypic changes. CONCLUSION: Our study shows that <g>TGF-beta1</g> induces A549 alveolar epithelial cells to undergo EMT via Smad2 activation. Our data support the concept of EMT in lung epithelial cells, and suggest the need for further studies to investigate the phenomenon.
16179636|a|RATIONALE: Myofibroblasts are primary effector cells in <d>idiopathic pulmonary fibrosis</d> IPF. Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents. OBJECTIVE: To show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 <g>PTEN</g> activity in vivo, and to identify a potential mechanism by which this occurs. METHODS: We used tissue sections of surgical lung biopsies from patients with IPF to localize expression of <g>PTEN</g> and alpha-smooth muscle actin alpha-SMA. We used cell culture of pten-/- and wild-type fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which <g>PTEN</g> inhibits alpha-SMA, fibroblast proliferation, and collagen production. RESULTS: In human lung specimens of IPF, myofibroblasts within fibroblastic foci demonstrated diminished <g>PTEN</g> expression. Furthermore, inhibition of <g>PTEN</g> in mice worsened bleomycin-induced fibrosis. In pten-/- fibroblasts, and in normal fibroblasts in which <g>PTEN</g> was inhibited, alpha-SMA, proliferation, and collagen production was upregulated. Addition of transforming growth factor-beta to wild-type cells, but not pten-/- cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In pten-/- cells, reconstitution of <g>PTEN</g> decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of <g>PTEN</g> in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of <g>PTEN</g> were capable of modulating the myofibroblast phenotype. CONCLUSIONS: The results indicate that in IPF, myofibroblasts have diminished <g>PTEN</g> expression. Inhibition of <g>PTEN</g> in vivo promotes fibrosis, and <g>PTEN</g> inhibits myofibroblast differentiation in vitro.
16179636|a|RATIONALE: Myofibroblasts are primary effector cells in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents. OBJECTIVE: To show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 <g>PTEN</g> activity in vivo, and to identify a potential mechanism by which this occurs. METHODS: We used tissue sections of surgical lung biopsies from patients with <d>IPF</d> to localize expression of <g>PTEN</g> and alpha-smooth muscle actin alpha-SMA. We used cell culture of pten-/- and wild-type fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which <g>PTEN</g> inhibits alpha-SMA, fibroblast proliferation, and collagen production. RESULTS: In human lung specimens of <d>IPF</d>, myofibroblasts within fibroblastic foci demonstrated diminished <g>PTEN</g> expression. Furthermore, inhibition of <g>PTEN</g> in mice worsened bleomycin-induced fibrosis. In pten-/- fibroblasts, and in normal fibroblasts in which <g>PTEN</g> was inhibited, alpha-SMA, proliferation, and collagen production was upregulated. Addition of transforming growth factor-beta to wild-type cells, but not pten-/- cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In pten-/- cells, reconstitution of <g>PTEN</g> decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of <g>PTEN</g> in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of <g>PTEN</g> were capable of modulating the myofibroblast phenotype. CONCLUSIONS: The results indicate that in <d>IPF</d>, myofibroblasts have diminished <g>PTEN</g> expression. Inhibition of <g>PTEN</g> in vivo promotes fibrosis, and <g>PTEN</g> inhibits myofibroblast differentiation in vitro.
16179636|a|RATIONALE: Myofibroblasts are primary effector cells in <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents. OBJECTIVE: To show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 <g>PTEN</g> activity in vivo, and to identify a potential mechanism by which this occurs. METHODS: We used tissue sections of surgical lung biopsies from patients with <d>IPF</d> to localize expression of <g>PTEN</g> and alpha-smooth muscle actin alpha-SMA. We used cell culture of <g>pten</g>-/- and wild-type fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which <g>PTEN</g> inhibits alpha-SMA, fibroblast proliferation, and collagen production. RESULTS: In human lung specimens of <d>IPF</d>, myofibroblasts within fibroblastic foci demonstrated diminished <g>PTEN</g> expression. Furthermore, inhibition of <g>PTEN</g> in mice worsened bleomycin-induced <d>fibrosis</d>. In <g>pten</g>-/- fibroblasts, and in normal fibroblasts in which <g>PTEN</g> was inhibited, alpha-SMA, proliferation, and collagen production was upregulated. Addition of transforming growth factor-beta to wild-type cells, but not <g>pten</g>-/- cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In <g>pten</g>-/- cells, reconstitution of <g>PTEN</g> decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of <g>PTEN</g> in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of <g>PTEN</g> were capable of modulating the myofibroblast phenotype. CONCLUSIONS: The results indicate that in <d>IPF</d>, myofibroblasts have diminished <g>PTEN</g> expression. Inhibition of <g>PTEN</g> in vivo promotes <d>fibrosis</d>, and <g>PTEN</g> inhibits myofibroblast differentiation in vitro.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic pulmonary fibrosis</d> IPF, proliferation of fibroblasts and increased matrix deposition result in pulmonary damage and respiratory insufficiency. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with IPF histologically usual interstital pneumonitis, UIP in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and UIP fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, tumor necrosis factor alpha TNFalpha, Transforming growth factor-beta TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of UIP fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and TNFalpha. This expression is more pronounced in UIP fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by UIP fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFalpha, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and UIP lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, UIP fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with UIP.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, proliferation of fibroblasts and increased matrix deposition result in pulmonary damage and respiratory insufficiency. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with <d>IPF</d> histologically usual interstital pneumonitis, UIP in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and UIP fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, tumor necrosis factor alpha TNFalpha, Transforming growth factor-beta TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of UIP fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and TNFalpha. This expression is more pronounced in UIP fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by UIP fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFalpha, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and UIP lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, UIP fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with UIP.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, proliferation of fibroblasts and increased matrix deposition result in <d>pulmonary damage</d> and respiratory insufficiency. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with <d>IPF</d> histologically usual interstital pneumonitis, UIP in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and UIP fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, tumor necrosis factor alpha TNFalpha, Transforming growth factor-beta TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of UIP fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and TNFalpha. This expression is more pronounced in UIP fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by UIP fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFalpha, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and UIP lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, UIP fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with UIP.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, proliferation of fibroblasts and increased matrix deposition result in <d>pulmonary damage</d> and <d>respiratory insufficiency</d>. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with <d>IPF</d> histologically usual interstital pneumonitis, UIP in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and UIP fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, tumor necrosis factor alpha TNFalpha, Transforming growth factor-beta TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of UIP fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and TNFalpha. This expression is more pronounced in UIP fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by UIP fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFalpha, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and UIP lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, UIP fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with UIP.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, proliferation of fibroblasts and increased matrix deposition result in <d>pulmonary damage</d> and <d>respiratory insufficiency</d>. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with <d>IPF</d> histologically usual interstital <d>pneumonitis</d>, UIP in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and UIP fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, tumor necrosis factor alpha TNFalpha, Transforming growth factor-beta TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of UIP fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and TNFalpha. This expression is more pronounced in UIP fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by UIP fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFalpha, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and UIP lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, UIP fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with UIP.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, proliferation of fibroblasts and increased matrix deposition result in <d>pulmonary damage</d> and <d>respiratory insufficiency</d>. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with <d>IPF</d> histologically usual interstital <d>pneumonitis</d>, <d>UIP</d> in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and <d>UIP</d> fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, tumor necrosis factor alpha TNFalpha, Transforming growth factor-beta TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of <d>UIP</d> fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and TNFalpha. This expression is more pronounced in <d>UIP</d> fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by <d>UIP</d> fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFalpha, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and <d>UIP</d> lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, <d>UIP</d> fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with <d>UIP</d>.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, proliferation of fibroblasts and increased matrix deposition result in <d>pulmonary damage</d> and <d>respiratory insufficiency</d>. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with <d>IPF</d> histologically usual interstital <d>pneumonitis</d>, <d>UIP</d> in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and <d>UIP</d> fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, <d>tumor necrosis factor alpha</d> TNFalpha, Transforming growth factor-beta TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of <d>UIP</d> fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and TNFalpha. This expression is more pronounced in <d>UIP</d> fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by <d>UIP</d> fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFalpha, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and <d>UIP</d> lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, <d>UIP</d> fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with <d>UIP</d>.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, proliferation of fibroblasts and increased matrix deposition result in <d>pulmonary damage</d> and <d>respiratory insufficiency</d>. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with <d>IPF</d> histologically usual interstital <d>pneumonitis</d>, <d>UIP</d> in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and <d>UIP</d> fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, <d>tumor necrosis factor alpha</d> <d>TNFalpha</d>, Transforming growth factor-beta TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of <d>UIP</d> fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and <d>TNFalpha</d>. This expression is more pronounced in <d>UIP</d> fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by <d>UIP</d> fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, <d>TNFalpha</d>, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and <d>UIP</d> lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, <d>UIP</d> fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with <d>UIP</d>.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, proliferation of fibroblasts and increased matrix deposition result in <d>pulmonary damage</d> and <d>respiratory insufficiency</d>. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with <d>IPF</d> histologically usual interstital <d>pneumonitis</d>, <d>UIP</d> in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and <d>UIP</d> fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, <d>tumor necrosis factor alpha</d> <d>TNFalpha</d>, <d>Transforming growth factor-beta</d> TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of <d>UIP</d> fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and <d>TNFalpha</d>. This expression is more pronounced in <d>UIP</d> fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by <d>UIP</d> fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, <d>TNFalpha</d>, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and <d>UIP</d> lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, <d>UIP</d> fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with <d>UIP</d>.
16211459|a|OBJECTIVES AND METHODS: In <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, proliferation of fibroblasts and increased matrix deposition result in <d>pulmonary damage</d> and <d>respiratory insufficiency</d>. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with <d>IPF</d> histologically usual interstital <d>pneumonitis</d>, <d>UIP</d> in order to compare proliferation [3H]thymidine incorporation, cell count and matrix protein expression immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence of normal and <d>UIP</d> fibroblasts in response to various growth factors. FINDINGS: The growth factors platelet-derived growth factor-BB PDGF, epidermal growth factor EGF, insulin growth factor-1 IGF-1, insulin-like growth factor-2 IGF-2, <d>tumor necrosis factor alpha</d> <d>TNFalpha</d>, <d>Transforming growth factor-beta</d> TGFbeta1, and fibroblast growth factor-2 FGF-2 stimulate proliferation of normal lung fibroblasts significantly more than proliferation of <d>UIP</d> fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta1, and <d>TNFalpha</d>. This expression is more pronounced in <d>UIP</d> fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by <d>UIP</d> fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, <d>TNFalpha</d>, TGFbeta1, and FGF-2. CONCLUSIONS: Fibroblasts from normal and <d>UIP</d> lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, <d>UIP</d> fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive <d>pulmonary fibrosis</d> in patients with <d>UIP</d>.
16246848|a|<d>Idiopathic pulmonary fibrosis</d> IPF; a progressive lung disease is characterized by parenchymal remodeling with enlarged air spaces called honeycomb cysts and palisades of fibroblasts called fibroblast foci. In IPF, lung epithelial cells covering honeycomb cysts and fibroblast foci aberrantly express the active conformation of the potent fibrogenic cytokine <g>transforming growth factor-beta1</g> TGF-beta1. Using explanted rat lung slices, we transfected alveolar epithelial cells with the retrovirus pMX containing a site-directed mutation in which Cys223 and Cys225 were substituted with serines, resulting in release of biologically active TGF-beta1 and fibroblast proliferation and remodeling that resembled IPF. Fibroblasts obtained from transfected explants and in culture for 6 weeks incorporated 6.59 +/- 1.55-fold more [3H]thymidine compared with control fibroblasts without transfection or fibroblasts obtained from transfected explants cultured with antibody to <g>fibroblast growth factor-2</g> FGF-2. Primary lung fibroblasts obtained from normal rat lungs cultured with TGF-beta1 expressed increased levels of phosphorylated <g>p38</g> MAPK and JNK, but not ERK1/2. The presence of TGF-beta1 caused an immediate release of extracellular FGF-2 from primary pulmonary fibroblasts; and in the presence of anti-FGF-2 antibody, phosphorylated <g>p38</g> MAPK and JNK were abrogated. TGF-beta inhibits cell proliferation by suppression of c-Myc and induction of p15INK46, p21CIP1, or p27KIP. Fibroblasts cultured with TGF-beta1 showed no regulation of c-Myc or induction of p15INK46, p21CIP1,or p27KIP. These findings suggest that pulmonary fibroblasts may not respond to the anti-proliferative effects of TGF-beta1, but proliferate in response to TGF-beta1 indirectly by the release of FGF-2, which induces phosphorylation of <g>p38</g> MAPK and JNK.
16246848|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d>; a progressive lung disease is characterized by parenchymal remodeling with enlarged air spaces called honeycomb cysts and palisades of fibroblasts called fibroblast foci. In <d>IPF</d>, lung epithelial cells covering honeycomb cysts and fibroblast foci aberrantly express the active conformation of the potent fibrogenic cytokine <g>transforming growth factor-beta1</g> TGF-beta1. Using explanted rat lung slices, we transfected alveolar epithelial cells with the retrovirus pMX containing a site-directed mutation in which Cys223 and Cys225 were substituted with serines, resulting in release of biologically active TGF-beta1 and fibroblast proliferation and remodeling that resembled <d>IPF</d>. Fibroblasts obtained from transfected explants and in culture for 6 weeks incorporated 6.59 +/- 1.55-fold more [3H]thymidine compared with control fibroblasts without transfection or fibroblasts obtained from transfected explants cultured with antibody to <g>fibroblast growth factor-2</g> FGF-2. Primary lung fibroblasts obtained from normal rat lungs cultured with TGF-beta1 expressed increased levels of phosphorylated <g>p38</g> MAPK and JNK, but not ERK1/2. The presence of TGF-beta1 caused an immediate release of extracellular FGF-2 from primary pulmonary fibroblasts; and in the presence of anti-FGF-2 antibody, phosphorylated <g>p38</g> MAPK and JNK were abrogated. TGF-beta inhibits cell proliferation by suppression of c-Myc and induction of p15INK46, p21CIP1, or p27KIP. Fibroblasts cultured with TGF-beta1 showed no regulation of c-Myc or induction of p15INK46, p21CIP1,or p27KIP. These findings suggest that pulmonary fibroblasts may not respond to the anti-proliferative effects of TGF-beta1, but proliferate in response to TGF-beta1 indirectly by the release of FGF-2, which induces phosphorylation of <g>p38</g> MAPK and JNK.
16246848|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d>; a progressive <d>lung disease</d> is characterized by parenchymal remodeling with enlarged air spaces called honeycomb cysts and palisades of fibroblasts called fibroblast foci. In <d>IPF</d>, lung epithelial cells covering honeycomb cysts and fibroblast foci aberrantly express the active conformation of the potent fibrogenic cytokine <g>transforming growth factor-beta1</g> TGF-beta1. Using explanted rat lung slices, we transfected alveolar epithelial cells with the retrovirus pMX containing a site-directed mutation in which Cys223 and Cys225 were substituted with serines, resulting in release of biologically active TGF-beta1 and fibroblast proliferation and remodeling that resembled <d>IPF</d>. Fibroblasts obtained from transfected explants and in culture for 6 weeks incorporated 6.59 +/- 1.55-fold more [3H]thymidine compared with control fibroblasts without transfection or fibroblasts obtained from transfected explants cultured with antibody to <g>fibroblast growth factor-2</g> FGF-2. Primary lung fibroblasts obtained from normal rat lungs cultured with TGF-beta1 expressed increased levels of phosphorylated <g>p38</g> MAPK and JNK, but not ERK1/2. The presence of TGF-beta1 caused an immediate release of extracellular FGF-2 from primary pulmonary fibroblasts; and in the presence of anti-FGF-2 antibody, phosphorylated <g>p38</g> MAPK and JNK were abrogated. TGF-beta inhibits cell proliferation by suppression of c-Myc and induction of p15INK46, p21CIP1, or p27KIP. Fibroblasts cultured with TGF-beta1 showed no regulation of c-Myc or induction of p15INK46, p21CIP1,or p27KIP. These findings suggest that pulmonary fibroblasts may not respond to the anti-proliferative effects of TGF-beta1, but proliferate in response to TGF-beta1 indirectly by the release of FGF-2, which induces phosphorylation of <g>p38</g> MAPK and JNK.
16573560|a|We investigated 30 patients with <d>idiopathic pulmonary fibrosis</d> IPF and 103 healthy volunteers for the cytokines polymorphisms of the IL-1alpha, IL-1beta, IL-1R, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, tumor necrosis factor-alpha, interferon-gamma, transforming growth factor-beta, IL-1beta, IL-2, IL-4, and IL-4RA genes. The strongest correlation of a genotype with the disease was found for gene polymorphisms at the promotor region of IL-4, where the CT genotypes at the positions -590 and -33 were more frequent in the IPF group P < 0.0001, Pcorr < 0.0022; vs P < 0.0001, Pcorr < 0.0022. Our results support the idea of the pathogenic role of cytokine gene polymorphisms in the etiology and pathogenesis of IPF, with emphasize on the IL-4 promotor gene polymorphisms.
16573560|a|We investigated 30 patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and 103 healthy volunteers for the cytokines polymorphisms of the IL-1alpha, IL-1beta, IL-1R, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, tumor necrosis factor-alpha, interferon-gamma, transforming growth factor-beta, IL-1beta, IL-2, IL-4, and IL-4RA genes. The strongest correlation of a genotype with the disease was found for gene polymorphisms at the promotor region of IL-4, where the CT genotypes at the positions -590 and -33 were more frequent in the <d>IPF</d> group P < 0.0001, Pcorr < 0.0022; vs P < 0.0001, Pcorr < 0.0022. Our results support the idea of the pathogenic role of cytokine gene polymorphisms in the etiology and pathogenesis of <d>IPF</d>, with emphasize on the IL-4 promotor gene polymorphisms.
16574935|a|RATIONALE AND OBJECTIVES: Hepatocyte growth factor HGF protects against lung fibrosis in several animal models. Pro-HGF activation to HGF is subjected to regulation by its activator HGFA, a serine protease, and HGFA-specific inhibitors HAI-1 and HAI-2. Our hypothesis was that fibroblasts from patients with <d>idiopathic pulmonary fibrosis</d> IPF had an altered capacity to activate pro-HGF in vitro compared with control fibroblasts. METHODS: We measured the kinetics of pro-HGF activation in human lung fibroblasts from control subjects and from patients with IPF by Western blot. HGFA, HAI-1, and HAI-2 expression was evaluated by immunohistochemistry, RNA protection assay, and Western blot. We evaluated the effect of TGF-beta1 and PGE2 on pro-HGF activation and HGFA, HAI-1, and HAI-2 expression. MAIN RESULTS: Lung fibroblasts activated pro-HGF in vitro. Pro-HGF activation was inhibited by serine protease inhibitors, by an anti-HGFA antibody, as well as by HAI-1 and HAI-2. Pro-HGF activation by IPF fibroblasts was reduced compared with control fibroblasts. In IPF fibroblasts, HGFA expression was lower and HAI-1 and HAI-2 expression was higher compared with control fibroblasts. PGE2 stimulated pro-HGF activation through increased expression of HGFA and decreased expression of its inhibitor HAI-2. In contrast, TGF-beta1 reduced the ability of lung fibroblasts to activate pro-HGF through decreased expression of HGFA and increased expression of its inhibitors. CONCLUSIONS: IPF fibroblasts have a low capacity to activate pro-HGF in vitro via a low level of HGFA expression and high levels of HAI-1 and HAI-2 expression, and PGE2 is able to partially correct this defect.
16574935|a|RATIONALE AND OBJECTIVES: <g>Hepatocyte growth factor</g> <g>HGF</g> protects against <d>lung fibrosis</d> in several animal models. Pro-<g>HGF</g> activation to <g>HGF</g> is subjected to regulation by its activator <g>HGF</g>A, a serine protease, and <g>HGF</g>A-specific inhibitors HAI-1 and HAI-2. Our hypothesis was that fibroblasts from patients with <d>idiopathic pulmonary fibrosis</d> IPF had an altered capacity to activate pro-<g>HGF</g> in vitro compared with control fibroblasts. METHODS: We measured the kinetics of pro-<g>HGF</g> activation in human lung fibroblasts from control subjects and from patients with IPF by Western blot. <g>HGF</g>A, HAI-1, and HAI-2 expression was evaluated by immunohistochemistry, RNA protection assay, and Western blot. We evaluated the effect of TGF-beta1 and PGE2 on pro-<g>HGF</g> activation and <g>HGF</g>A, HAI-1, and HAI-2 expression. MAIN RESULTS: Lung fibroblasts activated pro-<g>HGF</g> in vitro. Pro-<g>HGF</g> activation was inhibited by serine protease inhibitors, by an anti-<g>HGF</g>A antibody, as well as by HAI-1 and HAI-2. Pro-<g>HGF</g> activation by IPF fibroblasts was reduced compared with control fibroblasts. In IPF fibroblasts, <g>HGF</g>A expression was lower and HAI-1 and HAI-2 expression was higher compared with control fibroblasts. PGE2 stimulated pro-<g>HGF</g> activation through increased expression of <g>HGF</g>A and decreased expression of its inhibitor HAI-2. In contrast, TGF-beta1 reduced the ability of lung fibroblasts to activate pro-<g>HGF</g> through decreased expression of <g>HGF</g>A and increased expression of its inhibitors. CONCLUSIONS: IPF fibroblasts have a low capacity to activate pro-<g>HGF</g> in vitro via a low level of <g>HGF</g>A expression and high levels of HAI-1 and HAI-2 expression, and PGE2 is able to partially correct this defect.
16574935|a|RATIONALE AND OBJECTIVES: <g>Hepatocyte growth factor</g> <g>HGF</g> protects against <d>lung fibrosis</d> in several animal models. Pro-<g>HGF</g> activation to <g>HGF</g> is subjected to regulation by its activator <g>HGF</g>A, a serine protease, and <g>HGF</g>A-specific inhibitors <g>HAI-1</g> and <g>HAI-2</g>. Our hypothesis was that fibroblasts from patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> had an altered capacity to activate pro-<g>HGF</g> in vitro compared with control fibroblasts. METHODS: We measured the kinetics of pro-<g>HGF</g> activation in human lung fibroblasts from control subjects and from patients with <d>IPF</d> by Western blot. <g>HGF</g>A, <g>HAI-1</g>, and <g>HAI-2</g> expression was evaluated by immunohistochemistry, RNA protection assay, and Western blot. We evaluated the effect of TGF-beta1 and PGE2 on pro-<g>HGF</g> activation and <g>HGF</g>A, <g>HAI-1</g>, and <g>HAI-2</g> expression. MAIN RESULTS: Lung fibroblasts activated pro-<g>HGF</g> in vitro. Pro-<g>HGF</g> activation was inhibited by serine protease inhibitors, by an anti-<g>HGF</g>A antibody, as well as by <g>HAI-1</g> and <g>HAI-2</g>. Pro-<g>HGF</g> activation by <d>IPF</d> fibroblasts was reduced compared with control fibroblasts. In <d>IPF</d> fibroblasts, <g>HGF</g>A expression was lower and <g>HAI-1</g> and <g>HAI-2</g> expression was higher compared with control fibroblasts. PGE2 stimulated pro-<g>HGF</g> activation through increased expression of <g>HGF</g>A and decreased expression of its inhibitor <g>HAI-2</g>. In contrast, TGF-beta1 reduced the ability of lung fibroblasts to activate pro-<g>HGF</g> through decreased expression of <g>HGF</g>A and increased expression of its inhibitors. CONCLUSIONS: <d>IPF</d> fibroblasts have a low capacity to activate pro-<g>HGF</g> in vitro via a low level of <g>HGF</g>A expression and high levels of <g>HAI-1</g> and <g>HAI-2</g> expression, and PGE2 is able to partially correct this defect.
16607487|a|The idiopathic <d>interstitial pneumonias</d>, especially the idiopathic pulmonary fibrosis IPF, are life-threatening lung disorders, for which no effective treatment option exists. In view of IPF, the American Thoracic Society ATS/European Respiratory Society ERS consensus statement recommends a combined therapy with corticosteroids and azathioprine or cyclophosphamide, although data from conclusive clinical trials are yet missing and the recurrent clinical experience is that these drugs do not really help in IPF. Up to now, lung transplantation represents the last and only therapeutic option for IPF subjects. Based on new pathophysiological concepts of IPF, there are meanwhile a couple of different agents under preclinical and clinical assessment, and the increasing number of clinical trials ongoing in IPF raise the hope that an effective treatment comes into reach. The agents investigated and their targets are: acetylcysteine reactive oxygen species [ROS] scavenging, interferon-gamma 1b modulation of Th1/Th2 balance, direct antifibrotic effects, pirfenidone and GC 1008 blockade of transforming growth factor-beta, FG 3019 blockade of connective tissue growth factor, imatinib mesylate blockade of platelet-derived growth factor, bosentan blockade of endothelin, zileutin blockade of leukotrienes, etanercept blockade of tumor necrosis factor-alpha, heparin alveolar anticoagulation. Hopefully, these new therapeutic strategies may help to improve prognosis of IPF in the future.
16607487|a|The idiopathic <d>interstitial pneumonias</d>, especially the <d>idiopathic pulmonary fibrosis</d> IPF, are life-threatening lung disorders, for which no effective treatment option exists. In view of IPF, the American Thoracic Society ATS/European Respiratory Society ERS consensus statement recommends a combined therapy with corticosteroids and azathioprine or cyclophosphamide, although data from conclusive clinical trials are yet missing and the recurrent clinical experience is that these drugs do not really help in IPF. Up to now, lung transplantation represents the last and only therapeutic option for IPF subjects. Based on new pathophysiological concepts of IPF, there are meanwhile a couple of different agents under preclinical and clinical assessment, and the increasing number of clinical trials ongoing in IPF raise the hope that an effective treatment comes into reach. The agents investigated and their targets are: acetylcysteine reactive oxygen species [ROS] scavenging, interferon-gamma 1b modulation of Th1/Th2 balance, direct antifibrotic effects, pirfenidone and GC 1008 blockade of transforming growth factor-beta, FG 3019 blockade of connective tissue growth factor, imatinib mesylate blockade of platelet-derived growth factor, bosentan blockade of endothelin, zileutin blockade of leukotrienes, etanercept blockade of tumor necrosis factor-alpha, heparin alveolar anticoagulation. Hopefully, these new therapeutic strategies may help to improve prognosis of IPF in the future.
16607487|a|The idiopathic <d>interstitial pneumonias</d>, especially the <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, are life-threatening lung disorders, for which no effective treatment option exists. In view of <d>IPF</d>, the American Thoracic Society ATS/European Respiratory Society ERS consensus statement recommends a combined therapy with corticosteroids and azathioprine or cyclophosphamide, although data from conclusive clinical trials are yet missing and the recurrent clinical experience is that these drugs do not really help in <d>IPF</d>. Up to now, lung transplantation represents the last and only therapeutic option for <d>IPF</d> subjects. Based on new pathophysiological concepts of <d>IPF</d>, there are meanwhile a couple of different agents under preclinical and clinical assessment, and the increasing number of clinical trials ongoing in <d>IPF</d> raise the hope that an effective treatment comes into reach. The agents investigated and their targets are: acetylcysteine reactive oxygen species [ROS] scavenging, interferon-gamma 1b modulation of Th1/Th2 balance, direct antifibrotic effects, pirfenidone and GC 1008 blockade of transforming growth factor-beta, FG 3019 blockade of connective tissue growth factor, imatinib mesylate blockade of platelet-derived growth factor, bosentan blockade of endothelin, zileutin blockade of leukotrienes, etanercept blockade of tumor necrosis factor-alpha, heparin alveolar anticoagulation. Hopefully, these new therapeutic strategies may help to improve prognosis of <d>IPF</d> in the future.
16607487|a|The idiopathic <d>interstitial pneumonias</d>, especially the <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, are life-threatening <d>lung disorders</d>, for which no effective treatment option exists. In view of <d>IPF</d>, the American Thoracic Society ATS/European Respiratory Society ERS consensus statement recommends a combined therapy with corticosteroids and azathioprine or cyclophosphamide, although data from conclusive clinical trials are yet missing and the recurrent clinical experience is that these drugs do not really help in <d>IPF</d>. Up to now, lung transplantation represents the last and only therapeutic option for <d>IPF</d> subjects. Based on new pathophysiological concepts of <d>IPF</d>, there are meanwhile a couple of different agents under preclinical and clinical assessment, and the increasing number of clinical trials ongoing in <d>IPF</d> raise the hope that an effective treatment comes into reach. The agents investigated and their targets are: acetylcysteine reactive oxygen species [ROS] scavenging, interferon-gamma 1b modulation of Th1/Th2 balance, direct antifibrotic effects, pirfenidone and GC 1008 blockade of transforming growth factor-beta, FG 3019 blockade of connective tissue growth factor, imatinib mesylate blockade of platelet-derived growth factor, bosentan blockade of endothelin, zileutin blockade of leukotrienes, etanercept blockade of tumor necrosis factor-alpha, heparin alveolar anticoagulation. Hopefully, these new therapeutic strategies may help to improve prognosis of <d>IPF</d> in the future.
16607487|a|The idiopathic <d>interstitial pneumonias</d>, especially the <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, are life-threatening <d>lung disorders</d>, for which no effective treatment option exists. In view of <d>IPF</d>, the American <d>Thoracic</d> Society ATS/European Respiratory Society ERS consensus statement recommends a combined therapy with corticosteroids and azathioprine or cyclophosphamide, although data from conclusive clinical trials are yet missing and the recurrent clinical experience is that these drugs do not really help in <d>IPF</d>. Up to now, lung transplantation represents the last and only therapeutic option for <d>IPF</d> subjects. Based on new pathophysiological concepts of <d>IPF</d>, there are meanwhile a couple of different agents under preclinical and clinical assessment, and the increasing number of clinical trials ongoing in <d>IPF</d> raise the hope that an effective treatment comes into reach. The agents investigated and their targets are: acetylcysteine reactive oxygen species [ROS] scavenging, interferon-gamma 1b modulation of Th1/Th2 balance, direct antifibrotic effects, pirfenidone and GC 1008 blockade of transforming growth factor-beta, FG 3019 blockade of connective tissue growth factor, imatinib mesylate blockade of platelet-derived growth factor, bosentan blockade of endothelin, zileutin blockade of leukotrienes, etanercept blockade of tumor necrosis factor-alpha, heparin alveolar anticoagulation. Hopefully, these new therapeutic strategies may help to improve prognosis of <d>IPF</d> in the future.
16607487|a|The idiopathic <d>interstitial pneumonias</d>, especially the <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, are life-threatening <d>lung disorders</d>, for which no effective treatment option exists. In view of <d>IPF</d>, the American <d>Thoracic</d> Society ATS/European Respiratory Society ERS consensus statement recommends a combined therapy with corticosteroids and azathioprine or cyclophosphamide, although data from conclusive clinical trials are yet missing and the recurrent clinical experience is that these drugs do not really help in <d>IPF</d>. Up to now, lung transplantation represents the last and only therapeutic option for <d>IPF</d> subjects. Based on new pathophysiological concepts of <d>IPF</d>, there are meanwhile a couple of different agents under preclinical and clinical assessment, and the increasing number of clinical trials ongoing in <d>IPF</d> raise the hope that an effective treatment comes into reach. The agents investigated and their targets are: acetylcysteine reactive oxygen species [ROS] scavenging, interferon-gamma 1b modulation of <g>Th1</g>/Th2 balance, direct antifibrotic effects, pirfenidone and GC 1008 blockade of transforming growth factor-beta, FG 3019 blockade of connective tissue growth factor, imatinib mesylate blockade of platelet-derived growth factor, bosentan blockade of endothelin, zileutin blockade of leukotrienes, etanercept blockade of <g>tumor necrosis factor-alpha</g>, heparin <d>alveolar anticoagulation</d>. Hopefully, these new therapeutic strategies may help to improve prognosis of <d>IPF</d> in the future.
16738206|a|The currently accepted approach to treatment of <d>idiopathic pulmonary fibrosis</d> IPF is based on the assumption that it is a chronic inflammatory disease, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in IPF aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of IPF has largely come from the use of animal disease models in rodents. Most data suggest, from among the different factors, a prominent role for the transforming growth factor TGF-beta1 and platelet-derived growth factor pathways. Inflammation is a critical element of the initiation of fibrosis and data indicate that the Smad pathway is a necessary link to fibrosis through TGF-beta and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.
16738206|a|The currently accepted approach to treatment of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> is based on the assumption that it is a chronic inflammatory disease, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in <d>IPF</d> aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of <d>IPF</d> has largely come from the use of animal disease models in rodents. Most data suggest, from among the different factors, a prominent role for the transforming growth factor TGF-beta1 and platelet-derived growth factor pathways. Inflammation is a critical element of the initiation of fibrosis and data indicate that the Smad pathway is a necessary link to fibrosis through TGF-beta and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.
16738206|a|The currently accepted approach to treatment of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> is based on the assumption that it is a chronic <d>inflammatory disease</d>, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in <d>IPF</d> aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of <d>IPF</d> has largely come from the use of animal disease models in rodents. Most data suggest, from among the different factors, a prominent role for the transforming growth factor TGF-beta1 and platelet-derived growth factor pathways. Inflammation is a critical element of the initiation of fibrosis and data indicate that the Smad pathway is a necessary link to fibrosis through TGF-beta and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.
16738206|a|The currently accepted approach to treatment of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> is based on the assumption that it is a chronic <d>inflammatory disease</d>, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in <d>IPF</d> aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of <d>IPF</d> has largely come from the use of <d>animal disease</d> models in rodents. Most data suggest, from among the different factors, a prominent role for the transforming growth factor TGF-beta1 and platelet-derived growth factor pathways. Inflammation is a critical element of the initiation of fibrosis and data indicate that the Smad pathway is a necessary link to fibrosis through TGF-beta and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.
16738206|a|The currently accepted approach to treatment of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> is based on the assumption that it is a chronic <d>inflammatory disease</d>, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in <d>IPF</d> aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of <d>IPF</d> has largely come from the use of <d>animal disease</d> models in rodents. Most data suggest, from among the different factors, a prominent role for the <g>transforming growth factor TGF-beta1</g> and platelet-derived growth factor pathways. <d>Inflammation</d> is a critical element of the initiation of fibrosis and data indicate that the Smad pathway is a necessary link to fibrosis through TGF-beta and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.
16738206|a|The currently accepted approach to treatment of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is based on the assumption that it is a chronic <d>inflammatory disease</d>, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in <d>IPF</d> aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of <d>IPF</d> has largely come from the use of <d>animal disease</d> models in rodents. Most data suggest, from among the different factors, a prominent role for the <g>transforming growth factor TGF-beta1</g> and platelet-derived growth factor pathways. <d>Inflammation</d> is a critical element of the initiation of <d>fibrosis</d> and data indicate that the Smad pathway is a necessary link to <d>fibrosis</d> through TGF-beta and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.
16776827|a|BACKGROUND: <d>Idiopathic Pulmonary Fibrosis</d> IPF is a debilitating disease characterized by exaggerated extracellular matrix deposition and aggressive lung structural remodeling. Disease pathogenesis is driven by fibroblastic foci formation, consequent on growth factor overexpression and myofibroblast proliferation. We have previously shown that both CTGF overexpression and myofibroblast formation in IPF cell lines are dependent on <g>RhoA</g> signaling. As <g>RhoA</g>-mediated regulation is also involved in cell cycle progression, we hypothesise that this pathway is key to lung fibroblast turnover through modulation of <g>cyclin D1</g> kinetic expression. METHODS: Cyclin D1 expression was compared in primary IPF patient-derived fibroblasts and equivalent normal control cells. Quantitative real time PCR was employed to examine relative expression levels of <g>cyclin D1</g> mRNA; protein expression was confirmed by western blotting. Effects of Rho signaling were investigated using transient transfection of constitutively active and dominant negative <g>RhoA</g> constructs as well as pharmacological inhibitors. Cellular proliferation of lung fibroblasts was determined by BrdU incorporation ELISA. To further explore <g>RhoA</g> regulation of <g>cyclin D1</g> in lung fibroblasts and associated cell cycle progression, an established Rho inhibitor, Simvastatin, was incorporated in our studies. RESULTS: Cyclin D1 expression was upregulated in IPF compared to normal lung fibroblasts under exponential growth conditions p < 0.05. Serum deprivation inhibited <g>cyclin D1</g> expression, which was restored following treatment with fibrogenic growth factors TGF-beta1 and CTGF. <g>RhoA</g> inhibition, using a dominant negative mutant and a pharmacological inhibitor C3 exotoxin, suppressed levels of <g>cyclin D1</g> mRNA and protein in IPF fibroblasts, with significant abrogation of cell turnover p < 0.05. Furthermore, Simvastatin dose-dependently inhibited fibroblast <g>cyclin D1</g> gene and protein expression, inducing G1 cell cycle arrest. Similar trends were observed in control experiments using normal lung fibroblasts, though exhibited responses were lower in magnitude. CONCLUSION: These findings report for the first time that <g>cyclin D1</g> expression is deregulated in IPF through a <g>RhoA</g> dependent mechanism that influences lung fibroblast proliferation. This potentially unravels new molecular targets for future anti-IPF strategies; accordingly, Simvastatin inhibition of Rho-mediated <g>cyclin D1</g> expression in IPF fibroblasts merits further exploitation.
16776827|a|BACKGROUND: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a debilitating disease characterized by exaggerated extracellular matrix deposition and aggressive lung structural remodeling. Disease pathogenesis is driven by fibroblastic foci formation, consequent on growth factor overexpression and myofibroblast proliferation. We have previously shown that both CTGF overexpression and myofibroblast formation in <d>IPF</d> cell lines are dependent on <g>RhoA</g> signaling. As <g>RhoA</g>-mediated regulation is also involved in cell cycle progression, we hypothesise that this pathway is key to lung fibroblast turnover through modulation of <g>cyclin D1</g> kinetic expression. METHODS: Cyclin D1 expression was compared in primary <d>IPF</d> patient-derived fibroblasts and equivalent normal control cells. Quantitative real time PCR was employed to examine relative expression levels of <g>cyclin D1</g> mRNA; protein expression was confirmed by western blotting. Effects of Rho signaling were investigated using transient transfection of constitutively active and dominant negative <g>RhoA</g> constructs as well as pharmacological inhibitors. Cellular proliferation of lung fibroblasts was determined by BrdU incorporation ELISA. To further explore <g>RhoA</g> regulation of <g>cyclin D1</g> in lung fibroblasts and associated cell cycle progression, an established Rho inhibitor, Simvastatin, was incorporated in our studies. RESULTS: Cyclin D1 expression was upregulated in <d>IPF</d> compared to normal lung fibroblasts under exponential growth conditions p < 0.05. Serum deprivation inhibited <g>cyclin D1</g> expression, which was restored following treatment with fibrogenic growth factors TGF-beta1 and CTGF. <g>RhoA</g> inhibition, using a dominant negative mutant and a pharmacological inhibitor C3 exotoxin, suppressed levels of <g>cyclin D1</g> mRNA and protein in <d>IPF</d> fibroblasts, with significant abrogation of cell turnover p < 0.05. Furthermore, Simvastatin dose-dependently inhibited fibroblast <g>cyclin D1</g> gene and protein expression, inducing G1 cell cycle arrest. Similar trends were observed in control experiments using normal lung fibroblasts, though exhibited responses were lower in magnitude. CONCLUSION: These findings report for the first time that <g>cyclin D1</g> expression is deregulated in <d>IPF</d> through a <g>RhoA</g> dependent mechanism that influences lung fibroblast proliferation. This potentially unravels new molecular targets for future anti-<d>IPF</d> strategies; accordingly, Simvastatin inhibition of Rho-mediated <g>cyclin D1</g> expression in <d>IPF</d> fibroblasts merits further exploitation.
16776827|a|BACKGROUND: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a debilitating disease characterized by exaggerated extracellular matrix deposition and <d>aggressive lung structural remodeling</d>. Disease pathogenesis is driven by fibroblastic foci formation, consequent on growth factor overexpression and myofibroblast proliferation. We have previously shown that both CTGF overexpression and myofibroblast formation in <d>IPF</d> cell lines are dependent on <g>RhoA</g> signaling. As <g>RhoA</g>-mediated regulation is also involved in cell cycle progression, we hypothesise that this pathway is key to lung fibroblast turnover through modulation of <g>cyclin D1</g> kinetic expression. METHODS: Cyclin D1 expression was compared in primary <d>IPF</d> patient-derived fibroblasts and equivalent normal control cells. Quantitative real time PCR was employed to examine relative expression levels of <g>cyclin D1</g> mRNA; protein expression was confirmed by western blotting. Effects of Rho signaling were investigated using transient transfection of constitutively active and dominant negative <g>RhoA</g> constructs as well as pharmacological inhibitors. Cellular proliferation of lung fibroblasts was determined by BrdU incorporation ELISA. To further explore <g>RhoA</g> regulation of <g>cyclin D1</g> in lung fibroblasts and associated cell cycle progression, an established Rho inhibitor, Simvastatin, was incorporated in our studies. RESULTS: Cyclin D1 expression was upregulated in <d>IPF</d> compared to normal lung fibroblasts under exponential growth conditions p < 0.05. Serum deprivation inhibited <g>cyclin D1</g> expression, which was restored following treatment with fibrogenic growth factors TGF-beta1 and CTGF. <g>RhoA</g> inhibition, using a dominant negative mutant and a pharmacological inhibitor C3 exotoxin, suppressed levels of <g>cyclin D1</g> mRNA and protein in <d>IPF</d> fibroblasts, with significant abrogation of cell turnover p < 0.05. Furthermore, Simvastatin dose-dependently inhibited fibroblast <g>cyclin D1</g> gene and protein expression, inducing G1 cell cycle arrest. Similar trends were observed in control experiments using normal lung fibroblasts, though exhibited responses were lower in magnitude. CONCLUSION: These findings report for the first time that <g>cyclin D1</g> expression is deregulated in <d>IPF</d> through a <g>RhoA</g> dependent mechanism that influences lung fibroblast proliferation. This potentially unravels new molecular targets for future anti-<d>IPF</d> strategies; accordingly, Simvastatin inhibition of Rho-mediated <g>cyclin D1</g> expression in <d>IPF</d> fibroblasts merits further exploitation.
16787145|a|<d>Idiopathic pulmonary fibrosis</d> IPF is an under-recognised, rare, progressive disease of the lungs with unknown aetiology and high mortality. The currently advocated pathogenic mechanism is represented by progressive multifocal fibrosis. It is diagnosed based on clinical, radiographic, physiological and histopathological criteria. Existing therapeutic guidelines recommend anti-inflammatory and immunosuppressive combinations, despite proven limited efficacy. There is no therapy approved specifically for IPF, but several antifibrotic agents are currently under development for this indication. Pirfenidone is an antifibrotic agent potentially effective for IPF therapy, and preclinical and available clinical data support its use in IPF. Future clinical studies are expected to provide more consistent information on survival benefit, lung function and health-related quality of life.
16787145|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is an under-recognised, rare, progressive disease of the lungs with unknown aetiology and high mortality. The currently advocated pathogenic mechanism is represented by progressive multifocal fibrosis. It is diagnosed based on clinical, radiographic, physiological and histopathological criteria. Existing therapeutic guidelines recommend anti-inflammatory and immunosuppressive combinations, despite proven limited efficacy. There is no therapy approved specifically for <d>IPF</d>, but several antifibrotic agents are currently under development for this indication. Pirfenidone is an antifibrotic agent potentially effective for <d>IPF</d> therapy, and preclinical and available clinical data support its use in <d>IPF</d>. Future clinical studies are expected to provide more consistent information on survival benefit, lung function and health-related quality of life.
16787145|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is an under-recognised, rare, progressive disease of the lungs with unknown aetiology and high mortality. The currently advocated pathogenic mechanism is represented by progressive multifocal <d>fibrosis</d>. It is diagnosed based on clinical, radiographic, physiological and histopathological criteria. Existing therapeutic guidelines recommend anti-inflammatory and immunosuppressive combinations, despite proven limited efficacy. There is no therapy approved specifically for <d>IPF</d>, but several antifibrotic agents are currently under development for this indication. Pirfenidone is an antifibrotic agent potentially effective for <d>IPF</d> therapy, and preclinical and available clinical data support its use in <d>IPF</d>. Future clinical studies are expected to provide more consistent information on survival benefit, lung function and health-related quality of life.
16816361|a|<d>Idiopathic pulmonary fibrosis</d> IPF, ie, usual interstitial pneumonia in histopathology, is a disease characterized by tissue destruction and active areas of fibroproliferation in the lung. Gremlin Drm, a member of the cysteine knot family of bone morphogenetic protein BMP inhibitors, functions to antagonize BMP-4-mediated signals during lung development. We describe here consistent overexpression of <g>gremlin</g> in the lung interstitium of IPF patients. Quantitative real-time reverse transcriptase-polymerase chain reaction analyses revealed considerably higher levels of <g>gremlin</g> mRNA in lung biopsies from IPF patients, the highest level being 35-fold higher compared to controls. Lung fibroblasts isolated from IPF patients also expressed elevated levels of <g>gremlin</g>, which was associated with impaired responsiveness to endogenous and exogenous BMP-4. Transforming growth factor-beta-induced epithelial-to-mesenchymal transition of A549 lung epithelial cells in culture was also associated with induction of <g>gremlin</g> mRNA expression. In addition, A549 cells transfected to overexpress <g>gremlin</g> were more susceptible to transforming growth factor-beta-induced epithelial-to-mesenchymal transition. Gremlin-mediated inhibition of BMP-4 signaling pathways is likely to enhance the fibrotic response and reduce epithelial regeneration in the lung. The overexpression of this developmental gene in IPF may be a key event in the persistence of myofibroblasts in the lung interstitium and provides a potential target for therapeutic intervention.
16816361|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d>, ie, usual interstitial pneumonia in histopathology, is a disease characterized by tissue destruction and active areas of fibroproliferation in the lung. Gremlin Drm, a member of the cysteine knot family of bone morphogenetic protein BMP inhibitors, functions to antagonize BMP-4-mediated signals during lung development. We describe here consistent overexpression of <g>gremlin</g> in the lung interstitium of <d>IPF</d> patients. Quantitative real-time reverse transcriptase-polymerase chain reaction analyses revealed considerably higher levels of <g>gremlin</g> mRNA in lung biopsies from <d>IPF</d> patients, the highest level being 35-fold higher compared to controls. Lung fibroblasts isolated from <d>IPF</d> patients also expressed elevated levels of <g>gremlin</g>, which was associated with impaired responsiveness to endogenous and exogenous BMP-4. Transforming growth factor-beta-induced epithelial-to-mesenchymal transition of A549 lung epithelial cells in culture was also associated with induction of <g>gremlin</g> mRNA expression. In addition, A549 cells transfected to overexpress <g>gremlin</g> were more susceptible to transforming growth factor-beta-induced epithelial-to-mesenchymal transition. Gremlin-mediated inhibition of BMP-4 signaling pathways is likely to enhance the fibrotic response and reduce epithelial regeneration in the lung. The overexpression of this developmental gene in <d>IPF</d> may be a key event in the persistence of myofibroblasts in the lung interstitium and provides a potential target for therapeutic intervention.
16816361|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d>, ie, <d>usual interstitial pneumonia</d> in histopathology, is a disease characterized by tissue destruction and active areas of fibroproliferation in the lung. Gremlin Drm, a member of the cysteine knot family of bone morphogenetic protein BMP inhibitors, functions to antagonize BMP-4-mediated signals during lung development. We describe here consistent overexpression of <g>gremlin</g> in the lung interstitium of <d>IPF</d> patients. Quantitative real-time reverse transcriptase-polymerase chain reaction analyses revealed considerably higher levels of <g>gremlin</g> mRNA in lung biopsies from <d>IPF</d> patients, the highest level being 35-fold higher compared to controls. Lung fibroblasts isolated from <d>IPF</d> patients also expressed elevated levels of <g>gremlin</g>, which was associated with impaired responsiveness to endogenous and exogenous BMP-4. Transforming growth factor-beta-induced epithelial-to-mesenchymal transition of A549 lung epithelial cells in culture was also associated with induction of <g>gremlin</g> mRNA expression. In addition, A549 cells transfected to overexpress <g>gremlin</g> were more susceptible to transforming growth factor-beta-induced epithelial-to-mesenchymal transition. Gremlin-mediated inhibition of BMP-4 signaling pathways is likely to enhance the fibrotic response and reduce epithelial regeneration in the lung. The overexpression of this developmental gene in <d>IPF</d> may be a key event in the persistence of myofibroblasts in the lung interstitium and provides a potential target for therapeutic intervention.
16837501|a|Thalidomide exhibits diverse actions of anti-inflammation, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in sarcoidosis with lupus pernio is thought to be due to inhibition of tumour necrosis factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, interleukin IL-1beta, IL-6, <g>IL-8</g>, IL-10, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with sarcoidosis n = 8, hypersensitivity pneumonitis HP; n = 8 and idiopathic pulmonary fibrosis IPF; n = 12. In sarcoidosis and HP patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In IPF patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in sarcoidosis and HP patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for sarcoidosis, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis by reducing tumour necrosis factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16837501|a|Thalidomide exhibits diverse actions of anti-<d>inflammation</d>, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in sarcoidosis with lupus pernio is thought to be due to inhibition of tumour necrosis factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, interleukin IL-1beta, IL-6, <g>IL-8</g>, IL-10, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with sarcoidosis n = 8, hypersensitivity pneumonitis HP; n = 8 and idiopathic pulmonary fibrosis IPF; n = 12. In sarcoidosis and HP patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In IPF patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in sarcoidosis and HP patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for sarcoidosis, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis by reducing tumour necrosis factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16837501|a|Thalidomide exhibits diverse actions of anti-<d>inflammation</d>, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in <d>sarcoidosis</d> with lupus pernio is thought to be due to inhibition of tumour necrosis factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, interleukin IL-1beta, IL-6, <g>IL-8</g>, IL-10, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with <d>sarcoidosis</d> n = 8, hypersensitivity pneumonitis HP; n = 8 and idiopathic pulmonary fibrosis IPF; n = 12. In <d>sarcoidosis</d> and HP patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In IPF patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in <d>sarcoidosis</d> and HP patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for <d>sarcoidosis</d>, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis by reducing tumour necrosis factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16837501|a|Thalidomide exhibits diverse actions of anti-<d>inflammation</d>, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in <d>sarcoidosis</d> with <d>lupus pernio</d> is thought to be due to inhibition of tumour necrosis factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, interleukin IL-1beta, IL-6, <g>IL-8</g>, IL-10, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with <d>sarcoidosis</d> n = 8, hypersensitivity pneumonitis HP; n = 8 and idiopathic pulmonary fibrosis IPF; n = 12. In <d>sarcoidosis</d> and HP patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In IPF patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in <d>sarcoidosis</d> and HP patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for <d>sarcoidosis</d>, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis by reducing tumour necrosis factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16837501|a|Thalidomide exhibits diverse actions of anti-<d>inflammation</d>, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in <d>sarcoidosis</d> with <d>lupus pernio</d> is thought to be due to inhibition of <d>tumour</d> necrosis factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, interleukin IL-1beta, IL-6, <g>IL-8</g>, IL-10, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with <d>sarcoidosis</d> n = 8, hypersensitivity pneumonitis HP; n = 8 and idiopathic pulmonary fibrosis IPF; n = 12. In <d>sarcoidosis</d> and HP patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In IPF patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in <d>sarcoidosis</d> and HP patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for <d>sarcoidosis</d>, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis by reducing <d>tumour</d> necrosis factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16837501|a|Thalidomide exhibits diverse actions of anti-<d>inflammation</d>, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in <d>sarcoidosis</d> with <d>lupus pernio</d> is thought to be due to inhibition of <d>tumour</d> <d>necrosis</d> factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, interleukin IL-1beta, IL-6, <g>IL-8</g>, IL-10, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with <d>sarcoidosis</d> n = 8, hypersensitivity pneumonitis HP; n = 8 and idiopathic pulmonary fibrosis IPF; n = 12. In <d>sarcoidosis</d> and HP patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In IPF patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in <d>sarcoidosis</d> and HP patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for <d>sarcoidosis</d>, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis by reducing <d>tumour</d> <d>necrosis</d> factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16837501|a|Thalidomide exhibits diverse actions of anti-<d>inflammation</d>, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in <d>sarcoidosis</d> with <d>lupus pernio</d> is thought to be due to inhibition of <d>tumour</d> <d>necrosis</d> factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, <g>interleukin IL-1beta</g>, <g>IL-6</g>, <g>IL-8</g>, <g>IL-10</g>, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with <d>sarcoidosis</d> n = 8, <d>hypersensitivity pneumonitis</d> HP; n = 8 and idiopathic pulmonary fibrosis IPF; n = 12. In <d>sarcoidosis</d> and HP patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In IPF patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in <d>sarcoidosis</d> and HP patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for <d>sarcoidosis</d>, <d>hypersensitivity pneumonitis</d> and idiopathic pulmonary fibrosis by reducing <d>tumour</d> <d>necrosis</d> factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16837501|a|Thalidomide exhibits diverse actions of anti-<d>inflammation</d>, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in <d>sarcoidosis</d> with <d>lupus pernio</d> is thought to be due to inhibition of <d>tumour</d> <d>necrosis</d> factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, <g>interleukin IL-1beta</g>, <g>IL-6</g>, <g>IL-8</g>, <g>IL-10</g>, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with <d>sarcoidosis</d> n = 8, <d>hypersensitivity pneumonitis</d> <d>HP</d>; n = 8 and idiopathic pulmonary fibrosis IPF; n = 12. In <d>sarcoidosis</d> and <d>HP</d> patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In IPF patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in <d>sarcoidosis</d> and <d>HP</d> patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for <d>sarcoidosis</d>, <d>hypersensitivity pneumonitis</d> and idiopathic pulmonary fibrosis by reducing <d>tumour</d> <d>necrosis</d> factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16837501|a|Thalidomide exhibits diverse actions of anti-<d>inflammation</d>, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in <d>sarcoidosis</d> with <d>lupus pernio</d> is thought to be due to inhibition of <d>tumour</d> <d>necrosis</d> factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, <g>interleukin IL-1beta</g>, <g>IL-6</g>, <g>IL-8</g>, <g>IL-10</g>, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with <d>sarcoidosis</d> n = 8, <d>hypersensitivity pneumonitis</d> <d>HP</d>; n = 8 and <d>idiopathic pulmonary fibrosis</d> IPF; n = 12. In <d>sarcoidosis</d> and <d>HP</d> patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In IPF patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in <d>sarcoidosis</d> and <d>HP</d> patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for <d>sarcoidosis</d>, <d>hypersensitivity pneumonitis</d> and <d>idiopathic pulmonary fibrosis</d> by reducing <d>tumour</d> <d>necrosis</d> factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16837501|a|Thalidomide exhibits diverse actions of anti-<d>inflammation</d>, immunomodulation and anti-angiogenesis. The efficacy of thalidomide treatment in <d>sarcoidosis</d> with <d>lupus pernio</d> is thought to be due to inhibition of <d>tumour</d> <d>necrosis</d> factor <g>TNF-alpha</g>. The mechanisms that underlie the properties of thalidomide are still unclear in <d>interstitial lung disease</d>. The current authors investigated the potential inhibitory effects of thalidomide at concentrations of 0.1, 0.01 and 0.001 mM on the production of transforming growth factor-beta, <g>TNF-alpha</g>, <g>interleukin IL-1beta</g>, <g>IL-6</g>, <g>IL-8</g>, <g>IL-10</g>, IL-12p70, IL-12p40 and <g>IL-18</g> by alveolar macrophages from bronchoalveolar lavage in patients with <d>sarcoidosis</d> n = 8, <d>hypersensitivity pneumonitis</d> <d>HP</d>; n = 8 and <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>; n = 12. In <d>sarcoidosis</d> and <d>HP</d> patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride LPS-stimulated <g>TNF-alpha</g>, IL-12p40 and <g>IL-18</g> release. At the highest thalidomide concentration 0.1 mM, LPS-stimulated <g>IL-8</g> production was also suppressed. In <d>IPF</d> patients, although spontaneous production of <g>TNF-alpha</g>, IL-12p40, <g>IL-18</g> and <g>IL-8</g> was lower than in <d>sarcoidosis</d> and <d>HP</d> patients, with LPS stimulation the cytokines were significantly elevated and also partially inhibited by thalidomide. In conclusion, thalidomide has the potential to improve the therapeutic regimens for <d>sarcoidosis</d>, <d>hypersensitivity pneumonitis</d> and <d>idiopathic pulmonary fibrosis</d> by reducing <d>tumour</d> <d>necrosis</d> factor-alpha, interleukin-12p40, interleukin-18 and interleukin-8 production.
16842247|a|AIMS: Recent studies suggest the importance of oxidant stress in the progression of pulmonary fibrosis. The aim of this study was to investigate extracellular superoxide dismutase ECSOD, the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven <d>idiopathic pulmonary fibrosis</d> IPF related to usual interstitial pneumonia UIP. METHODS AND RESULTS: Fibrotic areas and fibroblastic foci in UIP lungs were notable for absence of ECSOD by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of ECSOD in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense ECSOD positivity in UIP was the interstitial mast cell. In order to investigate the mechanism for ECSOD depletion in fibrotic areas, alveolar epithelial cells were exposed to tumour necrosis factor-alpha and transforming growth factor TGF-beta1; TGF-beta suggested a trend towards decreased synthesis. Patients with UIP were also assessed to determine whether this disease is associated with a naturally occurring mutation in ECSOD Arg213Gly which leads to a loss of tissue binding of ECSOD. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 UIP patients and 61 control subjects. CONCLUSION: Overall, consistent with several other antioxidant enzymes, ECSOD is very low in fibrotic areas of UIP, which may further increase the oxidant burden in this disease.
16842247|a|AIMS: Recent studies suggest the importance of oxidant stress in the progression of pulmonary fibrosis. The aim of this study was to investigate extracellular superoxide dismutase ECSOD, the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven <d>idiopathic pulmonary fibrosis</d> IPF related to <d>usual interstitial pneumonia</d> UIP. METHODS AND RESULTS: Fibrotic areas and fibroblastic foci in UIP lungs were notable for absence of ECSOD by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of ECSOD in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense ECSOD positivity in UIP was the interstitial mast cell. In order to investigate the mechanism for ECSOD depletion in fibrotic areas, alveolar epithelial cells were exposed to tumour necrosis factor-alpha and transforming growth factor TGF-beta1; TGF-beta suggested a trend towards decreased synthesis. Patients with UIP were also assessed to determine whether this disease is associated with a naturally occurring mutation in ECSOD Arg213Gly which leads to a loss of tissue binding of ECSOD. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 UIP patients and 61 control subjects. CONCLUSION: Overall, consistent with several other antioxidant enzymes, ECSOD is very low in fibrotic areas of UIP, which may further increase the oxidant burden in this disease.
16842247|a|AIMS: Recent studies suggest the importance of oxidant stress in the progression of <d>pulmonary fibrosis</d>. The aim of this study was to investigate extracellular superoxide dismutase ECSOD, the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven <d>idiopathic <d>pulmonary fibrosis</d></d> IPF related to <d>usual interstitial pneumonia</d> UIP. METHODS AND RESULTS: Fibrotic areas and fibroblastic foci in UIP lungs were notable for absence of ECSOD by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of ECSOD in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense ECSOD positivity in UIP was the interstitial mast cell. In order to investigate the mechanism for ECSOD depletion in fibrotic areas, alveolar epithelial cells were exposed to tumour necrosis factor-alpha and transforming growth factor TGF-beta1; TGF-beta suggested a trend towards decreased synthesis. Patients with UIP were also assessed to determine whether this disease is associated with a naturally occurring mutation in ECSOD Arg213Gly which leads to a loss of tissue binding of ECSOD. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 UIP patients and 61 control subjects. CONCLUSION: Overall, consistent with several other antioxidant enzymes, ECSOD is very low in fibrotic areas of UIP, which may further increase the oxidant burden in this disease.
16842247|a|AIMS: Recent studies suggest the importance of oxidant stress in the progression of <d>pulmonary fibrosis</d>. The aim of this study was to investigate <g>extracellular superoxide dismutase</g> <g>ECSOD</g>, the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> related to <d>usual interstitial pneumonia</d> UIP. METHODS AND RESULTS: Fibrotic areas and fibroblastic foci in UIP lungs were notable for absence of <g>ECSOD</g> by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of <g>ECSOD</g> in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense <g>ECSOD</g> positivity in UIP was the interstitial mast cell. In order to investigate the mechanism for <g>ECSOD</g> depletion in fibrotic areas, alveolar epithelial cells were exposed to tumour necrosis factor-alpha and transforming growth factor TGF-beta1; TGF-beta suggested a trend towards decreased synthesis. Patients with UIP were also assessed to determine whether this disease is associated with a naturally occurring mutation in <g>ECSOD</g> Arg213Gly which leads to a loss of tissue binding of <g>ECSOD</g>. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 UIP patients and 61 control subjects. CONCLUSION: Overall, consistent with several other antioxidant enzymes, <g>ECSOD</g> is very low in fibrotic areas of UIP, which may further increase the oxidant burden in this disease.
16842247|a|AIMS: Recent studies suggest the importance of oxidant stress in the progression of <d>pulmonary fibrosis</d>. The aim of this study was to investigate <g>extracellular superoxide dismutase</g> <g>ECSOD</g>, the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> related to <d>usual interstitial pneumonia</d> <d>UIP</d>. METHODS AND RESULTS: Fibrotic areas and fibroblastic foci in <d>UIP</d> lungs were notable for absence of <g>ECSOD</g> by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of <g>ECSOD</g> in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense <g>ECSOD</g> positivity in <d>UIP</d> was the interstitial mast cell. In order to investigate the mechanism for <g>ECSOD</g> depletion in fibrotic areas, alveolar epithelial cells were exposed to tumour necrosis factor-alpha and transforming growth factor TGF-beta1; TGF-beta suggested a trend towards decreased synthesis. Patients with <d>UIP</d> were also assessed to determine whether this disease is associated with a naturally occurring mutation in <g>ECSOD</g> Arg213Gly which leads to a loss of tissue binding of <g>ECSOD</g>. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 <d>UIP</d> patients and 61 control subjects. CONCLUSION: Overall, consistent with several other antioxidant enzymes, <g>ECSOD</g> is very low in fibrotic areas of <d>UIP</d>, which may further increase the oxidant burden in this disease.
16842247|a|AIMS: Recent studies suggest the importance of oxidant stress in the progression of <d>pulmonary fibrosis</d>. The aim of this study was to investigate <g>extracellular superoxide dismutase</g> <g>ECSOD</g>, the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> related to <d>usual interstitial pneumonia</d> <d>UIP</d>. METHODS AND RESULTS: Fibrotic areas and fibroblastic foci in <d>UIP</d> lungs were notable for absence of <g>ECSOD</g> by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of <g>ECSOD</g> in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense <g>ECSOD</g> positivity in <d>UIP</d> was the interstitial mast cell. In order to investigate the mechanism for <g>ECSOD</g> depletion in fibrotic areas, alveolar epithelial cells were exposed to <d>tumour</d> necrosis factor-alpha and transforming growth factor TGF-beta1; TGF-beta suggested a trend towards decreased synthesis. Patients with <d>UIP</d> were also assessed to determine whether this disease is associated with a naturally occurring mutation in <g>ECSOD</g> Arg213Gly which leads to a loss of tissue binding of <g>ECSOD</g>. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 <d>UIP</d> patients and 61 control subjects. CONCLUSION: Overall, consistent with several other antioxidant enzymes, <g>ECSOD</g> is very low in fibrotic areas of <d>UIP</d>, which may further increase the oxidant burden in this disease.
16842247|a|AIMS: Recent studies suggest the importance of oxidant stress in the progression of <d>pulmonary fibrosis</d>. The aim of this study was to investigate <g>extracellular superoxide dismutase</g> <g>ECSOD</g>, the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> related to <d>usual interstitial pneumonia</d> <d>UIP</d>. METHODS AND RESULTS: Fibrotic areas and fibroblastic foci in <d>UIP</d> lungs were notable for absence of <g>ECSOD</g> by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of <g>ECSOD</g> in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense <g>ECSOD</g> positivity in <d>UIP</d> was the interstitial mast cell. In order to investigate the mechanism for <g>ECSOD</g> depletion in fibrotic areas, alveolar epithelial cells were exposed to <d>tumour</d> <d>necrosis</d> factor-alpha and transforming growth factor TGF-beta1; TGF-beta suggested a trend towards decreased synthesis. Patients with <d>UIP</d> were also assessed to determine whether this disease is associated with a naturally occurring mutation in <g>ECSOD</g> Arg213Gly which leads to a loss of tissue binding of <g>ECSOD</g>. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 <d>UIP</d> patients and 61 control subjects. CONCLUSION: Overall, consistent with several other antioxidant enzymes, <g>ECSOD</g> is very low in fibrotic areas of <d>UIP</d>, which may further increase the oxidant burden in this disease.
16908447|a|<d>Idiopathic pulmonary fibrosis</d> IPF is characterized by fibroblast expansion and extracellular matrix accumulation. However, the mechanisms involved in matrix remodeling have not been elucidated. In this study, the authors aimed to evaluate the expression of the tissue inhibitors of matrix metalloproteinases TIMPs in human fibroblasts and whole tissues from IPF and normal lungs. They also determined the role of mitogen-activated protein kinase MAPK in TIMP3 expression. TIMP1, TIMP2, and TIMP3 were highly expressed in lung fibroblasts. Transforming growth factor TGF-beta1, a profibrotic mediator, induced strong up-regulation of TIMP3 at the mRNA and protein levels. The authors examined whether the MAPK pathway was involved in TGF-beta1-induced TIMP3 expression. TGF-beta1 induced the phosphorylation of p38 and extracellular signal-regulated kinase ERK1/2. Biochemical blockade of p38 by SB203580, but not of the ERK MAPK pathway, inhibited the effect of this factor. The effect was also blocked by the tyrosine kinase inhibitor genistein and by antagonizing TGF-beta1 receptor type I activin-linked kinase [ALK5]. In IPF tissues TIMP3 gene expression was significantly increased and the protein was localized to fibroblastic foci and extracellular matrix. Our findings suggest that TGF-beta1-induced TIMP3 may be an important mediator in lung fibrogenesis.
16908447|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by fibroblast expansion and extracellular matrix accumulation. However, the mechanisms involved in matrix remodeling have not been elucidated. In this study, the authors aimed to evaluate the expression of the tissue inhibitors of matrix metalloproteinases TIMPs in human fibroblasts and whole tissues from <d>IPF</d> and normal lungs. They also determined the role of mitogen-activated protein kinase MAPK in TIMP3 expression. TIMP1, TIMP2, and TIMP3 were highly expressed in lung fibroblasts. Transforming growth factor TGF-beta1, a profibrotic mediator, induced strong up-regulation of TIMP3 at the mRNA and protein levels. The authors examined whether the MAPK pathway was involved in TGF-beta1-induced TIMP3 expression. TGF-beta1 induced the phosphorylation of p38 and extracellular signal-regulated kinase ERK1/2. Biochemical blockade of p38 by SB203580, but not of the ERK MAPK pathway, inhibited the effect of this factor. The effect was also blocked by the tyrosine kinase inhibitor genistein and by antagonizing TGF-beta1 receptor type I activin-linked kinase [ALK5]. In <d>IPF</d> tissues TIMP3 gene expression was significantly increased and the protein was localized to fibroblastic foci and extracellular matrix. Our findings suggest that TGF-beta1-induced TIMP3 may be an important mediator in lung fibrogenesis.
16933466|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is characterized by fibroblast expansion and extracellular matrix accumulation. Some secreted matrix metalloproteinases MMPs as MMP2 are highly upregulated in IPF lungs. Membrane-type MT-MMPs participate in the activation of pro-MMP2. However, they have not been examined in IPF. METHODS: Type I transmembrane MT-MMPs, MT1, MT2, MT3, and MT5-MMP were analyzed by real-time PCR and immunohistochemistry in IPF and normal lungs. MMP-2 was also immunolocalized and evaluated by gelatin zymography in BAL fluids. Additionally, the MT-MMPs were examined by real time PCR in lung fibroblasts stimulated with TGF-beta1 and IFN-gamma. RESULTS: MT1-MMP, was the most highly expressed followed by MT2- and MT5-MMP, and by a moderate expression of MT3-MMP. Regarding their localization, MT1- and MT2-MMPs were found in alveolar epithelial cells, MT3-MMP in fibroblasts from fibroblastic foci and alveolar epithelial cells and MT5-MMP in basal bronchiolar epithelial cells and in areas of squamous metaplasia. MMP2 was localized in alveolar and basal bronchiolar epithelial cells and fibroblasts, and increased active enzyme was observed in BAL fluids. In lung fibroblasts, TGF-beta1 induced a strong upregulation of MT3-MMP, both at the gene and protein level. This effect was blocked by genistein, a protein tyrosin kinase inhibitor and partially repressed by SB203580 a p38 MAP kinase inhibitor. IFN-gamma had no effect. CONCLUSIONS: MT-MMPs are expressed in IPF, in the same cell types as MMP2. Mostly by different types of epithelial cells a pivotal component in the aberrant remodeling of the lung microenvironment. Interestingly MT3-MMP that was found in fibroblastic foci was upregulated in vitro by TGF-beta1 a potent profibrotic mediator.
16933466|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by fibroblast expansion and extracellular matrix accumulation. Some secreted matrix metalloproteinases MMPs as MMP2 are highly upregulated in <d>IPF</d> lungs. Membrane-type MT-MMPs participate in the activation of pro-MMP2. However, they have not been examined in <d>IPF</d>. METHODS: Type I transmembrane MT-MMPs, MT1, MT2, MT3, and MT5-MMP were analyzed by real-time PCR and immunohistochemistry in <d>IPF</d> and normal lungs. MMP-2 was also immunolocalized and evaluated by gelatin zymography in BAL fluids. Additionally, the MT-MMPs were examined by real time PCR in lung fibroblasts stimulated with TGF-beta1 and IFN-gamma. RESULTS: MT1-MMP, was the most highly expressed followed by MT2- and MT5-MMP, and by a moderate expression of MT3-MMP. Regarding their localization, MT1- and MT2-MMPs were found in alveolar epithelial cells, MT3-MMP in fibroblasts from fibroblastic foci and alveolar epithelial cells and MT5-MMP in basal bronchiolar epithelial cells and in areas of squamous metaplasia. MMP2 was localized in alveolar and basal bronchiolar epithelial cells and fibroblasts, and increased active enzyme was observed in BAL fluids. In lung fibroblasts, TGF-beta1 induced a strong upregulation of MT3-MMP, both at the gene and protein level. This effect was blocked by genistein, a protein tyrosin kinase inhibitor and partially repressed by SB203580 a p38 MAP kinase inhibitor. IFN-gamma had no effect. CONCLUSIONS: MT-MMPs are expressed in <d>IPF</d>, in the same cell types as MMP2. Mostly by different types of epithelial cells a pivotal component in the aberrant remodeling of the lung microenvironment. Interestingly MT3-MMP that was found in fibroblastic foci was upregulated in vitro by TGF-beta1 a potent profibrotic mediator.
16933466|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by fibroblast expansion and extracellular matrix accumulation. Some secreted matrix metalloproteinases MMPs as <g>MMP2</g> are highly upregulated in <d>IPF</d> lungs. <g>Membrane-type MT-MMPs</g> participate in the activation of pro-<g>MMP2</g>. However, they have not been examined in <d>IPF</d>. METHODS: Type I transmembrane MT-MMPs, <g>MT1</g>, <g>MT2</g>, <g>MT3</g>, and <g>MT5-MMP</g> were analyzed by real-time PCR and immunohistochemistry in <d>IPF</d> and normal lungs. <g>MMP-2</g> was also immunolocalized and evaluated by gelatin zymography in BAL fluids. Additionally, the MT-MMPs were examined by real time PCR in lung fibroblasts stimulated with <g>TGF-beta1</g> and <g>IFN-gamma</g>. RESULTS: <g>MT1</g>-MMP, was the most highly expressed followed by <g>MT2</g>- and <g>MT5-MMP</g>, and by a moderate expression of <g>MT3</g>-MMP. Regarding their localization, <g>MT1</g>- and <g>MT2</g>-MMPs were found in <d>alveolar</d> epithelial cells, <g>MT3</g>-MMP in fibroblasts from fibroblastic foci and <d>alveolar</d> epithelial cells and <g>MT5-MMP</g> in basal bronchiolar epithelial cells and in areas of squamous metaplasia. <g>MMP2</g> was localized in <d>alveolar</d> and basal bronchiolar epithelial cells and fibroblasts, and increased active enzyme was observed in BAL fluids. In lung fibroblasts, <g>TGF-beta1</g> induced a strong upregulation of <g>MT3</g>-MMP, both at the gene and protein level. This effect was blocked by genistein, a protein tyrosin kinase inhibitor and partially repressed by SB203580 a p38 MAP kinase inhibitor. <g>IFN-gamma</g> had no effect. CONCLUSIONS: MT-MMPs are expressed in <d>IPF</d>, in the same cell types as <g>MMP2</g>. Mostly by different types of epithelial cells a pivotal component in the aberrant remodeling of the lung microenvironment. Interestingly <g>MT3</g>-MMP that was found in fibroblastic foci was upregulated in vitro by <g>TGF-beta1</g> a potent profibrotic mediator.
16933466|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by fibroblast expansion and extracellular matrix accumulation. Some secreted matrix metalloproteinases MMPs as <g>MMP2</g> are highly upregulated in <d>IPF</d> lungs. <g>Membrane-type MT-MMPs</g> participate in the activation of pro-<g>MMP2</g>. However, they have not been examined in <d>IPF</d>. METHODS: Type I transmembrane MT-MMPs, <g>MT1</g>, <g>MT2</g>, <g>MT3</g>, and <g>MT5-MMP</g> were analyzed by real-time PCR and immunohistochemistry in <d>IPF</d> and normal lungs. <g>MMP-2</g> was also immunolocalized and evaluated by gelatin zymography in BAL fluids. Additionally, the MT-MMPs were examined by real time PCR in lung fibroblasts stimulated with <g>TGF-beta1</g> and <g>IFN-gamma</g>. RESULTS: <g>MT1</g>-MMP, was the most highly expressed followed by <g>MT2</g>- and <g>MT5-MMP</g>, and by a moderate expression of <g>MT3</g>-MMP. Regarding their localization, <g>MT1</g>- and <g>MT2</g>-MMPs were found in <d>alveolar</d> epithelial cells, <g>MT3</g>-MMP in fibroblasts from fibroblastic foci and <d>alveolar</d> epithelial cells and <g>MT5-MMP</g> in basal bronchiolar epithelial cells and in areas of <d>squamous</d> metaplasia. <g>MMP2</g> was localized in <d>alveolar</d> and basal bronchiolar epithelial cells and fibroblasts, and increased active enzyme was observed in BAL fluids. In lung fibroblasts, <g>TGF-beta1</g> induced a strong upregulation of <g>MT3</g>-MMP, both at the gene and protein level. This effect was blocked by genistein, a protein tyrosin kinase inhibitor and partially repressed by SB203580 a p38 MAP kinase inhibitor. <g>IFN-gamma</g> had no effect. CONCLUSIONS: MT-MMPs are expressed in <d>IPF</d>, in the same cell types as <g>MMP2</g>. Mostly by different types of epithelial cells a pivotal component in the aberrant remodeling of the lung microenvironment. Interestingly <g>MT3</g>-MMP that was found in fibroblastic foci was upregulated in vitro by <g>TGF-beta1</g> a potent profibrotic mediator.
16948840|a|The molecular mechanisms of <d>Idiopathic Pulmonary Fibrosis</d> IPF remain elusive. Transforming Growth Factor beta 1<g>TGF-beta1</g> is a key effector cytokine in the development of lung fibrosis. We used microarray and computational biology strategies to identify genes whose expression is significantly altered in alveolar epithelial cells A549 in response to <g>TGF-beta1</g>, IL-4 and IL-13 and Epstein Barr virus. A549 cells were exposed to 10 ng/ml <g>TGF-beta1</g>, IL-4 and IL-13 at serial time points. Total RNA was used for hybridisation to Affymetrix Human Genome U133A microarrays. Each in vitro time-point was studied in duplicate and an average RMA value computed. Expression data for each time point was compared to control and a signal log ratio of 0.6 or greater taken to identify significant differential regulation. Using normalised RMA values and unsupervised Average Linkage Hierarchical Cluster Analysis, a list of 312 extracellular matrix ECM proteins or modulators of matrix turnover was curated via Onto-Compare and Gene-Ontology GO databases for baited cluster analysis of ECM associated genes. Interrogation of the dataset using ontological classification focused cluster analysis revealed coordinate differential expression of a large cohort of extracellular matrix associated genes. Of this grouping members of the ADAM A disintegrin and Metalloproteinase domain containing family of genes were differentially expressed. ADAM gene expression was also identified in EBV infected A549 cells as well as IL-13 and IL-4 stimulated cells. We probed pathologenomic activities activation and functional activity of ADAM19 and ADAMTS9 using siRNA and collagen assays. Knockdown of these genes resulted in diminished production of collagen in A549 cells exposed to <g>TGF-beta1</g>, suggesting a potential role for these molecules in ECM accumulation in IPF.
16948840|a|The molecular mechanisms of <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> remain elusive. Transforming Growth Factor beta 1<g>TGF-beta1</g> is a key effector cytokine in the development of lung fibrosis. We used microarray and computational biology strategies to identify genes whose expression is significantly altered in alveolar epithelial cells A549 in response to <g>TGF-beta1</g>, IL-4 and IL-13 and Epstein Barr virus. A549 cells were exposed to 10 ng/ml <g>TGF-beta1</g>, IL-4 and IL-13 at serial time points. Total RNA was used for hybridisation to Affymetrix Human Genome U133A microarrays. Each in vitro time-point was studied in duplicate and an average RMA value computed. Expression data for each time point was compared to control and a signal log ratio of 0.6 or greater taken to identify significant differential regulation. Using normalised RMA values and unsupervised Average Linkage Hierarchical Cluster Analysis, a list of 312 extracellular matrix ECM proteins or modulators of matrix turnover was curated via Onto-Compare and Gene-Ontology GO databases for baited cluster analysis of ECM associated genes. Interrogation of the dataset using ontological classification focused cluster analysis revealed coordinate differential expression of a large cohort of extracellular matrix associated genes. Of this grouping members of the ADAM A disintegrin and Metalloproteinase domain containing family of genes were differentially expressed. ADAM gene expression was also identified in EBV infected A549 cells as well as IL-13 and IL-4 stimulated cells. We probed pathologenomic activities activation and functional activity of ADAM19 and ADAMTS9 using siRNA and collagen assays. Knockdown of these genes resulted in diminished production of collagen in A549 cells exposed to <g>TGF-beta1</g>, suggesting a potential role for these molecules in ECM accumulation in <d>IPF</d>.
16948840|a|The molecular mechanisms of <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> remain elusive. Transforming Growth Factor beta 1<g>TGF-beta1</g> is a key effector cytokine in the development of <d>lung fibrosis</d>. We used microarray and computational biology strategies to identify genes whose expression is significantly altered in alveolar epithelial cells A549 in response to <g>TGF-beta1</g>, IL-4 and IL-13 and Epstein Barr virus. A549 cells were exposed to 10 ng/ml <g>TGF-beta1</g>, IL-4 and IL-13 at serial time points. Total RNA was used for hybridisation to Affymetrix Human Genome U133A microarrays. Each in vitro time-point was studied in duplicate and an average RMA value computed. Expression data for each time point was compared to control and a signal log ratio of 0.6 or greater taken to identify significant differential regulation. Using normalised RMA values and unsupervised Average Linkage Hierarchical Cluster Analysis, a list of 312 extracellular matrix ECM proteins or modulators of matrix turnover was curated via Onto-Compare and Gene-Ontology GO databases for baited cluster analysis of ECM associated genes. Interrogation of the dataset using ontological classification focused cluster analysis revealed coordinate differential expression of a large cohort of extracellular matrix associated genes. Of this grouping members of the ADAM A disintegrin and Metalloproteinase domain containing family of genes were differentially expressed. ADAM gene expression was also identified in EBV infected A549 cells as well as IL-13 and IL-4 stimulated cells. We probed pathologenomic activities activation and functional activity of ADAM19 and ADAMTS9 using siRNA and collagen assays. Knockdown of these genes resulted in diminished production of collagen in A549 cells exposed to <g>TGF-beta1</g>, suggesting a potential role for these molecules in ECM accumulation in <d>IPF</d>.
16948989|a|OBJECTIVE: Transforming growth factor ss1 TGF-ss1 is one of the key profibrotic mediators in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF. The purpose of this study was to investigate the prognostic value of quantifying TGF-ss1 levels in patients with IPF. PATIENTS AND METHODS: We conducted a prospective study of 29 IPF patients and 27 healthy controls. Enzyme-linked immunosorbent assays were used to quantify TGF-ss1 levels. RESULTS: Mean SD TGF-ss1 levels were significantly higher in the IPF patients than in the control subjects 11.1 [7.5] ng/mL vs 4 [2.4] ng/mL; P< .01. Weak inverse correlations were observed between TGF-ss1 levels and both forced vital capacity and total lung capacity. Thirteen IPF patients were evaluated at 8 1.2 months range, 5-9 months. The mean TGF-ss1 level was 18.2 15 ng/mL and there were no significant differences with respect to the initial measurement of 11.1 7.5 ng/mL. No correlation was observed between changes in respiratory function and changes in TGF-ss1 levels. CONCLUSIONS: Although plasma levels of TGF-beta1 were high in the patients with IPF, they do not appear to be a useful prognostic marker of disease activity or therapeutic response.
16948989|a|OBJECTIVE: Transforming growth factor ss1 TGF-ss1 is one of the key profibrotic mediators in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The purpose of this study was to investigate the prognostic value of quantifying TGF-ss1 levels in patients with <d>IPF</d>. PATIENTS AND METHODS: We conducted a prospective study of 29 <d>IPF</d> patients and 27 healthy controls. Enzyme-linked immunosorbent assays were used to quantify TGF-ss1 levels. RESULTS: Mean SD TGF-ss1 levels were significantly higher in the <d>IPF</d> patients than in the control subjects 11.1 [7.5] ng/mL vs 4 [2.4] ng/mL; P< .01. Weak inverse correlations were observed between TGF-ss1 levels and both forced vital capacity and total lung capacity. Thirteen <d>IPF</d> patients were evaluated at 8 1.2 months range, 5-9 months. The mean TGF-ss1 level was 18.2 15 ng/mL and there were no significant differences with respect to the initial measurement of 11.1 7.5 ng/mL. No correlation was observed between changes in respiratory function and changes in TGF-ss1 levels. CONCLUSIONS: Although plasma levels of TGF-beta1 were high in the patients with <d>IPF</d>, they do not appear to be a useful prognostic marker of disease activity or therapeutic response.
17163490|a|Fibroblasts play a major role in processes such as wound repair, scarring, and <d>fibrosis</d>. Differentiation into myofibroblasts, characterized by upregulation of smooth muscle alpha-actin smalpha in response to profibrotic agents such as <g>TGFbeta</g> is believed to be an important step in <d>fibrosis</d>. Therefore, elucidating mechanisms of myofibroblast differentiation might reveal novel targets in treating diseases such as idiopathic pulmonary <d>fibrosis</d> IPF. <g>MK2</g> is a kinase substrate of p38 MAP kinase that mediates some effects of p38 activation on the actin cytoskeleton. Using mouse embryonic fibroblasts MEF from <g>MK2</g> knockout <g>MK2</g>-/- mice, we demonstrate that disrupting expression of <g>MK2</g> expression reduces filamentous actin and stress fibers. It also causes <g>MK2</g>-/- MEF to express less smalpha than their corresponding wild-type WT MEF at baseline and in response to <g>TGFbeta</g>. Furthermore, <g>TGFbeta</g> causes downregulation of smalpha in <g>MK2</g>-/- MEF, instead of upregulation observed in WT MEF. Expression of other fibroblast markers, such as collagen, is not altered in <g>MK2</g>-/- MEF. Our results further suggest that downregulation of smalpha in <g>MK2</g>-/- MEF is not due to lack of activation of serum responsive promoter elements, but probably due to reduced smalpha message stability in these cells. These results indicate that <g>MK2</g> plays a key role in regulation of smalpha expression, and that targeting <g>MK2</g> might present a therapeutic approach in managing conditions such as pulmonary <d>fibrosis</d>.
17163490|a|Fibroblasts play a major role in processes such as wound repair, scarring, and <d>fibrosis</d>. Differentiation into myofibroblasts, characterized by upregulation of smooth muscle alpha-actin smalpha in response to profibrotic agents such as <g>TGFbeta</g> is believed to be an important step in <d>fibrosis</d>. Therefore, elucidating mechanisms of myofibroblast differentiation might reveal novel targets in treating diseases such as idiopathic pulmonary <d>fibrosis</d> IPF. <g>MK2</g> is a kinase substrate of <g>p38</g> MAP kinase that mediates some effects of <g>p38</g> activation on the actin cytoskeleton. Using mouse embryonic fibroblasts MEF from <g>MK2</g> knockout <g>MK2</g>-/- mice, we demonstrate that disrupting expression of <g>MK2</g> expression reduces filamentous actin and stress fibers. It also causes <g>MK2</g>-/- MEF to express less smalpha than their corresponding wild-type <d>WT MEF</d> at baseline and in response to <g>TGFbeta</g>. Furthermore, <g>TGFbeta</g> causes downregulation of smalpha in <g>MK2</g>-/- MEF, instead of upregulation observed in <d>WT MEF</d>. Expression of other fibroblast markers, such as collagen, is not altered in <g>MK2</g>-/- MEF. Our results further suggest that downregulation of smalpha in <g>MK2</g>-/- MEF is not due to lack of activation of serum responsive promoter elements, but probably due to reduced smalpha message stability in these cells. These results indicate that <g>MK2</g> plays a key role in regulation of smalpha expression, and that targeting <g>MK2</g> might present a therapeutic approach in managing conditions such as pulmonary <d>fibrosis</d>.
17178917|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive chronic disorder characterized by activation of fibroblasts and overproduction of extracellular matrix ECM. <g>Caveolin-1</g> cav-1, a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from IPF patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin BLM-induced pulmonary fibrosis, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor beta1 TGF-beta1, the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase JNK pathway. Interestingly, highly activated JNK was detected in IPF- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad-cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with pulmonary fibrosis.
17178917|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive chronic disorder characterized by activation of fibroblasts and overproduction of extracellular matrix ECM. <g>Caveolin-1</g> cav-1, a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from <d>IPF</d> patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin BLM-induced pulmonary fibrosis, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor beta1 TGF-beta1, the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase JNK pathway. Interestingly, highly activated JNK was detected in <d>IPF</d>- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad-cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with pulmonary fibrosis.
17178917|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>chronic disorder</d> characterized by activation of fibroblasts and overproduction of extracellular matrix ECM. <g>Caveolin-1</g> cav-1, a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from <d>IPF</d> patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin BLM-induced pulmonary fibrosis, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor beta1 TGF-beta1, the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase JNK pathway. Interestingly, highly activated JNK was detected in <d>IPF</d>- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad-cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with pulmonary fibrosis.
17178917|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive <d>chronic disorder</d> characterized by activation of fibroblasts and overproduction of extracellular matrix ECM. <g>Caveolin-1</g> cav-1, a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from <d>IPF</d> patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin BLM-induced <d>pulmonary fibrosis</d>, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor beta1 TGF-beta1, the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase JNK pathway. Interestingly, highly activated JNK was detected in <d>IPF</d>- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad-cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with <d>pulmonary fibrosis</d>.
17198680|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic, progressive, and often fatal pulmonary disorder, and its pathology is characterized by parenchymal fibrosis. To investigate the characteristics of fibroblasts in IPF, we obtained eight fibroblast cell lines from lungs with IPF and eight lines from normal lungs. We found that the fibroblasts from IPF spontaneously produced higher amounts of type I collagen and had lower expression levels of <g>SOCS1</g> than fibroblasts from normal lung. By using mouse fibroblasts, we demonstrated the causal relationship between them: the deficiency of <g>SOCS1</g> in fibroblasts resulted in increased collagen production, whereas overexpression of <g>SOCS1</g> suppressed collagen production. IFN-gamma suppressed spontaneous collagen production even in <g>SOCS1</g>-deficient fibroblasts, indicating that IFN-gamma inhibition is <g>SOCS1</g>-independent. In contrast, IFN-gamma suppressed the increase of collagen production induced by IL-4 in wild type fibroblasts but not <g>SOCS1</g>-deficient fibroblasts, suggesting IFN-gamma acted exclusively via <g>SOCS1</g> in this case. Following IFN-gamma stimulation, the amount of <g>SOCS1</g> mRNA expressed by IPF fibroblasts was comparable to that of normal fibroblasts. Thus, the extent of <g>SOCS1</g> increase after stimulation by IFN-gamma was significantly higher in IPF fibroblasts. The extent to which IFN-gamma inhibited collagen production was also larger in IPF fibroblasts than in normal fibroblasts. These results suggest that the exaggerated production of collagen observed in fibroblasts from IPF is causally related to the diminished expression of <g>SOCS1</g>, and IPF fibroblasts are more susceptible to IFN-gamma because of decreased expression of <g>SOCS1</g>.
17198680|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and often fatal pulmonary disorder, and its pathology is characterized by parenchymal fibrosis. To investigate the characteristics of fibroblasts in <d>IPF</d>, we obtained eight fibroblast cell lines from lungs with <d>IPF</d> and eight lines from normal lungs. We found that the fibroblasts from <d>IPF</d> spontaneously produced higher amounts of type I collagen and had lower expression levels of <g>SOCS1</g> than fibroblasts from normal lung. By using mouse fibroblasts, we demonstrated the causal relationship between them: the deficiency of <g>SOCS1</g> in fibroblasts resulted in increased collagen production, whereas overexpression of <g>SOCS1</g> suppressed collagen production. IFN-gamma suppressed spontaneous collagen production even in <g>SOCS1</g>-deficient fibroblasts, indicating that IFN-gamma inhibition is <g>SOCS1</g>-independent. In contrast, IFN-gamma suppressed the increase of collagen production induced by IL-4 in wild type fibroblasts but not <g>SOCS1</g>-deficient fibroblasts, suggesting IFN-gamma acted exclusively via <g>SOCS1</g> in this case. Following IFN-gamma stimulation, the amount of <g>SOCS1</g> mRNA expressed by <d>IPF</d> fibroblasts was comparable to that of normal fibroblasts. Thus, the extent of <g>SOCS1</g> increase after stimulation by IFN-gamma was significantly higher in <d>IPF</d> fibroblasts. The extent to which IFN-gamma inhibited collagen production was also larger in <d>IPF</d> fibroblasts than in normal fibroblasts. These results suggest that the exaggerated production of collagen observed in fibroblasts from <d>IPF</d> is causally related to the diminished expression of <g>SOCS1</g>, and <d>IPF</d> fibroblasts are more susceptible to IFN-gamma because of decreased expression of <g>SOCS1</g>.
17198680|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and often fatal <d>pulmonary disorder</d>, and its pathology is characterized by parenchymal fibrosis. To investigate the characteristics of fibroblasts in <d>IPF</d>, we obtained eight fibroblast cell lines from lungs with <d>IPF</d> and eight lines from normal lungs. We found that the fibroblasts from <d>IPF</d> spontaneously produced higher amounts of type I collagen and had lower expression levels of <g>SOCS1</g> than fibroblasts from normal lung. By using mouse fibroblasts, we demonstrated the causal relationship between them: the deficiency of <g>SOCS1</g> in fibroblasts resulted in increased collagen production, whereas overexpression of <g>SOCS1</g> suppressed collagen production. IFN-gamma suppressed spontaneous collagen production even in <g>SOCS1</g>-deficient fibroblasts, indicating that IFN-gamma inhibition is <g>SOCS1</g>-independent. In contrast, IFN-gamma suppressed the increase of collagen production induced by IL-4 in wild type fibroblasts but not <g>SOCS1</g>-deficient fibroblasts, suggesting IFN-gamma acted exclusively via <g>SOCS1</g> in this case. Following IFN-gamma stimulation, the amount of <g>SOCS1</g> mRNA expressed by <d>IPF</d> fibroblasts was comparable to that of normal fibroblasts. Thus, the extent of <g>SOCS1</g> increase after stimulation by IFN-gamma was significantly higher in <d>IPF</d> fibroblasts. The extent to which IFN-gamma inhibited collagen production was also larger in <d>IPF</d> fibroblasts than in normal fibroblasts. These results suggest that the exaggerated production of collagen observed in fibroblasts from <d>IPF</d> is causally related to the diminished expression of <g>SOCS1</g>, and <d>IPF</d> fibroblasts are more susceptible to IFN-gamma because of decreased expression of <g>SOCS1</g>.
17198680|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic, progressive, and often fatal <d>pulmonary disorder</d>, and its pathology is characterized by parenchymal <d>fibrosis</d>. To investigate the characteristics of fibroblasts in <d>IPF</d>, we obtained eight fibroblast cell lines from lungs with <d>IPF</d> and eight lines from normal lungs. We found that the fibroblasts from <d>IPF</d> spontaneously produced higher amounts of type I collagen and had lower expression levels of <g>SOCS1</g> than fibroblasts from normal lung. By using mouse fibroblasts, we demonstrated the causal relationship between them: the deficiency of <g>SOCS1</g> in fibroblasts resulted in increased collagen production, whereas overexpression of <g>SOCS1</g> suppressed collagen production. IFN-gamma suppressed spontaneous collagen production even in <g>SOCS1</g>-deficient fibroblasts, indicating that IFN-gamma inhibition is <g>SOCS1</g>-independent. In contrast, IFN-gamma suppressed the increase of collagen production induced by IL-4 in wild type fibroblasts but not <g>SOCS1</g>-deficient fibroblasts, suggesting IFN-gamma acted exclusively via <g>SOCS1</g> in this case. Following IFN-gamma stimulation, the amount of <g>SOCS1</g> mRNA expressed by <d>IPF</d> fibroblasts was comparable to that of normal fibroblasts. Thus, the extent of <g>SOCS1</g> increase after stimulation by IFN-gamma was significantly higher in <d>IPF</d> fibroblasts. The extent to which IFN-gamma inhibited collagen production was also larger in <d>IPF</d> fibroblasts than in normal fibroblasts. These results suggest that the exaggerated production of collagen observed in fibroblasts from <d>IPF</d> is causally related to the diminished expression of <g>SOCS1</g>, and <d>IPF</d> fibroblasts are more susceptible to IFN-gamma because of decreased expression of <g>SOCS1</g>.
17363768|a|RATIONALE: Idiopathic pulmonary <d>fibrosis</d> IPF is a chronic progressive fibrotic lung disorder of unknown cause. Several studies suggest an association between Epstein-Barr virus pulmonary infection and the development of IPF. OBJECTIVES: To determine whether reduction of gamma-herpesvirus reactivation from latency would alter progressive lung fibrogenesis in an animal model of virus-induced pulmonary <d>fibrosis</d>. METHODS: IFN-gamma receptor-deficient IFN-gammaR-/- mice infected intranasally with murine gamma-herpesvirus 68 MHV68 develop lung <d>fibrosis</d> that progresses for up to at least 180 days after initial infection. Viral replication during the chronic phase of infection was controlled by two methods: the administration of cidofovir, an antiviral drug effective at clearing lytic but not latent virus, and by using a mutant gamma-herpesvirus defective in virus reactivation from latency. MEASUREMENTS AND MAIN RESULTS: Ten percent of the asymptomatic MHV68-infected animals that received antiviral treatment beginning on Day 45 postinfection had severe pulmonary <d>fibrosis</d> compared with 40% of the control saline-treated animals. Absence of severe <d>fibrosis</d> was also observed in IFN-gammaR-/- mice infected with the defective reactivation mutant MHV68 v-cyclin stop. Decreased <d>fibrosis</d> was associated with lower levels of transforming growth factor-beta, vascular endothelial growth factor, and markers of macrophage alternative activation. When antiviral treatment was administered on Day 60 in symptomatic animals, survival improved from 20 to 80% compared with untreated symptomatic animals, but lung <d>fibrosis</d> persisted in 60% of the mice. CONCLUSIONS: MHV68-induced <d>fibrosis</d> is a result of viral lytic replication during chronic lung herpesvirus infection in mice. We speculate that antiviral therapy might help to control lung <d>fibrosis</d> in humans with IPF and associated herpesvirus infection.
17363768|a|RATIONALE: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic progressive fibrotic lung disorder of unknown cause. Several studies suggest an association between Epstein-Barr virus pulmonary infection and the development of <d>IPF</d>. OBJECTIVES: To determine whether reduction of gamma-herpesvirus reactivation from latency would alter progressive lung fibrogenesis in an animal model of virus-induced pulmonary <d>fibrosis</d>. METHODS: IFN-gamma receptor-deficient IFN-gammaR-/- mice infected intranasally with murine gamma-herpesvirus 68 MHV68 develop lung <d>fibrosis</d> that progresses for up to at least 180 days after initial infection. Viral replication during the chronic phase of infection was controlled by two methods: the administration of cidofovir, an antiviral drug effective at clearing lytic but not latent virus, and by using a mutant gamma-herpesvirus defective in virus reactivation from latency. MEASUREMENTS AND MAIN RESULTS: Ten percent of the asymptomatic MHV68-infected animals that received antiviral treatment beginning on Day 45 postinfection had severe pulmonary <d>fibrosis</d> compared with 40% of the control saline-treated animals. Absence of severe <d>fibrosis</d> was also observed in IFN-gammaR-/- mice infected with the defective reactivation mutant MHV68 v-cyclin stop. Decreased <d>fibrosis</d> was associated with lower levels of transforming growth factor-beta, vascular endothelial growth factor, and markers of macrophage alternative activation. When antiviral treatment was administered on Day 60 in symptomatic animals, survival improved from 20 to 80% compared with untreated symptomatic animals, but lung <d>fibrosis</d> persisted in 60% of the mice. CONCLUSIONS: MHV68-induced <d>fibrosis</d> is a result of viral lytic replication during chronic lung herpesvirus infection in mice. We speculate that antiviral therapy might help to control lung <d>fibrosis</d> in humans with <d>IPF</d> and associated herpesvirus infection.
17363768|a|RATIONALE: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic progressive <d>fibrotic lung disorder</d> of unknown cause. Several studies suggest an association between Epstein-Barr virus pulmonary infection and the development of <d>IPF</d>. OBJECTIVES: To determine whether reduction of gamma-herpesvirus reactivation from latency would alter progressive lung fibrogenesis in an animal model of virus-induced pulmonary <d>fibrosis</d>. METHODS: IFN-gamma receptor-deficient IFN-gammaR-/- mice infected intranasally with murine gamma-herpesvirus 68 MHV68 develop lung <d>fibrosis</d> that progresses for up to at least 180 days after initial infection. Viral replication during the chronic phase of infection was controlled by two methods: the administration of cidofovir, an antiviral drug effective at clearing lytic but not latent virus, and by using a mutant gamma-herpesvirus defective in virus reactivation from latency. MEASUREMENTS AND MAIN RESULTS: Ten percent of the asymptomatic MHV68-infected animals that received antiviral treatment beginning on Day 45 postinfection had severe pulmonary <d>fibrosis</d> compared with 40% of the control saline-treated animals. Absence of severe <d>fibrosis</d> was also observed in IFN-gammaR-/- mice infected with the defective reactivation mutant MHV68 v-cyclin stop. Decreased <d>fibrosis</d> was associated with lower levels of transforming growth factor-beta, vascular endothelial growth factor, and markers of macrophage alternative activation. When antiviral treatment was administered on Day 60 in symptomatic animals, survival improved from 20 to 80% compared with untreated symptomatic animals, but lung <d>fibrosis</d> persisted in 60% of the mice. CONCLUSIONS: MHV68-induced <d>fibrosis</d> is a result of viral lytic replication during chronic lung herpesvirus infection in mice. We speculate that antiviral therapy might help to control lung <d>fibrosis</d> in humans with <d>IPF</d> and associated herpesvirus infection.
17363768|a|RATIONALE: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic progressive <d>fibrotic lung disorder</d> of unknown cause. Several studies suggest an association between Epstein-Barr virus pulmonary infection and the development of <d>IPF</d>. OBJECTIVES: To determine whether reduction of gamma-herpesvirus reactivation from latency would alter progressive lung fibrogenesis in an animal model of virus-induced pulmonary <d>fibrosis</d>. METHODS: IFN-gamma receptor-deficient <g>IFN-gammaR</g>-/- mice infected intranasally with murine gamma-herpesvirus 68 MHV68 develop lung <d>fibrosis</d> that progresses for up to at least 180 days after <d>initial infection</d>. Viral replication during the chronic phase of infection was controlled by two methods: the administration of cidofovir, an antiviral drug effective at clearing lytic but not latent virus, and by using a mutant gamma-herpesvirus defective in virus reactivation from latency. MEASUREMENTS AND MAIN RESULTS: Ten percent of the asymptomatic MHV68-infected animals that received antiviral treatment beginning on Day 45 postinfection had severe pulmonary <d>fibrosis</d> compared with 40% of the control saline-treated animals. Absence of severe <d>fibrosis</d> was also observed in <g>IFN-gammaR</g>-/- mice infected with the defective reactivation mutant MHV68 v-cyclin stop. Decreased <d>fibrosis</d> was associated with lower levels of transforming growth factor-beta, vascular endothelial growth factor, and markers of macrophage alternative activation. When antiviral treatment was administered on Day 60 in symptomatic animals, survival improved from 20 to 80% compared with untreated symptomatic animals, but lung <d>fibrosis</d> persisted in 60% of the mice. CONCLUSIONS: MHV68-induced <d>fibrosis</d> is a result of viral lytic replication during chronic lung herpesvirus infection in mice. We speculate that antiviral therapy might help to control lung <d>fibrosis</d> in humans with <d>IPF</d> and associated herpesvirus infection.
17363768|a|RATIONALE: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic progressive <d>fibrotic lung disorder</d> of unknown cause. Several studies suggest an association between Epstein-Barr virus pulmonary <d>infection</d> and the development of <d>IPF</d>. OBJECTIVES: To determine whether reduction of gamma-herpesvirus reactivation from latency would alter progressive lung fibrogenesis in an animal model of virus-induced pulmonary <d>fibrosis</d>. METHODS: IFN-gamma receptor-deficient <g>IFN-gammaR</g>-/- mice infected intranasally with murine gamma-herpesvirus 68 MHV68 develop lung <d>fibrosis</d> that progresses for up to at least 180 days after <d>initial <d>infection</d></d>. Viral replication during the chronic phase of <d>infection</d> was controlled by two methods: the administration of cidofovir, an antiviral drug effective at clearing lytic but not latent virus, and by using a mutant gamma-herpesvirus defective in virus reactivation from latency. MEASUREMENTS AND MAIN RESULTS: Ten percent of the asymptomatic MHV68-infected animals that received antiviral treatment beginning on Day 45 post<d>infection</d> had severe pulmonary <d>fibrosis</d> compared with 40% of the control saline-treated animals. Absence of severe <d>fibrosis</d> was also observed in <g>IFN-gammaR</g>-/- mice infected with the defective reactivation mutant MHV68 v-cyclin stop. Decreased <d>fibrosis</d> was associated with lower levels of transforming growth factor-beta, vascular endothelial growth factor, and markers of macrophage alternative activation. When antiviral treatment was administered on Day 60 in symptomatic animals, survival improved from 20 to 80% compared with untreated symptomatic animals, but lung <d>fibrosis</d> persisted in 60% of the mice. CONCLUSIONS: MHV68-induced <d>fibrosis</d> is a result of viral lytic replication during chronic lung herpesvirus <d>infection</d> in mice. We speculate that antiviral therapy might help to control lung <d>fibrosis</d> in humans with <d>IPF</d> and associated herpesvirus <d>infection</d>.
17379848|a|<g>Endothelin-1</g> <g>ET-1</g> is implicated in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF, but the cellular mechanisms underlying the role it plays in this disease are not well characterized. Epithelial-mesenchymal transition EMT, which was recently demonstrated in alveolar epithelial cells AEC, may play an important role in the pathogenesis of IPF and other forms of pulmonary fibrosis. Whether <g>ET-1</g> contributes to the induction of EMT in AEC is unknown. The aims of this study were to evaluate AEC production of <g>ET-1</g> and to determine if <g>ET-1</g> induces EMT in AEC. We demonstrate that <g>ET-1</g> is produced at physiologically relevant levels by primary AEC and is secreted preferentially toward the basolateral surface. We also demonstrate that AEC express high levels of endothelin type A receptors ET-A and, to a lesser extent, type B receptors ET-B, suggesting autocrine or paracrine function for alveolar <g>ET-1</g>. In addition, <g>ET-1</g> induces EMT through ET-A activation. Furthermore, <g>TGF-beta1</g> synthesis is increased by <g>ET-1</g>, <g>ET-1</g> induces Smad3 phosphorylation, and <g>ET-1</g>-induced EMT is attenuated by a <g>TGF-beta1</g>-neutralizing antibody. Thus, <g>ET-1</g> is an important mediator of EMT in AEC, acting through ET-A-mediated <g>TGF-beta1</g> production. These findings increase our basic understanding of the role of <g>ET-1</g> in pulmonary fibrosis and suggest potential roles for AEC-derived <g>ET-1</g> in the pathogenesis of other alveolar epithelial-mediated lung diseases.
17379848|a|<g>Endothelin-1</g> <g>ET-1</g> is implicated in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, but the cellular mechanisms underlying the role it plays in this disease are not well characterized. Epithelial-mesenchymal transition EMT, which was recently demonstrated in alveolar epithelial cells AEC, may play an important role in the pathogenesis of <d>IPF</d> and other forms of pulmonary fibrosis. Whether <g>ET-1</g> contributes to the induction of EMT in AEC is unknown. The aims of this study were to evaluate AEC production of <g>ET-1</g> and to determine if <g>ET-1</g> induces EMT in AEC. We demonstrate that <g>ET-1</g> is produced at physiologically relevant levels by primary AEC and is secreted preferentially toward the basolateral surface. We also demonstrate that AEC express high levels of endothelin type A receptors ET-A and, to a lesser extent, type B receptors ET-B, suggesting autocrine or paracrine function for alveolar <g>ET-1</g>. In addition, <g>ET-1</g> induces EMT through ET-A activation. Furthermore, <g>TGF-beta1</g> synthesis is increased by <g>ET-1</g>, <g>ET-1</g> induces Smad3 phosphorylation, and <g>ET-1</g>-induced EMT is attenuated by a <g>TGF-beta1</g>-neutralizing antibody. Thus, <g>ET-1</g> is an important mediator of EMT in AEC, acting through ET-A-mediated <g>TGF-beta1</g> production. These findings increase our basic understanding of the role of <g>ET-1</g> in pulmonary fibrosis and suggest potential roles for AEC-derived <g>ET-1</g> in the pathogenesis of other alveolar epithelial-mediated lung diseases.
17379848|a|<g>Endothelin-1</g> <g>ET-1</g> is implicated in the pathogenesis of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, but the cellular mechanisms underlying the role it plays in this disease are not well characterized. Epithelial-mesenchymal transition EMT, which was recently demonstrated in alveolar epithelial cells AEC, may play an important role in the pathogenesis of <d>IPF</d> and other forms of <d>pulmonary fibrosis</d>. Whether <g>ET-1</g> contributes to the induction of EMT in AEC is unknown. The aims of this study were to evaluate AEC production of <g>ET-1</g> and to determine if <g>ET-1</g> induces EMT in AEC. We demonstrate that <g>ET-1</g> is produced at physiologically relevant levels by primary AEC and is secreted preferentially toward the basolateral surface. We also demonstrate that AEC express high levels of endothelin type A receptors ET-A and, to a lesser extent, type B receptors ET-B, suggesting autocrine or paracrine function for alveolar <g>ET-1</g>. In addition, <g>ET-1</g> induces EMT through ET-A activation. Furthermore, <g>TGF-beta1</g> synthesis is increased by <g>ET-1</g>, <g>ET-1</g> induces Smad3 phosphorylation, and <g>ET-1</g>-induced EMT is attenuated by a <g>TGF-beta1</g>-neutralizing antibody. Thus, <g>ET-1</g> is an important mediator of EMT in AEC, acting through ET-A-mediated <g>TGF-beta1</g> production. These findings increase our basic understanding of the role of <g>ET-1</g> in <d>pulmonary fibrosis</d> and suggest potential roles for AEC-derived <g>ET-1</g> in the pathogenesis of other alveolar epithelial-mediated lung diseases.
17379848|a|<g>Endothelin-1</g> <g>ET-1</g> is implicated in the pathogenesis of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, but the cellular mechanisms underlying the role it plays in this disease are not well characterized. Epithelial-mesenchymal transition EMT, which was recently demonstrated in alveolar epithelial cells AEC, may play an important role in the pathogenesis of <d>IPF</d> and other forms of <d>pulmonary fibrosis</d>. Whether <g>ET-1</g> contributes to the induction of EMT in AEC is unknown. The aims of this study were to evaluate AEC production of <g>ET-1</g> and to determine if <g>ET-1</g> induces EMT in AEC. We demonstrate that <g>ET-1</g> is produced at physiologically relevant levels by primary AEC and is secreted preferentially toward the basolateral surface. We also demonstrate that AEC express high levels of <g>endothelin type A receptors</g> <g>ET-A</g> and, to a lesser <g>extent, type B receptors</g> <g>ET-B</g>, suggesting autocrine or paracrine function for alveolar <g>ET-1</g>. In addition, <g>ET-1</g> induces EMT through <g>ET-A</g> activation. Furthermore, <g>TGF-beta1</g> synthesis is increased by <g>ET-1</g>, <g>ET-1</g> induces <g>Smad3</g> phosphorylation, and <g>ET-1</g>-induced EMT is attenuated by a <g>TGF-beta1</g>-neutralizing antibody. Thus, <g>ET-1</g> is an important mediator of EMT in AEC, acting through <g>ET-A</g>-mediated <g>TGF-beta1</g> production. These findings increase our basic understanding of the role of <g>ET-1</g> in <d>pulmonary fibrosis</d> and suggest potential roles for AEC-derived <g>ET-1</g> in the pathogenesis of other <d>alveolar epithelial-mediated lung diseases</d>.
17391951|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a deadly disease, largely unresponsive to treatment with corticosteroids and immunosuppressives. The aim of this randomized, prospective, open-label study was to characterize the molecular effects of <g>IFN-gamma</g>-1b and colchicine, on biomarkers expression associated with fibrosis TGF-beta, <g>CTGF</g> and immunomodulatory/antimicrobial activity <g>IFN-gamma</g>, in the lungs of patients with IPF. Fourteen 14 patients with an established diagnosis of IPF received either 200 microg of <g>IFN-gamma</g>-1b subcutaneously three times per week, or 1mg of oral colchicine per day, for 24 months. Using RT-PCR assay, we evaluated the transcription levels of transforming growth factor beta1 <g>TGF-beta1</g>, connective-tissue growth factor <g>CTGF</g>, and interferon-gamma <g>IFN-gamma</g> genes in lung tissue before and after treatment with <g>IFN-gamma</g>-1b or colchicine. Marked mRNA expression of <g>TGF-beta1</g> and <g>CTGF</g>, but complete lack of interferon-gamma was detected in fibrotic lung tissue at entry. After treatment, both groups exhibited increased expression of <g>IFN-gamma</g> gene at 6 months that was sustained at 24 months. The expression of <g>CTGF</g> and <g>TGF-beta1</g> remained almost stable before and after treatment, in the <g>IFN-gamma</g>-1b group, while <g>TGF-beta1</g> was statistically decreased after therapy, in the colchicine group p=0.0002. Significant difference in DLCO % pred, was found between the two treatment groups in favor of <g>IFN-gamma</g>-1b group p=0.04. In addition, the <g>IFN-gamma</g>-1b group showed stability in arterial PO2 while the colchicine group significantly deteriorated p=0.02. In conclusion, we report the effect of antifibrotic agents <g>IFN-gamma</g>-1b and colchicine in TGF-beta, <g>CTGF</g>, and endogenous <g>IFN-gamma</g> gene expression, in human fibrosis. However, extended studies are needed to verify the pathophysiological consequences of these findings.
17391951|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a deadly disease, largely unresponsive to treatment with corticosteroids and immunosuppressives. The aim of this randomized, prospective, open-label study was to characterize the molecular effects of <g>IFN-gamma</g>-1b and colchicine, on biomarkers expression associated with fibrosis TGF-beta, <g>CTGF</g> and immunomodulatory/antimicrobial activity <g>IFN-gamma</g>, in the lungs of patients with <d>IPF</d>. Fourteen 14 patients with an established diagnosis of <d>IPF</d> received either 200 microg of <g>IFN-gamma</g>-1b subcutaneously three times per week, or 1mg of oral colchicine per day, for 24 months. Using RT-PCR assay, we evaluated the transcription levels of transforming growth factor beta1 <g>TGF-beta1</g>, connective-tissue growth factor <g>CTGF</g>, and interferon-gamma <g>IFN-gamma</g> genes in lung tissue before and after treatment with <g>IFN-gamma</g>-1b or colchicine. Marked mRNA expression of <g>TGF-beta1</g> and <g>CTGF</g>, but complete lack of interferon-gamma was detected in fibrotic lung tissue at entry. After treatment, both groups exhibited increased expression of <g>IFN-gamma</g> gene at 6 months that was sustained at 24 months. The expression of <g>CTGF</g> and <g>TGF-beta1</g> remained almost stable before and after treatment, in the <g>IFN-gamma</g>-1b group, while <g>TGF-beta1</g> was statistically decreased after therapy, in the colchicine group p=0.0002. Significant difference in DLCO % pred, was found between the two treatment groups in favor of <g>IFN-gamma</g>-1b group p=0.04. In addition, the <g>IFN-gamma</g>-1b group showed stability in arterial PO2 while the colchicine group significantly deteriorated p=0.02. In conclusion, we report the effect of antifibrotic agents <g>IFN-gamma</g>-1b and colchicine in TGF-beta, <g>CTGF</g>, and endogenous <g>IFN-gamma</g> gene expression, in human fibrosis. However, extended studies are needed to verify the pathophysiological consequences of these findings.
17391951|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a deadly disease, largely unresponsive to treatment with corticosteroids and immunosuppressives. The aim of this randomized, prospective, open-label study was to characterize the molecular effects of <g>IFN-gamma</g>-1b and colchicine, on biomarkers expression associated with <d>fibrosis</d> TGF-beta, <g>CTGF</g> and immunomodulatory/antimicrobial activity <g>IFN-gamma</g>, in the lungs of patients with <d>IPF</d>. Fourteen 14 patients with an established diagnosis of <d>IPF</d> received either 200 microg of <g>IFN-gamma</g>-1b subcutaneously three times per week, or 1mg of oral colchicine per day, for 24 months. Using RT-PCR assay, we evaluated the transcription levels of transforming growth factor beta1 <g>TGF-beta1</g>, connective-tissue growth factor <g>CTGF</g>, and interferon-gamma <g>IFN-gamma</g> genes in lung tissue before and after treatment with <g>IFN-gamma</g>-1b or colchicine. Marked mRNA expression of <g>TGF-beta1</g> and <g>CTGF</g>, but complete lack of interferon-gamma was detected in fibrotic lung tissue at entry. After treatment, both groups exhibited increased expression of <g>IFN-gamma</g> gene at 6 months that was sustained at 24 months. The expression of <g>CTGF</g> and <g>TGF-beta1</g> remained almost stable before and after treatment, in the <g>IFN-gamma</g>-1b group, while <g>TGF-beta1</g> was statistically decreased after therapy, in the colchicine group p=0.0002. Significant difference in DLCO % pred, was found between the two treatment groups in favor of <g>IFN-gamma</g>-1b group p=0.04. In addition, the <g>IFN-gamma</g>-1b group showed stability in arterial PO2 while the colchicine group significantly deteriorated p=0.02. In conclusion, we report the effect of antifibrotic agents <g>IFN-gamma</g>-1b and colchicine in TGF-beta, <g>CTGF</g>, and endogenous <g>IFN-gamma</g> gene expression, in human <d>fibrosis</d>. However, extended studies are needed to verify the pathophysiological consequences of these findings.
17496059|a|Patients with <d>interstitial lung diseases</d>, such as idiopathic pulmonary fibrosis IPF and bronchopulmonary dysplasia BPD, suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor TGF-beta1 induces epithelial-mesenchymal transition EMT of alveolar epithelial cells AEC to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide NO attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase eNOS and inducible nitric oxide synthase iNOS are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein-1 x min-1 with 67% derived from eNOS. TGF-beta1 50 pM suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin alpha-SMA expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD.
17496059|a|Patients with <d>interstitial lung diseases</d>, such as <d>idiopathic pulmonary fibrosis</d> IPF and bronchopulmonary dysplasia BPD, suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor TGF-beta1 induces epithelial-mesenchymal transition EMT of alveolar epithelial cells AEC to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide NO attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase eNOS and inducible nitric oxide synthase iNOS are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein-1 x min-1 with 67% derived from eNOS. TGF-beta1 50 pM suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin alpha-SMA expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD.
17496059|a|Patients with <d>interstitial lung diseases</d>, such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and bronchopulmonary dysplasia BPD, suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor TGF-beta1 induces epithelial-mesenchymal transition EMT of alveolar epithelial cells AEC to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide NO attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase eNOS and inducible nitric oxide synthase iNOS are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein-1 x min-1 with 67% derived from eNOS. TGF-beta1 50 pM suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin alpha-SMA expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as <d>IPF</d> and BPD.
17496059|a|Patients with <d>interstitial lung diseases</d>, such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>bronchopulmonary dysplasia</d> BPD, suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor TGF-beta1 induces epithelial-mesenchymal transition EMT of alveolar epithelial cells AEC to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide NO attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase eNOS and inducible nitric oxide synthase iNOS are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein-1 x min-1 with 67% derived from eNOS. TGF-beta1 50 pM suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin alpha-SMA expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as <d>IPF</d> and BPD.
17496059|a|Patients with <d>interstitial lung diseases</d>, such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>bronchopulmonary dysplasia</d> <d>BPD</d>, suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor TGF-beta1 induces epithelial-mesenchymal transition EMT of alveolar epithelial cells AEC to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide NO attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase eNOS and inducible nitric oxide synthase iNOS are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein-1 x min-1 with 67% derived from eNOS. TGF-beta1 50 pM suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin alpha-SMA expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as <d>IPF</d> and <d>BPD</d>.
17496059|a|Patients with <d>interstitial lung diseases</d>, such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>bronchopulmonary dysplasia</d> <d>BPD</d>, suffer from <d>lung fibrosis</d> secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor TGF-beta1 induces epithelial-mesenchymal transition EMT of alveolar epithelial cells AEC to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide NO attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase eNOS and inducible nitric oxide synthase iNOS are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein-1 x min-1 with 67% derived from eNOS. TGF-beta1 50 pM suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin alpha-SMA expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as <d>IPF</d> and <d>BPD</d>.
17496059|a|Patients with <d>interstitial lung diseases</d>, such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>bronchopulmonary dysplasia</d> <d>BPD</d>, suffer from <d>lung fibrosis</d> secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. <g>Transforming growth factor TGF-beta1</g> induces epithelial-mesenchymal transition EMT of alveolar epithelial cells AEC to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide NO attenuates ECM accumulation, enhances lung growth, and <d>decreases alveolar myofibroblast</d> number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase eNOS and inducible nitric oxide synthase iNOS are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein-1 x min-1 with 67% derived from eNOS. TGF-beta1 50 pM suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin alpha-SMA expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as <d>IPF</d> and <d>BPD</d>.
17498688|a|<d>Idiopathic pulmonary fibrosis</d> IPF is the most common lung disease predisposing lung cancer. To clarify the early phase of epithelial abnormalities in IPF, we used an in vitro squamous metaplasia model, transforming growth factor beta1 TGF beta1-treated airway epithelial cells BEAS-2B. The model repeated the expression of squamous epithelial character, such as involucrin, and keratin 6 and 14. DNA microarray analysis disclosed a unique expression signature in TGF beta1-treated airway epithelial cells, 20 specifically up-regulated genes including <g>p63</g>, jagged 1 jag1 and the genes of structure proteins. Western blotting and RT-PCR analysis revealed that DeltaN<g>p63</g>alpha was the dominant isoform of <g>p63</g> in our experimental model. Immunohistochemical analysis demonstrated the expression of <g>p63</g> and jag1 in lung tissues of IPF. Inhibition of <g>p63</g> with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14. Interestingly, the up-regulation of <g>p63</g> was totally suppressed by N-acetyl-l-cysteine NAC, but not by dexamethasone or pirfenidone. Thus, the <g>p63</g>-jag1 pathway may be up-regulated at an early phase of epithelial abnormalities in IPF, which can be overcome by NAC even in the TGF beta1-rich milieu.
17498688|a|<d>Idiopathic pulmonary fibrosis</d> IPF is the most common <d>lung disease</d> predisposing lung cancer. To clarify the early phase of epithelial abnormalities in IPF, we used an in vitro squamous metaplasia model, transforming growth factor beta1 TGF beta1-treated airway epithelial cells BEAS-2B. The model repeated the expression of squamous epithelial character, such as involucrin, and keratin 6 and 14. DNA microarray analysis disclosed a unique expression signature in TGF beta1-treated airway epithelial cells, 20 specifically up-regulated genes including <g>p63</g>, jagged 1 jag1 and the genes of structure proteins. Western blotting and RT-PCR analysis revealed that DeltaN<g>p63</g>alpha was the dominant isoform of <g>p63</g> in our experimental model. Immunohistochemical analysis demonstrated the expression of <g>p63</g> and jag1 in lung tissues of IPF. Inhibition of <g>p63</g> with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14. Interestingly, the up-regulation of <g>p63</g> was totally suppressed by N-acetyl-l-cysteine NAC, but not by dexamethasone or pirfenidone. Thus, the <g>p63</g>-jag1 pathway may be up-regulated at an early phase of epithelial abnormalities in IPF, which can be overcome by NAC even in the TGF beta1-rich milieu.
17498688|a|<d>Idiopathic pulmonary fibrosis</d> IPF is the most common <d>lung disease</d> predisposing <d>lung cancer</d>. To clarify the early phase of epithelial abnormalities in IPF, we used an in vitro squamous metaplasia model, transforming growth factor beta1 TGF beta1-treated airway epithelial cells BEAS-2B. The model repeated the expression of squamous epithelial character, such as involucrin, and keratin 6 and 14. DNA microarray analysis disclosed a unique expression signature in TGF beta1-treated airway epithelial cells, 20 specifically up-regulated genes including <g>p63</g>, jagged 1 jag1 and the genes of structure proteins. Western blotting and RT-PCR analysis revealed that DeltaN<g>p63</g>alpha was the dominant isoform of <g>p63</g> in our experimental model. Immunohistochemical analysis demonstrated the expression of <g>p63</g> and jag1 in lung tissues of IPF. Inhibition of <g>p63</g> with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14. Interestingly, the up-regulation of <g>p63</g> was totally suppressed by N-acetyl-l-cysteine NAC, but not by dexamethasone or pirfenidone. Thus, the <g>p63</g>-jag1 pathway may be up-regulated at an early phase of epithelial abnormalities in IPF, which can be overcome by NAC even in the TGF beta1-rich milieu.
17498688|a|<d>Idiopathic pulmonary fibrosis</d> IPF is the most common <d>lung disease</d> predisposing <d>lung cancer</d>. To clarify the early phase of <d>epithelial abnormalities</d> in IPF, we used an in vitro squamous metaplasia model, transforming growth factor beta1 TGF beta1-treated airway epithelial cells BEAS-2B. The model repeated the expression of squamous epithelial character, such as involucrin, and keratin 6 and 14. DNA microarray analysis disclosed a unique expression signature in TGF beta1-treated airway epithelial cells, 20 specifically up-regulated genes including <g>p63</g>, jagged 1 jag1 and the genes of structure proteins. Western blotting and RT-PCR analysis revealed that DeltaN<g>p63</g>alpha was the dominant isoform of <g>p63</g> in our experimental model. Immunohistochemical analysis demonstrated the expression of <g>p63</g> and jag1 in lung tissues of IPF. Inhibition of <g>p63</g> with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14. Interestingly, the up-regulation of <g>p63</g> was totally suppressed by N-acetyl-l-cysteine NAC, but not by dexamethasone or pirfenidone. Thus, the <g>p63</g>-jag1 pathway may be up-regulated at an early phase of <d>epithelial abnormalities</d> in IPF, which can be overcome by NAC even in the TGF beta1-rich milieu.
17498688|a|<d>Idiopathic pulmonary fibrosis</d> IPF is the most common <d>lung disease</d> predisposing <d>lung cancer</d>. To clarify the early phase of <d>epithelial abnormalities</d> in IPF, we used an in vitro <d>squamous metaplasia</d> model, transforming growth factor beta1 TGF beta1-treated airway epithelial cells BEAS-2B. The model repeated the expression of squamous epithelial character, such as involucrin, and keratin 6 and 14. DNA microarray analysis disclosed a unique expression signature in TGF beta1-treated airway epithelial cells, 20 specifically up-regulated genes including <g>p63</g>, jagged 1 jag1 and the genes of structure proteins. Western blotting and RT-PCR analysis revealed that DeltaN<g>p63</g>alpha was the dominant isoform of <g>p63</g> in our experimental model. Immunohistochemical analysis demonstrated the expression of <g>p63</g> and jag1 in lung tissues of IPF. Inhibition of <g>p63</g> with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14. Interestingly, the up-regulation of <g>p63</g> was totally suppressed by N-acetyl-l-cysteine NAC, but not by dexamethasone or pirfenidone. Thus, the <g>p63</g>-jag1 pathway may be up-regulated at an early phase of <d>epithelial abnormalities</d> in IPF, which can be overcome by NAC even in the TGF beta1-rich milieu.
17498688|a|<d>Idiopathic pulmonary fibrosis</d> IPF is the most common <d>lung disease</d> predisposing <d>lung cancer</d>. To clarify the early phase of <d>epithelial abnormalities</d> in IPF, we used an in vitro <d><d>squamous</d> metaplasia</d> model, <g>transforming growth factor beta1</g> <g>TGF beta1</g>-treated airway epithelial cells BEAS-2B. The model repeated the expression of <d>squamous</d> epithelial character, such as involucrin, and keratin 6 and 14. DNA microarray analysis disclosed a unique expression signature in <g>TGF beta1</g>-treated airway epithelial cells, 20 specifically up-regulated genes including <g>p63</g>, jagged 1 jag1 and the genes of structure proteins. Western blotting and RT-PCR analysis revealed that DeltaN<g>p63</g>alpha was the dominant isoform of <g>p63</g> in our experimental model. Immunohistochemical analysis demonstrated the expression of <g>p63</g> and jag1 in lung tissues of IPF. Inhibition of <g>p63</g> with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14. Interestingly, the up-regulation of <g>p63</g> was totally suppressed by N-acetyl-l-cysteine NAC, but not by dexamethasone or pirfenidone. Thus, the <g>p63</g>-jag1 pathway may be up-regulated at an early phase of <d>epithelial abnormalities</d> in IPF, which can be overcome by NAC even in the <g>TGF beta1</g>-rich milieu.
17504233|a|<g>Angiotensin II</g> <g>ANGII</g> has been identified as a proapoptotic and profibrotic factor in experimental <d>lung fibrosis</d> models, and patients with the ID/DD polymorphism of ANG converting enzyme ACE, which confers higher levels of ACE, are predisposed to <d>lung fibrosis</d> Hum. Pathol. 32:521-528, 2001. Previous work from this laboratory has shown that human lung myofibroblasts isolated from patients with Idiopathic Pulmonary Fibrosis IPF synthesize the <g>ANGII</g> precursor angiotensinogen AGT constitutively. In attempts to understand the mechanisms and consequences of constitutive AGT synthesis by myofibroblasts, we studied myofibroblast-rich primary cultures of lung fibroblasts from patients with IPF HIPF isolates, primary fibroblasts from normal human lung NLFs, the IMR90 and WI38 human lung fibroblasts cell lines, and paraffin sections of lung biopsies from patients with IPF. Compared to the normal NLF isolates, HIPF primary fibroblast isolates constitutively synthesized more AGT and <g>TGF-beta</g>1 mRNA, and released more AGT protein, <g>ANGII</g> and active <g>TGF-beta</g>1 protein into serum-free conditioned media both p<0.01. Incubation of HIPF fibrotic isolates with the <g>ANGII</g> receptor antagonist saralasin reduced both <g>TGF-beta</g>1 mRNA and active protein, suggesting that the constitutive expression of AGT drives the higher expression of <g>TGF-beta</g>1 by the HIPF cells. Consistent with this premise, treatment of either the primary NLFs or the WI38 cell line with 10-7 M <g>ANGII</g> increased both <g>TGF-beta</g>1 mRNA and soluble active <g>TGF-beta</g>1 protein. Moreover, induction of the myofibroblast transition in the IMR90 cell line with 2 ng/ml <g>TGF-beta</g>1 increased steady state AGT mRNA levels by realtime PCR 8-fold, p<0.01 and induced expression of an AGT promoter-luciferase reporter construct by over 10-fold p<0.001. Antisense oligonucleotides against <g>TGF-beta</g>1 mRNA or <g>TGF-beta</g> neutralizing antibodies, when applied to the fibrotic HIPF cells in serum-free medium, significantly reduced AGT expression. In lung sections from IPF patient biopsies, immunoreactive AGT/ANGI proteins were detected in myofibroblasts, epithelial cells and presumptive alveolar macrophages. Together, these data support the existence of an angiotensin/<g>TGF-beta</g>1 "autocrine loop" in human lung myofibroblasts and also suggest ANG peptide expression by epithelia and macrophages in the IPF lung. These findings may explain the ability of ACE inhibitors and ANG receptor antagonists to block experimental <d>lung fibrosis</d> in animals, and support the need for evaluation of these agents for potential treatment of human IPF. This manuscript discusses the data described above and their implications regarding IPF pathogenesis.
17504233|a|<g>Angiotensin II</g> <g>ANGII</g> has been identified as a proapoptotic and profibrotic factor in experimental <d>lung fibrosis</d> models, and patients with the ID/DD polymorphism of <g>ANG converting enzyme</g> <g>ACE</g>, which confers higher levels of <g>ACE</g>, are predisposed to <d>lung fibrosis</d> Hum. Pathol. 32:521-528, 2001. Previous work from this laboratory has shown that human lung myofibroblasts isolated from patients with <d>Idiopathic Pulmonary Fibrosis</d> IPF synthesize the <g>ANGII</g> precursor angiotensinogen AGT constitutively. In attempts to understand the mechanisms and consequences of constitutive AGT synthesis by myofibroblasts, we studied myofibroblast-rich primary cultures of lung fibroblasts from patients with IPF HIPF isolates, primary fibroblasts from normal human lung NLFs, the IMR90 and WI38 human lung fibroblasts cell lines, and paraffin sections of lung biopsies from patients with IPF. Compared to the normal NLF isolates, HIPF primary fibroblast isolates constitutively synthesized more AGT and <g>TGF-beta</g>1 mRNA, and released more AGT protein, <g>ANGII</g> and active <g>TGF-beta</g>1 protein into serum-free conditioned media both p<0.01. Incubation of HIPF fibrotic isolates with the <g>ANGII</g> receptor antagonist saralasin reduced both <g>TGF-beta</g>1 mRNA and active protein, suggesting that the constitutive expression of AGT drives the higher expression of <g>TGF-beta</g>1 by the HIPF cells. Consistent with this premise, treatment of either the primary NLFs or the WI38 cell line with 10-7 M <g>ANGII</g> increased both <g>TGF-beta</g>1 mRNA and soluble active <g>TGF-beta</g>1 protein. Moreover, induction of the myofibroblast transition in the IMR90 cell line with 2 ng/ml <g>TGF-beta</g>1 increased steady state AGT mRNA levels by realtime PCR 8-fold, p<0.01 and induced expression of an AGT promoter-luciferase reporter construct by over 10-fold p<0.001. Antisense oligonucleotides against <g>TGF-beta</g>1 mRNA or <g>TGF-beta</g> neutralizing antibodies, when applied to the fibrotic HIPF cells in serum-free medium, significantly reduced AGT expression. In lung sections from IPF patient biopsies, immunoreactive AGT/ANGI proteins were detected in myofibroblasts, epithelial cells and presumptive alveolar macrophages. Together, these data support the existence of an angiotensin/<g>TGF-beta</g>1 "autocrine loop" in human lung myofibroblasts and also suggest ANG peptide expression by epithelia and macrophages in the IPF lung. These findings may explain the ability of <g>ACE</g> inhibitors and ANG receptor antagonists to block experimental <d>lung fibrosis</d> in animals, and support the need for evaluation of these agents for potential treatment of human IPF. This manuscript discusses the data described above and their implications regarding IPF pathogenesis.
17504233|a|<g>Angiotensin II</g> <g>ANGII</g> has been identified as a proapoptotic and profibrotic factor in experimental <d>lung fibrosis</d> models, and patients with the ID/DD polymorphism of <g>ANG converting enzyme</g> <g>ACE</g>, which confers higher levels of <g>ACE</g>, are predisposed to <d>lung fibrosis</d> Hum. Pathol. 32:521-528, 2001. Previous work from this laboratory has shown that human lung myofibroblasts isolated from patients with <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> synthesize the <g>ANGII</g> precursor angiotensinogen AGT constitutively. In attempts to understand the mechanisms and consequences of constitutive AGT synthesis by myofibroblasts, we studied myofibroblast-rich primary cultures of lung fibroblasts from patients with <d>IPF</d> H<d>IPF</d> isolates, primary fibroblasts from normal human lung NLFs, the IMR90 and WI38 human lung fibroblasts cell lines, and paraffin sections of lung biopsies from patients with <d>IPF</d>. Compared to the normal NLF isolates, H<d>IPF</d> primary fibroblast isolates constitutively synthesized more AGT and <g>TGF-beta</g>1 mRNA, and released more AGT protein, <g>ANGII</g> and active <g>TGF-beta</g>1 protein into serum-free conditioned media both p<0.01. Incubation of H<d>IPF</d> fibrotic isolates with the <g>ANGII</g> receptor antagonist saralasin reduced both <g>TGF-beta</g>1 mRNA and active protein, suggesting that the constitutive expression of AGT drives the higher expression of <g>TGF-beta</g>1 by the H<d>IPF</d> cells. Consistent with this premise, treatment of either the primary NLFs or the WI38 cell line with 10-7 M <g>ANGII</g> increased both <g>TGF-beta</g>1 mRNA and soluble active <g>TGF-beta</g>1 protein. Moreover, induction of the myofibroblast transition in the IMR90 cell line with 2 ng/ml <g>TGF-beta</g>1 increased steady state AGT mRNA levels by realtime PCR 8-fold, p<0.01 and induced expression of an AGT promoter-luciferase reporter construct by over 10-fold p<0.001. Antisense oligonucleotides against <g>TGF-beta</g>1 mRNA or <g>TGF-beta</g> neutralizing antibodies, when applied to the fibrotic H<d>IPF</d> cells in serum-free medium, significantly reduced AGT expression. In lung sections from <d>IPF</d> patient biopsies, immunoreactive AGT/ANGI proteins were detected in myofibroblasts, epithelial cells and presumptive alveolar macrophages. Together, these data support the existence of an angiotensin/<g>TGF-beta</g>1 "autocrine loop" in human lung myofibroblasts and also suggest ANG peptide expression by epithelia and macrophages in the <d>IPF</d> lung. These findings may explain the ability of <g>ACE</g> inhibitors and ANG receptor antagonists to block experimental <d>lung fibrosis</d> in animals, and support the need for evaluation of these agents for potential treatment of human <d>IPF</d>. This manuscript discusses the data described above and their implications regarding <d>IPF</d> pathogenesis.
17579094|a|Pulmonary fibrosis in humans can occur as a result of a large number of conditions. In idiopathic <d>pulmonary fibrosis</d> IPF, pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for IPF. We have recently reported that IL-6 and TGF-beta1 plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid ATRA prevented bleomycin-induced lung fibrosis through the inhibition of these cytokines. Thalidomide Thal has been used in the treatment of multiple myeloma through the inhibitory effect on IL-6-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced <d>pulmonary fibrosis</d> in mice. We performed histological examinations and quantitative measurements of IL-6, TGF-beta1, collagen type Ialpha1 COL1A1, vascular endothelial growth factor VEGF, angiopoietin-1 Ang-1 and angiopoietin-2 Ang-2 in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced fibrosis in mouse lung tissues. Thal decreased the expressions of IL-6, TGF-beta1, VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1 production of IL-6, TGF-beta1, VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2 both IL-6-dependent proliferation and TGF-beta1-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on <d>pulmonary fibrosis</d>. These data may provide a rationale to explore clinical use of Thal for the prevention of <d>pulmonary fibrosis</d>.
17579094|a|<d>Pulmonary fibrosis</d> in humans can occur as a result of a large number of conditions. In idiopathic <d>pulmonary fibrosis</d> IPF, pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for IPF. We have recently reported that IL-6 and TGF-beta1 plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid ATRA prevented bleomycin-induced lung fibrosis through the inhibition of these cytokines. Thalidomide Thal has been used in the treatment of multiple myeloma through the inhibitory effect on IL-6-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced <d>pulmonary fibrosis</d> in mice. We performed histological examinations and quantitative measurements of IL-6, TGF-beta1, collagen type Ialpha1 COL1A1, vascular endothelial growth factor VEGF, angiopoietin-1 Ang-1 and angiopoietin-2 Ang-2 in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced fibrosis in mouse lung tissues. Thal decreased the expressions of IL-6, TGF-beta1, VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1 production of IL-6, TGF-beta1, VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2 both IL-6-dependent proliferation and TGF-beta1-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on <d>pulmonary fibrosis</d>. These data may provide a rationale to explore clinical use of Thal for the prevention of <d>pulmonary fibrosis</d>.
17579094|a|<d>Pulmonary fibrosis</d> in humans can occur as a result of a large number of conditions. In idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for <d>IPF</d>. We have recently reported that IL-6 and TGF-beta1 plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid ATRA prevented bleomycin-induced lung fibrosis through the inhibition of these cytokines. Thalidomide Thal has been used in the treatment of multiple myeloma through the inhibitory effect on IL-6-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced <d>pulmonary fibrosis</d> in mice. We performed histological examinations and quantitative measurements of IL-6, TGF-beta1, collagen type Ialpha1 COL1A1, vascular endothelial growth factor VEGF, angiopoietin-1 Ang-1 and angiopoietin-2 Ang-2 in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced fibrosis in mouse lung tissues. Thal decreased the expressions of IL-6, TGF-beta1, VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1 production of IL-6, TGF-beta1, VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2 both IL-6-dependent proliferation and TGF-beta1-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on <d>pulmonary fibrosis</d>. These data may provide a rationale to explore clinical use of Thal for the prevention of <d>pulmonary fibrosis</d>.
17579094|a|<d>Pulmonary <d>fibrosis</d></d> in humans can occur as a result of a large number of conditions. In idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>, pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for <d>IPF</d>. We have recently reported that <g>IL-6</g> and <g>TGF-beta1</g> plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid ATRA prevented bleomycin-induced lung <d>fibrosis</d> through the inhibition of these cytokines. Thalidomide Thal has been used in the treatment of multiple myeloma through the inhibitory effect on <g>IL-6</g>-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced <d>pulmonary <d>fibrosis</d></d> in mice. We performed histological examinations and quantitative measurements of <g>IL-6</g>, <g>TGF-beta1</g>, collagen type Ialpha1 COL1A1, vascular endothelial growth factor VEGF, angiopoietin-1 Ang-1 and angiopoietin-2 Ang-2 in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced <d>fibrosis</d> in mouse lung tissues. Thal decreased the expressions of <g>IL-6</g>, <g>TGF-beta1</g>, VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1 production of <g>IL-6</g>, <g>TGF-beta1</g>, VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2 both <g>IL-6</g>-dependent proliferation and <g>TGF-beta1</g>-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on <d>pulmonary <d>fibrosis</d></d>. These data may provide a rationale to explore clinical use of Thal for the prevention of <d>pulmonary <d>fibrosis</d></d>.
17579094|a|<d>Pulmonary <d>fibrosis</d></d> in humans can occur as a result of a large number of conditions. In idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>, pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for <d>IPF</d>. We have recently reported that <g>IL-6</g> and <g>TGF-beta1</g> plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid ATRA prevented bleomycin-induced lung <d>fibrosis</d> through the inhibition of these cytokines. Thalidomide Thal has been used in the treatment of multiple <d>myeloma</d> through the inhibitory effect on <g>IL-6</g>-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced <d>pulmonary <d>fibrosis</d></d> in mice. We performed histological examinations and quantitative measurements of <g>IL-6</g>, <g>TGF-beta1</g>, collagen type Ialpha1 COL1A1, vascular endothelial growth factor VEGF, angiopoietin-1 Ang-1 and angiopoietin-2 Ang-2 in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced <d>fibrosis</d> in mouse lung tissues. Thal decreased the expressions of <g>IL-6</g>, <g>TGF-beta1</g>, VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1 production of <g>IL-6</g>, <g>TGF-beta1</g>, VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2 both <g>IL-6</g>-dependent proliferation and <g>TGF-beta1</g>-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on <d>pulmonary <d>fibrosis</d></d>. These data may provide a rationale to explore clinical use of Thal for the prevention of <d>pulmonary <d>fibrosis</d></d>.
17631612|a|Epithelial-mesenchymal transition EMT, a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to fibrosis following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor <g>TGF-beta</g> induces EMT in alveolar epithelial cells AEC in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II AT2 cells in lung tissue from patients with idiopathic pulmonary fibrosis IPF, suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to fibrosis in adult tissues following injury, focusing especially on the critical role of <g>TGF-beta</g> and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of <d>fibrotic lung disease</d>. Treatment for fibrosis of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
17631612|a|Epithelial-mesenchymal transition EMT, a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to <d>fibrosis</d> following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor <g>TGF-beta</g> induces EMT in alveolar epithelial cells AEC in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II AT2 cells in lung tissue from patients with idiopathic pulmonary <d>fibrosis</d> IPF, suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung <d>fibrosis</d>. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to <d>fibrosis</d> in adult tissues following injury, focusing especially on the critical role of <g>TGF-beta</g> and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of <d>fibrotic lung disease</d>. Treatment for <d>fibrosis</d> of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
17631612|a|Epithelial-mesenchymal transition EMT, a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to <d>fibrosis</d> following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor <g>TGF-beta</g> induces EMT in alveolar epithelial cells AEC in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to <d>hyperplastic type II</d> AT2 cells in lung tissue from patients with idiopathic pulmonary <d>fibrosis</d> IPF, suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung <d>fibrosis</d>. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to <d>fibrosis</d> in adult tissues following injury, focusing especially on the critical role of <g>TGF-beta</g> and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of <d>fibrotic lung disease</d>. Treatment for <d>fibrosis</d> of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
17631612|a|Epithelial-mesenchymal transition EMT, a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to <d>fibrosis</d> following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor <g>TGF-beta</g> induces EMT in alveolar epithelial cells AEC in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to <d>hyperplastic type II</d> AT2 cells in lung tissue from patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung <d>fibrosis</d>. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to <d>fibrosis</d> in adult tissues following injury, focusing especially on the critical role of <g>TGF-beta</g> and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of <d>fibrotic lung disease</d>. Treatment for <d>fibrosis</d> of the lung in diseases such as <d>IPF</d> has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
17631612|a|Epithelial-mesenchymal transition EMT, a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to <d>fibrosis</d> following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor <g>TGF-beta</g> induces EMT in alveolar epithelial cells AEC in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to <d>hyperplastic type II</d> AT2 cells in lung tissue from patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung <d>fibrosis</d>. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to <d>fibrosis</d> in adult tissues following injury, focusing especially on the critical role of <g>TGF-beta</g> and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of <d>fibrotic lung disease</d>. Treatment for <d>fibrosis</d> of the lung in diseases such as <d>IPF</d> has heretofore focused largely on amelioration of potential inciting processes such as <d>inflammation</d>. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
17710235|a|<d>Pulmonary fibrosis</d> is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis IPF have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors PPARs play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious fibrosis. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.
17710235|a|<d>Pulmonary fibrosis</d> is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in <d>loss of alveolar function</d>, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis IPF have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors PPARs play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious fibrosis. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.
17710235|a|<d>Pulmonary fibrosis</d> is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in <d>loss of alveolar function</d>, destruction of normal lung architecture, and <d>respiratory distress</d>. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis IPF have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors PPARs play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious fibrosis. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.
17710235|a|<d>Pulmonary <d>fibrosis</d></d> is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in <d>loss of alveolar function</d>, destruction of normal lung architecture, and <d>respiratory distress</d>. Some types of <d>fibrosis</d> respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary <d>fibrosis</d> IPF have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary <d>fibrosis</d>, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors PPARs play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac <d>fibrosis</d> in animal models. In the mouse model of lung <d>fibrosis</d> induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious <d>fibrosis</d>. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in <d>fibrosis</d>. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung <d>fibrosis</d> in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.
17710235|a|<d>Pulmonary <d>fibrosis</d></d> is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in <d>loss of alveolar function</d>, destruction of normal lung architecture, and <d>respiratory distress</d>. Some types of <d>fibrosis</d> respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary <d>fibrosis</d>, and there is variability in survival even among individuals with biopsy-proven <d>IPF</d>. Evidence is accumulating that the peroxisome proliferator-activated receptors PPARs play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac <d>fibrosis</d> in animal models. In the mouse model of lung <d>fibrosis</d> induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious <d>fibrosis</d>. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in <d>fibrosis</d>. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung <d>fibrosis</d> in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.
17710235|a|<d>Pulmonary <d>fibrosis</d></d> is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in <d>loss of alveolar function</d>, destruction of normal lung architecture, and <d>respiratory distress</d>. Some types of <d>fibrosis</d> respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary <d>fibrosis</d>, and there is variability in survival even among individuals with biopsy-proven <d>IPF</d>. Evidence is accumulating that the peroxisome proliferator-activated receptors PPARs play important roles in regulating processes related to fibrogenesis, including cellular differentiation, <d>inflammation</d>, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac <d>fibrosis</d> in animal models. In the mouse model of lung <d>fibrosis</d> induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious <d>fibrosis</d>. PPARbeta/delta appears to play a critical role in regulating the transition from <d>inflammation</d> to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in <d>fibrosis</d>. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung <d>fibrosis</d> in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.
17934117|a|Idiopathic <d>pulmonary fibrosis</d> IPF is one of a group of interstitial lung diseases that are characterized by excessive matrix deposition and destruction of the normal lung architecture. Long-term survival of IPF patients is poor, with a 5-year survival rate of only 20%. Despite a lack of evidence-based benefit, IPF has historically been treated with corticosteroids and/or cytotoxic agents such as prednisone. Given the poor efficacy of these drugs, novel therapeutic strategies are required for the management of IPF. This demands a better understanding of the molecular mechanisms underlying the pathogenesis and progression of this disease. The primary effector cell in fibrosis is the myofibroblast; these cells are highly synthetic for collagen, have a contractile phenotype, and are characterized by the presence of alpha-smooth muscle actin stress fibers. They may be derived by activation/proliferation of resident lung fibroblasts, epithelial-mesenchymal differentiation, or recruitment of circulating fibroblastic stem cells fibrocytes. From a therapeutic viewpoint, interfering with the pathways that lead to myofibroblast expansion should be of considerable benefit in the treatment of IPF. This review will highlight some of the key molecules involved in this process and the clinical trials that have ensued.
17934117|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is one of a group of interstitial lung diseases that are characterized by excessive matrix deposition and destruction of the normal lung architecture. Long-term survival of <d>IPF</d> patients is poor, with a 5-year survival rate of only 20%. Despite a lack of evidence-based benefit, <d>IPF</d> has historically been treated with corticosteroids and/or cytotoxic agents such as prednisone. Given the poor efficacy of these drugs, novel therapeutic strategies are required for the management of <d>IPF</d>. This demands a better understanding of the molecular mechanisms underlying the pathogenesis and progression of this disease. The primary effector cell in fibrosis is the myofibroblast; these cells are highly synthetic for collagen, have a contractile phenotype, and are characterized by the presence of alpha-smooth muscle actin stress fibers. They may be derived by activation/proliferation of resident lung fibroblasts, epithelial-mesenchymal differentiation, or recruitment of circulating fibroblastic stem cells fibrocytes. From a therapeutic viewpoint, interfering with the pathways that lead to myofibroblast expansion should be of considerable benefit in the treatment of <d>IPF</d>. This review will highlight some of the key molecules involved in this process and the clinical trials that have ensued.
17934117|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is one of a group of <d>interstitial lung diseases</d> that are characterized by excessive matrix deposition and destruction of the normal lung architecture. Long-term survival of <d>IPF</d> patients is poor, with a 5-year survival rate of only 20%. Despite a lack of evidence-based benefit, <d>IPF</d> has historically been treated with corticosteroids and/or cytotoxic agents such as prednisone. Given the poor efficacy of these drugs, novel therapeutic strategies are required for the management of <d>IPF</d>. This demands a better understanding of the molecular mechanisms underlying the pathogenesis and progression of this disease. The primary effector cell in fibrosis is the myofibroblast; these cells are highly synthetic for collagen, have a contractile phenotype, and are characterized by the presence of alpha-smooth muscle actin stress fibers. They may be derived by activation/proliferation of resident lung fibroblasts, epithelial-mesenchymal differentiation, or recruitment of circulating fibroblastic stem cells fibrocytes. From a therapeutic viewpoint, interfering with the pathways that lead to myofibroblast expansion should be of considerable benefit in the treatment of <d>IPF</d>. This review will highlight some of the key molecules involved in this process and the clinical trials that have ensued.
17934117|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is one of a group of <d>interstitial lung diseases</d> that are characterized by excessive matrix deposition and destruction of the normal lung architecture. Long-term survival of <d>IPF</d> patients is poor, with a 5-year survival rate of only 20%. Despite a lack of evidence-based benefit, <d>IPF</d> has historically been treated with corticosteroids and/or cytotoxic agents such as prednisone. Given the poor efficacy of these drugs, novel therapeutic strategies are required for the management of <d>IPF</d>. This demands a better understanding of the molecular mechanisms underlying the pathogenesis and progression of this disease. The primary effector cell in <d>fibrosis</d> is the myofibroblast; these cells are highly synthetic for collagen, have a contractile phenotype, and are characterized by the presence of alpha-smooth muscle actin stress fibers. They may be derived by activation/proliferation of resident lung fibroblasts, epithelial-mesenchymal differentiation, or recruitment of circulating fibroblastic stem cells fibrocytes. From a therapeutic viewpoint, interfering with the pathways that lead to myofibroblast expansion should be of considerable benefit in the treatment of <d>IPF</d>. This review will highlight some of the key molecules involved in this process and the clinical trials that have ensued.
17975199|a|RATIONALE: Members of the transforming growth factor TGF-beta superfamily, including TGF-betas and bone morphogenetic proteins BMPs, are essential for the maintenance of tissue homeostasis and regeneration after injury. We have observed that the BMP antagonist, gremlin, is highly up-regulated in idiopathic <d>pulmonary fibrosis</d> IPF. OBJECTIVES: To investigate the role of gremlin in the regulation of BMP signaling in <d>pulmonary fibrosis</d>. METHODS: Progressive asbestos-induced fibrosis in the mouse was used as a model of human IPF. TGF-beta and BMP expression and signaling activities were measured from murine and human fibrotic lungs. The mechanism of gremlin induction was analyzed in cultured lung epithelial cells. In addition, the possible therapeutic role of gremlin inhibition was tested by administration of BMP-7 to mice after asbestos exposure. MEASUREMENTS AND MAIN RESULTS: <g>Gremlin</g> mRNA levels were up-regulated in the asbestos-exposed mouse lungs, which is in agreement with the human IPF biopsy data. Down-regulation of BMP signaling was demonstrated by reduced levels of Smad1/5/8 and enhanced Smad2 phosphorylation in asbestos-treated lungs. Accordingly, analyses of cultured human bronchial epithelial cells indicated that asbestos-induced gremlin expression could be prevented by inhibitors of the TGF-beta receptor and also by inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase pathways. BMP-7 treatment significantly reduced hydroxyproline contents in the asbestos-treated mice. CONCLUSIONS: The TGF-beta and BMP signaling balance is important for lung regenerative events and is significantly perturbed in <d>pulmonary fibrosis</d>. Rescue of BMP signaling activity may represent a potential beneficial strategy for treating human <d>pulmonary fibrosis</d>.
17975199|a|RATIONALE: Members of the transforming growth factor TGF-beta superfamily, including TGF-betas and bone morphogenetic proteins <g>BMP</g>s, are essential for the maintenance of tissue homeostasis and regeneration after injury. We have observed that the <g>BMP</g> antagonist, <g>gremlin</g>, is highly up-regulated in idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. OBJECTIVES: To investigate the role of <g>gremlin</g> in the regulation of <g>BMP</g> signaling in <d>pulmonary fibrosis</d>. METHODS: Progressive asbestos-induced fibrosis in the mouse was used as a model of human <d>IPF</d>. TGF-beta and <g>BMP</g> expression and signaling activities were measured from murine and human fibrotic lungs. The mechanism of <g>gremlin</g> induction was analyzed in cultured lung epithelial cells. In addition, the possible therapeutic role of <g>gremlin</g> inhibition was tested by administration of <g>BMP</g>-7 to mice after asbestos exposure. MEASUREMENTS AND MAIN RESULTS: <g>Gremlin</g> mRNA levels were up-regulated in the asbestos-exposed mouse lungs, which is in agreement with the human <d>IPF</d> biopsy data. Down-regulation of <g>BMP</g> signaling was demonstrated by reduced levels of Smad1/5/8 and enhanced Smad2 phosphorylation in asbestos-treated lungs. Accordingly, analyses of cultured human bronchial epithelial cells indicated that asbestos-induced <g>gremlin</g> expression could be prevented by inhibitors of the TGF-beta receptor and also by inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase pathways. <g>BMP</g>-7 treatment significantly reduced hydroxyproline contents in the asbestos-treated mice. CONCLUSIONS: The TGF-beta and <g>BMP</g> signaling balance is important for lung regenerative events and is significantly perturbed in <d>pulmonary fibrosis</d>. Rescue of <g>BMP</g> signaling activity may represent a potential beneficial strategy for treating human <d>pulmonary fibrosis</d>.
17975199|a|RATIONALE: Members of the transforming growth factor TGF-beta superfamily, including TGF-betas and bone morphogenetic proteins <g>BMP</g>s, are essential for the maintenance of tissue homeostasis and regeneration after injury. We have observed that the <g>BMP</g> antagonist, <g>gremlin</g>, is highly up-regulated in idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. OBJECTIVES: To investigate the role of <g>gremlin</g> in the regulation of <g>BMP</g> signaling in <d>pulmonary <d>fibrosis</d></d>. METHODS: Progressive asbestos-induced <d>fibrosis</d> in the mouse was used as a model of human <d>IPF</d>. TGF-beta and <g>BMP</g> expression and signaling activities were measured from murine and human fibrotic lungs. The mechanism of <g>gremlin</g> induction was analyzed in cultured lung epithelial cells. In addition, the possible therapeutic role of <g>gremlin</g> inhibition was tested by administration of <g>BMP</g>-7 to mice after asbestos exposure. MEASUREMENTS AND MAIN RESULTS: <g>Gremlin</g> mRNA levels were up-regulated in the asbestos-exposed mouse lungs, which is in agreement with the human <d>IPF</d> biopsy data. Down-regulation of <g>BMP</g> signaling was demonstrated by reduced levels of Smad1/5/8 and enhanced Smad2 phosphorylation in asbestos-treated lungs. Accordingly, analyses of cultured human bronchial epithelial cells indicated that asbestos-induced <g>gremlin</g> expression could be prevented by inhibitors of the TGF-beta receptor and also by inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase pathways. <g>BMP</g>-7 treatment significantly reduced hydroxyproline contents in the asbestos-treated mice. CONCLUSIONS: The TGF-beta and <g>BMP</g> signaling balance is important for lung regenerative events and is significantly perturbed in <d>pulmonary <d>fibrosis</d></d>. Rescue of <g>BMP</g> signaling activity may represent a potential beneficial strategy for treating human <d>pulmonary <d>fibrosis</d></d>.
17982242|a|<d>Idiopathic pulmonary fibrosis</d> IPF comprises an aggregate of mesenchymal cells. However, the cellular origin of these mesenchymal phenotypes remains unclear. <g>Transforming growth factor beta1</g> TGF-beta1 has been known as the main cytokine involved in the pathogenesis of IPF. We examined whether the potent fibrogenic cytokine TGF-beta1 could induce the epithelial-to-mesenchymal transition EMT in the human alveolar epithelial cell line, A549, and determined whether snail expression is associated with the phenotypic changes observed in the A549 cells. EMT was investigated with cells morphology changes under phase-contrast microscopy, western blotting, and indirect immunofluorescence stains. E-cadherin and transcription factor, snail, were also evaluated by measuring mRNA levels using reverse transcriptase-polymerase chain reaction RT-PCR analysis. The data showed that TGF-beta1 induced A549 cells with epithelial cell characteristics to undergo EMT in a concentration-dependent manner. Following TGF-beta1 treatment, A549 cells induced EMT characterized by cells morphological changes, loss of epithelial markers Ecaherin and cytokeratin, increased stress fiber reorganization by F-actin, and cytokeratin replacement by vimentin. Although IL-1beta failed to induce A549 cells to undergo EMT, the combination of TGF-beta1 and IL-1beta showed synergy effects in cells morphology changes and the expression of mesenchymal markers. The snail expression study using RT-PCR analysis provided that loss of E-cadherin expression was associated with snail expression. Stimulation of A54 cells with TGF-beta1 plus IL-1beta revealed a higher level of snail expression. Our data showed that EMT of A549 cells might be closely associated with snail expression.
17982242|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> comprises an aggregate of mesenchymal cells. However, the cellular origin of these mesenchymal phenotypes remains unclear. <g>Transforming growth factor beta1</g> TGF-beta1 has been known as the main cytokine involved in the pathogenesis of <d>IPF</d>. We examined whether the potent fibrogenic cytokine TGF-beta1 could induce the epithelial-to-mesenchymal transition EMT in the human alveolar epithelial cell line, A549, and determined whether snail expression is associated with the phenotypic changes observed in the A549 cells. EMT was investigated with cells morphology changes under phase-contrast microscopy, western blotting, and indirect immunofluorescence stains. E-cadherin and transcription factor, snail, were also evaluated by measuring mRNA levels using reverse transcriptase-polymerase chain reaction RT-PCR analysis. The data showed that TGF-beta1 induced A549 cells with epithelial cell characteristics to undergo EMT in a concentration-dependent manner. Following TGF-beta1 treatment, A549 cells induced EMT characterized by cells morphological changes, loss of epithelial markers Ecaherin and cytokeratin, increased stress fiber reorganization by F-actin, and cytokeratin replacement by vimentin. Although IL-1beta failed to induce A549 cells to undergo EMT, the combination of TGF-beta1 and IL-1beta showed synergy effects in cells morphology changes and the expression of mesenchymal markers. The snail expression study using RT-PCR analysis provided that loss of E-cadherin expression was associated with snail expression. Stimulation of A54 cells with TGF-beta1 plus IL-1beta revealed a higher level of snail expression. Our data showed that EMT of A549 cells might be closely associated with snail expression.
18093617|a|Pirfenidone 5-methyl-1-phenyl-2-1H-pyridone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of <d>fibrosis</d> in animal models and patients with idiopathic pulmonary <d>fibrosis</d> IPF. Heat shock protein HSP 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen and plays an important role in the pathogenesis of IPF. The present study evaluated the in vitro effects of pirfenidone on expression of <g>HSP47</g> and collagen type I in cultured normal human lung fibroblasts NHLF. Expression levels of <g>HSP47</g> and collagen type I in NHLF stimulated by transforming growth factor <g>TGF-beta1</g> were evaluated genetically, immunologically and immunocytochemically. Treatment with <g>TGF-beta1</g> stimulated both mRNA and protein expressions of both <g>HSP47</g> and collagen type I in NHLF, and pirfenidone significantly inhibited this <g>TGF-beta1</g>-enhanced expression in a dose-dependent manner. We concluded that the anti-fibrotic effect of pirfenidone may be mediated not only through direct inhibition of collagen type I expression but also at least partly through inhibition of <g>HSP47</g> expression in lung fibroblasts, with a resultant reduction of collagen synthesis in lung <d>fibrosis</d>.
18093617|a|Pirfenidone 5-methyl-1-phenyl-2-1H-pyridone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of <d>fibrosis</d> in animal models and patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. Heat shock protein HSP 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen and plays an important role in the pathogenesis of <d>IPF</d>. The present study evaluated the in vitro effects of pirfenidone on expression of <g>HSP47</g> and collagen type I in cultured normal human lung fibroblasts NHLF. Expression levels of <g>HSP47</g> and collagen type I in NHLF stimulated by transforming growth factor <g>TGF-beta1</g> were evaluated genetically, immunologically and immunocytochemically. Treatment with <g>TGF-beta1</g> stimulated both mRNA and protein expressions of both <g>HSP47</g> and collagen type I in NHLF, and pirfenidone significantly inhibited this <g>TGF-beta1</g>-enhanced expression in a dose-dependent manner. We concluded that the anti-fibrotic effect of pirfenidone may be mediated not only through direct inhibition of collagen type I expression but also at least partly through inhibition of <g>HSP47</g> expression in lung fibroblasts, with a resultant reduction of collagen synthesis in lung <d>fibrosis</d>.
18177235|a|Idiopathic <d>pulmonary fibrosis</d> IPF is the most common idiopathic interstitial pneumonia. IPF is a disease with poor prognosis and an aggressive nature, and poses major challenges to clinicians. Thus, a large part of research in the area has focused on the pathogenesis on IPF. Characteristic features in IPF include fibrotic lesions devoid of inflammatory cell infiltrates. There are experimental models of lung fibrosis e.g., bleomycin-induced fibrosis, but they typically contain a prominent inflammatory pattern in the lung, which leads to relatively diffuse lung fibrosis. Nonetheless, experimental models have provided important information about the progression and pathways contributing to the lung fibrosis, including activation of transforming growth factor beta TGF-beta. Both patient material and experimental models of lung fibrosis have displayed marked elevation of several markers of oxidant burden and signs for disturbed antioxidant/oxidant balance. Several studies also suggest that reactive oxygen species can cause activation of growth-regulatory cytokines, including TGF-beta. In addition, there are indications that endogenous and exogenous antioxidants/redox modulators can influence fibrogenesis, protect the lung against fibrosis, and prevent its progression. Factors that restore the antioxidant capacity and prevent sustained activation of growth-regulatory cytokines may have a therapeutic role in IPF.
18177235|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is the most common idiopathic interstitial pneumonia. <d>IPF</d> is a disease with poor prognosis and an aggressive nature, and poses major challenges to clinicians. Thus, a large part of research in the area has focused on the pathogenesis on <d>IPF</d>. Characteristic features in <d>IPF</d> include fibrotic lesions devoid of inflammatory cell infiltrates. There are experimental models of lung fibrosis e.g., bleomycin-induced fibrosis, but they typically contain a prominent inflammatory pattern in the lung, which leads to relatively diffuse lung fibrosis. Nonetheless, experimental models have provided important information about the progression and pathways contributing to the lung fibrosis, including activation of transforming growth factor beta TGF-beta. Both patient material and experimental models of lung fibrosis have displayed marked elevation of several markers of oxidant burden and signs for disturbed antioxidant/oxidant balance. Several studies also suggest that reactive oxygen species can cause activation of growth-regulatory cytokines, including TGF-beta. In addition, there are indications that endogenous and exogenous antioxidants/redox modulators can influence fibrogenesis, protect the lung against fibrosis, and prevent its progression. Factors that restore the antioxidant capacity and prevent sustained activation of growth-regulatory cytokines may have a therapeutic role in <d>IPF</d>.
18177235|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is the most common <d>idiopathic interstitial pneumonia</d>. <d>IPF</d> is a disease with poor prognosis and an aggressive nature, and poses major challenges to clinicians. Thus, a large part of research in the area has focused on the pathogenesis on <d>IPF</d>. Characteristic features in <d>IPF</d> include fibrotic lesions devoid of inflammatory cell infiltrates. There are experimental models of lung fibrosis e.g., bleomycin-induced fibrosis, but they typically contain a prominent inflammatory pattern in the lung, which leads to relatively diffuse lung fibrosis. Nonetheless, experimental models have provided important information about the progression and pathways contributing to the lung fibrosis, including activation of transforming growth factor beta TGF-beta. Both patient material and experimental models of lung fibrosis have displayed marked elevation of several markers of oxidant burden and signs for disturbed antioxidant/oxidant balance. Several studies also suggest that reactive oxygen species can cause activation of growth-regulatory cytokines, including TGF-beta. In addition, there are indications that endogenous and exogenous antioxidants/redox modulators can influence fibrogenesis, protect the lung against fibrosis, and prevent its progression. Factors that restore the antioxidant capacity and prevent sustained activation of growth-regulatory cytokines may have a therapeutic role in <d>IPF</d>.
18177235|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is the most common <d>idiopathic interstitial pneumonia</d>. <d>IPF</d> is a disease with poor prognosis and an aggressive nature, and poses major challenges to clinicians. Thus, a large part of research in the area has focused on the pathogenesis on <d>IPF</d>. Characteristic features in <d>IPF</d> include <d>fibrotic lesions</d> devoid of inflammatory cell infiltrates. There are experimental models of lung fibrosis e.g., bleomycin-induced fibrosis, but they typically contain a prominent inflammatory pattern in the lung, which leads to relatively diffuse lung fibrosis. Nonetheless, experimental models have provided important information about the progression and pathways contributing to the lung fibrosis, including activation of transforming growth factor beta TGF-beta. Both patient material and experimental models of lung fibrosis have displayed marked elevation of several markers of oxidant burden and signs for disturbed antioxidant/oxidant balance. Several studies also suggest that reactive oxygen species can cause activation of growth-regulatory cytokines, including TGF-beta. In addition, there are indications that endogenous and exogenous antioxidants/redox modulators can influence fibrogenesis, protect the lung against fibrosis, and prevent its progression. Factors that restore the antioxidant capacity and prevent sustained activation of growth-regulatory cytokines may have a therapeutic role in <d>IPF</d>.
18177235|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is the most common <d>idiopathic interstitial pneumonia</d>. <d>IPF</d> is a disease with poor prognosis and an aggressive nature, and poses major challenges to clinicians. Thus, a large part of research in the area has focused on the pathogenesis on <d>IPF</d>. Characteristic features in <d>IPF</d> include <d>fibrotic lesions</d> devoid of inflammatory cell infiltrates. There are experimental models of <d>lung fibrosis</d> e.g., bleomycin-induced fibrosis, but they typically contain a prominent inflammatory pattern in the lung, which leads to relatively diffuse <d>lung fibrosis</d>. Nonetheless, experimental models have provided important information about the progression and pathways contributing to the <d>lung fibrosis</d>, including activation of transforming growth factor beta TGF-beta. Both patient material and experimental models of <d>lung fibrosis</d> have displayed marked elevation of several markers of oxidant burden and signs for disturbed antioxidant/oxidant balance. Several studies also suggest that reactive oxygen species can cause activation of growth-regulatory cytokines, including TGF-beta. In addition, there are indications that endogenous and exogenous antioxidants/redox modulators can influence fibrogenesis, protect the lung against fibrosis, and prevent its progression. Factors that restore the antioxidant capacity and prevent sustained activation of growth-regulatory cytokines may have a therapeutic role in <d>IPF</d>.
18177235|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is the most common <d>idiopathic interstitial pneumonia</d>. <d>IPF</d> is a disease with poor prognosis and an aggressive nature, and poses major challenges to clinicians. Thus, a large part of research in the area has focused on the pathogenesis on <d>IPF</d>. Characteristic features in <d>IPF</d> include <d>fibrotic lesions</d> devoid of inflammatory cell infiltrates. There are experimental models of <d>lung <d>fibrosis</d></d> e.g., bleomycin-induced <d>fibrosis</d>, but they typically contain a prominent inflammatory pattern in the lung, which leads to relatively diffuse <d>lung <d>fibrosis</d></d>. Nonetheless, experimental models have provided important information about the progression and pathways contributing to the <d>lung <d>fibrosis</d></d>, including activation of transforming growth factor beta TGF-beta. Both patient material and experimental models of <d>lung <d>fibrosis</d></d> have displayed marked elevation of several markers of oxidant burden and signs for disturbed antioxidant/oxidant balance. Several studies also suggest that reactive oxygen species can cause activation of growth-regulatory cytokines, including TGF-beta. In addition, there are indications that endogenous and exogenous antioxidants/redox modulators can influence fibrogenesis, protect the lung against <d>fibrosis</d>, and prevent its progression. Factors that restore the antioxidant capacity and prevent sustained activation of growth-regulatory cytokines may have a therapeutic role in <d>IPF</d>.
18245174|a|Enhanced transforming growth factor TGF -beta signaling contributes to idiopathic pulmonary fibrosis IPF, a progressive and fatal disease characterized by alveolar epithelial type II ATII cell hyperplasia, myofibroblast accumulation, and excessive extracellular matrix deposition. <g>TGF-beta</g> is a potent inducer of lung fibrosis, and it regulates the ATII cell phenotype; however, direct <g>TGF-beta</g> target genes controlling the ATII cell phenotype remain elusive. Here, we identified the transgelin tagln gene as a novel immediate target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells using a <g>Smad3</g> chromatin immunoprecipitation ChIP screen. Direct ChIP confirmed the rapid and specific binding of <g>Smad3</g> to the tagln promoter. Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase Alk 5-mediated <g>TGF-beta</g> signaling. <g>TGF-beta</g> treatment resulted in rapid up-regulation of tagln, but not tagln2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction RT-PCR, Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in ATII cells of mice during bleomycin-induced lung fibrosis, as well as in lung specimen obtained from IPF patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using siRNA inhibited <g>TGF-beta</g>-induced migration of lung epithelial A549 cells, as well as primary ATII cells. We thus identified tagln as a novel target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells. Increased ATII cell expression of tagln in experimental and idiopathic pulmonary fibrosis may contribute to <g>TGF-beta</g>-dependent ATII cell injury, repair, and <d>migration in lung fibrosis</d>.
18245174|a|Enhanced transforming growth factor TGF -beta signaling contributes to <d>idiopathic pulmonary fibrosis</d> IPF, a progressive and fatal disease characterized by alveolar epithelial type II ATII cell hyperplasia, myofibroblast accumulation, and excessive extracellular matrix deposition. <g>TGF-beta</g> is a potent inducer of lung fibrosis, and it regulates the ATII cell phenotype; however, direct <g>TGF-beta</g> target genes controlling the ATII cell phenotype remain elusive. Here, we identified the transgelin tagln gene as a novel immediate target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells using a <g>Smad3</g> chromatin immunoprecipitation ChIP screen. Direct ChIP confirmed the rapid and specific binding of <g>Smad3</g> to the tagln promoter. Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase Alk 5-mediated <g>TGF-beta</g> signaling. <g>TGF-beta</g> treatment resulted in rapid up-regulation of tagln, but not tagln2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction RT-PCR, Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in ATII cells of mice during bleomycin-induced lung fibrosis, as well as in lung specimen obtained from IPF patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using siRNA inhibited <g>TGF-beta</g>-induced migration of lung epithelial A549 cells, as well as primary ATII cells. We thus identified tagln as a novel target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells. Increased ATII cell expression of tagln in experimental and <d>idiopathic pulmonary fibrosis</d> may contribute to <g>TGF-beta</g>-dependent ATII cell injury, repair, and <d>migration in lung fibrosis</d>.
18245174|a|Enhanced transforming growth factor TGF -beta signaling contributes to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a progressive and fatal disease characterized by alveolar epithelial type II ATII cell hyperplasia, myofibroblast accumulation, and excessive extracellular matrix deposition. <g>TGF-beta</g> is a potent inducer of lung fibrosis, and it regulates the ATII cell phenotype; however, direct <g>TGF-beta</g> target genes controlling the ATII cell phenotype remain elusive. Here, we identified the transgelin tagln gene as a novel immediate target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells using a <g>Smad3</g> chromatin immunoprecipitation ChIP screen. Direct ChIP confirmed the rapid and specific binding of <g>Smad3</g> to the tagln promoter. Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase Alk 5-mediated <g>TGF-beta</g> signaling. <g>TGF-beta</g> treatment resulted in rapid up-regulation of tagln, but not tagln2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction RT-PCR, Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in ATII cells of mice during bleomycin-induced lung fibrosis, as well as in lung specimen obtained from <d>IPF</d> patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using siRNA inhibited <g>TGF-beta</g>-induced migration of lung epithelial A549 cells, as well as primary ATII cells. We thus identified tagln as a novel target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells. Increased ATII cell expression of tagln in experimental and <d>idiopathic pulmonary fibrosis</d> may contribute to <g>TGF-beta</g>-dependent ATII cell injury, repair, and <d>migration in lung fibrosis</d>.
18245174|a|Enhanced transforming growth factor TGF -beta signaling contributes to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive and fatal disease</d> characterized by alveolar epithelial type II ATII cell hyperplasia, myofibroblast accumulation, and excessive extracellular matrix deposition. <g>TGF-beta</g> is a potent inducer of lung fibrosis, and it regulates the ATII cell phenotype; however, direct <g>TGF-beta</g> target genes controlling the ATII cell phenotype remain elusive. Here, we identified the transgelin tagln gene as a novel immediate target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells using a <g>Smad3</g> chromatin immunoprecipitation ChIP screen. Direct ChIP confirmed the rapid and specific binding of <g>Smad3</g> to the tagln promoter. Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase Alk 5-mediated <g>TGF-beta</g> signaling. <g>TGF-beta</g> treatment resulted in rapid up-regulation of tagln, but not tagln2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction RT-PCR, Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in ATII cells of mice during bleomycin-induced lung fibrosis, as well as in lung specimen obtained from <d>IPF</d> patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using siRNA inhibited <g>TGF-beta</g>-induced migration of lung epithelial A549 cells, as well as primary ATII cells. We thus identified tagln as a novel target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells. Increased ATII cell expression of tagln in experimental and <d>idiopathic pulmonary fibrosis</d> may contribute to <g>TGF-beta</g>-dependent ATII cell injury, repair, and <d>migration in lung fibrosis</d>.
18245174|a|Enhanced transforming growth factor TGF -beta signaling contributes to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive and fatal disease</d> characterized by <d>alveolar epithelial type II</d> ATII cell hyperplasia, myofibroblast accumulation, and excessive extracellular matrix deposition. <g>TGF-beta</g> is a potent inducer of lung fibrosis, and it regulates the ATII cell phenotype; however, direct <g>TGF-beta</g> target genes controlling the ATII cell phenotype remain elusive. Here, we identified the transgelin tagln gene as a novel immediate target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells using a <g>Smad3</g> chromatin immunoprecipitation ChIP screen. Direct ChIP confirmed the rapid and specific binding of <g>Smad3</g> to the tagln promoter. Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase Alk 5-mediated <g>TGF-beta</g> signaling. <g>TGF-beta</g> treatment resulted in rapid up-regulation of tagln, but not tagln2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction RT-PCR, Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in ATII cells of mice during bleomycin-induced lung fibrosis, as well as in lung specimen obtained from <d>IPF</d> patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using siRNA inhibited <g>TGF-beta</g>-induced migration of lung epithelial A549 cells, as well as primary ATII cells. We thus identified tagln as a novel target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in ATII cells. Increased ATII cell expression of tagln in experimental and <d>idiopathic pulmonary fibrosis</d> may contribute to <g>TGF-beta</g>-dependent ATII cell injury, repair, and <d>migration in lung fibrosis</d>.
18245174|a|Enhanced transforming growth factor TGF -beta signaling contributes to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive and fatal disease</d> characterized by <d>alveolar epithelial type II</d> <d>ATII</d> cell hyperplasia, myofibroblast accumulation, and excessive extracellular matrix deposition. <g>TGF-beta</g> is a potent inducer of lung fibrosis, and it regulates the <d>ATII</d> cell phenotype; however, direct <g>TGF-beta</g> target genes controlling the <d>ATII</d> cell phenotype remain elusive. Here, we identified the transgelin tagln gene as a novel immediate target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in <d>ATII</d> cells using a <g>Smad3</g> chromatin immunoprecipitation ChIP screen. Direct ChIP confirmed the rapid and specific binding of <g>Smad3</g> to the tagln promoter. Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase Alk 5-mediated <g>TGF-beta</g> signaling. <g>TGF-beta</g> treatment resulted in rapid up-regulation of tagln, but not tagln2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction RT-PCR, Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in <d>ATII</d> cells of mice during bleomycin-induced lung fibrosis, as well as in lung specimen obtained from <d>IPF</d> patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using siRNA inhibited <g>TGF-beta</g>-induced migration of lung epithelial A549 cells, as well as primary <d>ATII</d> cells. We thus identified tagln as a novel target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in <d>ATII</d> cells. Increased <d>ATII</d> cell expression of tagln in experimental and <d>idiopathic pulmonary fibrosis</d> may contribute to <g>TGF-beta</g>-dependent <d>ATII</d> cell injury, repair, and <d>migration in lung fibrosis</d>.
18245174|a|Enhanced transforming growth factor TGF -beta signaling contributes to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive and fatal disease</d> characterized by <d>alveolar epithelial type II</d> <d>ATII</d> cell <d>hyperplasia</d>, myofibroblast accumulation, and excessive extracellular matrix deposition. <g>TGF-beta</g> is a potent inducer of lung fibrosis, and it regulates the <d>ATII</d> cell phenotype; however, direct <g>TGF-beta</g> target genes controlling the <d>ATII</d> cell phenotype remain elusive. Here, we identified the transgelin tagln gene as a novel immediate target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in <d>ATII</d> cells using a <g>Smad3</g> chromatin immunoprecipitation ChIP screen. Direct ChIP confirmed the rapid and specific binding of <g>Smad3</g> to the tagln promoter. Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase Alk 5-mediated <g>TGF-beta</g> signaling. <g>TGF-beta</g> treatment resulted in rapid up-regulation of tagln, but not tagln2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction RT-PCR, Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in <d>ATII</d> cells of mice during bleomycin-induced lung fibrosis, as well as in lung specimen obtained from <d>IPF</d> patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using siRNA inhibited <g>TGF-beta</g>-induced migration of lung epithelial A549 cells, as well as primary <d>ATII</d> cells. We thus identified tagln as a novel target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in <d>ATII</d> cells. Increased <d>ATII</d> cell expression of tagln in experimental and <d>idiopathic pulmonary fibrosis</d> may contribute to <g>TGF-beta</g>-dependent <d>ATII</d> cell injury, repair, and <d>migration in lung fibrosis</d>.
18245174|a|Enhanced transforming growth factor TGF -beta signaling contributes to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive and fatal disease</d> characterized by <d>alveolar epithelial type II</d> <d>ATII</d> cell <d>hyperplasia</d>, myofibroblast accumulation, and excessive extracellular matrix deposition. <g>TGF-beta</g> is a potent <d>inducer of lung fibrosis</d>, and it regulates the <d>ATII</d> cell phenotype; however, direct <g>TGF-beta</g> target genes controlling the <d>ATII</d> cell phenotype remain elusive. Here, we identified the transgelin tagln gene as a novel immediate target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in <d>ATII</d> cells using a <g>Smad3</g> chromatin immunoprecipitation ChIP screen. Direct ChIP confirmed the rapid and specific binding of <g>Smad3</g> to the tagln promoter. Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase Alk 5-mediated <g>TGF-beta</g> signaling. <g>TGF-beta</g> treatment resulted in rapid up-regulation of tagln, but not tagln2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction RT-PCR, Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in <d>ATII</d> cells of mice during bleomycin-induced lung fibrosis, as well as in lung specimen obtained from <d>IPF</d> patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using siRNA inhibited <g>TGF-beta</g>-induced migration of lung epithelial A549 cells, as well as primary <d>ATII</d> cells. We thus identified tagln as a novel target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in <d>ATII</d> cells. Increased <d>ATII</d> cell expression of tagln in experimental and <d>idiopathic pulmonary fibrosis</d> may contribute to <g>TGF-beta</g>-dependent <d>ATII</d> cell injury, repair, and <d>migration in lung fibrosis</d>.
18245174|a|Enhanced transforming growth factor TGF -beta signaling contributes to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive and fatal disease</d> characterized by <d>alveolar epithelial type II</d> <d>ATII</d> cell <d>hyperplasia</d>, myofibroblast accumulation, and excessive extracellular matrix deposition. <g>TGF-beta</g> is a potent <d>inducer of <d>lung fibrosis</d></d>, and it regulates the <d>ATII</d> cell phenotype; however, direct <g>TGF-beta</g> target genes controlling the <d>ATII</d> cell phenotype remain elusive. Here, we identified the <g>transgelin</g> <g>tagln</g> gene as a novel immediate target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in <d>ATII</d> cells using a <g>Smad3</g> chromatin immunoprecipitation ChIP screen. Direct ChIP confirmed the rapid and specific binding of <g>Smad3</g> to the <g>tagln</g> promoter. Luciferase assays demonstrated transactivation of the <g>tagln</g> promoter by activin-like kinase Alk 5-mediated <g>TGF-beta</g> signaling. <g>TGF-beta</g> treatment resulted in rapid up-regulation of <g>tagln</g>, but not <g>tagln</g>2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction RT-PCR, Western blotting, and immunofluorescence. In vivo, <g>tagln</g> expression was significantly increased in <d>ATII</d> cells of mice during bleomycin-induced <d>lung fibrosis</d>, as well as in lung specimen obtained from <d>IPF</d> patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of <g>tagln</g> using siRNA inhibited <g>TGF-beta</g>-induced migration of lung epithelial A549 cells, as well as primary <d>ATII</d> cells. We thus identified <g>tagln</g> as a novel target of <g>TGF-beta</g>/<g>Smad3</g>-dependent gene expression in <d>ATII</d> cells. Increased <d>ATII</d> cell expression of <g>tagln</g> in experimental and <d>idiopathic pulmonary fibrosis</d> may contribute to <g>TGF-beta</g>-dependent <d>ATII</d> cell injury, repair, and <d>migration in <d>lung fibrosis</d></d>.
18344408|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a chronic progressive disorder with a poor prognosis. Epithelial instability is a crucial step in the development and progression of the disease, including neoplastic transformation. Few tissue markers for epithelial instability have been reported in IPF. Squamous cell carcinoma antigen SCCA is a serine protease inhibitor typically expressed by dysplastic and neoplastic cells of epithelial origin, more often in squamous cell tumours. At present, no information is available on its expression in IPF. METHODS: SCCA and transforming growth factor beta TGFbeta expression in surgical lung biopsies from 22 patients with IPF and 20 control cases was examined. An in vitro study using A549 pneumocytes was also conducted to investigate the relationship between SCCA and TGFbeta expression. SCCA and TGFbeta epithelial expression was evaluated by immunohistochemistry and reverse transcription-PCR RT-PCR. SCCA values were correlated with different pathological and clinical parameters. Time course analysis of TGFbeta expression in A549 pneumocytes incubated with different SCCA concentrations was assessed by real time RT-PCR. RESULTS: SCCA was expressed in many metaplastic alveolar epithelial cells in all IPF cases with a mean value of 24.9% while it was seen in only two control patients in up to 5% of metaplastic cells. In patients with IPF, SCCA correlated positively with extension of fibroblastic foci r = 0.49, p = 0.02, expression of TGFbeta r = 0.78, p<0.0001 and with carbon monoxide transfer factor decline after 9 months of follow-up r = 0.59, p = 0.01. In vitro experiments showed that incubation of cultured cells with SCCA induced TGFbeta expression, with a peak at 24 h. CONCLUSION: Our findings provide for the first time a potential mechanism by which SCCA secreted from metaplastic epithelial cells may exert a profibrotic effect in IPF. SCCA could be an important biomarker in this incurable disease.
18344408|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive disorder with a poor prognosis. Epithelial instability is a crucial step in the development and progression of the disease, including neoplastic transformation. Few tissue markers for epithelial instability have been reported in <d>IPF</d>. Squamous cell carcinoma antigen SCCA is a serine protease inhibitor typically expressed by dysplastic and neoplastic cells of epithelial origin, more often in squamous cell tumours. At present, no information is available on its expression in <d>IPF</d>. METHODS: SCCA and transforming growth factor beta TGFbeta expression in surgical lung biopsies from 22 patients with <d>IPF</d> and 20 control cases was examined. An in vitro study using A549 pneumocytes was also conducted to investigate the relationship between SCCA and TGFbeta expression. SCCA and TGFbeta epithelial expression was evaluated by immunohistochemistry and reverse transcription-PCR RT-PCR. SCCA values were correlated with different pathological and clinical parameters. Time course analysis of TGFbeta expression in A549 pneumocytes incubated with different SCCA concentrations was assessed by real time RT-PCR. RESULTS: SCCA was expressed in many metaplastic alveolar epithelial cells in all <d>IPF</d> cases with a mean value of 24.9% while it was seen in only two control patients in up to 5% of metaplastic cells. In patients with <d>IPF</d>, SCCA correlated positively with extension of fibroblastic foci r = 0.49, p = 0.02, expression of TGFbeta r = 0.78, p<0.0001 and with carbon monoxide transfer factor decline after 9 months of follow-up r = 0.59, p = 0.01. In vitro experiments showed that incubation of cultured cells with SCCA induced TGFbeta expression, with a peak at 24 h. CONCLUSION: Our findings provide for the first time a potential mechanism by which SCCA secreted from metaplastic epithelial cells may exert a profibrotic effect in <d>IPF</d>. SCCA could be an important biomarker in this incurable disease.
18344408|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive disorder with a poor prognosis. Epithelial instability is a crucial step in the development and progression of the disease, including <d>neoplastic transformation</d>. Few tissue markers for epithelial instability have been reported in <d>IPF</d>. Squamous cell carcinoma antigen SCCA is a serine protease inhibitor typically expressed by dysplastic and neoplastic cells of epithelial origin, more often in squamous cell tumours. At present, no information is available on its expression in <d>IPF</d>. METHODS: SCCA and transforming growth factor beta TGFbeta expression in surgical lung biopsies from 22 patients with <d>IPF</d> and 20 control cases was examined. An in vitro study using A549 pneumocytes was also conducted to investigate the relationship between SCCA and TGFbeta expression. SCCA and TGFbeta epithelial expression was evaluated by immunohistochemistry and reverse transcription-PCR RT-PCR. SCCA values were correlated with different pathological and clinical parameters. Time course analysis of TGFbeta expression in A549 pneumocytes incubated with different SCCA concentrations was assessed by real time RT-PCR. RESULTS: SCCA was expressed in many metaplastic alveolar epithelial cells in all <d>IPF</d> cases with a mean value of 24.9% while it was seen in only two control patients in up to 5% of metaplastic cells. In patients with <d>IPF</d>, SCCA correlated positively with extension of fibroblastic foci r = 0.49, p = 0.02, expression of TGFbeta r = 0.78, p<0.0001 and with carbon monoxide transfer factor decline after 9 months of follow-up r = 0.59, p = 0.01. In vitro experiments showed that incubation of cultured cells with SCCA induced TGFbeta expression, with a peak at 24 h. CONCLUSION: Our findings provide for the first time a potential mechanism by which SCCA secreted from metaplastic epithelial cells may exert a profibrotic effect in <d>IPF</d>. SCCA could be an important biomarker in this incurable disease.
18344408|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive disorder with a poor prognosis. Epithelial instability is a crucial step in the development and progression of the disease, including <d>neoplastic transformation</d>. Few tissue markers for epithelial instability have been reported in <d>IPF</d>. <d>Squamous cell carcinoma</d> antigen SCCA is a serine protease inhibitor typically expressed by dysplastic and neoplastic cells of epithelial origin, more often in squamous cell tumours. At present, no information is available on its expression in <d>IPF</d>. METHODS: SCCA and transforming growth factor beta TGFbeta expression in surgical lung biopsies from 22 patients with <d>IPF</d> and 20 control cases was examined. An in vitro study using A549 pneumocytes was also conducted to investigate the relationship between SCCA and TGFbeta expression. SCCA and TGFbeta epithelial expression was evaluated by immunohistochemistry and reverse transcription-PCR RT-PCR. SCCA values were correlated with different pathological and clinical parameters. Time course analysis of TGFbeta expression in A549 pneumocytes incubated with different SCCA concentrations was assessed by real time RT-PCR. RESULTS: SCCA was expressed in many metaplastic alveolar epithelial cells in all <d>IPF</d> cases with a mean value of 24.9% while it was seen in only two control patients in up to 5% of metaplastic cells. In patients with <d>IPF</d>, SCCA correlated positively with extension of fibroblastic foci r = 0.49, p = 0.02, expression of TGFbeta r = 0.78, p<0.0001 and with carbon monoxide transfer factor decline after 9 months of follow-up r = 0.59, p = 0.01. In vitro experiments showed that incubation of cultured cells with SCCA induced TGFbeta expression, with a peak at 24 h. CONCLUSION: Our findings provide for the first time a potential mechanism by which SCCA secreted from metaplastic epithelial cells may exert a profibrotic effect in <d>IPF</d>. SCCA could be an important biomarker in this incurable disease.
18344408|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive disorder with a poor prognosis. Epithelial instability is a crucial step in the development and progression of the disease, including <d>neoplastic transformation</d>. Few tissue markers for epithelial instability have been reported in <d>IPF</d>. <d>Squamous cell carcinoma</d> antigen SCCA is a serine protease inhibitor typically expressed by dysplastic and neoplastic cells of epithelial origin, more often in <d>squamous cell tumours</d>. At present, no information is available on its expression in <d>IPF</d>. METHODS: SCCA and transforming growth factor beta TGFbeta expression in surgical lung biopsies from 22 patients with <d>IPF</d> and 20 control cases was examined. An in vitro study using A549 pneumocytes was also conducted to investigate the relationship between SCCA and TGFbeta expression. SCCA and TGFbeta epithelial expression was evaluated by immunohistochemistry and reverse transcription-PCR RT-PCR. SCCA values were correlated with different pathological and clinical parameters. Time course analysis of TGFbeta expression in A549 pneumocytes incubated with different SCCA concentrations was assessed by real time RT-PCR. RESULTS: SCCA was expressed in many metaplastic alveolar epithelial cells in all <d>IPF</d> cases with a mean value of 24.9% while it was seen in only two control patients in up to 5% of metaplastic cells. In patients with <d>IPF</d>, SCCA correlated positively with extension of fibroblastic foci r = 0.49, p = 0.02, expression of TGFbeta r = 0.78, p<0.0001 and with carbon monoxide transfer factor decline after 9 months of follow-up r = 0.59, p = 0.01. In vitro experiments showed that incubation of cultured cells with SCCA induced TGFbeta expression, with a peak at 24 h. CONCLUSION: Our findings provide for the first time a potential mechanism by which SCCA secreted from metaplastic epithelial cells may exert a profibrotic effect in <d>IPF</d>. SCCA could be an important biomarker in this incurable disease.
18395486|a|One of the hallmarks of idiopathic pulmonary fibrosis with a usual interstitial pneumonia histological pathology <d>IPF</d>/UIP is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of lung fibrosis have elucidated a pro-fibrotic pathway involving IL-13 driving CCL2, which in turn drives TGFbeta1 in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human <d>IPF</d>/UIP fibroblasts. <d>IPF</d>/UIP fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to TGFbeta1 but were relatively non-responsive to IL-13 or CCL2, whereas, <d>IPF</d>/UIP cells were hyper-responsive to TGFbeta1, IL-13 and CCL2. Interestingly, TGFbeta1, CCL2 and IL-13 all upregulated TGFbeta receptor and IL-13 receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of CCL2, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between TGFbeta1, IL-13 and CCL2 in <d>IPF</d>/UIP, where these three mediators feedback on each other, promoting the fibrotic response.
18395486|a|One of the hallmarks of idiopathic pulmonary fibrosis with a usual interstitial pneumonia histological pathology <d>IPF</d>/<d>UIP</d> is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of lung fibrosis have elucidated a pro-fibrotic pathway involving IL-13 driving CCL2, which in turn drives TGFbeta1 in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human <d>IPF</d>/<d>UIP</d> fibroblasts. <d>IPF</d>/<d>UIP</d> fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to TGFbeta1 but were relatively non-responsive to IL-13 or CCL2, whereas, <d>IPF</d>/<d>UIP</d> cells were hyper-responsive to TGFbeta1, IL-13 and CCL2. Interestingly, TGFbeta1, CCL2 and IL-13 all upregulated TGFbeta receptor and IL-13 receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of CCL2, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between TGFbeta1, IL-13 and CCL2 in <d>IPF</d>/<d>UIP</d>, where these three mediators feedback on each other, promoting the fibrotic response.
18395486|a|One of the hallmarks of <d>idiopathic pulmonary fibrosis</d> with a usual interstitial pneumonia histological pathology <d>IPF</d>/<d>UIP</d> is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of lung fibrosis have elucidated a pro-fibrotic pathway involving <g>IL-13</g> driving <g>CCL2</g>, which in turn drives <g>TGFbeta1</g> in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human <d>IPF</d>/<d>UIP</d> fibroblasts. <d>IPF</d>/<d>UIP</d> fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to <g>TGFbeta1</g> but were relatively non-responsive to <g>IL-13</g> or <g>CCL2</g>, whereas, <d>IPF</d>/<d>UIP</d> cells were hyper-responsive to <g>TGFbeta1</g>, <g>IL-13</g> and <g>CCL2</g>. Interestingly, <g>TGFbeta1</g>, <g>CCL2</g> and <g>IL-13</g> all upregulated TGFbeta receptor and <g>IL-13</g> receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of <g>CCL2</g>, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between <g>TGFbeta1</g>, <g>IL-13</g> and <g>CCL2</g> in <d>IPF</d>/<d>UIP</d>, where these three mediators feedback on each other, promoting the fibrotic response.
18395486|a|One of the hallmarks of <d>idiopathic pulmonary fibrosis</d> with a usual <d>interstitial pneumonia</d> histological pathology <d>IPF</d>/<d>UIP</d> is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of lung fibrosis have elucidated a pro-fibrotic pathway involving <g>IL-13</g> driving <g>CCL2</g>, which in turn drives <g>TGFbeta1</g> in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human <d>IPF</d>/<d>UIP</d> fibroblasts. <d>IPF</d>/<d>UIP</d> fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to <g>TGFbeta1</g> but were relatively non-responsive to <g>IL-13</g> or <g>CCL2</g>, whereas, <d>IPF</d>/<d>UIP</d> cells were hyper-responsive to <g>TGFbeta1</g>, <g>IL-13</g> and <g>CCL2</g>. Interestingly, <g>TGFbeta1</g>, <g>CCL2</g> and <g>IL-13</g> all upregulated TGFbeta receptor and <g>IL-13</g> receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of <g>CCL2</g>, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between <g>TGFbeta1</g>, <g>IL-13</g> and <g>CCL2</g> in <d>IPF</d>/<d>UIP</d>, where these three mediators feedback on each other, promoting the fibrotic response.
18395486|a|One of the hallmarks of <d>idiopathic pulmonary fibrosis</d> with a usual <d>interstitial pneumonia</d> histological pathology <d>IPF</d>/<d>UIP</d> is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of <d>lung fibrosis</d> have elucidated a pro-fibrotic pathway involving <g>IL-13</g> driving <g>CCL2</g>, which in turn drives <g>TGFbeta1</g> in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human <d>IPF</d>/<d>UIP</d> fibroblasts. <d>IPF</d>/<d>UIP</d> fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to <g>TGFbeta1</g> but were relatively non-responsive to <g>IL-13</g> or <g>CCL2</g>, whereas, <d>IPF</d>/<d>UIP</d> cells were hyper-responsive to <g>TGFbeta1</g>, <g>IL-13</g> and <g>CCL2</g>. Interestingly, <g>TGFbeta1</g>, <g>CCL2</g> and <g>IL-13</g> all upregulated TGFbeta receptor and <g>IL-13</g> receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of <g>CCL2</g>, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between <g>TGFbeta1</g>, <g>IL-13</g> and <g>CCL2</g> in <d>IPF</d>/<d>UIP</d>, where these three mediators feedback on each other, promoting the fibrotic response.
18395486|a|One of the hallmarks of <d>idiopathic <d>pulmonary fibrosis</d></d> with a usual <d>interstitial pneumonia</d> histological pathology <d>IPF</d>/<d>UIP</d> is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of <d>lung fibrosis</d> have elucidated a pro-fibrotic pathway involving <g>IL-13</g> driving <g>CCL2</g>, which in turn drives <g>TGFbeta1</g> in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human <d>IPF</d>/<d>UIP</d> fibroblasts. <d>IPF</d>/<d>UIP</d> fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to <g>TGFbeta1</g> but were relatively non-responsive to <g>IL-13</g> or <g>CCL2</g>, whereas, <d>IPF</d>/<d>UIP</d> cells were hyper-responsive to <g>TGFbeta1</g>, <g>IL-13</g> and <g>CCL2</g>. Interestingly, <g>TGFbeta1</g>, <g>CCL2</g> and <g>IL-13</g> all upregulated TGFbeta receptor and <g>IL-13</g> receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of <g>CCL2</g>, during bleomycin-induced <d>pulmonary fibrosis</d> significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between <g>TGFbeta1</g>, <g>IL-13</g> and <g>CCL2</g> in <d>IPF</d>/<d>UIP</d>, where these three mediators feedback on each other, promoting the fibrotic response.
18402687|a|BACKGROUND: Idiopathic pulmonary <d>fibrosis</d> IPF is a treatment resistant disease with poor prognosis. Numerous compounds have been demonstrated to efficiently prevent pulmonary <d>fibrosis</d> PF in animal models but only a few were successful when given to animals with established <d>fibrosis</d>. Major concerns of current PF models are spontaneous resolution and high variability of <d>fibrosis</d>, and the lack of assessment methods that can allow to monitor the effect of drugs in individual animals over time. We used a model of experimental PF in rats and compare parameters obtained in living animals with conventional assessment tools that require removal of the lungs. METHODS: PF was induced in rats by adenoviral gene transfer of transforming growth factor-beta. Morphological and functional changes were assessed for up to 56 days by micro-CT, lung compliance measured via a mechanical ventilator and VO2max and compared to histomorphometry and hydroxyproline content. RESULTS: Standard histological and collagen assessment confirmed the persistent fibrotic phenotype as described before. The histomorphological scores correlated both to radiological r2 = 0.29, p < 0.01 and functional changes r2 = 0.51, p < 0.0001. VO2max did not correlate with <d>fibrosis</d>. CONCLUSION: The progression of pulmonary <d>fibrosis</d> can be reliably assessed and followed in living animals over time using invasive, non-terminal compliance measurements and micro-CT. This approach directly translates to the management of patients with IPF and allows to monitor therapeutic effects in drug intervention studies.
18402687|a|BACKGROUND: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a treatment resistant disease with poor prognosis. Numerous compounds have been demonstrated to efficiently prevent pulmonary <d>fibrosis</d> PF in animal models but only a few were successful when given to animals with established <d>fibrosis</d>. Major concerns of current PF models are spontaneous resolution and high variability of <d>fibrosis</d>, and the lack of assessment methods that can allow to monitor the effect of drugs in individual animals over time. We used a model of experimental PF in rats and compare parameters obtained in living animals with conventional assessment tools that require removal of the lungs. METHODS: PF was induced in rats by adenoviral gene transfer of transforming growth factor-beta. Morphological and functional changes were assessed for up to 56 days by micro-CT, lung compliance measured via a mechanical ventilator and VO2max and compared to histomorphometry and hydroxyproline content. RESULTS: Standard histological and collagen assessment confirmed the persistent fibrotic phenotype as described before. The histomorphological scores correlated both to radiological r2 = 0.29, p < 0.01 and functional changes r2 = 0.51, p < 0.0001. VO2max did not correlate with <d>fibrosis</d>. CONCLUSION: The progression of pulmonary <d>fibrosis</d> can be reliably assessed and followed in living animals over time using invasive, non-terminal compliance measurements and micro-CT. This approach directly translates to the management of patients with <d>IPF</d> and allows to monitor therapeutic effects in drug intervention studies.
18569384|a|<g>Tumor necrosis factor-alpha</g> <g>TNFalpha</g> and <g>transforming growth factor-beta1</g> <g>TGFbeta1</g> are potent peptide growth factors that are likely to play important roles in the development of <d>interstitial pulmonary fibrosis</d> IPF. Previously we showed that <g>TNFalpha</g> and <g>TGFbeta1</g> are up-regulated in macrophages, epithelial and mesenchymal cells early after exposure to chrysotile asbestos, particularly at sites of fiber deposition in vivo. We also showed that <g>TNFalpha</g> receptor knockout mice are resistant to asbestos-induced fibrosis. Importantly, vectors that over-express <g>TNFalpha</g> cause inflammation and fibrogenesis along with increased <g>TGFbeta1</g> production in C57Bl/6 mice. Recently we reported that <g>TNFalpha</g> activates the extracellular regulated kinase pathway in fibroblasts leading to a 200-400% increase in <g>TGFbeta1</g> mRNA and protein. The mechanism of <g>TNFalpha</g> induction of <g>TGFbeta1</g> expression appears to be complex, involving both transcriptional and post-transcriptional mechanisms. In asbestos-exposed animals, this <g>TGFbeta1</g> is produced on alveolar surfaces in a latent form controlled by binding of a latent associated peptide [LAP] that must be activated for the <g>TGFbeta1</g> to bind to its receptors and induce its multiple biological effects. Thus, we recently reported that, in vitro, reactive oxygen species ROS derived from chrysotile and crocidolite asbestos activate <g>TGFbeta1</g> by oxidation of the LAP. Now, in preliminary findings, we have shown that over-expression of latent <g>TGFbeta1</g> prior to asbestos exposure of fibrogenic-resistant <g>TNFalpha</g> receptor knockout mice produces asbestos lesions with the same severity as seen in normal C57/Bl6 mice. This finding plus the demonstration of increased amounts of <g>TGFbeta1</g>, increased Smad activation and amelioration of the developing disease by treating the mice with an anti-oxidant all support the concept that, in vivo, latent <g>TGFbeta1</g> is activated by asbestos-generated oxygen radicals and consequently mediates at least a component of the consequent fibrogenesis. Taken together, these findings support the postulate that <g>TNFalpha</g> controls fibrogenesis by regulating <g>TGFbeta1</g> expression and that one mechanism through which ROS induce lung fibrosis is by activating latent <g>TGFbeta1</g>.
18569384|a|<g>Tumor necrosis factor-alpha</g> <g>TNFalpha</g> and <g>transforming growth factor-beta1</g> <g>TGFbeta1</g> are potent peptide growth factors that are likely to play important roles in the development of <d>interstitial pulmonary fibrosis</d> <d>IPF</d>. Previously we showed that <g>TNFalpha</g> and <g>TGFbeta1</g> are up-regulated in macrophages, epithelial and mesenchymal cells early after exposure to chrysotile asbestos, particularly at sites of fiber deposition in vivo. We also showed that <g>TNFalpha</g> receptor knockout mice are resistant to asbestos-induced fibrosis. Importantly, vectors that over-express <g>TNFalpha</g> cause inflammation and fibrogenesis along with increased <g>TGFbeta1</g> production in C57Bl/6 mice. Recently we reported that <g>TNFalpha</g> activates the extracellular regulated kinase pathway in fibroblasts leading to a 200-400% increase in <g>TGFbeta1</g> mRNA and protein. The mechanism of <g>TNFalpha</g> induction of <g>TGFbeta1</g> expression appears to be complex, involving both transcriptional and post-transcriptional mechanisms. In asbestos-exposed animals, this <g>TGFbeta1</g> is produced on alveolar surfaces in a latent form controlled by binding of a latent associated peptide [LAP] that must be activated for the <g>TGFbeta1</g> to bind to its receptors and induce its multiple biological effects. Thus, we recently reported that, in vitro, reactive oxygen species ROS derived from chrysotile and crocidolite asbestos activate <g>TGFbeta1</g> by oxidation of the LAP. Now, in preliminary findings, we have shown that over-expression of latent <g>TGFbeta1</g> prior to asbestos exposure of fibrogenic-resistant <g>TNFalpha</g> receptor knockout mice produces asbestos lesions with the same severity as seen in normal C57/Bl6 mice. This finding plus the demonstration of increased amounts of <g>TGFbeta1</g>, increased Smad activation and amelioration of the developing disease by treating the mice with an anti-oxidant all support the concept that, in vivo, latent <g>TGFbeta1</g> is activated by asbestos-generated oxygen radicals and consequently mediates at least a component of the consequent fibrogenesis. Taken together, these findings support the postulate that <g>TNFalpha</g> controls fibrogenesis by regulating <g>TGFbeta1</g> expression and that one mechanism through which ROS induce lung fibrosis is by activating latent <g>TGFbeta1</g>.
18569384|a|<g>Tumor necrosis factor-alpha</g> <g>TNFalpha</g> and <g>transforming growth factor-beta1</g> <g>TGFbeta1</g> are potent peptide growth factors that are likely to play important roles in the development of <d>interstitial pulmonary <d>fibrosis</d></d> <d>IPF</d>. Previously we showed that <g>TNFalpha</g> and <g>TGFbeta1</g> are up-regulated in macrophages, epithelial and mesenchymal cells early after exposure to chrysotile asbestos, particularly at sites of fiber deposition in vivo. We also showed that <g>TNFalpha</g> receptor knockout mice are resistant to asbestos-induced <d>fibrosis</d>. Importantly, vectors that over-express <g>TNFalpha</g> cause inflammation and fibrogenesis along with increased <g>TGFbeta1</g> production in C57Bl/6 mice. Recently we reported that <g>TNFalpha</g> activates the extracellular regulated kinase pathway in fibroblasts leading to a 200-400% increase in <g>TGFbeta1</g> mRNA and protein. The mechanism of <g>TNFalpha</g> induction of <g>TGFbeta1</g> expression appears to be complex, involving both transcriptional and post-transcriptional mechanisms. In asbestos-exposed animals, this <g>TGFbeta1</g> is produced on alveolar surfaces in a latent form controlled by binding of a latent associated peptide [LAP] that must be activated for the <g>TGFbeta1</g> to bind to its receptors and induce its multiple biological effects. Thus, we recently reported that, in vitro, reactive oxygen species ROS derived from chrysotile and crocidolite asbestos activate <g>TGFbeta1</g> by oxidation of the LAP. Now, in preliminary findings, we have shown that over-expression of latent <g>TGFbeta1</g> prior to asbestos exposure of fibrogenic-resistant <g>TNFalpha</g> receptor knockout mice produces asbestos lesions with the same severity as seen in normal C57/Bl6 mice. This finding plus the demonstration of increased amounts of <g>TGFbeta1</g>, increased Smad activation and amelioration of the developing disease by treating the mice with an anti-oxidant all support the concept that, in vivo, latent <g>TGFbeta1</g> is activated by asbestos-generated oxygen radicals and consequently mediates at least a component of the consequent fibrogenesis. Taken together, these findings support the postulate that <g>TNFalpha</g> controls fibrogenesis by regulating <g>TGFbeta1</g> expression and that one mechanism through which ROS induce lung <d>fibrosis</d> is by activating latent <g>TGFbeta1</g>.
18569384|a|<g>Tumor necrosis factor-alpha</g> <g>TNFalpha</g> and <g>transforming growth factor-beta1</g> <g>TGFbeta1</g> are potent peptide growth factors that are likely to play important roles in the development of <d>interstitial pulmonary <d>fibrosis</d></d> <d>IPF</d>. Previously we showed that <g>TNFalpha</g> and <g>TGFbeta1</g> are up-regulated in macrophages, epithelial and mesenchymal cells early after exposure to chrysotile asbestos, particularly at sites of fiber deposition in vivo. We also showed that <g>TNFalpha</g> receptor knockout mice are resistant to asbestos-induced <d>fibrosis</d>. Importantly, vectors that over-express <g>TNFalpha</g> cause <d>inflammation</d> and fibrogenesis along with increased <g>TGFbeta1</g> production in C57Bl/6 mice. Recently we reported that <g>TNFalpha</g> activates the extracellular regulated kinase pathway in fibroblasts leading to a 200-400% increase in <g>TGFbeta1</g> mRNA and protein. The mechanism of <g>TNFalpha</g> induction of <g>TGFbeta1</g> expression appears to be complex, involving both transcriptional and post-transcriptional mechanisms. In asbestos-exposed animals, this <g>TGFbeta1</g> is produced on alveolar surfaces in a latent form controlled by binding of a latent associated peptide [LAP] that must be activated for the <g>TGFbeta1</g> to bind to its receptors and induce its multiple biological effects. Thus, we recently reported that, in vitro, reactive oxygen species ROS derived from chrysotile and crocidolite asbestos activate <g>TGFbeta1</g> by oxidation of the LAP. Now, in preliminary findings, we have shown that over-expression of latent <g>TGFbeta1</g> prior to asbestos exposure of fibrogenic-resistant <g>TNFalpha</g> receptor knockout mice produces asbestos lesions with the same severity as seen in normal C57/Bl6 mice. This finding plus the demonstration of increased amounts of <g>TGFbeta1</g>, increased Smad activation and amelioration of the developing disease by treating the mice with an anti-oxidant all support the concept that, in vivo, latent <g>TGFbeta1</g> is activated by asbestos-generated oxygen radicals and consequently mediates at least a component of the consequent fibrogenesis. Taken together, these findings support the postulate that <g>TNFalpha</g> controls fibrogenesis by regulating <g>TGFbeta1</g> expression and that one mechanism through which ROS induce lung <d>fibrosis</d> is by activating latent <g>TGFbeta1</g>.
18569384|a|<g>Tumor necrosis factor-alpha</g> <g>TNFalpha</g> and <g>transforming growth factor-beta1</g> <g>TGFbeta1</g> are potent peptide growth factors that are likely to play important roles in the development of <d>interstitial pulmonary <d>fibrosis</d></d> <d>IPF</d>. Previously we showed that <g>TNFalpha</g> and <g>TGFbeta1</g> are up-regulated in macrophages, epithelial and mesenchymal cells early after exposure to chrysotile asbestos, particularly at sites of fiber deposition in vivo. We also showed that <g>TNFalpha</g> receptor knockout mice are resistant to asbestos-induced <d>fibrosis</d>. Importantly, vectors that over-express <g>TNFalpha</g> cause <d>inflammation</d> and fibrogenesis along with increased <g>TGFbeta1</g> production in C57Bl/6 mice. Recently we reported that <g>TNFalpha</g> activates the extracellular regulated kinase pathway in fibroblasts leading to a 200-400% increase in <g>TGFbeta1</g> mRNA and protein. The mechanism of <g>TNFalpha</g> induction of <g>TGFbeta1</g> expression appears to be complex, involving both transcriptional and post-transcriptional mechanisms. In asbestos-exposed animals, this <g>TGFbeta1</g> is produced on alveolar surfaces in a latent form controlled by binding of a latent associated peptide [LAP] that must be activated for the <g>TGFbeta1</g> to bind to its receptors and induce its multiple biological effects. Thus, we recently reported that, in vitro, reactive oxygen species ROS derived from chrysotile and crocidolite asbestos activate <g>TGFbeta1</g> by oxidation of the LAP. Now, in preliminary findings, we have shown that over-expression of latent <g>TGFbeta1</g> prior to asbestos exposure of fibrogenic-resistant <g>TNFalpha</g> receptor knockout mice produces <d>asbestos lesions</d> with the same severity as seen in normal C57/Bl6 mice. This finding plus the demonstration of increased amounts of <g>TGFbeta1</g>, increased Smad activation and amelioration of the developing disease by treating the mice with an anti-oxidant all support the concept that, in vivo, latent <g>TGFbeta1</g> is activated by asbestos-generated oxygen radicals and consequently mediates at least a component of the consequent fibrogenesis. Taken together, these findings support the postulate that <g>TNFalpha</g> controls fibrogenesis by regulating <g>TGFbeta1</g> expression and that one mechanism through which ROS induce lung <d>fibrosis</d> is by activating latent <g>TGFbeta1</g>.
18621908|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation, and ECM protein deposition. Epstein-Barr virus EBV has previously been localized to alveolar epithelial cells of IPF patients and is associated with a poor prognosis. In this study, we utilized a microarray-based differential gene expression analysis strategy to identify molecular drivers of EBV-associated lung fibrosis. Two cell lines, primary human alveolar epithelial cells type 2 and A549 cells, were infected with EBV. EBV lytic phase induction increased active and total transforming growth factor-beta1 <g>TGFbeta1</g> transcript expression in association with reduced cell proliferation and increased caspase 3/7 activity. Exposing EBV-infected cells to ganciclovir resulted in <g>TGFbeta1</g> deregulation and reduced expression of EBV early response genes, BRLF1 and BZLF1. We targeted the BRLF1 and BZLF1 gene products, Rta and Zta, by silencing RNA, and this resulted in the normalization of <g>TGFbeta1</g> transcript and cell proliferation levels. Our study using a viral cell line model complements existing human and animal model data and further provides evidence to suggest that viral epithelial cell injury may play a role in IPF.
18621908|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation, and ECM protein deposition. Epstein-Barr virus EBV has previously been localized to alveolar epithelial cells of <d>IPF</d> patients and is associated with a poor prognosis. In this study, we utilized a microarray-based differential gene expression analysis strategy to identify molecular drivers of EBV-associated lung fibrosis. Two cell lines, primary human alveolar epithelial cells type 2 and A549 cells, were infected with EBV. EBV lytic phase induction increased active and total transforming growth factor-beta1 <g>TGFbeta1</g> transcript expression in association with reduced cell proliferation and increased caspase 3/7 activity. Exposing EBV-infected cells to ganciclovir resulted in <g>TGFbeta1</g> deregulation and reduced expression of EBV early response genes, BRLF1 and BZLF1. We targeted the BRLF1 and BZLF1 gene products, Rta and Zta, by silencing RNA, and this resulted in the normalization of <g>TGFbeta1</g> transcript and cell proliferation levels. Our study using a viral cell line model complements existing human and animal model data and further provides evidence to suggest that viral epithelial cell injury may play a role in <d>IPF</d>.
18621908|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a refractory and lethal <d>interstitial lung disease</d> characterized by alveolar epithelial cells apoptosis, fibroblast proliferation, and ECM protein deposition. Epstein-Barr virus EBV has previously been localized to alveolar epithelial cells of <d>IPF</d> patients and is associated with a poor prognosis. In this study, we utilized a microarray-based differential gene expression analysis strategy to identify molecular drivers of EBV-associated lung fibrosis. Two cell lines, primary human alveolar epithelial cells type 2 and A549 cells, were infected with EBV. EBV lytic phase induction increased active and total transforming growth factor-beta1 <g>TGFbeta1</g> transcript expression in association with reduced cell proliferation and increased caspase 3/7 activity. Exposing EBV-infected cells to ganciclovir resulted in <g>TGFbeta1</g> deregulation and reduced expression of EBV early response genes, BRLF1 and BZLF1. We targeted the BRLF1 and BZLF1 gene products, Rta and Zta, by silencing RNA, and this resulted in the normalization of <g>TGFbeta1</g> transcript and cell proliferation levels. Our study using a viral cell line model complements existing human and animal model data and further provides evidence to suggest that viral epithelial cell injury may play a role in <d>IPF</d>.
18621908|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a refractory and lethal <d>interstitial lung disease</d> characterized by alveolar epithelial cells apoptosis, fibroblast proliferation, and ECM protein deposition. Epstein-Barr virus EBV has previously been localized to alveolar epithelial cells of <d>IPF</d> patients and is associated with a poor prognosis. In this study, we utilized a microarray-based differential gene expression analysis strategy to identify molecular drivers of EBV-associated lung <d>fibrosis</d>. Two cell lines, primary human alveolar epithelial cells type 2 and A549 cells, were infected with EBV. EBV lytic phase induction increased active and total transforming growth factor-beta1 <g>TGFbeta1</g> transcript expression in association with reduced cell proliferation and increased caspase 3/7 activity. Exposing EBV-infected cells to ganciclovir resulted in <g>TGFbeta1</g> deregulation and reduced expression of EBV early response genes, BRLF1 and BZLF1. We targeted the BRLF1 and BZLF1 gene products, Rta and Zta, by silencing RNA, and this resulted in the normalization of <g>TGFbeta1</g> transcript and cell proliferation levels. Our study using a viral cell line model complements existing human and animal model data and further provides evidence to suggest that viral epithelial cell injury may play a role in <d>IPF</d>.
18621908|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a refractory and lethal <d>interstitial lung disease</d> characterized by alveolar epithelial cells apoptosis, fibroblast proliferation, and ECM protein deposition. Epstein-Barr virus <d>EBV</d> has previously been localized to alveolar epithelial cells of <d>IPF</d> patients and is associated with a poor prognosis. In this study, we utilized a microarray-based differential gene expression analysis strategy to identify molecular drivers of <d>EBV</d>-associated lung <d>fibrosis</d>. Two cell lines, primary human alveolar epithelial cells type 2 and A549 cells, were infected with <d>EBV</d>. <d>EBV</d> lytic phase induction increased active and total transforming growth factor-beta1 <g>TGFbeta1</g> transcript expression in association with reduced cell proliferation and increased caspase 3/7 activity. Exposing <d>EBV</d>-infected cells to ganciclovir resulted in <g>TGFbeta1</g> deregulation and reduced expression of <d>EBV</d> early response genes, BRLF1 and BZLF1. We targeted the BRLF1 and BZLF1 gene products, Rta and Zta, by silencing RNA, and this resulted in the normalization of <g>TGFbeta1</g> transcript and cell proliferation levels. Our study using a viral cell line model complements existing human and animal model data and further provides evidence to suggest that viral epithelial cell injury may play a role in <d>IPF</d>.
18795102|a|BACKGROUND: As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast-the primary effector of the fibroproliferative response. We have recently shown that aberrant <g>beta 1 integrin</g> signaling in fibrotic fibroblasts results in defective PTEN function, unrestrained Akt signaling and subsequent activation of the translation initiation machinery. How this pathological integrin signaling alters the gene expression pathway has not been elucidated. RESULTS: Using a systems approach to study this question in a prototype <d>fibrotic disease</d>, Idiopathic Pulmonary Fibrosis IPF; here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition EMT. In accord with this, we found systems-level indications for TGF-beta -driven EMT as one source of IPF myofibroblasts. CONCLUSIONS: These findings establish the power of systems level genome-wide analysis to provide mechanistic insights into fibrotic disorders such as IPF. Our data point to derangements of translational control downstream of aberrant <g>beta 1 integrin</g> signaling as a fundamental component of IPF pathobiology and indicates that TGF-beta -driven EMT is one source for IPF myofibroblasts.
18795102|a|BACKGROUND: As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast-the primary effector of the fibroproliferative response. We have recently shown that aberrant <g>beta 1 integrin</g> signaling in fibrotic fibroblasts results in defective PTEN function, unrestrained Akt signaling and subsequent activation of the translation initiation machinery. How this pathological integrin signaling alters the gene expression pathway has not been elucidated. RESULTS: Using a systems approach to study this question in a prototype <d>fibrotic disease</d>, <d>Idiopathic Pulmonary Fibrosis</d> IPF; here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition EMT. In accord with this, we found systems-level indications for TGF-beta -driven EMT as one source of IPF myofibroblasts. CONCLUSIONS: These findings establish the power of systems level genome-wide analysis to provide mechanistic insights into fibrotic disorders such as IPF. Our data point to derangements of translational control downstream of aberrant <g>beta 1 integrin</g> signaling as a fundamental component of IPF pathobiology and indicates that TGF-beta -driven EMT is one source for IPF myofibroblasts.
18795102|a|BACKGROUND: As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast-the primary effector of the fibroproliferative response. We have recently shown that aberrant <g>beta 1 integrin</g> signaling in fibrotic fibroblasts results in defective PTEN function, unrestrained Akt signaling and subsequent activation of the translation initiation machinery. How this pathological integrin signaling alters the gene expression pathway has not been elucidated. RESULTS: Using a systems approach to study this question in a prototype <d>fibrotic disease</d>, <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d>; here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing <d>IPF</d> and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of <d>IPF</d> myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, <d>IPF</d> cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for <d>IPF</d> myofibroblasts through the epithelial to mesenchymal transition EMT. In accord with this, we found systems-level indications for TGF-beta -driven EMT as one source of <d>IPF</d> myofibroblasts. CONCLUSIONS: These findings establish the power of systems level genome-wide analysis to provide mechanistic insights into fibrotic disorders such as <d>IPF</d>. Our data point to derangements of translational control downstream of aberrant <g>beta 1 integrin</g> signaling as a fundamental component of <d>IPF</d> pathobiology and indicates that TGF-beta -driven EMT is one source for <d>IPF</d> myofibroblasts.
18795102|a|BACKGROUND: As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast-the primary effector of the fibroproliferative response. We have recently shown that aberrant <g>beta 1 integrin</g> signaling in fibrotic fibroblasts results in defective PTEN function, unrestrained Akt signaling and subsequent activation of the translation initiation machinery. How this pathological integrin signaling alters the gene expression pathway has not been elucidated. RESULTS: Using a systems approach to study this question in a prototype <d>fibrotic disease</d>, <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d>; here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing <d>IPF</d> and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of <d>IPF</d> myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, <d>IPF</d> cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for <d>IPF</d> myofibroblasts through the epithelial to mesenchymal transition EMT. In accord with this, we found systems-level indications for <g>TGF-beta</g> -driven EMT as one source of <d>IPF</d> myofibroblasts. CONCLUSIONS: These findings establish the power of systems level genome-wide analysis to provide mechanistic insights into <d>fibrotic disorders</d> such as <d>IPF</d>. Our data point to derangements of translational control downstream of aberrant <g>beta 1 integrin</g> signaling as a fundamental component of <d>IPF</d> pathobiology and indicates that <g>TGF-beta</g> -driven EMT is one source for <d>IPF</d> myofibroblasts.
19104143|a|Idiopathic <d>pulmonary fibrosis</d> IPF is characterized by progressive myofibroblast accumulation and collagen deposition. One possible source of myofibroblasts is epithelial cells that undergo epithelial-mesenchymal transition EMT, a process frequently mediated by TGF-beta. In this issue of the JCI, Kim et al. report that epithelial cell-specific deletion of alpha3 integrin prevents EMT in mice, thereby protecting against bleomycin-induced fibrosis see the related article beginning on page 213. The authors propose a novel mechanism linking TGF-beta and beta-catenin signaling in EMT through integrin-dependent association of tyrosine-phosphorylated beta-catenin and pSmad2 and suggest targeted disruption of this interaction as a potential therapeutic approach.
19104143|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is characterized by progressive myofibroblast accumulation and collagen deposition. One possible source of myofibroblasts is epithelial cells that undergo epithelial-mesenchymal transition EMT, a process frequently mediated by TGF-beta. In this issue of the JCI, Kim et al. report that epithelial cell-specific deletion of alpha3 integrin prevents EMT in mice, thereby protecting against bleomycin-induced fibrosis see the related article beginning on page 213. The authors propose a novel mechanism linking TGF-beta and beta-catenin signaling in EMT through integrin-dependent association of tyrosine-phosphorylated beta-catenin and pSmad2 and suggest targeted disruption of this interaction as a potential therapeutic approach.
19104143|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characterized by progressive myofibroblast accumulation and collagen deposition. One possible source of myofibroblasts is epithelial cells that undergo epithelial-mesenchymal transition EMT, a process frequently mediated by <g>TGF-beta</g>. In this issue of the JCI, Kim et al. report that epithelial cell-specific deletion of alpha3 integrin prevents EMT in mice, thereby protecting against bleomycin-induced <d>fibrosis</d> see the related article beginning on page 213. The authors propose a novel mechanism linking <g>TGF-beta</g> and beta-catenin signaling in EMT through integrin-dependent association of tyrosine-phosphorylated beta-catenin and pSmad2 and suggest targeted disruption of this interaction as a potential therapeutic approach.
19104148|a|Pulmonary fibrosis, in particular idiopathic <d>pulmonary fibrosis</d> IPF, results from aberrant wound healing and scarification. One population of fibroblasts involved in the fibrotic process is thought to originate from lung epithelial cells via epithelial-mesenchymal transition EMT. Indeed, alveolar epithelial cells AECs undergo EMT in vivo during experimental fibrosis and ex vivo in response to TGF-beta1. As the ECM critically regulates AEC responses to TGF-beta1, we explored the role of the prominent epithelial integrin alpha3beta1 in experimental fibrosis by generating mice with lung epithelial cell-specific loss of alpha3 integrin expression. These mice had a normal acute response to bleomycin injury, but they exhibited markedly decreased accumulation of lung myofibroblasts and type I collagen and did not progress to fibrosis. Signaling through <g>beta-catenin</g> has been implicated in EMT; we found that in primary AECs, alpha3 integrin was required for <g>beta-catenin</g> phosphorylation at tyrosine residue 654 Y654, formation of the pY654-<g>beta-catenin</g>/pSmad2 complex, and initiation of EMT, both in vitro and in vivo during the fibrotic phase following bleomycin injury. Finally, analysis of lung tissue from IPF patients revealed the presence of pY654-<g>beta-catenin</g>/pSmad2 complexes and showed accumulation of pY654-<g>beta-catenin</g> in myofibroblasts. These findings demonstrate epithelial integrin-dependent profibrotic crosstalk between <g>beta-catenin</g> and Smad signaling and support the hypothesis that EMT is an important contributor to pathologic fibrosis.
19104148|a|<d>Pulmonary fibrosis</d>, in particular idiopathic <d>pulmonary fibrosis</d> IPF, results from aberrant wound healing and scarification. One population of fibroblasts involved in the fibrotic process is thought to originate from lung epithelial cells via epithelial-mesenchymal transition EMT. Indeed, alveolar epithelial cells AECs undergo EMT in vivo during experimental fibrosis and ex vivo in response to TGF-beta1. As the ECM critically regulates AEC responses to TGF-beta1, we explored the role of the prominent epithelial integrin alpha3beta1 in experimental fibrosis by generating mice with lung epithelial cell-specific loss of alpha3 integrin expression. These mice had a normal acute response to bleomycin injury, but they exhibited markedly decreased accumulation of lung myofibroblasts and type I collagen and did not progress to fibrosis. Signaling through <g>beta-catenin</g> has been implicated in EMT; we found that in primary AECs, alpha3 integrin was required for <g>beta-catenin</g> phosphorylation at tyrosine residue 654 Y654, formation of the pY654-<g>beta-catenin</g>/pSmad2 complex, and initiation of EMT, both in vitro and in vivo during the fibrotic phase following bleomycin injury. Finally, analysis of lung tissue from IPF patients revealed the presence of pY654-<g>beta-catenin</g>/pSmad2 complexes and showed accumulation of pY654-<g>beta-catenin</g> in myofibroblasts. These findings demonstrate epithelial integrin-dependent profibrotic crosstalk between <g>beta-catenin</g> and Smad signaling and support the hypothesis that EMT is an important contributor to pathologic fibrosis.
19104148|a|<d>Pulmonary fibrosis</d>, in particular idiopathic <d>pulmonary fibrosis</d> IPF, results from aberrant wound healing and scarification. One population of fibroblasts involved in the fibrotic process is thought to originate from lung epithelial cells via epithelial-mesenchymal transition EMT. Indeed, <d>alveolar epithelial</d> cells AECs undergo EMT in vivo during experimental fibrosis and ex vivo in response to TGF-beta1. As the ECM critically regulates AEC responses to TGF-beta1, we explored the role of the prominent epithelial integrin alpha3beta1 in experimental fibrosis by generating mice with lung epithelial cell-specific loss of alpha3 integrin expression. These mice had a normal acute response to bleomycin injury, but they exhibited markedly decreased accumulation of lung myofibroblasts and type I collagen and did not progress to fibrosis. Signaling through <g>beta-catenin</g> has been implicated in EMT; we found that in primary AECs, alpha3 integrin was required for <g>beta-catenin</g> phosphorylation at tyrosine residue 654 Y654, formation of the pY654-<g>beta-catenin</g>/pSmad2 complex, and initiation of EMT, both in vitro and in vivo during the fibrotic phase following bleomycin injury. Finally, analysis of lung tissue from IPF patients revealed the presence of pY654-<g>beta-catenin</g>/pSmad2 complexes and showed accumulation of pY654-<g>beta-catenin</g> in myofibroblasts. These findings demonstrate epithelial integrin-dependent profibrotic crosstalk between <g>beta-catenin</g> and Smad signaling and support the hypothesis that EMT is an important contributor to pathologic fibrosis.
19104148|a|<d>Pulmonary <d>fibrosis</d></d>, in particular idiopathic <d>pulmonary <d>fibrosis</d></d> IPF, results from aberrant wound healing and scarification. One population of fibroblasts involved in the fibrotic process is thought to originate from lung epithelial cells via epithelial-mesenchymal transition EMT. Indeed, <d>alveolar epithelial</d> cells AECs undergo EMT in vivo during experimental <d>fibrosis</d> and ex vivo in response to TGF-beta1. As the ECM critically regulates AEC responses to TGF-beta1, we explored the role of the prominent epithelial integrin alpha3beta1 in experimental <d>fibrosis</d> by generating mice with lung epithelial cell-specific loss of alpha3 integrin expression. These mice had a normal acute response to bleomycin injury, but they exhibited markedly decreased accumulation of lung myofibroblasts and type I collagen and did not progress to <d>fibrosis</d>. Signaling through <g>beta-catenin</g> has been implicated in EMT; we found that in primary AECs, alpha3 integrin was required for <g>beta-catenin</g> phosphorylation at tyrosine residue 654 Y654, formation of the pY654-<g>beta-catenin</g>/pSmad2 complex, and initiation of EMT, both in vitro and in vivo during the fibrotic phase following bleomycin injury. Finally, analysis of lung tissue from IPF patients revealed the presence of pY654-<g>beta-catenin</g>/pSmad2 complexes and showed accumulation of pY654-<g>beta-catenin</g> in myofibroblasts. These findings demonstrate epithelial integrin-dependent profibrotic crosstalk between <g>beta-catenin</g> and Smad signaling and support the hypothesis that EMT is an important contributor to pathologic <d>fibrosis</d>.
21475793|a|Patients with <d>idiopathic pulmonary fibrosis</d> IPF have an increased risk of developing lung cancer. To identify key molecules involved in malignant transformation in IPF, we analyzed the expression profiles of lung and lung tumor tissue from patients with lung cancer and IPF lung cancer/IPF using cDNA arrays and real-time quantitative reverse transcriptase-polymerase chain reaction RT-PCR. Reduced expression of the <g>Smad4</g> gene was identified in all eight tumor samples from the lung cancer/IPF patients using real-time RT-PCR. Expression levels of <g>Smad4</g> were significantly lower in tumors from lung cancer/IPF patients than in those from lung cancer patients without IPF or in lung cancer cell lines p<0.01. Mutational analysis of TGF-b type II receptor and <g>Smad4</g> was performed using polymerase chain reaction-single strand conformation polymorphism PCR-SSCP. The methylation status of the <g>Smad4</g> promoter was analyzed using methylation-specific PCR with subsequent sequence analysis. No mutations were detected in the eight tumor samples, but hypermethylated regions were detected in the <g>Smad4</g> promoter in two of the eight tumors with reduced <g>Smad4</g> expression. Promoter reporter assays showed that the activity of the <g>Smad4</g> promoter containing the sequence of the methylated region was significantly stronger than that of the <g>Smad4</g> promoter with a deleted methylated region p<0.002. Our findings indicate that the loss of the growth inhibitory response to TGF-b signaling may be crucial in pulmonary carcinogensis or in the progression of lung cancer in IPF patients in whom TGF-b is overexpressed; hypermethylation of the <g>Smad4</g> promoter region may be one mechanism by which this occurs. These findings are useful for the development of preventive measures or treatment for lung cancer patients with IPF.
21475793|a|Patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> have an increased risk of developing lung cancer. To identify key molecules involved in malignant transformation in <d>IPF</d>, we analyzed the expression profiles of lung and lung tumor tissue from patients with lung cancer and <d>IPF</d> lung cancer/<d>IPF</d> using cDNA arrays and real-time quantitative reverse transcriptase-polymerase chain reaction RT-PCR. Reduced expression of the <g>Smad4</g> gene was identified in all eight tumor samples from the lung cancer/<d>IPF</d> patients using real-time RT-PCR. Expression levels of <g>Smad4</g> were significantly lower in tumors from lung cancer/<d>IPF</d> patients than in those from lung cancer patients without <d>IPF</d> or in lung cancer cell lines p<0.01. Mutational analysis of TGF-b type II receptor and <g>Smad4</g> was performed using polymerase chain reaction-single strand conformation polymorphism PCR-SSCP. The methylation status of the <g>Smad4</g> promoter was analyzed using methylation-specific PCR with subsequent sequence analysis. No mutations were detected in the eight tumor samples, but hypermethylated regions were detected in the <g>Smad4</g> promoter in two of the eight tumors with reduced <g>Smad4</g> expression. Promoter reporter assays showed that the activity of the <g>Smad4</g> promoter containing the sequence of the methylated region was significantly stronger than that of the <g>Smad4</g> promoter with a deleted methylated region p<0.002. Our findings indicate that the loss of the growth inhibitory response to TGF-b signaling may be crucial in pulmonary carcinogensis or in the progression of lung cancer in <d>IPF</d> patients in whom TGF-b is overexpressed; hypermethylation of the <g>Smad4</g> promoter region may be one mechanism by which this occurs. These findings are useful for the development of preventive measures or treatment for lung cancer patients with <d>IPF</d>.
21475793|a|Patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> have an increased risk of developing <d>lung cancer</d>. To identify key molecules involved in malignant transformation in <d>IPF</d>, we analyzed the expression profiles of lung and lung tumor tissue from patients with <d>lung cancer</d> and <d>IPF</d> <d>lung cancer</d>/<d>IPF</d> using cDNA arrays and real-time quantitative reverse transcriptase-polymerase chain reaction RT-PCR. Reduced expression of the <g>Smad4</g> gene was identified in all eight tumor samples from the <d>lung cancer</d>/<d>IPF</d> patients using real-time RT-PCR. Expression levels of <g>Smad4</g> were significantly lower in tumors from <d>lung cancer</d>/<d>IPF</d> patients than in those from <d>lung cancer</d> patients without <d>IPF</d> or in <d>lung cancer</d> cell lines p<0.01. Mutational analysis of TGF-b type II receptor and <g>Smad4</g> was performed using polymerase chain reaction-single strand conformation polymorphism PCR-SSCP. The methylation status of the <g>Smad4</g> promoter was analyzed using methylation-specific PCR with subsequent sequence analysis. No mutations were detected in the eight tumor samples, but hypermethylated regions were detected in the <g>Smad4</g> promoter in two of the eight tumors with reduced <g>Smad4</g> expression. Promoter reporter assays showed that the activity of the <g>Smad4</g> promoter containing the sequence of the methylated region was significantly stronger than that of the <g>Smad4</g> promoter with a deleted methylated region p<0.002. Our findings indicate that the loss of the growth inhibitory response to TGF-b signaling may be crucial in pulmonary carcinogensis or in the progression of <d>lung cancer</d> in <d>IPF</d> patients in whom TGF-b is overexpressed; hypermethylation of the <g>Smad4</g> promoter region may be one mechanism by which this occurs. These findings are useful for the development of preventive measures or treatment for <d>lung cancer</d> patients with <d>IPF</d>.
21475793|a|Patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> have an increased risk of developing <d>lung cancer</d>. To identify key molecules involved in malignant transformation in <d>IPF</d>, we analyzed the expression profiles of lung and <d>lung tumor</d> tissue from patients with <d>lung cancer</d> and <d>IPF</d> <d>lung cancer</d>/<d>IPF</d> using cDNA arrays and real-time quantitative reverse transcriptase-polymerase chain reaction RT-PCR. Reduced expression of the <g>Smad4</g> gene was identified in all eight tumor samples from the <d>lung cancer</d>/<d>IPF</d> patients using real-time RT-PCR. Expression levels of <g>Smad4</g> were significantly lower in tumors from <d>lung cancer</d>/<d>IPF</d> patients than in those from <d>lung cancer</d> patients without <d>IPF</d> or in <d>lung cancer</d> cell lines p<0.01. Mutational analysis of TGF-b type II receptor and <g>Smad4</g> was performed using polymerase chain reaction-single strand conformation polymorphism PCR-SSCP. The methylation status of the <g>Smad4</g> promoter was analyzed using methylation-specific PCR with subsequent sequence analysis. No mutations were detected in the eight tumor samples, but hypermethylated regions were detected in the <g>Smad4</g> promoter in two of the eight tumors with reduced <g>Smad4</g> expression. Promoter reporter assays showed that the activity of the <g>Smad4</g> promoter containing the sequence of the methylated region was significantly stronger than that of the <g>Smad4</g> promoter with a deleted methylated region p<0.002. Our findings indicate that the loss of the growth inhibitory response to TGF-b signaling may be crucial in pulmonary carcinogensis or in the progression of <d>lung cancer</d> in <d>IPF</d> patients in whom TGF-b is overexpressed; hypermethylation of the <g>Smad4</g> promoter region may be one mechanism by which this occurs. These findings are useful for the development of preventive measures or treatment for <d>lung cancer</d> patients with <d>IPF</d>.
21475793|a|Patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> have an increased risk of developing <d>lung cancer</d>. To identify key molecules involved in malignant transformation in <d>IPF</d>, we analyzed the expression profiles of lung and <d>lung <d>tumor</d></d> tissue from patients with <d>lung cancer</d> and <d>IPF</d> <d>lung cancer</d>/<d>IPF</d> using cDNA arrays and real-time quantitative reverse transcriptase-polymerase chain reaction RT-PCR. Reduced expression of the <g>Smad4</g> gene was identified in all eight <d>tumor</d> samples from the <d>lung cancer</d>/<d>IPF</d> patients using real-time RT-PCR. Expression levels of <g>Smad4</g> were significantly lower in <d>tumor</d>s from <d>lung cancer</d>/<d>IPF</d> patients than in those from <d>lung cancer</d> patients without <d>IPF</d> or in <d>lung cancer</d> cell lines p<0.01. Mutational analysis of TGF-b type II receptor and <g>Smad4</g> was performed using polymerase chain reaction-single strand conformation polymorphism PCR-SSCP. The methylation status of the <g>Smad4</g> promoter was analyzed using methylation-specific PCR with subsequent sequence analysis. No mutations were detected in the eight <d>tumor</d> samples, but hypermethylated regions were detected in the <g>Smad4</g> promoter in two of the eight <d>tumor</d>s with reduced <g>Smad4</g> expression. Promoter reporter assays showed that the activity of the <g>Smad4</g> promoter containing the sequence of the methylated region was significantly stronger than that of the <g>Smad4</g> promoter with a deleted methylated region p<0.002. Our findings indicate that the loss of the growth inhibitory response to TGF-b signaling may be crucial in pulmonary carcinogensis or in the progression of <d>lung cancer</d> in <d>IPF</d> patients in whom TGF-b is overexpressed; hypermethylation of the <g>Smad4</g> promoter region may be one mechanism by which this occurs. These findings are useful for the development of preventive measures or treatment for <d>lung cancer</d> patients with <d>IPF</d>.
21475793|a|Patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> have an increased risk of developing <d>lung cancer</d>. To identify key molecules involved in malignant transformation in <d>IPF</d>, we analyzed the expression profiles of lung and <d>lung <d>tumor</d></d> tissue from patients with <d>lung cancer</d> and <d>IPF</d> <d>lung cancer</d>/<d>IPF</d> using cDNA arrays and real-time quantitative reverse transcriptase-polymerase chain reaction RT-PCR. Reduced expression of the <g>Smad4</g> gene was identified in all eight <d>tumor</d> samples from the <d>lung cancer</d>/<d>IPF</d> patients using real-time RT-PCR. Expression levels of <g>Smad4</g> were significantly lower in <d>tumor</d>s from <d>lung cancer</d>/<d>IPF</d> patients than in those from <d>lung cancer</d> patients without <d>IPF</d> or in <d>lung cancer</d> cell lines p<0.01. Mutational analysis of <g>TGF-b</g> type II receptor and <g>Smad4</g> was performed using polymerase chain reaction-single strand conformation polymorphism PCR-SSCP. The methylation status of the <g>Smad4</g> promoter was analyzed using methylation-specific PCR with subsequent sequence analysis. No mutations were detected in the eight <d>tumor</d> samples, but hypermethylated regions were detected in the <g>Smad4</g> promoter in two of the eight <d>tumor</d>s with reduced <g>Smad4</g> expression. Promoter reporter assays showed that the activity of the <g>Smad4</g> promoter containing the sequence of the methylated region was significantly stronger than that of the <g>Smad4</g> promoter with a deleted methylated region p<0.002. Our findings indicate that the loss of the growth inhibitory response to <g>TGF-b</g> signaling may be <d>crucial in pulmonary carcinogensis</d> or in the progression of <d>lung cancer</d> in <d>IPF</d> patients in whom <g>TGF-b</g> is overexpressed; hypermethylation of the <g>Smad4</g> promoter region may be one mechanism by which this occurs. These findings are useful for the development of preventive measures or treatment for <d>lung cancer</d> patients with <d>IPF</d>.
19117745|a|BACKGROUND: The aim of our study is to investigate correlations of TH1/TH2 cytokine gene polymorphisms and bronchoalveolar lavage fluid BALF cytokine values in <d>interstitial lung diseases</d> ILD. METHODS: In 16 sarcoidosis, 7 idiopathic pulmonary fibrosis IPF and 8 hypersensitivity pneumonitis HP patients we evaluated IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10, -12, IFN-gamma, TGF-beta1 and TNF-alpha gene polymorphisms in peripheral blood, and MCP-1,MIP-1 alpha, MIP-1 beta, RANTES, ENA-78, FGF, G-CSF, GM-CSF, IFN-gamma, IL-1 alpha, IL-1RA, IL-1 beta, -2, -4, -5, -6, -8, -10, -17, TNF-alpha, Tpo and VEGF values in BALF. RESULTS: We found higher TNF-alpha values in IL-1R pst 1970 TT homozygotes regardless of diagnosis p=0.0126. In the sarcoidosis group IL-4R alpha+1902AA and IL-10-1082G allele correlated with higher BALF ENA-78 levels p=0.0258, p=0.0230. In the HP group the IL-6-174CG and IL-6nt565AG correlated with higher ENA-78 BALF levels p=0.0253. In the IPF group the IL-1 beta +3962 CC homozygotes had lower IL-1RA BALF values p=0.046. BALF chemokine values did not differ between ILD subgroups, except for IL-8, which was higher in stage III sarcoidosis patients compared to stage I. CONCLUSION: Our results show a probable influence of gene polymorphisms, namely IL-4R alpha and IL-10 on ENA-78 BALF levels in sarcoidosis, IL-6 on ENA-78 BALF levels in HP and IL-1-beta on IL-1RA BALF values in the IPF group. The TNF-alpha BALF values correlated with IL-1R pst 1970 gene polymorphisms.
19117745|a|BACKGROUND: The aim of our study is to investigate correlations of TH1/TH2 cytokine gene polymorphisms and bronchoalveolar lavage fluid BALF cytokine values in <d>interstitial lung diseases</d> <d>ILD</d>. METHODS: In 16 sarcoidosis, 7 idiopathic pulmonary fibrosis IPF and 8 hypersensitivity pneumonitis HP patients we evaluated IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10, -12, IFN-gamma, TGF-beta1 and TNF-alpha gene polymorphisms in peripheral blood, and MCP-1,MIP-1 alpha, MIP-1 beta, RANTES, ENA-78, FGF, G-CSF, GM-CSF, IFN-gamma, IL-1 alpha, IL-1RA, IL-1 beta, -2, -4, -5, -6, -8, -10, -17, TNF-alpha, Tpo and VEGF values in BALF. RESULTS: We found higher TNF-alpha values in IL-1R pst 1970 TT homozygotes regardless of diagnosis p=0.0126. In the sarcoidosis group IL-4R alpha+1902AA and IL-10-1082G allele correlated with higher BALF ENA-78 levels p=0.0258, p=0.0230. In the HP group the IL-6-174CG and IL-6nt565AG correlated with higher ENA-78 BALF levels p=0.0253. In the IPF group the IL-1 beta +3962 CC homozygotes had lower IL-1RA BALF values p=0.046. BALF chemokine values did not differ between <d>ILD</d> subgroups, except for IL-8, which was higher in stage III sarcoidosis patients compared to stage I. CONCLUSION: Our results show a probable influence of gene polymorphisms, namely IL-4R alpha and IL-10 on ENA-78 BALF levels in sarcoidosis, IL-6 on ENA-78 BALF levels in HP and IL-1-beta on IL-1RA BALF values in the IPF group. The TNF-alpha BALF values correlated with IL-1R pst 1970 gene polymorphisms.
19117745|a|BACKGROUND: The aim of our study is to investigate correlations of TH1/TH2 cytokine gene polymorphisms and bronchoalveolar lavage fluid BALF cytokine values in <d>interstitial lung diseases</d> <d>ILD</d>. METHODS: In 16 <d>sarcoidosis</d>, 7 idiopathic pulmonary fibrosis IPF and 8 hypersensitivity pneumonitis HP patients we evaluated IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10, -12, IFN-gamma, TGF-beta1 and TNF-alpha gene polymorphisms in peripheral blood, and MCP-1,MIP-1 alpha, MIP-1 beta, RANTES, ENA-78, FGF, G-CSF, GM-CSF, IFN-gamma, IL-1 alpha, IL-1RA, IL-1 beta, -2, -4, -5, -6, -8, -10, -17, TNF-alpha, Tpo and VEGF values in BALF. RESULTS: We found higher TNF-alpha values in IL-1R pst 1970 TT homozygotes regardless of diagnosis p=0.0126. In the <d>sarcoidosis</d> group IL-4R alpha+1902AA and IL-10-1082G allele correlated with higher BALF ENA-78 levels p=0.0258, p=0.0230. In the HP group the IL-6-174CG and IL-6nt565AG correlated with higher ENA-78 BALF levels p=0.0253. In the IPF group the IL-1 beta +3962 CC homozygotes had lower IL-1RA BALF values p=0.046. BALF chemokine values did not differ between <d>ILD</d> subgroups, except for IL-8, which was higher in stage III <d>sarcoidosis</d> patients compared to stage I. CONCLUSION: Our results show a probable influence of gene polymorphisms, namely IL-4R alpha and IL-10 on ENA-78 BALF levels in <d>sarcoidosis</d>, IL-6 on ENA-78 BALF levels in HP and IL-1-beta on IL-1RA BALF values in the IPF group. The TNF-alpha BALF values correlated with IL-1R pst 1970 gene polymorphisms.
19117745|a|BACKGROUND: The aim of our study is to investigate correlations of TH1/TH2 cytokine gene polymorphisms and bronchoalveolar lavage fluid BALF cytokine values in <d>interstitial lung diseases</d> <d>ILD</d>. METHODS: In 16 <d>sarcoidosis</d>, 7 <d>idiopathic pulmonary fibrosis</d> IPF and 8 hypersensitivity pneumonitis HP patients we evaluated IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10, -12, IFN-gamma, TGF-beta1 and TNF-alpha gene polymorphisms in peripheral blood, and MCP-1,MIP-1 alpha, MIP-1 beta, RANTES, ENA-78, FGF, G-CSF, GM-CSF, IFN-gamma, IL-1 alpha, IL-1RA, IL-1 beta, -2, -4, -5, -6, -8, -10, -17, TNF-alpha, Tpo and VEGF values in BALF. RESULTS: We found higher TNF-alpha values in IL-1R pst 1970 TT homozygotes regardless of diagnosis p=0.0126. In the <d>sarcoidosis</d> group IL-4R alpha+1902AA and IL-10-1082G allele correlated with higher BALF ENA-78 levels p=0.0258, p=0.0230. In the HP group the IL-6-174CG and IL-6nt565AG correlated with higher ENA-78 BALF levels p=0.0253. In the IPF group the IL-1 beta +3962 CC homozygotes had lower IL-1RA BALF values p=0.046. BALF chemokine values did not differ between <d>ILD</d> subgroups, except for IL-8, which was higher in stage III <d>sarcoidosis</d> patients compared to stage I. CONCLUSION: Our results show a probable influence of gene polymorphisms, namely IL-4R alpha and IL-10 on ENA-78 BALF levels in <d>sarcoidosis</d>, IL-6 on ENA-78 BALF levels in HP and IL-1-beta on IL-1RA BALF values in the IPF group. The TNF-alpha BALF values correlated with IL-1R pst 1970 gene polymorphisms.
19117745|a|BACKGROUND: The aim of our study is to investigate correlations of TH1/TH2 cytokine gene polymorphisms and bronchoalveolar lavage fluid BALF cytokine values in <d>interstitial lung diseases</d> <d>ILD</d>. METHODS: In 16 <d>sarcoidosis</d>, 7 <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and 8 hypersensitivity pneumonitis HP patients we evaluated IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10, -12, IFN-gamma, TGF-beta1 and TNF-alpha gene polymorphisms in peripheral blood, and MCP-1,MIP-1 alpha, MIP-1 beta, RANTES, ENA-78, FGF, G-CSF, GM-CSF, IFN-gamma, IL-1 alpha, IL-1RA, IL-1 beta, -2, -4, -5, -6, -8, -10, -17, TNF-alpha, Tpo and VEGF values in BALF. RESULTS: We found higher TNF-alpha values in IL-1R pst 1970 TT homozygotes regardless of diagnosis p=0.0126. In the <d>sarcoidosis</d> group IL-4R alpha+1902AA and IL-10-1082G allele correlated with higher BALF ENA-78 levels p=0.0258, p=0.0230. In the HP group the IL-6-174CG and IL-6nt565AG correlated with higher ENA-78 BALF levels p=0.0253. In the <d>IPF</d> group the IL-1 beta +3962 CC homozygotes had lower IL-1RA BALF values p=0.046. BALF chemokine values did not differ between <d>ILD</d> subgroups, except for IL-8, which was higher in stage III <d>sarcoidosis</d> patients compared to stage I. CONCLUSION: Our results show a probable influence of gene polymorphisms, namely IL-4R alpha and IL-10 on ENA-78 BALF levels in <d>sarcoidosis</d>, IL-6 on ENA-78 BALF levels in HP and IL-1-beta on IL-1RA BALF values in the <d>IPF</d> group. The TNF-alpha BALF values correlated with IL-1R pst 1970 gene polymorphisms.
19117745|a|BACKGROUND: The aim of our study is to investigate correlations of TH1/TH2 cytokine gene polymorphisms and bronchoalveolar lavage fluid BALF cytokine values in <d>interstitial lung diseases</d> <d>ILD</d>. METHODS: In 16 <d>sarcoidosis</d>, 7 <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and 8 <d>hypersensitivity pneumonitis</d> HP patients we evaluated IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10, -12, IFN-gamma, TGF-beta1 and TNF-alpha gene polymorphisms in peripheral blood, and MCP-1,MIP-1 alpha, MIP-1 beta, RANTES, ENA-78, FGF, G-CSF, GM-CSF, IFN-gamma, IL-1 alpha, IL-1RA, IL-1 beta, -2, -4, -5, -6, -8, -10, -17, TNF-alpha, Tpo and VEGF values in BALF. RESULTS: We found higher TNF-alpha values in IL-1R pst 1970 TT homozygotes regardless of diagnosis p=0.0126. In the <d>sarcoidosis</d> group IL-4R alpha+1902AA and IL-10-1082G allele correlated with higher BALF ENA-78 levels p=0.0258, p=0.0230. In the HP group the IL-6-174CG and IL-6nt565AG correlated with higher ENA-78 BALF levels p=0.0253. In the <d>IPF</d> group the IL-1 beta +3962 CC homozygotes had lower IL-1RA BALF values p=0.046. BALF chemokine values did not differ between <d>ILD</d> subgroups, except for IL-8, which was higher in stage III <d>sarcoidosis</d> patients compared to stage I. CONCLUSION: Our results show a probable influence of gene polymorphisms, namely IL-4R alpha and IL-10 on ENA-78 BALF levels in <d>sarcoidosis</d>, IL-6 on ENA-78 BALF levels in HP and IL-1-beta on IL-1RA BALF values in the <d>IPF</d> group. The TNF-alpha BALF values correlated with IL-1R pst 1970 gene polymorphisms.
19117745|a|BACKGROUND: The aim of our study is to investigate correlations of TH1/TH2 cytokine gene polymorphisms and bronchoalveolar lavage fluid BALF cytokine values in <d>interstitial lung diseases</d> <d>ILD</d>. METHODS: In 16 <d>sarcoidosis</d>, 7 <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and 8 <d>hypersensitivity pneumonitis</d> <d>HP</d> patients we evaluated IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10, -12, IFN-gamma, TGF-beta1 and TNF-alpha gene polymorphisms in peripheral blood, and MCP-1,MIP-1 alpha, MIP-1 beta, RANTES, ENA-78, FGF, G-CSF, GM-CSF, IFN-gamma, IL-1 alpha, IL-1RA, IL-1 beta, -2, -4, -5, -6, -8, -10, -17, TNF-alpha, Tpo and VEGF values in BALF. RESULTS: We found higher TNF-alpha values in IL-1R pst 1970 TT homozygotes regardless of diagnosis p=0.0126. In the <d>sarcoidosis</d> group IL-4R alpha+1902AA and IL-10-1082G allele correlated with higher BALF ENA-78 levels p=0.0258, p=0.0230. In the <d>HP</d> group the IL-6-174CG and IL-6nt565AG correlated with higher ENA-78 BALF levels p=0.0253. In the <d>IPF</d> group the IL-1 beta +3962 CC homozygotes had lower IL-1RA BALF values p=0.046. BALF chemokine values did not differ between <d>ILD</d> subgroups, except for IL-8, which was higher in stage III <d>sarcoidosis</d> patients compared to stage I. CONCLUSION: Our results show a probable influence of gene polymorphisms, namely IL-4R alpha and IL-10 on ENA-78 BALF levels in <d>sarcoidosis</d>, IL-6 on ENA-78 BALF levels in <d>HP</d> and IL-1-beta on IL-1RA BALF values in the <d>IPF</d> group. The TNF-alpha BALF values correlated with IL-1R pst 1970 gene polymorphisms.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary fibrotic diseases is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, idiopathic pulmonary fibrosis IPF, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following lung injury, and highlights the pathogenesis of some of the most widespread pulmonary fibrotic diseases. A three phase model of wound repair is reviewed that includes; 1 injury; 2 inflammation; and 3 repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary <d>fibrotic diseases</d> is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, idiopathic pulmonary fibrosis IPF, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following lung injury, and highlights the pathogenesis of some of the most widespread pulmonary <d>fibrotic diseases</d>. A three phase model of wound repair is reviewed that includes; 1 injury; 2 inflammation; and 3 repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary <d>fibrotic diseases</d> is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, <d>idiopathic pulmonary fibrosis</d> IPF, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following lung injury, and highlights the pathogenesis of some of the most widespread pulmonary <d>fibrotic diseases</d>. A three phase model of wound repair is reviewed that includes; 1 injury; 2 inflammation; and 3 repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary <d>fibrotic diseases</d> is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following lung injury, and highlights the pathogenesis of some of the most widespread pulmonary <d>fibrotic diseases</d>. A three phase model of wound repair is reviewed that includes; 1 injury; 2 inflammation; and 3 repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary <d>fibrotic diseases</d> is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following <d>lung injury</d>, and highlights the pathogenesis of some of the most widespread pulmonary <d>fibrotic diseases</d>. A three phase model of wound repair is reviewed that includes; 1 injury; 2 inflammation; and 3 repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary <d>fibrotic diseases</d> is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following <d>lung injury</d>, and highlights the pathogenesis of some of the most widespread pulmonary <d>fibrotic diseases</d>. A three phase model of wound repair is reviewed that includes; 1 <d>injury; 2 inflammation</d>; and 3 repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary <d>fibrotic diseases</d> is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following <d>lung injury</d>, and highlights the pathogenesis of some of the most widespread pulmonary <d>fibrotic diseases</d>. A three phase model of wound repair is reviewed that includes; 1 <d>injury; 2 inflammation</d>; and 3 repair. In most <d>pulmonary fibrotic conditions dysregulation</d> at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary <d>fibrotic diseases</d> is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following <d>lung injury</d>, and highlights the pathogenesis of some of the most widespread pulmonary <d>fibrotic diseases</d>. A three phase model of wound repair is reviewed that includes; 1 <d>injury; 2 inflammation</d>; and 3 repair. In most <d>pulmonary fibrotic conditions dysregulation</d> at one or more of these phases has been reported. <d>Chronic inflammation</d> can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary <d>fibrotic diseases</d> is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following <d>lung injury</d>, and highlights the pathogenesis of some of the most widespread pulmonary <d>fibrotic diseases</d>. A three phase model of wound repair is reviewed that includes; 1 <d>injury; 2 inflammation</d>; and 3 repair. In most <d>pulmonary fibrotic conditions dysregulation</d> at one or more of these phases has been reported. <d>Chronic inflammation</d> can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or <g>TGFbeta1</g> production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these <d>dysregulated healing</d> responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
19129758|a|<d>Pulmonary fibrosis</d> and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary <d>fibrotic diseases</d> is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following <d>lung injury</d>, and highlights the pathogenesis of some of the most widespread pulmonary <d>fibrotic diseases</d>. A three phase model of wound repair is reviewed that includes; 1 <d>injury; 2 inflammation</d>; and 3 repair. In most <d>pulmonary fibrotic conditions dysregulation</d> at one or more of these phases has been reported. <d>Chronic inflammation</d> can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or <g>TGFbeta1</g> production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these <d>dysregulated healing</d> responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of <d>pulmonary fibrosis</d>.
19355895|a|<d>Idiopathic Pulmonary Fibrosis</d> IPF is characterized by injury and loss of lung epithelial cells, accumulation of fibroblasts/myofibroblasts and abnormal remodeling of the lung parenchyma. The prognosis for IPF patients is poor and current therapies are largely ineffective in preventing respiratory failure. Current therapeutic approaches target epithelial cell replacement, manipulation of fibroblasts/myofibroblasts, modulation of procoagulant/fibrinolytic activities, cytokine and growth factor production, angiogenesis, and reduction of oxidative stress. Myofibroblasts are the primary effector cells in fibrosis. These cells may be derived by the activation and proliferation of resident lung fibroblasts, from epithelial-mesenchymal transition EMT, or through recruitment of circulating fibrocytes. Transforming growth factor beta <g>TGFbeta</g> is a profibrotic factor that increases fibroblast proliferation, stimulates the synthesis and deposition of connective tissue, and inhibits connective tissue breakdown. <g>TGFbeta</g> acts through the promoter of the type 1 collagen gene causing increased collagen synthesis. In addition, <g>TGFbeta</g> induces EMT in alveolar epithelial cells AECs in vitro and in vivo. AECs exhibit substantial plasticity and may serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. Therapeutic interventions interfering with the pathways that lead to myofibroblast expansion and AEC apoptosis should be of considerable benefit in the treatment of IPF. This review will focus on the critical role of <g>TGFbeta</g> on AECs EMT and myofibroblasts in the development of fibrosis.
19355895|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is characterized by injury and loss of lung epithelial cells, accumulation of fibroblasts/myofibroblasts and abnormal remodeling of the lung parenchyma. The prognosis for <d>IPF</d> patients is poor and current therapies are largely ineffective in preventing respiratory failure. Current therapeutic approaches target epithelial cell replacement, manipulation of fibroblasts/myofibroblasts, modulation of procoagulant/fibrinolytic activities, cytokine and growth factor production, angiogenesis, and reduction of oxidative stress. Myofibroblasts are the primary effector cells in fibrosis. These cells may be derived by the activation and proliferation of resident lung fibroblasts, from epithelial-mesenchymal transition EMT, or through recruitment of circulating fibrocytes. Transforming growth factor beta <g>TGFbeta</g> is a profibrotic factor that increases fibroblast proliferation, stimulates the synthesis and deposition of connective tissue, and inhibits connective tissue breakdown. <g>TGFbeta</g> acts through the promoter of the type 1 collagen gene causing increased collagen synthesis. In addition, <g>TGFbeta</g> induces EMT in alveolar epithelial cells AECs in vitro and in vivo. AECs exhibit substantial plasticity and may serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. Therapeutic interventions interfering with the pathways that lead to myofibroblast expansion and AEC apoptosis should be of considerable benefit in the treatment of <d>IPF</d>. This review will focus on the critical role of <g>TGFbeta</g> on AECs EMT and myofibroblasts in the development of fibrosis.
19355895|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is characterized by injury and loss of lung epithelial cells, accumulation of fibroblasts/myofibroblasts and abnormal remodeling of the lung parenchyma. The prognosis for <d>IPF</d> patients is poor and current therapies are largely ineffective in preventing <d>respiratory failure</d>. Current therapeutic approaches target epithelial cell replacement, manipulation of fibroblasts/myofibroblasts, modulation of procoagulant/fibrinolytic activities, cytokine and growth factor production, angiogenesis, and reduction of oxidative stress. Myofibroblasts are the primary effector cells in fibrosis. These cells may be derived by the activation and proliferation of resident lung fibroblasts, from epithelial-mesenchymal transition EMT, or through recruitment of circulating fibrocytes. Transforming growth factor beta <g>TGFbeta</g> is a profibrotic factor that increases fibroblast proliferation, stimulates the synthesis and deposition of connective tissue, and inhibits connective tissue breakdown. <g>TGFbeta</g> acts through the promoter of the type 1 collagen gene causing increased collagen synthesis. In addition, <g>TGFbeta</g> induces EMT in alveolar epithelial cells AECs in vitro and in vivo. AECs exhibit substantial plasticity and may serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. Therapeutic interventions interfering with the pathways that lead to myofibroblast expansion and AEC apoptosis should be of considerable benefit in the treatment of <d>IPF</d>. This review will focus on the critical role of <g>TGFbeta</g> on AECs EMT and myofibroblasts in the development of fibrosis.
19355895|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is characterized by injury and loss of lung epithelial cells, accumulation of fibroblasts/myofibroblasts and abnormal remodeling of the lung parenchyma. The prognosis for <d>IPF</d> patients is poor and current therapies are largely ineffective in preventing <d>respiratory failure</d>. Current therapeutic approaches target epithelial cell replacement, manipulation of fibroblasts/myofibroblasts, modulation of procoagulant/fibrinolytic activities, cytokine and growth factor production, angiogenesis, and reduction of oxidative stress. Myofibroblasts are the primary effector cells in <d>fibrosis</d>. These cells may be derived by the activation and proliferation of resident lung fibroblasts, from epithelial-mesenchymal transition EMT, or through recruitment of circulating fibrocytes. Transforming growth factor beta <g>TGFbeta</g> is a profibrotic factor that increases fibroblast proliferation, stimulates the synthesis and deposition of connective tissue, and inhibits connective tissue breakdown. <g>TGFbeta</g> acts through the promoter of the type 1 collagen gene causing increased collagen synthesis. In addition, <g>TGFbeta</g> induces EMT in alveolar epithelial cells AECs in vitro and in vivo. AECs exhibit substantial plasticity and may serve as a source of fibroblasts and/or myofibroblasts in lung <d>fibrosis</d>. Therapeutic interventions interfering with the pathways that lead to myofibroblast expansion and AEC apoptosis should be of considerable benefit in the treatment of <d>IPF</d>. This review will focus on the critical role of <g>TGFbeta</g> on AECs EMT and myofibroblasts in the development of <d>fibrosis</d>.
19361498|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix protein deposition. EBV, localised to alveolar epithelial cells of pulmonary fibrosis patients is associated with a poor prognosis. A strategy based on microarray-differential gene expression analysis to identify molecular drivers of EBV-associated lung fibrosis was utilized. Alveolar epithelial cells were infected with EBV to identify genes whose expression was altered following TGFbeta1-mediated lytic phase. EBV lytic reactivation by TGFbeta1 drives a selective alteration in <g>CUX1</g> variant a NCBI accession number NM_181552 expression, inducing activation of non-canonical Wnt pathway mediators, implicating it in Epithelial Mesenchymal Transition EMT, the molecular event underpinning scar production in tissue fibrosis. The role of EBV in EMT can be attenuated by antiviral strategies and inhibition of Wnt signaling by using All-Trans Retinoic Acids ATRA. Activation of non-canonical Wnt signaling pathway by EBV in epithelial cells suggests a novel mechanism of EMT via <g>CUX1</g> signaling. These data present a framework for further description of the link between infectious agents and fibrosis, a significant disease burden.
19361498|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix protein deposition. EBV, localised to alveolar epithelial cells of pulmonary fibrosis patients is associated with a poor prognosis. A strategy based on microarray-differential gene expression analysis to identify molecular drivers of EBV-associated lung fibrosis was utilized. Alveolar epithelial cells were infected with EBV to identify genes whose expression was altered following TGFbeta1-mediated lytic phase. EBV lytic reactivation by TGFbeta1 drives a selective alteration in <g>CUX1</g> variant a NCBI accession number NM_181552 expression, inducing activation of non-canonical Wnt pathway mediators, implicating it in Epithelial Mesenchymal Transition EMT, the molecular event underpinning scar production in tissue fibrosis. The role of EBV in EMT can be attenuated by antiviral strategies and inhibition of Wnt signaling by using All-Trans Retinoic Acids ATRA. Activation of non-canonical Wnt signaling pathway by EBV in epithelial cells suggests a novel mechanism of EMT via <g>CUX1</g> signaling. These data present a framework for further description of the link between infectious agents and fibrosis, a significant disease burden.
19361498|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a refractory and lethal <d>interstitial lung disease</d> characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix protein deposition. EBV, localised to alveolar epithelial cells of pulmonary fibrosis patients is associated with a poor prognosis. A strategy based on microarray-differential gene expression analysis to identify molecular drivers of EBV-associated lung fibrosis was utilized. Alveolar epithelial cells were infected with EBV to identify genes whose expression was altered following TGFbeta1-mediated lytic phase. EBV lytic reactivation by TGFbeta1 drives a selective alteration in <g>CUX1</g> variant a NCBI accession number NM_181552 expression, inducing activation of non-canonical Wnt pathway mediators, implicating it in Epithelial Mesenchymal Transition EMT, the molecular event underpinning scar production in tissue fibrosis. The role of EBV in EMT can be attenuated by antiviral strategies and inhibition of Wnt signaling by using All-Trans Retinoic Acids ATRA. Activation of non-canonical Wnt signaling pathway by EBV in epithelial cells suggests a novel mechanism of EMT via <g>CUX1</g> signaling. These data present a framework for further description of the link between infectious agents and fibrosis, a significant disease burden.
19361498|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a refractory and lethal <d>interstitial lung disease</d> characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix protein deposition. EBV, localised to alveolar epithelial cells of pulmonary <d>fibrosis</d> patients is associated with a poor prognosis. A strategy based on microarray-differential gene expression analysis to identify molecular drivers of EBV-associated lung <d>fibrosis</d> was utilized. Alveolar epithelial cells were infected with EBV to identify genes whose expression was altered following TGFbeta1-mediated lytic phase. EBV lytic reactivation by TGFbeta1 drives a selective alteration in <g>CUX1</g> variant a NCBI accession number NM_181552 expression, inducing activation of non-canonical Wnt pathway mediators, implicating it in Epithelial Mesenchymal Transition EMT, the molecular event underpinning scar production in tissue <d>fibrosis</d>. The role of EBV in EMT can be attenuated by antiviral strategies and inhibition of Wnt signaling by using All-Trans Retinoic Acids ATRA. Activation of non-canonical Wnt signaling pathway by EBV in epithelial cells suggests a novel mechanism of EMT via <g>CUX1</g> signaling. These data present a framework for further description of the link between infectious agents and <d>fibrosis</d>, a significant disease burden.
19381013|a|Idiopathic pulmonary fibrosis IPF can lead to the development of secondary pulmonary <d>hypertension</d> PH and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of IPF, we explored the role of the proangiogenic and antiapoptotic growth factor <g>VEGF</g> in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active TGF-beta1 induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and increased pulmonary arterial pressure PAP. Immunohistochemistry and mRNA analysis revealed decreased levels of <g>VEGF</g> and its receptor, which were inversely correlated with PAP and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of IPF rats with adenoviral delivery of <g>VEGF</g> resulted in reduced endothelial apoptosis, increased vascularization, and improved PAP due to reduced remodeling but worsened PF. These data show that experimental pulmonary fibrosis PF leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of <g>VEGF</g> ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, <g>VEGF</g>-based therapies should be used with caution.
19381013|a|Idiopathic pulmonary <d>fibrosis</d> IPF can lead to the development of secondary pulmonary <d>hypertension</d> PH and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of IPF, we explored the role of the proangiogenic and antiapoptotic growth factor <g>VEGF</g> in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active TGF-beta1 induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and increased pulmonary arterial pressure PAP. Immunohistochemistry and mRNA analysis revealed decreased levels of <g>VEGF</g> and its receptor, which were inversely correlated with PAP and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of IPF rats with adenoviral delivery of <g>VEGF</g> resulted in reduced endothelial apoptosis, increased vascularization, and improved PAP due to reduced remodeling but worsened PF. These data show that experimental pulmonary <d>fibrosis</d> PF leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of <g>VEGF</g> ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, <g>VEGF</g>-based therapies should be used with caution.
19381013|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> can lead to the development of secondary pulmonary <d>hypertension</d> PH and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of <d>IPF</d>, we explored the role of the proangiogenic and antiapoptotic growth factor <g>VEGF</g> in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active TGF-beta1 induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and increased pulmonary arterial pressure PAP. Immunohistochemistry and mRNA analysis revealed decreased levels of <g>VEGF</g> and its receptor, which were inversely correlated with PAP and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of <d>IPF</d> rats with adenoviral delivery of <g>VEGF</g> resulted in reduced endothelial apoptosis, increased vascularization, and improved PAP due to reduced remodeling but worsened PF. These data show that experimental pulmonary <d>fibrosis</d> PF leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of <g>VEGF</g> ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, <g>VEGF</g>-based therapies should be used with caution.
19381013|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> can lead to the development of secondary pulmonary <d>hypertension</d> PH and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of <d>IPF</d>, we explored the role of the proangiogenic and antiapoptotic growth factor <g>VEGF</g> in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active <g>TGF-beta1</g> induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and <d>increased pulmonary arterial pressure</d> PAP. Immunohistochemistry and mRNA analysis revealed decreased levels of <g>VEGF</g> and its receptor, which were inversely correlated with PAP and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of <d>IPF</d> rats with adenoviral delivery of <g>VEGF</g> resulted in reduced endothelial apoptosis, increased vascularization, and improved PAP due to reduced remodeling but worsened PF. These data show that experimental pulmonary <d>fibrosis</d> PF leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of <g>VEGF</g> ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, <g>VEGF</g>-based therapies should be used with caution.
19381013|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> can lead to the development of secondary pulmonary <d>hypertension</d> PH and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of <d>IPF</d>, we explored the role of the proangiogenic and antiapoptotic growth factor <g>VEGF</g> in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active <g>TGF-beta1</g> induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and <d>increased pulmonary arterial pressure</d> <d>PAP</d>. Immunohistochemistry and mRNA analysis revealed decreased levels of <g>VEGF</g> and its receptor, which were inversely correlated with <d>PAP</d> and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of <d>IPF</d> rats with adenoviral delivery of <g>VEGF</g> resulted in reduced endothelial apoptosis, increased vascularization, and improved <d>PAP</d> due to reduced remodeling but worsened PF. These data show that experimental pulmonary <d>fibrosis</d> PF leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of <g>VEGF</g> ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, <g>VEGF</g>-based therapies should be used with caution.
19381013|a|Idiopathic pulmonary <d>fibrosis</d> <d>I<d>PF</d></d> can lead to the development of secondary pulmonary <d>hypertension</d> PH and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of <d>I<d>PF</d></d>, we explored the role of the proangiogenic and antiapoptotic growth factor <g>VEGF</g> in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active <g>TGF-beta1</g> induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and <d>increased pulmonary arterial pressure</d> <d>PAP</d>. Immunohistochemistry and mRNA analysis revealed decreased levels of <g>VEGF</g> and its receptor, which were inversely correlated with <d>PAP</d> and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of <d>I<d>PF</d></d> rats with adenoviral delivery of <g>VEGF</g> resulted in reduced endothelial apoptosis, increased vascularization, and improved <d>PAP</d> due to reduced remodeling but worsened <d>PF</d>. These data show that experimental pulmonary <d>fibrosis</d> <d>PF</d> leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of <g>VEGF</g> ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, <g>VEGF</g>-based therapies should be used with caution.
19393328|a|BACKGROUND: Excessive production of <g>TGF-beta1</g> plays a key role in the tissue remodeling or fibrotic process observed in <d>bronchial asthma</d>, chronic pulmonary disease COPD, and idiopathic pulmonary fibrosis IPF. <g>TGF-beta1</g> has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species. OBJECTIVES: The aim of this study was to evaluate whether the antioxidant N-acetyl-l-cysteine NAC can affect <g>TGF-beta1</g>-mediated tissue remodeling in fibroblasts or modulate the production of fibronectin and vascular endothelial growth factor VEGF which are believed to be important mediators of tissue repair and remodeling. METHODS: To accomplish this, human fetal lung fibroblasts HFL-1 were used to assess the effect of NAC on the <g>TGF-beta1</g>-mediated contraction of floating gels and the <g>TGF-beta1</g>-induced mediator production. In addition, the effect of NAC on the <g>TGF-beta1</g>-induced differentiation to myofibroblasts was evaluated by assessing alpha-smooth muscle actin alpha-SMA expression. RESULTS: NAC significantly abolished the <g>TGF-beta1</g>-augmented gel contraction at 3mM, gel size 63.4+/-2.6% vs. 39.1+/-4.1%; p<0.01 compared with control in a concentration-dependent manner. NAC also significantly inhibited the <g>TGF-beta1</g>-augmented fibronectin p<0.01 and VEGF p<0.01 production in the media of both the three-dimensional gel and monolayer culture. Furthermore, NAC reversed the <g>TGF-beta1</g>-stimulated alpha-SMA expression p<0.01. CONCLUSION: These results suggest that NAC can affect the <g>TGF-beta1</g>-induced tissue remodeling or fibrotic process in vitro.
19393328|a|BACKGROUND: Excessive production of <g>TGF-beta1</g> plays a key role in the tissue remodeling or fibrotic process observed in <d>bronchial asthma</d>, <d>chronic pulmonary disease</d> COPD, and idiopathic pulmonary fibrosis IPF. <g>TGF-beta1</g> has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species. OBJECTIVES: The aim of this study was to evaluate whether the antioxidant N-acetyl-l-cysteine NAC can affect <g>TGF-beta1</g>-mediated tissue remodeling in fibroblasts or modulate the production of fibronectin and vascular endothelial growth factor VEGF which are believed to be important mediators of tissue repair and remodeling. METHODS: To accomplish this, human fetal lung fibroblasts HFL-1 were used to assess the effect of NAC on the <g>TGF-beta1</g>-mediated contraction of floating gels and the <g>TGF-beta1</g>-induced mediator production. In addition, the effect of NAC on the <g>TGF-beta1</g>-induced differentiation to myofibroblasts was evaluated by assessing alpha-smooth muscle actin alpha-SMA expression. RESULTS: NAC significantly abolished the <g>TGF-beta1</g>-augmented gel contraction at 3mM, gel size 63.4+/-2.6% vs. 39.1+/-4.1%; p<0.01 compared with control in a concentration-dependent manner. NAC also significantly inhibited the <g>TGF-beta1</g>-augmented fibronectin p<0.01 and VEGF p<0.01 production in the media of both the three-dimensional gel and monolayer culture. Furthermore, NAC reversed the <g>TGF-beta1</g>-stimulated alpha-SMA expression p<0.01. CONCLUSION: These results suggest that NAC can affect the <g>TGF-beta1</g>-induced tissue remodeling or fibrotic process in vitro.
19393328|a|BACKGROUND: Excessive production of <g>TGF-beta1</g> plays a key role in the tissue remodeling or fibrotic process observed in <d>bronchial asthma</d>, <d>chronic pulmonary disease</d> <d>COPD</d>, and idiopathic pulmonary fibrosis IPF. <g>TGF-beta1</g> has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species. OBJECTIVES: The aim of this study was to evaluate whether the antioxidant N-acetyl-l-cysteine NAC can affect <g>TGF-beta1</g>-mediated tissue remodeling in fibroblasts or modulate the production of fibronectin and vascular endothelial growth factor VEGF which are believed to be important mediators of tissue repair and remodeling. METHODS: To accomplish this, human fetal lung fibroblasts HFL-1 were used to assess the effect of NAC on the <g>TGF-beta1</g>-mediated contraction of floating gels and the <g>TGF-beta1</g>-induced mediator production. In addition, the effect of NAC on the <g>TGF-beta1</g>-induced differentiation to myofibroblasts was evaluated by assessing alpha-smooth muscle actin alpha-SMA expression. RESULTS: NAC significantly abolished the <g>TGF-beta1</g>-augmented gel contraction at 3mM, gel size 63.4+/-2.6% vs. 39.1+/-4.1%; p<0.01 compared with control in a concentration-dependent manner. NAC also significantly inhibited the <g>TGF-beta1</g>-augmented fibronectin p<0.01 and VEGF p<0.01 production in the media of both the three-dimensional gel and monolayer culture. Furthermore, NAC reversed the <g>TGF-beta1</g>-stimulated alpha-SMA expression p<0.01. CONCLUSION: These results suggest that NAC can affect the <g>TGF-beta1</g>-induced tissue remodeling or fibrotic process in vitro.
19393328|a|BACKGROUND: Excessive production of <g>TGF-beta1</g> plays a key role in the tissue remodeling or fibrotic process observed in <d>bronchial asthma</d>, <d>chronic pulmonary disease</d> <d>COPD</d>, and <d>idiopathic pulmonary fibrosis</d> IPF. <g>TGF-beta1</g> has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species. OBJECTIVES: The aim of this study was to evaluate whether the antioxidant N-acetyl-l-cysteine NAC can affect <g>TGF-beta1</g>-mediated tissue remodeling in fibroblasts or modulate the production of fibronectin and vascular endothelial growth factor VEGF which are believed to be important mediators of tissue repair and remodeling. METHODS: To accomplish this, human fetal lung fibroblasts HFL-1 were used to assess the effect of NAC on the <g>TGF-beta1</g>-mediated contraction of floating gels and the <g>TGF-beta1</g>-induced mediator production. In addition, the effect of NAC on the <g>TGF-beta1</g>-induced differentiation to myofibroblasts was evaluated by assessing alpha-smooth muscle actin alpha-SMA expression. RESULTS: NAC significantly abolished the <g>TGF-beta1</g>-augmented gel contraction at 3mM, gel size 63.4+/-2.6% vs. 39.1+/-4.1%; p<0.01 compared with control in a concentration-dependent manner. NAC also significantly inhibited the <g>TGF-beta1</g>-augmented fibronectin p<0.01 and VEGF p<0.01 production in the media of both the three-dimensional gel and monolayer culture. Furthermore, NAC reversed the <g>TGF-beta1</g>-stimulated alpha-SMA expression p<0.01. CONCLUSION: These results suggest that NAC can affect the <g>TGF-beta1</g>-induced tissue remodeling or fibrotic process in vitro.
19393328|a|BACKGROUND: Excessive production of <g>TGF-beta1</g> plays a key role in the tissue remodeling or fibrotic process observed in <d>bronchial asthma</d>, <d>chronic pulmonary disease</d> <d>COPD</d>, and <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. <g>TGF-beta1</g> has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species. OBJECTIVES: The aim of this study was to evaluate whether the antioxidant N-acetyl-l-cysteine NAC can affect <g>TGF-beta1</g>-mediated tissue remodeling in fibroblasts or modulate the production of fibronectin and vascular endothelial growth factor VEGF which are believed to be important mediators of tissue repair and remodeling. METHODS: To accomplish this, human fetal lung fibroblasts HFL-1 were used to assess the effect of NAC on the <g>TGF-beta1</g>-mediated contraction of floating gels and the <g>TGF-beta1</g>-induced mediator production. In addition, the effect of NAC on the <g>TGF-beta1</g>-induced differentiation to myofibroblasts was evaluated by assessing alpha-smooth muscle actin alpha-SMA expression. RESULTS: NAC significantly abolished the <g>TGF-beta1</g>-augmented gel contraction at 3mM, gel size 63.4+/-2.6% vs. 39.1+/-4.1%; p<0.01 compared with control in a concentration-dependent manner. NAC also significantly inhibited the <g>TGF-beta1</g>-augmented fibronectin p<0.01 and VEGF p<0.01 production in the media of both the three-dimensional gel and monolayer culture. Furthermore, NAC reversed the <g>TGF-beta1</g>-stimulated alpha-SMA expression p<0.01. CONCLUSION: These results suggest that NAC can affect the <g>TGF-beta1</g>-induced tissue remodeling or fibrotic process in vitro.
19411308|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a disease of unknown etiology characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells PMC are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor <g>TGF-beta1</g>, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with IPF. High levels of <g>TGF-beta1</g> in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by <g>TGF-beta1</g> undergo epithelial-mesenchymal transition EMT and respond with haptotactic migration to a gradient of <g>TGF-beta1</g> and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin alpha-SMA, fibroblast specific protein-1 FSP-1, and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to <g>TGF-beta1</g>, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in IPF.
19411308|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a disease of unknown etiology characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells PMC are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor <g>TGF-beta1</g>, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with <d>IPF</d>. High levels of <g>TGF-beta1</g> in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by <g>TGF-beta1</g> undergo epithelial-mesenchymal transition EMT and respond with haptotactic migration to a gradient of <g>TGF-beta1</g> and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin alpha-SMA, fibroblast specific protein-1 FSP-1, and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to <g>TGF-beta1</g>, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in <d>IPF</d>.
19411308|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a disease of unknown etiology characterized by the development of <d>subpleural foci of myofibroblasts</d> that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells PMC are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor <g>TGF-beta1</g>, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with <d>IPF</d>. High levels of <g>TGF-beta1</g> in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by <g>TGF-beta1</g> undergo epithelial-mesenchymal transition EMT and respond with haptotactic migration to a gradient of <g>TGF-beta1</g> and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin alpha-SMA, fibroblast specific protein-1 FSP-1, and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to <g>TGF-beta1</g>, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in <d>IPF</d>.
19411308|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a disease of unknown etiology characterized by the development of <d>subpleural foci of myofibroblasts</d> that contribute to the exuberant <d>fibrosis</d> noted in the pulmonary parenchyma. Pleural mesothelial cells PMC are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal <d>fibrosis</d> remains to be identified. Transforming growth factor <g>TGF-beta1</g>, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with <d>IPF</d>. High levels of <g>TGF-beta1</g> in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by <g>TGF-beta1</g> undergo epithelial-mesenchymal transition EMT and respond with haptotactic migration to a gradient of <g>TGF-beta1</g> and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin alpha-SMA, fibroblast specific protein-1 FSP-1, and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to <g>TGF-beta1</g>, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in <d>IPF</d>.
19411308|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a disease of unknown etiology characterized by the development of <d>subpleural foci of myofibroblasts</d> that contribute to the exuberant <d>fibrosis</d> noted in the <d>pulmonary parenchyma</d>. Pleural mesothelial cells PMC are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of <d>pulmonary parenchyma</d>l <d>fibrosis</d> remains to be identified. Transforming growth factor <g>TGF-beta1</g>, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with <d>IPF</d>. High levels of <g>TGF-beta1</g> in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by <g>TGF-beta1</g> undergo epithelial-mesenchymal transition EMT and respond with haptotactic migration to a gradient of <g>TGF-beta1</g> and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin alpha-SMA, fibroblast specific protein-1 FSP-1, and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to <g>TGF-beta1</g>, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in <d>IPF</d>.
19411308|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a disease of unknown etiology characterized by the development of <d>subpleural foci of myofibroblasts</d> that contribute to the exuberant <d>fibrosis</d> noted in the <d>pulmonary parenchyma</d>. <d>Pleural mesothelial cells</d> PMC are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of <d>pulmonary parenchyma</d>l <d>fibrosis</d> remains to be identified. Transforming growth factor <g>TGF-beta1</g>, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with <d>IPF</d>. High levels of <g>TGF-beta1</g> in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by <g>TGF-beta1</g> undergo epithelial-mesenchymal transition EMT and respond with haptotactic migration to a gradient of <g>TGF-beta1</g> and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin alpha-SMA, fibroblast specific protein-1 FSP-1, and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to <g>TGF-beta1</g>, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in <d>IPF</d>.
19411308|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a disease of unknown etiology characterized by the development of <d>subpleural foci of myofibroblasts</d> that contribute to the exuberant <d>fibrosis</d> noted in the <d>pulmonary parenchyma</d>. <d>Pleural mesothelial cells</d> <d>PMC</d> are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of <d>PMC</d> in the pathogenesis of <d>pulmonary parenchyma</d>l <d>fibrosis</d> remains to be identified. Transforming growth factor <g>TGF-beta1</g>, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with <d>IPF</d>. High levels of <g>TGF-beta1</g> in the subpleural milieu may play a key role in the transition of normal <d>PMC</d> to myofibroblasts. Here we demonstrate that <d>PMC</d> activated by <g>TGF-beta1</g> undergo epithelial-mesenchymal transition EMT and respond with haptotactic migration to a gradient of <g>TGF-beta1</g> and that the transition of <d>PMC</d> to myofibroblasts is dependent on smad-2 signaling. The EMT of <d>PMC</d> was marked by upregulation of alpha-smooth muscle actin alpha-SMA, fibroblast specific protein-1 FSP-1, and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming <d>PMC</d>. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of <d>PMC</d> to myofibroblasts and significantly inhibited the <d>PMC</d> haptotaxis. We conclude that <d>PMC</d> undergo EMT when exposed to <g>TGF-beta1</g>, involving smad-2 signaling, and <d>PMC</d> may be a possible source of myofibroblasts in <d>IPF</d>.
19460787|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a devastating disease with poor prognosis. Leukotrienes play an important role in IPF, and leukotriene LTB4 is one of the key eicosanoids in IPF. In this study, we investigated whether ONO-4057, a LTB4 receptor BLTR antagonist is capable of preventing bleomycin-induced <d>pulmonary fibrosis</d>. On day 1, C57BL/6 male mice were given a single intratracheal injection of bleomycin 2.5 mg x kg-1, and ONO-4057 1.0 mg x kg-1 or vehicle alone, administered by intraperitoneal injection on days 1-5 each week for 3 weeks after the bleomycin injection. ONO-4057 reduced the total cell count in bronchoalveolar lavage fluid BALF on days 7, 14 and 21 and the Ashcroft score and the lung hydroxyproline content on days 14 and 21. The LTB4, interleukin IL-6, IL-13, transforming growth factor TGF-beta levels in BALF and the TGF-beta expression in lung tissue, assessed by immunohistochemistry were decreased on day 7, whereas interferon IFN-gamma level in BALF was increased on day 14. The results of this study indicated that the BLTR antagonist inhibited the development of bleomycin-induced <d>pulmonary fibrosis</d> in mice by decreasing inflammation and altering TGF-beta, IL-6, IL-13 and IFN-gamma.
19460787|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a devastating disease with poor prognosis. Leukotrienes play an important role in <d>IPF</d>, and leukotriene LTB4 is one of the key eicosanoids in <d>IPF</d>. In this study, we investigated whether ONO-4057, a LTB4 receptor BLTR antagonist is capable of preventing bleomycin-induced <d>pulmonary fibrosis</d>. On day 1, C57BL/6 male mice were given a single intratracheal injection of bleomycin 2.5 mg x kg-1, and ONO-4057 1.0 mg x kg-1 or vehicle alone, administered by intraperitoneal injection on days 1-5 each week for 3 weeks after the bleomycin injection. ONO-4057 reduced the total cell count in bronchoalveolar lavage fluid BALF on days 7, 14 and 21 and the Ashcroft score and the lung hydroxyproline content on days 14 and 21. The LTB4, interleukin IL-6, IL-13, transforming growth factor TGF-beta levels in BALF and the TGF-beta expression in lung tissue, assessed by immunohistochemistry were decreased on day 7, whereas interferon IFN-gamma level in BALF was increased on day 14. The results of this study indicated that the BLTR antagonist inhibited the development of bleomycin-induced <d>pulmonary fibrosis</d> in mice by decreasing inflammation and altering TGF-beta, IL-6, IL-13 and IFN-gamma.
19487460|a|Diminished <g>cyclooxygenase 2</g> COX-2 expression in fibroblasts, with a resultant defect in the production of the antifibrotic mediator prostaglandin E2, plays a key role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF. Here, we have characterized the molecular mechanism. We found that COX-2 mRNA levels in fibroblasts from patients with IPF F-IPF were significantly lower than those in fibroblasts from nonfibrotic lungs F-NL after transforming growth factor beta1 and interleukin-1beta treatment but that COX-2 mRNA degradation rates were similar, suggesting defective transcription. A reporter gene assay showed that there were no clear differences between F-IPF and F-NL in transcription factor involvement and activation in COX-2 gene transcription. However, a chromatin immunoprecipitation assay revealed that transcription factor binding to the COX-2 promoter in F-IPF was reduced compared to that in F-NL, an effect that was dynamically linked to reduced histone H3 and H4 acetylation due to decreased recruitment of histone acetyltransferases HATs and increased recruitment of transcriptional corepressor complexes to the COX-2 promoter. The treatment of F-IPF with histone deacetylase HDAC inhibitors together with cytokines increased histone H3 and H4 acetylation. Both HDAC inhibitors and the overexpression of HATs restored cytokine-induced COX-2 mRNA and protein expression in F-IPF. The results demonstrate that epigenetic abnormality in the form of histone hypoacetylation is responsible for diminished COX-2 expression in IPF.
19543300|a|AIM: The pro-fibrogenic cytokine transforming growth factor-beta 1 TGF-beta1 has attracted much attention for its potential role in the etiology of idiopathic <d>pulmonary fibrosis</d> IPF. Here, we demonstrate that MS80, a novel sulfated oligosaccharide extracted from seaweed, can bind TGF-beta1. The aim of the present study was to determine whether MS80 is capable of combating TGF-beta1-mediated pulmonary fibrotic events both in vitro and in vivo, and to investigate the possible underlying mechanisms. METHODS: Surface plasmon resonance was used to uncover the binding profiles between the compound and TGF-beta. MTT assay, flow cytometry, Western blot analysis, BCA protein assay and SDS-PAGE gelatin zymography were used to probe the antifibrotic mechanisms of MS80. The in vivo fibrotic efficacy was evaluated in a bleomycin instillation-induced rat model. RESULTS: We report that MS80, a new kind of sulfated oligosaccharide extracted from seaweed, inhibits TGF-beta1-induced <d>pulmonary fibrosis</d> in vitro and bleomycin-induced <d>pulmonary fibrosis</d> in vivo. Our results indicated that MS80 competitively inhibited heparin/HS-TGF-beta1 interaction through its high binding affinity for TGF-beta1. Moreover, MS80 arrested TGF-beta1-induced human embryo pulmonary fibroblast HEPF cell proliferation, collagen deposition and matrix metalloproteinase MMP activity. Intriguingly, MS80 deactivated both the ERK and p38 signaling pathways. MS80 was also a potent suppressor of bleomycin-induced rat <d>pulmonary fibrosis</d> in vivo, as evidenced by improved pathological settings and decreased lung collagen contents. CONCLUSION: MS80 in particular, and perhaps oligosaccharide in general, offer better pharmacological profiles with appreciably few side effects and represent a promising class of drug candidates for IPF therapy.Acta Pharmacologica Sinica 2009 30: 973-979; doi: 10.1038/aps.2009.86; published online 22 June 2009.
19543300|a|AIM: The pro-fibrogenic cytokine transforming growth factor-beta 1 <g>TGF-beta1</g> has attracted much attention for its potential role in the etiology of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. Here, we demonstrate that MS80, a novel sulfated oligosaccharide extracted from seaweed, can bind <g>TGF-beta1</g>. The aim of the present study was to determine whether MS80 is capable of combating <g>TGF-beta1</g>-mediated pulmonary fibrotic events both in vitro and in vivo, and to investigate the possible underlying mechanisms. METHODS: Surface plasmon resonance was used to uncover the binding profiles between the compound and TGF-beta. MTT assay, flow cytometry, Western blot analysis, BCA protein assay and SDS-PAGE gelatin zymography were used to probe the antifibrotic mechanisms of MS80. The in vivo fibrotic efficacy was evaluated in a bleomycin instillation-induced rat model. RESULTS: We report that MS80, a new kind of sulfated oligosaccharide extracted from seaweed, inhibits <g>TGF-beta1</g>-induced <d>pulmonary fibrosis</d> in vitro and bleomycin-induced <d>pulmonary fibrosis</d> in vivo. Our results indicated that MS80 competitively inhibited heparin/HS-<g>TGF-beta1</g> interaction through its high binding affinity for <g>TGF-beta1</g>. Moreover, MS80 arrested <g>TGF-beta1</g>-induced human embryo pulmonary fibroblast HEPF cell proliferation, collagen deposition and matrix metalloproteinase MMP activity. Intriguingly, MS80 deactivated both the ERK and p38 signaling pathways. MS80 was also a potent suppressor of bleomycin-induced rat <d>pulmonary fibrosis</d> in vivo, as evidenced by improved pathological settings and decreased lung collagen contents. CONCLUSION: MS80 in particular, and perhaps oligosaccharide in general, offer better pharmacological profiles with appreciably few side effects and represent a promising class of drug candidates for <d>IPF</d> therapy.Acta Pharmacologica Sinica 2009 30: 973-979; doi: 10.1038/aps.2009.86; published online 22 June 2009.
19597127|a|<d>Idiopathic pulmonary fibrosis</d> IPF histopathology of usual interstitial pneumonia [UIP] is a progressive disease with poor prognosis. Characteristic features of IPF/UIP include fibroblastic foci, which are patchy lesions of focal, disarranged myofibroblasts. GATA-6 is a transcription factor linked with cell differentiation. Its role in the development of IPF has not previously been investigated. We hypothesized that GATA-6 participates in the differentiation of fibroblasts into myofibroblasts in IPF/UIP lungs. The expression patterns of GATA-6, the mesenchymal marker alpha-smooth muscle actin alpha-SMA, and markers for proliferation Ki67 and apoptosis caspase-3 were analyzed in human IPF/UIP tissue samples. The effects of GATA-6 overexpression and silencing were studied in cell cultures. The results show that the alpha-SMA-positive fibroblastic foci in IPF/UIP lungs are positive for GATA-6, but negative for Ki67 and caspase-3. Cultured human IPF/UIP fibroblasts expressed GATA-6 mRNA, whereas cells from the normal adult lung did not. In cultured A549 lung epithelial cells, the induction of GATA-6 by transforming growth factor-beta1 resulted in simultaneous expression of alpha-SMA and decrease of E-cadherin. The inhibition of GATA-6 expression in fibroblasts showed that GATA-6 mediates the alpha-SMA-inducing signal of transforming growth factor-beta1. In conclusion, the hallmark of IPF/UIP histopathology, the fibroblast focus, consists of differentiated, quiescent cells that prominently express GATA-6.
19597127|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> histopathology of usual interstitial pneumonia [UIP] is a progressive disease with poor prognosis. Characteristic features of <d>IPF</d>/UIP include fibroblastic foci, which are patchy lesions of focal, disarranged myofibroblasts. GATA-6 is a transcription factor linked with cell differentiation. Its role in the development of <d>IPF</d> has not previously been investigated. We hypothesized that GATA-6 participates in the differentiation of fibroblasts into myofibroblasts in <d>IPF</d>/UIP lungs. The expression patterns of GATA-6, the mesenchymal marker alpha-smooth muscle actin alpha-SMA, and markers for proliferation Ki67 and apoptosis caspase-3 were analyzed in human <d>IPF</d>/UIP tissue samples. The effects of GATA-6 overexpression and silencing were studied in cell cultures. The results show that the alpha-SMA-positive fibroblastic foci in <d>IPF</d>/UIP lungs are positive for GATA-6, but negative for Ki67 and caspase-3. Cultured human <d>IPF</d>/UIP fibroblasts expressed GATA-6 mRNA, whereas cells from the normal adult lung did not. In cultured A549 lung epithelial cells, the induction of GATA-6 by transforming growth factor-beta1 resulted in simultaneous expression of alpha-SMA and decrease of E-cadherin. The inhibition of GATA-6 expression in fibroblasts showed that GATA-6 mediates the alpha-SMA-inducing signal of transforming growth factor-beta1. In conclusion, the hallmark of <d>IPF</d>/UIP histopathology, the fibroblast focus, consists of differentiated, quiescent cells that prominently express GATA-6.
19597127|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> histopathology of <d>usual interstitial pneumonia</d> [UIP] is a progressive disease with poor prognosis. Characteristic features of <d>IPF</d>/UIP include fibroblastic foci, which are patchy lesions of focal, disarranged myofibroblasts. GATA-6 is a transcription factor linked with cell differentiation. Its role in the development of <d>IPF</d> has not previously been investigated. We hypothesized that GATA-6 participates in the differentiation of fibroblasts into myofibroblasts in <d>IPF</d>/UIP lungs. The expression patterns of GATA-6, the mesenchymal marker alpha-smooth muscle actin alpha-SMA, and markers for proliferation Ki67 and apoptosis caspase-3 were analyzed in human <d>IPF</d>/UIP tissue samples. The effects of GATA-6 overexpression and silencing were studied in cell cultures. The results show that the alpha-SMA-positive fibroblastic foci in <d>IPF</d>/UIP lungs are positive for GATA-6, but negative for Ki67 and caspase-3. Cultured human <d>IPF</d>/UIP fibroblasts expressed GATA-6 mRNA, whereas cells from the normal adult lung did not. In cultured A549 lung epithelial cells, the induction of GATA-6 by transforming growth factor-beta1 resulted in simultaneous expression of alpha-SMA and decrease of E-cadherin. The inhibition of GATA-6 expression in fibroblasts showed that GATA-6 mediates the alpha-SMA-inducing signal of transforming growth factor-beta1. In conclusion, the hallmark of <d>IPF</d>/UIP histopathology, the fibroblast focus, consists of differentiated, quiescent cells that prominently express GATA-6.
19597127|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> histopathology of <d>usual interstitial pneumonia</d> [<d>UIP</d>] is a progressive disease with poor prognosis. Characteristic features of <d>IPF</d>/<d>UIP</d> include fibroblastic foci, which are patchy lesions of focal, disarranged myofibroblasts. GATA-6 is a transcription factor linked with cell differentiation. Its role in the development of <d>IPF</d> has not previously been investigated. We hypothesized that GATA-6 participates in the differentiation of fibroblasts into myofibroblasts in <d>IPF</d>/<d>UIP</d> lungs. The expression patterns of GATA-6, the mesenchymal marker alpha-smooth muscle actin alpha-SMA, and markers for proliferation Ki67 and apoptosis caspase-3 were analyzed in human <d>IPF</d>/<d>UIP</d> tissue samples. The effects of GATA-6 overexpression and silencing were studied in cell cultures. The results show that the alpha-SMA-positive fibroblastic foci in <d>IPF</d>/<d>UIP</d> lungs are positive for GATA-6, but negative for Ki67 and caspase-3. Cultured human <d>IPF</d>/<d>UIP</d> fibroblasts expressed GATA-6 mRNA, whereas cells from the normal adult lung did not. In cultured A549 lung epithelial cells, the induction of GATA-6 by transforming growth factor-beta1 resulted in simultaneous expression of alpha-SMA and decrease of E-cadherin. The inhibition of GATA-6 expression in fibroblasts showed that GATA-6 mediates the alpha-SMA-inducing signal of transforming growth factor-beta1. In conclusion, the hallmark of <d>IPF</d>/<d>UIP</d> histopathology, the fibroblast focus, consists of differentiated, quiescent cells that prominently express GATA-6.
19597127|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> histopathology of <d>usual interstitial pneumonia</d> [<d>UIP</d>] is a progressive disease with poor prognosis. Characteristic features of <d>IPF</d>/<d>UIP</d> include <d>fibroblastic foci</d>, which are patchy lesions of focal, disarranged myofibroblasts. GATA-6 is a transcription factor linked with cell differentiation. Its role in the development of <d>IPF</d> has not previously been investigated. We hypothesized that GATA-6 participates in the differentiation of fibroblasts into myofibroblasts in <d>IPF</d>/<d>UIP</d> lungs. The expression patterns of GATA-6, the mesenchymal marker alpha-smooth muscle actin alpha-SMA, and markers for proliferation Ki67 and apoptosis caspase-3 were analyzed in human <d>IPF</d>/<d>UIP</d> tissue samples. The effects of GATA-6 overexpression and silencing were studied in cell cultures. The results show that the alpha-SMA-positive <d>fibroblastic foci</d> in <d>IPF</d>/<d>UIP</d> lungs are positive for GATA-6, but negative for Ki67 and caspase-3. Cultured human <d>IPF</d>/<d>UIP</d> fibroblasts expressed GATA-6 mRNA, whereas cells from the normal adult lung did not. In cultured A549 lung epithelial cells, the induction of GATA-6 by transforming growth factor-beta1 resulted in simultaneous expression of alpha-SMA and decrease of E-cadherin. The inhibition of GATA-6 expression in fibroblasts showed that GATA-6 mediates the alpha-SMA-inducing signal of transforming growth factor-beta1. In conclusion, the hallmark of <d>IPF</d>/<d>UIP</d> histopathology, the fibroblast focus, consists of differentiated, quiescent cells that prominently express GATA-6.
19614606|a|IPF idiopathic <d>pulmonary fibrosis</d> is a chronic progressive disease of unknown aetiology without effective treatment. IPF is characterized by excessive collagen deposition within the lung. Recent evidence suggests that the lung epithelium plays a key role in driving the fibrotic response. The current paradigm suggests that, after epithelial injury, there is impaired epithelial proliferation and enhanced epithelial apoptosis. This in turn promotes lung fibrosis through impaired basement membrane repair and increased epithelial-mesenchymal transition. Furthermore, fibroblasts are recruited to the wounded area and adopt a myofibroblast phenotype, with the up-regulation of matrix-synthesizing genes and down-regulation of matrix-degradation genes. There is compelling evidence that the cytokine <g>TGFbeta</g> transforming growth factor beta plays a central role in this process. In normal lung, <g>TGFbeta</g> is maintained in an inactive state that is tightly regulated temporally and spatially. One of the major <g>TGFbeta</g>-activation pathways involves integrins, and the role of the alphavbeta6 integrin has been particularly well described in the pathogenesis of IPF. Owing to the pleiotropic nature of <g>TGFbeta</g>, strategies that inhibit activation of <g>TGFbeta</g> in a cell- or disease-specific manner are attractive for the treatment of chronic fibrotic lung conditions. Therefore the molecular pathways that lead to integrin-mediated <g>TGFbeta</g> activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with IPF.
19614606|a|<d>IPF</d> idiopathic <d>pulmonary fibrosis</d> is a chronic progressive disease of unknown aetiology without effective treatment. <d>IPF</d> is characterized by excessive collagen deposition within the lung. Recent evidence suggests that the lung epithelium plays a key role in driving the fibrotic response. The current paradigm suggests that, after epithelial injury, there is impaired epithelial proliferation and enhanced epithelial apoptosis. This in turn promotes lung fibrosis through impaired basement membrane repair and increased epithelial-mesenchymal transition. Furthermore, fibroblasts are recruited to the wounded area and adopt a myofibroblast phenotype, with the up-regulation of matrix-synthesizing genes and down-regulation of matrix-degradation genes. There is compelling evidence that the cytokine <g>TGFbeta</g> transforming growth factor beta plays a central role in this process. In normal lung, <g>TGFbeta</g> is maintained in an inactive state that is tightly regulated temporally and spatially. One of the major <g>TGFbeta</g>-activation pathways involves integrins, and the role of the alphavbeta6 integrin has been particularly well described in the pathogenesis of <d>IPF</d>. Owing to the pleiotropic nature of <g>TGFbeta</g>, strategies that inhibit activation of <g>TGFbeta</g> in a cell- or disease-specific manner are attractive for the treatment of chronic fibrotic lung conditions. Therefore the molecular pathways that lead to integrin-mediated <g>TGFbeta</g> activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with <d>IPF</d>.
19614606|a|<d>IPF</d> idiopathic <d>pulmonary fibrosis</d> is a chronic progressive disease of unknown aetiology without effective treatment. <d>IPF</d> is characterized by excessive collagen deposition within the lung. Recent evidence suggests that the lung epithelium plays a key role in driving the fibrotic response. The current paradigm suggests that, after <d>epithelial injury</d>, there is impaired epithelial proliferation and enhanced epithelial apoptosis. This in turn promotes lung fibrosis through impaired basement membrane repair and increased epithelial-mesenchymal transition. Furthermore, fibroblasts are recruited to the wounded area and adopt a myofibroblast phenotype, with the up-regulation of matrix-synthesizing genes and down-regulation of matrix-degradation genes. There is compelling evidence that the cytokine <g>TGFbeta</g> transforming growth factor beta plays a central role in this process. In normal lung, <g>TGFbeta</g> is maintained in an inactive state that is tightly regulated temporally and spatially. One of the major <g>TGFbeta</g>-activation pathways involves integrins, and the role of the alphavbeta6 integrin has been particularly well described in the pathogenesis of <d>IPF</d>. Owing to the pleiotropic nature of <g>TGFbeta</g>, strategies that inhibit activation of <g>TGFbeta</g> in a cell- or disease-specific manner are attractive for the treatment of chronic fibrotic lung conditions. Therefore the molecular pathways that lead to integrin-mediated <g>TGFbeta</g> activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with <d>IPF</d>.
19614606|a|<d>IPF</d> idiopathic <d>pulmonary <d>fibrosis</d></d> is a chronic progressive disease of unknown aetiology without effective treatment. <d>IPF</d> is characterized by excessive collagen deposition within the lung. Recent evidence suggests that the lung epithelium plays a key role in driving the fibrotic response. The current paradigm suggests that, after <d>epithelial injury</d>, there is impaired epithelial proliferation and enhanced epithelial apoptosis. This in turn promotes lung <d>fibrosis</d> through impaired basement membrane repair and increased epithelial-mesenchymal transition. Furthermore, fibroblasts are recruited to the wounded area and adopt a myofibroblast phenotype, with the up-regulation of matrix-synthesizing genes and down-regulation of matrix-degradation genes. There is compelling evidence that the cytokine <g>TGFbeta</g> transforming growth factor beta plays a central role in this process. In normal lung, <g>TGFbeta</g> is maintained in an inactive state that is tightly regulated temporally and spatially. One of the major <g>TGFbeta</g>-activation pathways involves integrins, and the role of the alphavbeta6 integrin has been particularly well described in the pathogenesis of <d>IPF</d>. Owing to the pleiotropic nature of <g>TGFbeta</g>, strategies that inhibit activation of <g>TGFbeta</g> in a cell- or disease-specific manner are attractive for the treatment of chronic fibrotic lung conditions. Therefore the molecular pathways that lead to integrin-mediated <g>TGFbeta</g> activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with <d>IPF</d>.
19614606|a|<d>IPF</d> idiopathic <d>pulmonary <d>fibrosis</d></d> is a chronic progressive disease of unknown aetiology without effective treatment. <d>IPF</d> is characterized by excessive collagen deposition within the lung. Recent evidence suggests that the lung epithelium plays a key role in driving the fibrotic response. The current paradigm suggests that, after <d>epithelial injury</d>, there is impaired epithelial proliferation and enhanced epithelial apoptosis. This in turn promotes lung <d>fibrosis</d> through <d>impaired basement membrane repair</d> and increased epithelial-mesenchymal transition. Furthermore, fibroblasts are recruited to the wounded area and adopt a myofibroblast phenotype, with the up-regulation of matrix-synthesizing genes and down-regulation of matrix-degradation genes. There is compelling evidence that the cytokine <g>TGFbeta</g> transforming growth factor beta plays a central role in this process. In normal lung, <g>TGFbeta</g> is maintained in an inactive state that is tightly regulated temporally and spatially. One of the major <g>TGFbeta</g>-activation pathways involves integrins, and the role of the alphavbeta6 integrin has been particularly well described in the pathogenesis of <d>IPF</d>. Owing to the pleiotropic nature of <g>TGFbeta</g>, strategies that inhibit activation of <g>TGFbeta</g> in a cell- or disease-specific manner are attractive for the treatment of chronic fibrotic lung conditions. Therefore the molecular pathways that lead to integrin-mediated <g>TGFbeta</g> activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with <d>IPF</d>.
19614606|a|<d>IPF</d> idiopathic <d>pulmonary <d>fibrosis</d></d> is a chronic progressive disease of unknown aetiology without effective treatment. <d>IPF</d> is characterized by excessive collagen deposition within the lung. Recent evidence suggests that the lung epithelium plays a key role in driving the fibrotic response. The current paradigm suggests that, after <d>epithelial injury</d>, there is impaired epithelial proliferation and enhanced epithelial apoptosis. This in turn promotes lung <d>fibrosis</d> through <d>impaired basement membrane repair</d> and increased epithelial-mesenchymal transition. Furthermore, fibroblasts are recruited to the wounded area and adopt a myofibroblast phenotype, with the up-regulation of matrix-synthesizing genes and down-regulation of matrix-degradation genes. There is compelling evidence that the cytokine <g>TGFbeta</g> <g>transforming growth factor beta</g> plays a central role in this process. In normal lung, <g>TGFbeta</g> is maintained in an inactive state that is tightly regulated temporally and spatially. One of the major <g>TGFbeta</g>-activation pathways involves integrins, and the role of the alphavbeta6 integrin has been particularly well described in the pathogenesis of <d>IPF</d>. Owing to the pleiotropic nature of <g>TGFbeta</g>, strategies that inhibit activation of <g>TGFbeta</g> in a cell- or disease-specific manner are attractive for the treatment of chronic <d>fibrotic lung conditions</d>. Therefore the molecular pathways that lead to integrin-mediated <g>TGFbeta</g> activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with <d>IPF</d>.
19648289|a|The ability of <g>transforming growth factor-beta1</g> <g>TGF-beta1</g> to induce epithelial-mesenchymal transition EMT in alveolar epithelial cells AEC in vitro and in vivo, together with the demonstration of EMT in biopsies of <d>idiopathic pulmonary fibrosis</d> IPF patients, suggests a role for <g>TGF-beta1</g>-induced EMT in disease pathogenesis. We investigated the effects of N-acetylcysteine NAC on <g>TGF-beta1</g>-induced EMT in a rat epithelial cell line RLE-6TN and in primary rat alveolar epithelial cells AEC. RLE-6TN cells exposed to <g>TGF-beta1</g> for 5 days underwent EMT as evidenced by acquisition of a fibroblast-like morphology, downregulation of the epithelial-specific protein zonula occludens-1, and induction of the mesenchymal-specific proteins alpha-smooth muscle actin alpha-SMA and vimentin. These changes were inhibited by NAC, which also prevented Smad3 phosphorylation. Similarly, primary alveolar epithelial type II cells exposed to <g>TGF-beta1</g> also underwent EMT that was prevented by NAC. <g>TGF-beta1</g> decreased cellular GSH levels by 50-80%, whereas NAC restored them to approximately 150% of those found in <g>TGF-beta1</g>-treated cells. Treatment with glutathione monoethyl ester similarly prevented an increase in mesenchymal marker expression. Consistent with its role as an antioxidant and cellular redox stabilizer, NAC dramatically reduced intracellular reactive oxygen species production in the presence of <g>TGF-beta1</g>. Finally, inhibition of intracellular ROS generation during <g>TGF-beta1</g> treatment prevented alveolar EMT, but treatment with H2O2 alone did not induce EMT. We conclude that NAC prevents EMT in AEC in vitro, at least in part through replenishment of intracellular GSH stores and limitation of <g>TGF-beta1</g>-induced intracellular ROS generation. We speculate that beneficial effects of NAC on pulmonary function in IPF may be mediated by inhibitory effects on alveolar EMT.
19648289|a|The ability of <g>transforming growth factor-beta1</g> <g>TGF-beta1</g> to induce epithelial-mesenchymal transition EMT in alveolar epithelial cells AEC in vitro and in vivo, together with the demonstration of EMT in biopsies of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> patients, suggests a role for <g>TGF-beta1</g>-induced EMT in disease pathogenesis. We investigated the effects of N-acetylcysteine NAC on <g>TGF-beta1</g>-induced EMT in a rat epithelial cell line RLE-6TN and in primary rat alveolar epithelial cells AEC. RLE-6TN cells exposed to <g>TGF-beta1</g> for 5 days underwent EMT as evidenced by acquisition of a fibroblast-like morphology, downregulation of the epithelial-specific protein zonula occludens-1, and induction of the mesenchymal-specific proteins alpha-smooth muscle actin alpha-SMA and vimentin. These changes were inhibited by NAC, which also prevented Smad3 phosphorylation. Similarly, primary alveolar epithelial type II cells exposed to <g>TGF-beta1</g> also underwent EMT that was prevented by NAC. <g>TGF-beta1</g> decreased cellular GSH levels by 50-80%, whereas NAC restored them to approximately 150% of those found in <g>TGF-beta1</g>-treated cells. Treatment with glutathione monoethyl ester similarly prevented an increase in mesenchymal marker expression. Consistent with its role as an antioxidant and cellular redox stabilizer, NAC dramatically reduced intracellular reactive oxygen species production in the presence of <g>TGF-beta1</g>. Finally, inhibition of intracellular ROS generation during <g>TGF-beta1</g> treatment prevented alveolar EMT, but treatment with H2O2 alone did not induce EMT. We conclude that NAC prevents EMT in AEC in vitro, at least in part through replenishment of intracellular GSH stores and limitation of <g>TGF-beta1</g>-induced intracellular ROS generation. We speculate that beneficial effects of NAC on pulmonary function in <d>IPF</d> may be mediated by inhibitory effects on alveolar EMT.
19648289|a|The ability of <g>transforming growth factor-beta1</g> <g>TGF-beta1</g> to induce epithelial-mesenchymal transition EMT in alveolar epithelial cells AEC in vitro and in vivo, together with the demonstration of EMT in biopsies of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> patients, suggests a role for <g>TGF-beta1</g>-induced EMT in disease pathogenesis. We investigated the effects of N-acetylcysteine NAC on <g>TGF-beta1</g>-induced EMT in a rat epithelial cell line RLE-6TN and in primary rat alveolar epithelial cells AEC. RLE-6TN cells exposed to <g>TGF-beta1</g> for 5 days underwent EMT as evidenced by acquisition of a fibroblast-like morphology, downregulation of the epithelial-specific protein zonula occludens-1, and induction of the mesenchymal-specific proteins <g>alpha-smooth muscle actin</g> <g>alpha-SMA</g> and vimentin. These changes were inhibited by NAC, which also prevented <g>Smad3</g> phosphorylation. Similarly, primary alveolar epithelial type II cells exposed to <g>TGF-beta1</g> also underwent EMT that was prevented by NAC. <g>TGF-beta1</g> decreased cellular GSH levels by 50-80%, whereas NAC restored them to approximately 150% of those found in <g>TGF-beta1</g>-treated cells. Treatment with glutathione monoethyl ester similarly prevented an increase in mesenchymal marker expression. Consistent with its role as an antioxidant and cellular redox stabilizer, NAC dramatically reduced intracellular reactive oxygen species production in the presence of <g>TGF-beta1</g>. Finally, inhibition of intracellular ROS generation during <g>TGF-beta1</g> treatment prevented <d>alveolar EMT</d>, but treatment with H2O2 alone did not induce EMT. We conclude that NAC prevents EMT in AEC in vitro, at least in part through replenishment of intracellular GSH stores and limitation of <g>TGF-beta1</g>-induced intracellular ROS generation. We speculate that beneficial effects of NAC on pulmonary function in <d>IPF</d> may be mediated by inhibitory effects on <d>alveolar EMT</d>.
19700647|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a devastating disease with no known effective pharmacological therapy. The fibroblastic foci of IPF contain activated myofibroblasts that are the major synthesizers of type I collagen. Transforming growth factor <g>TGF-beta1</g> promotes differentiation of fibroblasts into myofibroblasts in vitro and in vivo. In the current study, we investigated the molecular link between <g>TGF-beta1</g>-mediated myofibroblast differentiation and <g>histone deacetylase</g> HDAC activity. Treatment of normal human lung fibroblasts NHLFs with the pan-HDAC inhibitor trichostatin A TSA inhibited <g>TGF-beta1</g>-mediated alpha-smooth muscle actin alpha-SMA and alpha1 type I collagen mRNA induction. TSA also blocked the <g>TGF-beta1</g>-driven contractile response in NHLFs. The inhibition of alpha-SMA expression by TSA was associated with reduced phosphorylation of Akt, and a pharmacological inhibitor of Akt blocked <g>TGF-beta1</g>-mediated alpha-SMA induction in a dose-dependent manner. HDAC4 knockdown was effective in inhibiting <g>TGF-beta1</g>-stimulated alpha-SMA expression as well as the phosphorylation of Akt. Moreover, the inhibitors of protein phosphatase 2A and 1 PP2A and PP1 rescued the <g>TGF-beta1</g>-mediated alpha-SMA induction from the inhibitory effect of TSA. Together, these data demonstrate that the differentiation of NHLFs to myofibroblasts is HDAC4 dependent and requires phosphorylation of Akt.
19700647|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating disease with no known effective pharmacological therapy. The fibroblastic foci of <d>IPF</d> contain activated myofibroblasts that are the major synthesizers of type I collagen. Transforming growth factor <g>TGF-beta1</g> promotes differentiation of fibroblasts into myofibroblasts in vitro and in vivo. In the current study, we investigated the molecular link between <g>TGF-beta1</g>-mediated myofibroblast differentiation and <g>histone deacetylase</g> HDAC activity. Treatment of normal human lung fibroblasts NHLFs with the pan-HDAC inhibitor trichostatin A TSA inhibited <g>TGF-beta1</g>-mediated alpha-smooth muscle actin alpha-SMA and alpha1 type I collagen mRNA induction. TSA also blocked the <g>TGF-beta1</g>-driven contractile response in NHLFs. The inhibition of alpha-SMA expression by TSA was associated with reduced phosphorylation of Akt, and a pharmacological inhibitor of Akt blocked <g>TGF-beta1</g>-mediated alpha-SMA induction in a dose-dependent manner. HDAC4 knockdown was effective in inhibiting <g>TGF-beta1</g>-stimulated alpha-SMA expression as well as the phosphorylation of Akt. Moreover, the inhibitors of protein phosphatase 2A and 1 PP2A and PP1 rescued the <g>TGF-beta1</g>-mediated alpha-SMA induction from the inhibitory effect of TSA. Together, these data demonstrate that the differentiation of NHLFs to myofibroblasts is HDAC4 dependent and requires phosphorylation of Akt.
19701206|a|Members of the NADPH oxidase NOX family of enzymes, which catalyze the reduction of O2 to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, NOX-2 gp91phox, is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis. Transforming growth factor-beta1 TGF-beta1 induces NOX-4 expression in lung mesenchymal cells via SMAD-3, a receptor-regulated protein that modulates gene transcription. NOX-4-dependent generation of hydrogen peroxide H2O2 is required for TGF-beta1-induced myofibroblast differentiation, extracellular matrix ECM production and contractility. NOX-4 is upregulated in lungs of mice subjected to noninfectious injury and in cases of human idiopathic pulmonary fibrosis IPF. Genetic or pharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models of <d>lung injury</d>. These studies support a function for NOX4 in tissue fibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders.
19701206|a|Members of the NADPH oxidase NOX family of enzymes, which catalyze the reduction of O2 to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, <g>NOX-2</g> gp91phox, is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the <g>NOX4</g> isoform in tissue repair functions of myofibroblasts and fibrogenesis. <g>Transforming growth factor-beta1</g> <g>TGF-beta1</g> induces <g>NOX-4</g> expression in lung mesenchymal cells via <g>SMAD-3</g>, a receptor-regulated protein that modulates gene transcription. <g>NOX-4</g>-dependent generation of hydrogen peroxide H2O2 is required for <g>TGF-beta1</g>-induced myofibroblast differentiation, extracellular matrix ECM production and contractility. <g>NOX-4</g> is upregulated in lungs of mice subjected to <d>noninfectious injury</d> and in cases of human idiopathic pulmonary fibrosis IPF. Genetic or pharmacologic targeting of <g>NOX-4</g> abrogates fibrogenesis in two murine models of <d>lung injury</d>. These studies support a function for <g>NOX4</g> in tissue fibrogenesis and provide proof of concept for therapeutic targeting of <g>NOX-4</g> in recalcitrant fibrotic disorders.
19701206|a|Members of the NADPH oxidase NOX family of enzymes, which catalyze the reduction of O2 to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, <g>NOX-2</g> gp91phox, is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the <g>NOX4</g> isoform in tissue repair functions of myofibroblasts and fibrogenesis. <g>Transforming growth factor-beta1</g> <g>TGF-beta1</g> induces <g>NOX-4</g> expression in lung mesenchymal cells via <g>SMAD-3</g>, a receptor-regulated protein that modulates gene transcription. <g>NOX-4</g>-dependent generation of hydrogen peroxide H2O2 is required for <g>TGF-beta1</g>-induced myofibroblast differentiation, extracellular matrix ECM production and contractility. <g>NOX-4</g> is upregulated in lungs of mice subjected to <d>noninfectious injury</d> and in cases of human <d>idiopathic pulmonary fibrosis</d> IPF. Genetic or pharmacologic targeting of <g>NOX-4</g> abrogates fibrogenesis in two murine models of <d>lung injury</d>. These studies support a function for <g>NOX4</g> in tissue fibrogenesis and provide proof of concept for therapeutic targeting of <g>NOX-4</g> in recalcitrant fibrotic disorders.
19701206|a|Members of the NADPH oxidase NOX family of enzymes, which catalyze the reduction of O2 to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, <g>NOX-2</g> gp91phox, is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the <g>NOX4</g> isoform in tissue repair functions of myofibroblasts and fibrogenesis. <g>Transforming growth factor-beta1</g> <g>TGF-beta1</g> induces <g>NOX-4</g> expression in lung mesenchymal cells via <g>SMAD-3</g>, a receptor-regulated protein that modulates gene transcription. <g>NOX-4</g>-dependent generation of hydrogen peroxide H2O2 is required for <g>TGF-beta1</g>-induced myofibroblast differentiation, extracellular matrix ECM production and contractility. <g>NOX-4</g> is upregulated in lungs of mice subjected to <d>noninfectious injury</d> and in cases of human <d>idiopathic pulmonary fibrosis</d> IPF. Genetic or pharmacologic targeting of <g>NOX-4</g> abrogates fibrogenesis in two murine models of <d>lung injury</d>. These studies support a function for <g>NOX4</g> in tissue fibrogenesis and provide proof of concept for therapeutic targeting of <g>NOX-4</g> in recalcitrant <d>fibrotic disorders</d>.
19850962|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a fatal interstitial lung disease characterised by accumulation of activated myofibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of myofibroblasts may be attributed, in part, to the process of transforming growth factor beta1 TGFbeta1-induced epithelial-mesenchymal transition EMT, the phenotypic switching of epithelial to fibroblast-like cells. Although alveolar epithelial type II ATII cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in IPF. METHODS: Using quantitative reverse transcription-PCR RT-PCR, immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in TGFbeta1-induced EMT in ATII cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human IPF in vivo. RESULTS: TGFbeta1 treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA siRNA-mediated SNAI depletion attenuated TGFbeta1-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human IPF and localised to hyperplastic ATII cells in vivo. CONCLUSIONS: The results demonstrate that TGFbeta1-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human IPF in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.
19850962|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fatal interstitial lung disease characterised by accumulation of activated myofibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of myofibroblasts may be attributed, in part, to the process of transforming growth factor beta1 TGFbeta1-induced epithelial-mesenchymal transition EMT, the phenotypic switching of epithelial to fibroblast-like cells. Although alveolar epithelial type II ATII cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in <d>IPF</d>. METHODS: Using quantitative reverse transcription-PCR RT-PCR, immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in TGFbeta1-induced EMT in ATII cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human <d>IPF</d> in vivo. RESULTS: TGFbeta1 treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA siRNA-mediated SNAI depletion attenuated TGFbeta1-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human <d>IPF</d> and localised to hyperplastic ATII cells in vivo. CONCLUSIONS: The results demonstrate that TGFbeta1-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human <d>IPF</d> in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.
19850962|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fatal <d>interstitial lung disease</d> characterised by accumulation of activated myofibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of myofibroblasts may be attributed, in part, to the process of transforming growth factor beta1 TGFbeta1-induced epithelial-mesenchymal transition EMT, the phenotypic switching of epithelial to fibroblast-like cells. Although alveolar epithelial type II ATII cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in <d>IPF</d>. METHODS: Using quantitative reverse transcription-PCR RT-PCR, immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in TGFbeta1-induced EMT in ATII cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human <d>IPF</d> in vivo. RESULTS: TGFbeta1 treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA siRNA-mediated SNAI depletion attenuated TGFbeta1-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human <d>IPF</d> and localised to hyperplastic ATII cells in vivo. CONCLUSIONS: The results demonstrate that TGFbeta1-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human <d>IPF</d> in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.
19850962|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fatal <d>interstitial lung disease</d> characterised by accumulation of activated myofibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of myofibroblasts may be attributed, in part, to the process of <g>transforming growth factor beta1</g> <g>TGFbeta1</g>-induced epithelial-mesenchymal transition EMT, the phenotypic switching of epithelial to fibroblast-like cells. Although <d>alveolar epithelial type II</d> ATII cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in <d>IPF</d>. METHODS: Using quantitative reverse transcription-PCR RT-PCR, immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in <g>TGFbeta1</g>-induced EMT in ATII cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human <d>IPF</d> in vivo. RESULTS: <g>TGFbeta1</g> treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA siRNA-mediated SNAI depletion attenuated <g>TGFbeta1</g>-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human <d>IPF</d> and localised to hyperplastic ATII cells in vivo. CONCLUSIONS: The results demonstrate that <g>TGFbeta1</g>-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human <d>IPF</d> in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.
19850962|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fatal <d>interstitial lung disease</d> characterised by accumulation of activated myofibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of myofibroblasts may be attributed, in part, to the process of <g>transforming growth factor beta1</g> <g>TGFbeta1</g>-induced epithelial-mesenchymal transition EMT, the phenotypic switching of epithelial to fibroblast-like cells. Although <d>alveolar epithelial type II</d> <d>ATII</d> cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in <d>IPF</d>. METHODS: Using quantitative reverse transcription-PCR RT-PCR, immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in <g>TGFbeta1</g>-induced EMT in <d>ATII</d> cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human <d>IPF</d> in vivo. RESULTS: <g>TGFbeta1</g> treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in <d>ATII</d> cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA siRNA-mediated SNAI depletion attenuated <g>TGFbeta1</g>-induced <d>ATII</d> cell migration and EMT. SNAI expression was elevated in experimental and human <d>IPF</d> and localised to hyperplastic <d>ATII</d> cells in vivo. CONCLUSIONS: The results demonstrate that <g>TGFbeta1</g>-induced EMT in <d>ATII</d> cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human <d>IPF</d> in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.
19850962|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fatal <d>interstitial lung disease</d> characterised by accumulation of activated myofibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of myofibroblasts may be attributed, in part, to the process of <g>transforming growth factor beta1</g> <g>TGFbeta1</g>-induced epithelial-mesenchymal transition EMT, the phenotypic switching of epithelial to fibroblast-like cells. Although <d>alveolar epithelial type II</d> <d>ATII</d> cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in <d>IPF</d>. METHODS: Using quantitative reverse transcription-PCR RT-PCR, immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of <g>SNAI1</g> and <g>SNAI2</g> in <g>TGFbeta1</g>-induced EMT in <d>ATII</d> cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human <d>IPF</d> in vivo. RESULTS: <g>TGFbeta1</g> treatment increased the expression and nuclear accumulation of <g>SNAI1</g> and <g>SNAI2</g>, in concert with induction of EMT in <d>ATII</d> cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA siRNA-mediated SNAI depletion attenuated <g>TGFbeta1</g>-induced <d>ATII</d> cell migration and EMT. SNAI expression was elevated in experimental and human <d>IPF</d> and localised to hyperplastic <d>ATII</d> cells in vivo. CONCLUSIONS: The results demonstrate that <g>TGFbeta1</g>-induced EMT in <d>ATII</d> cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased <g>SNAI1</g> and <g>SNAI2</g> expression in experimental and human <d>IPF</d> in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in <d>idiopathic pulmonary fibrosis</d>.
19924381|a|Smoking is a risk factor for idiopathic pulmonary fibrosis IPF, but the mechanism of the association remains unknown. The aim of this study was to investigate the effects of <d>cigarette smoke extract</d> CSE on A549 cells and human lung fibroblasts treated with transforming growth factor-beta1. A transwell two-chamber coculture system was used to study the proliferation, differentiation, morphologic changes and soluble factors production of A549 cells and myofibroblasts. Low concentrations of CSE promoted myofibroblasts proliferation; however, high concentrations of CSE inhibited their proliferation. Low concentrations of CSE also markedly increased extracellular secretion of hydrogen peroxide, inhibited proliferation, induced apoptosis and produced epithelial-mesenchymal transition EMT in cocultured A549 cells. This cigarette smoke-induced A549 cells EMT may become a new pathophysiological concept in the development of IPF. CSE possibly takes part in the development and progress of IPF by increasing oxidative stress.
19924381|a|Smoking is a risk factor for <d>idiopathic pulmonary fibrosis</d> IPF, but the mechanism of the association remains unknown. The aim of this study was to investigate the effects of <d>cigarette smoke extract</d> CSE on A549 cells and human lung fibroblasts treated with <g>transforming growth factor-beta1</g>. A transwell two-chamber coculture system was used to study the proliferation, differentiation, morphologic changes and soluble factors production of A549 cells and myofibroblasts. Low concentrations of CSE promoted myofibroblasts proliferation; however, high concentrations of CSE inhibited their proliferation. Low concentrations of CSE also markedly increased extracellular secretion of hydrogen peroxide, inhibited proliferation, induced apoptosis and produced epithelial-mesenchymal transition EMT in cocultured A549 cells. This cigarette smoke-induced A549 cells EMT may become a new pathophysiological concept in the development of IPF. CSE possibly takes part in the development and progress of IPF by increasing oxidative stress.
19924381|a|Smoking is a risk factor for <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, but the mechanism of the association remains unknown. The aim of this study was to investigate the effects of <d>cigarette smoke extract</d> CSE on A549 cells and human lung fibroblasts treated with <g>transforming growth factor-beta1</g>. A transwell two-chamber coculture system was used to study the proliferation, differentiation, morphologic changes and soluble factors production of A549 cells and myofibroblasts. Low concentrations of CSE promoted myofibroblasts proliferation; however, high concentrations of CSE inhibited their proliferation. Low concentrations of CSE also markedly increased extracellular secretion of hydrogen peroxide, inhibited proliferation, induced apoptosis and produced epithelial-mesenchymal transition EMT in cocultured A549 cells. This cigarette smoke-induced A549 cells EMT may become a new pathophysiological concept in the development of <d>IPF</d>. CSE possibly takes part in the development and progress of <d>IPF</d> by increasing oxidative stress.
19924381|a|Smoking is a risk factor for <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, but the mechanism of the association remains unknown. The aim of this study was to investigate the effects of <d>cigarette smoke extract</d> <d>CSE</d> on A549 cells and human lung fibroblasts treated with <g>transforming growth factor-beta1</g>. A transwell two-chamber coculture system was used to study the proliferation, differentiation, morphologic changes and soluble factors production of A549 cells and myofibroblasts. Low concentrations of <d>CSE</d> promoted myofibroblasts proliferation; however, high concentrations of <d>CSE</d> inhibited their proliferation. Low concentrations of <d>CSE</d> also markedly increased extracellular secretion of hydrogen peroxide, inhibited proliferation, induced apoptosis and produced epithelial-mesenchymal transition EMT in cocultured A549 cells. This cigarette smoke-induced A549 cells EMT may become a new pathophysiological concept in the development of <d>IPF</d>. <d>CSE</d> possibly takes part in the development and progress of <d>IPF</d> by increasing oxidative stress.
19966781|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix ECM proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta TGF-beta functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced <d>pulmonary fibrosis</d>, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A2 cPLA2 suppresses bleomycin-induced <d>pulmonary fibrosis</d>, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F PGF receptor FP selectively attenuates <d>pulmonary fibrosis</d> while maintaining similar levels of alveolar inflammation and TGF-beta stimulation as compared to wild-type WT mice, and that FP deficiency and inhibition of TGF-beta signaling additively decrease fibrosis. Furthermore, PGF2alpha is abundant in bronchoalveolar lavage fluid BALF of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-beta. These findings show that PGF2alpha-FP signaling facilitates <d>pulmonary fibrosis</d> independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF.
19966781|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix ECM proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for <d>IPF</d> does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta TGF-beta functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced <d>pulmonary fibrosis</d>, an animal model of <d>IPF</d>, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A2 cPLA2 suppresses bleomycin-induced <d>pulmonary fibrosis</d>, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F PGF receptor FP selectively attenuates <d>pulmonary fibrosis</d> while maintaining similar levels of alveolar inflammation and TGF-beta stimulation as compared to wild-type WT mice, and that FP deficiency and inhibition of TGF-beta signaling additively decrease fibrosis. Furthermore, PGF2alpha is abundant in bronchoalveolar lavage fluid BALF of subjects with <d>IPF</d> and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-beta. These findings show that PGF2alpha-FP signaling facilitates <d>pulmonary fibrosis</d> independently of TGF-beta and suggests this signaling pathway as a therapeutic target for <d>IPF</d>.
19966781|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix ECM proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for <d>IPF</d> does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta <g>TGF-beta</g> functions are crucial in <d>fibrosis</d>, antagonizing this pathway in bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, an animal model of <d>IPF</d>, does not prevent <d>fibrosis</d> completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A2 cPLA2 suppresses bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F PGF receptor FP selectively attenuates <d>pulmonary <d>fibrosis</d></d> while maintaining similar levels of alveolar inflammation and <g>TGF-beta</g> stimulation as compared to wild-type WT mice, and that FP deficiency and inhibition of <g>TGF-beta</g> signaling additively decrease <d>fibrosis</d>. Furthermore, PGF2alpha is abundant in bronchoalveolar lavage fluid BALF of subjects with <d>IPF</d> and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of <g>TGF-beta</g>. These findings show that PGF2alpha-FP signaling facilitates <d>pulmonary <d>fibrosis</d></d> independently of <g>TGF-beta</g> and suggests this signaling pathway as a therapeutic target for <d>IPF</d>.
19966781|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix ECM proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for <d>IPF</d> does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta <g>TGF-beta</g> functions are crucial in <d>fibrosis</d>, antagonizing this pathway in bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, an animal model of <d>IPF</d>, does not prevent <d>fibrosis</d> completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of <g>cytosolic phospholipase A2</g> <g>cPLA2</g> suppresses bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of <g>prostaglandin F PGF receptor</g> FP selectively attenuates <d>pulmonary <d>fibrosis</d></d> while maintaining similar levels of <d>alveolar inflammation</d> and <g>TGF-beta</g> stimulation as compared to wild-type WT mice, and that FP deficiency and inhibition of <g>TGF-beta</g> signaling additively decrease <d>fibrosis</d>. Furthermore, PGF2alpha is abundant in bronchoalveolar lavage fluid BALF of subjects with <d>IPF</d> and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of <g>TGF-beta</g>. These findings show that PGF2alpha-FP signaling facilitates <d>pulmonary <d>fibrosis</d></d> independently of <g>TGF-beta</g> and suggests this signaling pathway as a therapeutic target for <d>IPF</d>.
19966781|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix ECM proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for <d>IPF</d> does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta <g>TGF-beta</g> functions are crucial in <d>fibrosis</d>, antagonizing this pathway in bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, an animal model of <d>IPF</d>, does not prevent <d>fibrosis</d> completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of <g>cytosolic phospholipase A2</g> <g>cPLA2</g> suppresses bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of <g>prostaglandin F PGF receptor</g> FP selectively attenuates <d>pulmonary <d>fibrosis</d></d> while maintaining similar levels of <d>alveolar inflammation</d> and <g>TGF-beta</g> stimulation as compared to <d>wild-type</d> WT mice, and that FP deficiency and inhibition of <g>TGF-beta</g> signaling additively decrease <d>fibrosis</d>. Furthermore, PGF2alpha is abundant in bronchoalveolar lavage fluid BALF of subjects with <d>IPF</d> and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of <g>TGF-beta</g>. These findings show that PGF2alpha-FP signaling facilitates <d>pulmonary <d>fibrosis</d></d> independently of <g>TGF-beta</g> and suggests this signaling pathway as a therapeutic target for <d>IPF</d>.
19966781|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix ECM proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for <d>IPF</d> does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta <g>TGF-beta</g> functions are crucial in <d>fibrosis</d>, antagonizing this pathway in bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, an animal model of <d>IPF</d>, does not prevent <d>fibrosis</d> completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of <g>cytosolic phospholipase A2</g> <g>cPLA2</g> suppresses bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of <g>prostaglandin F PGF receptor</g> FP selectively attenuates <d>pulmonary <d>fibrosis</d></d> while maintaining similar levels of <d>alveolar inflammation</d> and <g>TGF-beta</g> stimulation as compared to <d>wild-type</d> <d>WT</d> mice, and that FP deficiency and inhibition of <g>TGF-beta</g> signaling additively decrease <d>fibrosis</d>. Furthermore, PGF2alpha is abundant in bronchoalveolar lavage fluid BALF of subjects with <d>IPF</d> and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of <g>TGF-beta</g>. These findings show that PGF2alpha-FP signaling facilitates <d>pulmonary <d>fibrosis</d></d> independently of <g>TGF-beta</g> and suggests this signaling pathway as a therapeutic target for <d>IPF</d>.
19966781|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix ECM proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for <d>IPF</d> does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta <g>TGF-beta</g> functions are crucial in <d>fibrosis</d>, antagonizing this pathway in bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, an animal model of <d>IPF</d>, does not prevent <d>fibrosis</d> completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of <g>cytosolic phospholipase A2</g> <g>cPLA2</g> suppresses bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of <g>prostaglandin F PGF receptor</g> FP selectively attenuates <d>pulmonary <d>fibrosis</d></d> while maintaining similar levels of <d>alveolar inflammation</d> and <g>TGF-beta</g> stimulation as compared to <d>wild-type</d> <d>WT</d> mice, and that <d>FP deficiency</d> and inhibition of <g>TGF-beta</g> signaling additively decrease <d>fibrosis</d>. Furthermore, PGF2alpha is abundant in bronchoalveolar lavage fluid BALF of subjects with <d>IPF</d> and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of <g>TGF-beta</g>. These findings show that PGF2alpha-FP signaling facilitates <d>pulmonary <d>fibrosis</d></d> independently of <g>TGF-beta</g> and suggests this signaling pathway as a therapeutic target for <d>IPF</d>.
20061390|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a poorly understood progressive disease characterized by the accumulation of scar tissue in the lung interstitium. A hallmark of the disease is areas of injury to type II alveolar epithelial cells with attendant accumulation of fibroblasts in areas called fibroblastic foci. In an effort to better characterize the lung fibroblast phenotype in IPF patients, we isolated fibroblasts from patients with IPF and looked for activation of signaling proteins, which could help explain the exaggerated fibrogenic response in IPF. We found that IPF fibroblasts constitutively expressed increased basal levels of <g>SPARC</g>, plasminogen activator inhibitor-1 PAI-1, and active <g>beta-catenin</g> compared with control cells. Control of basal PAI-1 expression in IPF fibroblasts was regulated by <g>SPARC</g>-mediated activation of Akt, leading to inhibition of glycogen synthase kinase-3beta and activation of <g>beta-catenin</g>. Additionally, IPF fibroblasts but not control fibroblasts were resistant to plasminogen-induced apoptosis and were sensitized to plasminogen-mediated apoptosis by inhibition of <g>SPARC</g> or <g>beta-catenin</g>. These findings uncover a newly discovered regulatory pathway in IPF fibroblasts that is characterized by elevated <g>SPARC</g>, giving rise to activated <g>beta-catenin</g>, which regulates expression of downstream genes, such as PAI-1, and confers an apoptosis-resistant phenotype. Disruption of this pathway may represent a novel therapeutic target in IPF.
20061390|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a poorly understood progressive disease characterized by the accumulation of scar tissue in the lung interstitium. A hallmark of the disease is areas of injury to type II alveolar epithelial cells with attendant accumulation of fibroblasts in areas called fibroblastic foci. In an effort to better characterize the lung fibroblast phenotype in <d>IPF</d> patients, we isolated fibroblasts from patients with <d>IPF</d> and looked for activation of signaling proteins, which could help explain the exaggerated fibrogenic response in <d>IPF</d>. We found that <d>IPF</d> fibroblasts constitutively expressed increased basal levels of <g>SPARC</g>, plasminogen activator inhibitor-1 PAI-1, and active <g>beta-catenin</g> compared with control cells. Control of basal PAI-1 expression in <d>IPF</d> fibroblasts was regulated by <g>SPARC</g>-mediated activation of Akt, leading to inhibition of glycogen synthase kinase-3beta and activation of <g>beta-catenin</g>. Additionally, <d>IPF</d> fibroblasts but not control fibroblasts were resistant to plasminogen-induced apoptosis and were sensitized to plasminogen-mediated apoptosis by inhibition of <g>SPARC</g> or <g>beta-catenin</g>. These findings uncover a newly discovered regulatory pathway in <d>IPF</d> fibroblasts that is characterized by elevated <g>SPARC</g>, giving rise to activated <g>beta-catenin</g>, which regulates expression of downstream genes, such as PAI-1, and confers an apoptosis-resistant phenotype. Disruption of this pathway may represent a novel therapeutic target in <d>IPF</d>.
20061443|a|Idiopathic pulmonary <d>fibrosis</d> IPF is a progressive and typically fatal lung disease for which no effective therapy has been identified. The disease is characterized by excessive collagen deposition, possibly in response to dysregulated wound healing. Mediators normally involved in would healing induce proliferation of fibroblasts and their differentiation to myofibroblasts that actively secrete collagen. Curcumin, a polyphenolic compound from turmeric, has been shown to exert a variety of biological effects. Effects on IPF and associated cell types remain unclear, however. We accordingly tested the ability of curcumin to inhibit proliferation and differentiation to myofibroblasts by human lung fibroblasts, including those from IPF patients. To further examine the potential usefulness of curcumin in IPF, we examined its ability to reduce <d>fibrosis</d> in bleomycin-treated mice. We show that curcumin effectively reduces profibrotic effects in both normal and IPF fibroblasts in vitro and that this reduction is accompanied by inhibition of key steps in the transforming growth factor-b TGF-b signaling pathway. In vivo, oral curcumin treatment showed no effect on important measures of bleomycin-induced injury in mice, whereas intraperitoneal curcumin administration effectively inhibited inflammation and collagen deposition along with a trend toward improved survival. Intraperitoneal curcumin reduced fibrotic progression even when administered after the acute bleomycin-induced inflammation had subsided. These results encourage further research on alternative formulations and routes of administration for this potentially attractive IPF therapy.
20061443|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive and typically fatal lung disease for which no effective therapy has been identified. The disease is characterized by excessive collagen deposition, possibly in response to dysregulated wound healing. Mediators normally involved in would healing induce proliferation of fibroblasts and their differentiation to myofibroblasts that actively secrete collagen. Curcumin, a polyphenolic compound from turmeric, has been shown to exert a variety of biological effects. Effects on <d>IPF</d> and associated cell types remain unclear, however. We accordingly tested the ability of curcumin to inhibit proliferation and differentiation to myofibroblasts by human lung fibroblasts, including those from <d>IPF</d> patients. To further examine the potential usefulness of curcumin in <d>IPF</d>, we examined its ability to reduce <d>fibrosis</d> in bleomycin-treated mice. We show that curcumin effectively reduces profibrotic effects in both normal and <d>IPF</d> fibroblasts in vitro and that this reduction is accompanied by inhibition of key steps in the transforming growth factor-b TGF-b signaling pathway. In vivo, oral curcumin treatment showed no effect on important measures of bleomycin-induced injury in mice, whereas intraperitoneal curcumin administration effectively inhibited inflammation and collagen deposition along with a trend toward improved survival. Intraperitoneal curcumin reduced fibrotic progression even when administered after the acute bleomycin-induced inflammation had subsided. These results encourage further research on alternative formulations and routes of administration for this potentially attractive <d>IPF</d> therapy.
20061443|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive and typically fatal <d>lung disease</d> for which no effective therapy has been identified. The disease is characterized by excessive collagen deposition, possibly in response to dysregulated wound healing. Mediators normally involved in would healing induce proliferation of fibroblasts and their differentiation to myofibroblasts that actively secrete collagen. Curcumin, a polyphenolic compound from turmeric, has been shown to exert a variety of biological effects. Effects on <d>IPF</d> and associated cell types remain unclear, however. We accordingly tested the ability of curcumin to inhibit proliferation and differentiation to myofibroblasts by human lung fibroblasts, including those from <d>IPF</d> patients. To further examine the potential usefulness of curcumin in <d>IPF</d>, we examined its ability to reduce <d>fibrosis</d> in bleomycin-treated mice. We show that curcumin effectively reduces profibrotic effects in both normal and <d>IPF</d> fibroblasts in vitro and that this reduction is accompanied by inhibition of key steps in the transforming growth factor-b TGF-b signaling pathway. In vivo, oral curcumin treatment showed no effect on important measures of bleomycin-induced injury in mice, whereas intraperitoneal curcumin administration effectively inhibited inflammation and collagen deposition along with a trend toward improved survival. Intraperitoneal curcumin reduced fibrotic progression even when administered after the acute bleomycin-induced inflammation had subsided. These results encourage further research on alternative formulations and routes of administration for this potentially attractive <d>IPF</d> therapy.
20061443|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive and typically fatal <d>lung disease</d> for which no effective therapy has been identified. The disease is characterized by excessive collagen deposition, possibly in response to dysregulated wound healing. Mediators normally involved in would healing induce proliferation of fibroblasts and their differentiation to myofibroblasts that actively secrete collagen. Curcumin, a polyphenolic compound from turmeric, has been shown to exert a variety of biological effects. Effects on <d>IPF</d> and associated cell types remain unclear, however. We accordingly tested the ability of curcumin to inhibit proliferation and differentiation to myofibroblasts by human lung fibroblasts, including those from <d>IPF</d> patients. To further examine the potential usefulness of curcumin in <d>IPF</d>, we examined its ability to reduce <d>fibrosis</d> in bleomycin-treated mice. We show that curcumin effectively reduces profibrotic effects in both normal and <d>IPF</d> fibroblasts in vitro and that this reduction is accompanied by inhibition of key steps in the <g>transforming growth factor-b</g> <g>TGF-b</g> signaling pathway. In vivo, oral curcumin treatment showed no effect on important measures of bleomycin-induced injury in mice, whereas intraperitoneal curcumin administration effectively inhibited <d>inflammation</d> and collagen deposition along with a trend toward improved survival. Intraperitoneal curcumin reduced fibrotic progression even when administered after the acute bleomycin-induced <d>inflammation</d> had subsided. These results encourage further research on alternative formulations and routes of administration for this potentially attractive <d>IPF</d> therapy.
20081107|a|<d>Idiopathic pulmonary arterial hypertension</d> PAH is a life-threatening condition characterized by pulmonary arteriolar remodeling. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of pulmonary hypertension PH. Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1 18 PAH subjects and 2 8 subjects with PH secondary to idiopathic pulmonary fibrosis IPF and 3 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-beta, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and PH secondary to IPF: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b558 and beta-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and PH secondary to IPF are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms.
20081107|a|<d>Idiopathic pulmonary arterial hypertension</d> PAH is a life-threatening condition characterized by <d>pulmonary arteriolar remodeling</d>. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of pulmonary hypertension PH. Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1 18 PAH subjects and 2 8 subjects with PH secondary to idiopathic pulmonary fibrosis IPF and 3 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-beta, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and PH secondary to IPF: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b558 and beta-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and PH secondary to IPF are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms.
20081107|a|<d>Idiopathic pulmonary arterial hypertension</d> PAH is a life-threatening condition characterized by <d>pulmonary arteriolar remodeling</d>. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of <d>pulmonary hypertension</d> PH. Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1 18 PAH subjects and 2 8 subjects with PH secondary to idiopathic pulmonary fibrosis IPF and 3 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-beta, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and PH secondary to IPF: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b558 and beta-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and PH secondary to IPF are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms.
20081107|a|<d>Idiopathic pulmonary arterial hypertension</d> PAH is a life-threatening condition characterized by <d>pulmonary arteriolar remodeling</d>. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of <d>pulmonary hypertension</d> <d>PH</d>. Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1 18 PAH subjects and 2 8 subjects with <d>PH</d> secondary to idiopathic pulmonary fibrosis IPF and 3 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-beta, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and <d>PH</d> secondary to IPF: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b558 and beta-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and <d>PH</d> secondary to IPF are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms.
20081107|a|<d>Idiopathic pulmonary arterial hypertension</d> PAH is a life-threatening condition characterized by <d>pulmonary arteriolar remodeling</d>. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of <d>pulmonary hypertension</d> <d>PH</d>. Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1 18 PAH subjects and 2 8 subjects with <d>PH</d> secondary to <d>idiopathic pulmonary fibrosis</d> IPF and 3 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-beta, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and <d>PH</d> secondary to IPF: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b558 and beta-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and <d>PH</d> secondary to IPF are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms.
20081107|a|<d>Idiopathic pulmonary arterial hypertension</d> PAH is a life-threatening condition characterized by <d>pulmonary arteriolar remodeling</d>. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of <d>pulmonary hypertension</d> <d>PH</d>. Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1 18 PAH subjects and 2 8 subjects with <d>PH</d> secondary to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and 3 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-beta, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and <d>PH</d> secondary to <d>IPF</d>: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b558 and beta-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and <d>PH</d> secondary to <d>IPF</d> are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms.
20160152|a|It is estimated that, combined, 400,000 people are diagnosed with idiopathic <d>pulmonary fibrosis</d> IPF or acute lung injury/acute respiratory distress syndrome annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with acute lung injury as well as in the progressive fibrosis of IPF. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor TGF-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue fibrosis and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative acute respiratory distress syndrome or IPF, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases.
20160152|a|It is estimated that, combined, 400,000 people are diagnosed with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> or acute lung injury/acute respiratory distress syndrome annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with acute lung injury as well as in the progressive fibrosis of <d>IPF</d>. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor TGF-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue fibrosis and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative acute respiratory distress syndrome or <d>IPF</d>, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases.
20160152|a|It is estimated that, combined, 400,000 people are diagnosed with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> or <d>acute lung injury</d>/acute respiratory distress syndrome annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with <d>acute lung injury</d> as well as in the progressive fibrosis of <d>IPF</d>. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor TGF-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue fibrosis and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative acute respiratory distress syndrome or <d>IPF</d>, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases.
20160152|a|It is estimated that, combined, 400,000 people are diagnosed with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> or <d>acute lung injury</d>/<d>acute respiratory distress syndrome</d> annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with <d>acute lung injury</d> as well as in the progressive fibrosis of <d>IPF</d>. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor TGF-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue fibrosis and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative <d>acute respiratory distress syndrome</d> or <d>IPF</d>, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases.
20160152|a|It is estimated that, combined, 400,000 people are diagnosed with idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> or <d>acute lung injury</d>/<d>acute respiratory distress syndrome</d> annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with <d>acute lung injury</d> as well as in the progressive <d>fibrosis</d> of <d>IPF</d>. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor TGF-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue <d>fibrosis</d> and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative <d>acute respiratory distress syndrome</d> or <d>IPF</d>, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases.
20176803|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of <d>pulmonary fibrosis</d> and identify a critical mechanistic role for IL-17A. After exposure to bleomycin BLM, but not Schistosoma mansoni eggs, IL-17A produced by CD4+ and gammadelta+ T cells induced significant neutrophilia and <d>pulmonary fibrosis</d>. Studies conducted with C57BL/6 il17a-/- mice confirmed an essential role for IL-17A. Mechanistically, using ifngamma-/-, il10-/-, il10-/-il12p40-/-, and il10-/-il17a-/- mice and TGF-beta blockade, we demonstrate that IL-17A-driven fibrosis is suppressed by IL-10 and facilitated by IFN-gamma and IL-12/23p40. BLM-induced IL-17A production was also TGF-beta dependent, and recombinant IL-17A-mediated fibrosis required TGF-beta, suggesting cooperative roles for IL-17A and TGF-beta in the development of fibrosis. Finally, we show that fibrosis induced by <g>IL-1beta</g>, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and <g>IL-1beta</g> were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis.
20176803|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of <d>pulmonary fibrosis</d> and identify a critical mechanistic role for <g>IL-17A</g>. After exposure to bleomycin BLM, but not Schistosoma mansoni eggs, <g>IL-17A</g> produced by CD4+ and gammadelta+ T cells induced significant neutrophilia and <d>pulmonary fibrosis</d>. Studies conducted with C57BL/6 il17a-/- mice confirmed an essential role for <g>IL-17A</g>. Mechanistically, using ifngamma-/-, il10-/-, il10-/-il12p40-/-, and il10-/-il17a-/- mice and TGF-beta blockade, we demonstrate that <g>IL-17A</g>-driven fibrosis is suppressed by IL-10 and facilitated by IFN-gamma and IL-12/23p40. BLM-induced <g>IL-17A</g> production was also TGF-beta dependent, and recombinant <g>IL-17A</g>-mediated fibrosis required TGF-beta, suggesting cooperative roles for <g>IL-17A</g> and TGF-beta in the development of fibrosis. Finally, we show that fibrosis induced by <g>IL-1beta</g>, which mimics BLM-induced fibrosis, is also highly dependent on <g>IL-17A</g>. <g>IL-17A</g> and <g>IL-1beta</g> were also increased in the bronchoalveolar lavage fluid of patients with <d>IPF</d>. Together, these studies identify a critical role for <g>IL-17A</g> in fibrosis, illustrating the potential utility of targeting <g>IL-17A</g> in the treatment of drug and inflammation-induced fibrosis.
20176803|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a destructive <d>inflammatory disease</d> with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of <d>pulmonary fibrosis</d> and identify a critical mechanistic role for <g>IL-17A</g>. After exposure to bleomycin BLM, but not Schistosoma mansoni eggs, <g>IL-17A</g> produced by CD4+ and gammadelta+ T cells induced significant neutrophilia and <d>pulmonary fibrosis</d>. Studies conducted with C57BL/6 il17a-/- mice confirmed an essential role for <g>IL-17A</g>. Mechanistically, using ifngamma-/-, il10-/-, il10-/-il12p40-/-, and il10-/-il17a-/- mice and TGF-beta blockade, we demonstrate that <g>IL-17A</g>-driven fibrosis is suppressed by IL-10 and facilitated by IFN-gamma and IL-12/23p40. BLM-induced <g>IL-17A</g> production was also TGF-beta dependent, and recombinant <g>IL-17A</g>-mediated fibrosis required TGF-beta, suggesting cooperative roles for <g>IL-17A</g> and TGF-beta in the development of fibrosis. Finally, we show that fibrosis induced by <g>IL-1beta</g>, which mimics BLM-induced fibrosis, is also highly dependent on <g>IL-17A</g>. <g>IL-17A</g> and <g>IL-1beta</g> were also increased in the bronchoalveolar lavage fluid of patients with <d>IPF</d>. Together, these studies identify a critical role for <g>IL-17A</g> in fibrosis, illustrating the potential utility of targeting <g>IL-17A</g> in the treatment of drug and inflammation-induced fibrosis.
20176803|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a destructive <d>inflammatory disease</d> with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of <d>pulmonary fibrosis</d> and identify a critical mechanistic role for <g>IL-17A</g>. After exposure to bleomycin BLM, but not Schistosoma mansoni eggs, <g>IL-17A</g> produced by CD4+ and gammadelta+ T cells induced significant <d>neutrophilia</d> and <d>pulmonary fibrosis</d>. Studies conducted with C57BL/6 il17a-/- mice confirmed an essential role for <g>IL-17A</g>. Mechanistically, using ifngamma-/-, il10-/-, il10-/-il12p40-/-, and il10-/-il17a-/- mice and TGF-beta blockade, we demonstrate that <g>IL-17A</g>-driven fibrosis is suppressed by IL-10 and facilitated by IFN-gamma and IL-12/23p40. BLM-induced <g>IL-17A</g> production was also TGF-beta dependent, and recombinant <g>IL-17A</g>-mediated fibrosis required TGF-beta, suggesting cooperative roles for <g>IL-17A</g> and TGF-beta in the development of fibrosis. Finally, we show that fibrosis induced by <g>IL-1beta</g>, which mimics BLM-induced fibrosis, is also highly dependent on <g>IL-17A</g>. <g>IL-17A</g> and <g>IL-1beta</g> were also increased in the bronchoalveolar lavage fluid of patients with <d>IPF</d>. Together, these studies identify a critical role for <g>IL-17A</g> in fibrosis, illustrating the potential utility of targeting <g>IL-17A</g> in the treatment of drug and inflammation-induced fibrosis.
20176803|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a destructive <d>inflammatory disease</d> with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of <d>pulmonary <d>fibrosis</d></d> and identify a critical mechanistic role for <g>IL-17A</g>. After exposure to bleomycin BLM, but not Schistosoma mansoni eggs, <g>IL-17A</g> produced by CD4+ and gammadelta+ T cells induced significant <d>neutrophilia</d> and <d>pulmonary <d>fibrosis</d></d>. Studies conducted with C57BL/6 il17a-/- mice confirmed an essential role for <g>IL-17A</g>. Mechanistically, using ifngamma-/-, il10-/-, il10-/-<g>il12p40</g>-/-, and il10-/-il17a-/- mice and <g>TGF-beta</g> blockade, we demonstrate that <g>IL-17A</g>-driven <d>fibrosis</d> is suppressed by IL-10 and facilitated by IFN-gamma and IL-12/23p40. BLM-induced <g>IL-17A</g> production was also <g>TGF-beta</g> dependent, and recombinant <g>IL-17A</g>-mediated <d>fibrosis</d> required <g>TGF-beta</g>, suggesting cooperative roles for <g>IL-17A</g> and <g>TGF-beta</g> in the development of <d>fibrosis</d>. Finally, we show that <d>fibrosis</d> induced by <g>IL-1beta</g>, which mimics BLM-induced <d>fibrosis</d>, is also highly dependent on <g>IL-17A</g>. <g>IL-17A</g> and <g>IL-1beta</g> were also increased in the bronchoalveolar lavage fluid of patients with <d>IPF</d>. Together, these studies identify a critical role for <g>IL-17A</g> in <d>fibrosis</d>, illustrating the potential utility of targeting <g>IL-17A</g> in the treatment of drug and inflammation-induced <d>fibrosis</d>.
20176803|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a destructive <d>inflammatory disease</d> with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of <d>pulmonary <d>fibrosis</d></d> and identify a critical mechanistic role for <g>IL-17A</g>. After exposure to bleomycin BLM, but not Schistosoma mansoni eggs, <g>IL-17A</g> produced by CD4+ and gammadelta+ T cells induced significant <d>neutrophilia</d> and <d>pulmonary <d>fibrosis</d></d>. Studies conducted with C57BL/6 il17a-/- mice confirmed an essential role for <g>IL-17A</g>. Mechanistically, using ifngamma-/-, il10-/-, il10-/-<g>il12p40</g>-/-, and il10-/-il17a-/- mice and <g>TGF-beta</g> blockade, we demonstrate that <g>IL-17A</g>-driven <d>fibrosis</d> is suppressed by <g>IL-10</g> and facilitated by <g>IFN-gamma</g> and IL-12/23p40. BLM-induced <g>IL-17A</g> production was also <g>TGF-beta</g> dependent, and recombinant <g>IL-17A</g>-mediated <d>fibrosis</d> required <g>TGF-beta</g>, suggesting cooperative roles for <g>IL-17A</g> and <g>TGF-beta</g> in the development of <d>fibrosis</d>. Finally, we show that <d>fibrosis</d> induced by <g>IL-1beta</g>, which mimics BLM-induced <d>fibrosis</d>, is also highly dependent on <g>IL-17A</g>. <g>IL-17A</g> and <g>IL-1beta</g> were also increased in the bronchoalveolar lavage fluid of patients with <d>IPF</d>. Together, these studies identify a critical role for <g>IL-17A</g> in <d>fibrosis</d>, illustrating the potential utility of targeting <g>IL-17A</g> in the treatment of drug and <d>inflammation</d>-induced <d>fibrosis</d>.
20388759|a|BACKGROUND AND AIM: There is a growing body of evidence demonstrating that <g>plasminogen activator inhibitor-1</g> PAI-1 is involved in the progression of <d>pulmonary fibrosis</d>. In fact, PAI-1 knockout mice are protected from bleomycin-induced <d>pulmonary fibrosis</d>. This study was conducted to determine whether the intrapulmonary administration of small interfering RNA siRNA targeting PAI-1 PAI-1-siRNA limits the development of bleomycin-induced <d>pulmonary fibrosis</d>. METHODS: Lung biopsies from patients with idiopathic <d>pulmonary fibrosis</d> IPF were stained for PAI-1. The distribution of siRNA in the lung, the PAI-1 level in bronchoalveolar BAL fluid and the extent of fibrotic changes in the lung were evaluated following the intranasal administration of PAI-1-siRNA in a mouse model of bleomycin-induced <d>pulmonary fibrosis</d>. The effect of PAI-1-siRNA on the epithelial to mesenchymal transition EMT was also evaluated using a mouse lung epithelial cell line, LA-4. RESULTS: PAI-1 was overexpressed in the hyperplastic type 2 pneumocytes lining the honeycomb lesions of patients with IPF. The single intranasal instillation of PAI-1-siRNA resulted in the diffuse uptake of siRNA into the epithelial cells lining the dense fibrotic lesions. The repeated administration of PAI-1-siRNA initiated during either the inflammatory or the fibrotic phase into bleomycin-injured mice reduced the PAI-1 level in BAL fluid and limited the accumulation of collagen in the lungs. EMT induced by transforming growth factor beta TGFbeta in LA-4 cells was inhibited by transfection with PAI-1-siRNA. CONCLUSIONS: The direct suppression of PAI-1 in the lung by the intrapulmonary administration of PAI-1-siRNA attenuated the development and progression of <d>pulmonary fibrosis</d>. The inhibition of EMT may be, at least in part, involved in this effect.
20388759|a|BACKGROUND AND AIM: There is a growing body of evidence demonstrating that <g>plasminogen activator inhibitor-1</g> <g>PAI-1</g> is involved in the progression of <d>pulmonary fibrosis</d>. In fact, <g>PAI-1</g> knockout mice are protected from bleomycin-induced <d>pulmonary fibrosis</d>. This study was conducted to determine whether the intrapulmonary administration of small interfering RNA siRNA targeting <g>PAI-1</g> <g>PAI-1</g>-siRNA limits the development of bleomycin-induced <d>pulmonary fibrosis</d>. METHODS: Lung biopsies from patients with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> were stained for <g>PAI-1</g>. The distribution of siRNA in the lung, the <g>PAI-1</g> level in bronchoalveolar BAL fluid and the extent of fibrotic changes in the lung were evaluated following the intranasal administration of <g>PAI-1</g>-siRNA in a mouse model of bleomycin-induced <d>pulmonary fibrosis</d>. The effect of <g>PAI-1</g>-siRNA on the epithelial to mesenchymal transition EMT was also evaluated using a mouse lung epithelial cell line, LA-4. RESULTS: <g>PAI-1</g> was overexpressed in the hyperplastic type 2 pneumocytes lining the honeycomb lesions of patients with <d>IPF</d>. The single intranasal instillation of <g>PAI-1</g>-siRNA resulted in the diffuse uptake of siRNA into the epithelial cells lining the dense fibrotic lesions. The repeated administration of <g>PAI-1</g>-siRNA initiated during either the inflammatory or the fibrotic phase into bleomycin-injured mice reduced the <g>PAI-1</g> level in BAL fluid and limited the accumulation of collagen in the lungs. EMT induced by transforming growth factor beta TGFbeta in LA-4 cells was inhibited by transfection with <g>PAI-1</g>-siRNA. CONCLUSIONS: The direct suppression of <g>PAI-1</g> in the lung by the intrapulmonary administration of <g>PAI-1</g>-siRNA attenuated the development and progression of <d>pulmonary fibrosis</d>. The inhibition of EMT may be, at least in part, involved in this effect.
20388759|a|BACKGROUND AND AIM: There is a growing body of evidence demonstrating that <g>plasminogen activator inhibitor-1</g> <g>PAI-1</g> is involved in the progression of <d>pulmonary fibrosis</d>. In fact, <g>PAI-1</g> knockout mice are protected from bleomycin-induced <d>pulmonary fibrosis</d>. This study was conducted to determine whether the intrapulmonary administration of small interfering RNA siRNA targeting <g>PAI-1</g> <g>PAI-1</g>-siRNA limits the development of bleomycin-induced <d>pulmonary fibrosis</d>. METHODS: Lung biopsies from patients with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> were stained for <g>PAI-1</g>. The distribution of siRNA in the lung, the <g>PAI-1</g> level in bronchoalveolar BAL fluid and the extent of fibrotic changes in the lung were evaluated following the intranasal administration of <g>PAI-1</g>-siRNA in a mouse model of bleomycin-induced <d>pulmonary fibrosis</d>. The effect of <g>PAI-1</g>-siRNA on the epithelial to mesenchymal transition EMT was also evaluated using a mouse lung epithelial cell line, LA-4. RESULTS: <g>PAI-1</g> was overexpressed in the <d>hyperplastic type 2</d> pneumocytes lining the honeycomb lesions of patients with <d>IPF</d>. The single intranasal instillation of <g>PAI-1</g>-siRNA resulted in the diffuse uptake of siRNA into the epithelial cells lining the dense fibrotic lesions. The repeated administration of <g>PAI-1</g>-siRNA initiated during either the inflammatory or the fibrotic phase into bleomycin-injured mice reduced the <g>PAI-1</g> level in BAL fluid and limited the accumulation of collagen in the lungs. EMT induced by transforming growth factor beta TGFbeta in LA-4 cells was inhibited by transfection with <g>PAI-1</g>-siRNA. CONCLUSIONS: The direct suppression of <g>PAI-1</g> in the lung by the intrapulmonary administration of <g>PAI-1</g>-siRNA attenuated the development and progression of <d>pulmonary fibrosis</d>. The inhibition of EMT may be, at least in part, involved in this effect.
20388759|a|BACKGROUND AND AIM: There is a growing body of evidence demonstrating that <g>plasminogen activator inhibitor-1</g> <g>PAI-1</g> is involved in the progression of <d>pulmonary fibrosis</d>. In fact, <g>PAI-1</g> knockout mice are protected from bleomycin-induced <d>pulmonary fibrosis</d>. This study was conducted to determine whether the intrapulmonary administration of small interfering RNA siRNA targeting <g>PAI-1</g> <g>PAI-1</g>-siRNA limits the development of bleomycin-induced <d>pulmonary fibrosis</d>. METHODS: Lung biopsies from patients with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> were stained for <g>PAI-1</g>. The distribution of siRNA in the lung, the <g>PAI-1</g> level in bronchoalveolar BAL fluid and the extent of fibrotic changes in the lung were evaluated following the intranasal administration of <g>PAI-1</g>-siRNA in a mouse model of bleomycin-induced <d>pulmonary fibrosis</d>. The effect of <g>PAI-1</g>-siRNA on the epithelial to mesenchymal transition EMT was also evaluated using a mouse lung epithelial cell line, LA-4. RESULTS: <g>PAI-1</g> was overexpressed in the <d>hyperplastic type 2</d> pneumocytes lining the honeycomb lesions of patients with <d>IPF</d>. The single intranasal instillation of <g>PAI-1</g>-siRNA resulted in the diffuse uptake of siRNA into the epithelial cells lining the dense <d>fibrotic lesions</d>. The repeated administration of <g>PAI-1</g>-siRNA initiated during either the inflammatory or the fibrotic phase into bleomycin-injured mice reduced the <g>PAI-1</g> level in BAL fluid and limited the accumulation of collagen in the lungs. EMT induced by transforming growth factor beta TGFbeta in LA-4 cells was inhibited by transfection with <g>PAI-1</g>-siRNA. CONCLUSIONS: The direct suppression of <g>PAI-1</g> in the lung by the intrapulmonary administration of <g>PAI-1</g>-siRNA attenuated the development and progression of <d>pulmonary fibrosis</d>. The inhibition of EMT may be, at least in part, involved in this effect.
20395557|a|RATIONALE: <d>Idiopathic pulmonary fibrosis</d> IPF is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation. OBJECTIVES: To determine changes in expression and role of microRNAs in IPF. METHODS: RNA from 10 control and 10 IPF tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the <g>let-7d</g> promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of <g>let-7d</g> in response to transforming growth factor-beta. HMGA2, a <g>let-7d</g> target, was localized by immunohistochemistry. In mice, <g>let-7d</g> was inhibited by intratracheal administration of a <g>let-7d</g> antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry. MEASUREMENTS AND MAIN RESULTS: Eighteen microRNAs including <g>let-7d</g> were significantly decreased in IPF. Transforming growth factor-beta down-regulated <g>let-7d</g> expression, and SMAD3 binding to the <g>let-7d</g> promoter was demonstrated. Inhibition of <g>let-7d</g> caused increases in mesenchymal markers N-cadherin-2, vimentin, and alpha-smooth muscle actin ACTA2 as well as HMGA2 in multiple epithelial cell lines. <g>let-7d</g> was significantly reduced in IPF lungs and the number of epithelial cells expressing <g>let-7d</g> correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of IPF lungs. <g>let-7d</g> inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC pulmonary-associated surfactant protein C expressing alveolar epithelial cells. CONCLUSIONS: Our results indicate a role for microRNAs in IPF. The down-regulation of <g>let-7d</g> in IPF and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis. Clinical trial registered with www.clinicaltrials.gov NCT 00258544.
20395557|a|RATIONALE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation. OBJECTIVES: To determine changes in expression and role of microRNAs in <d>IPF</d>. METHODS: RNA from 10 control and 10 <d>IPF</d> tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the <g>let-7d</g> promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of <g>let-7d</g> in response to transforming growth factor-beta. HMGA2, a <g>let-7d</g> target, was localized by immunohistochemistry. In mice, <g>let-7d</g> was inhibited by intratracheal administration of a <g>let-7d</g> antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry. MEASUREMENTS AND MAIN RESULTS: Eighteen microRNAs including <g>let-7d</g> were significantly decreased in <d>IPF</d>. Transforming growth factor-beta down-regulated <g>let-7d</g> expression, and SMAD3 binding to the <g>let-7d</g> promoter was demonstrated. Inhibition of <g>let-7d</g> caused increases in mesenchymal markers N-cadherin-2, vimentin, and alpha-smooth muscle actin ACTA2 as well as HMGA2 in multiple epithelial cell lines. <g>let-7d</g> was significantly reduced in <d>IPF</d> lungs and the number of epithelial cells expressing <g>let-7d</g> correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of <d>IPF</d> lungs. <g>let-7d</g> inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC pulmonary-associated surfactant protein C expressing alveolar epithelial cells. CONCLUSIONS: Our results indicate a role for microRNAs in <d>IPF</d>. The down-regulation of <g>let-7d</g> in <d>IPF</d> and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis. Clinical trial registered with www.clinicaltrials.gov NCT 00258544.
20395557|a|RATIONALE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and usually lethal <d>fibrotic lung disease</d> characterized by profound changes in epithelial cell phenotype and fibroblast proliferation. OBJECTIVES: To determine changes in expression and role of microRNAs in <d>IPF</d>. METHODS: RNA from 10 control and 10 <d>IPF</d> tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the <g>let-7d</g> promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of <g>let-7d</g> in response to transforming growth factor-beta. HMGA2, a <g>let-7d</g> target, was localized by immunohistochemistry. In mice, <g>let-7d</g> was inhibited by intratracheal administration of a <g>let-7d</g> antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry. MEASUREMENTS AND MAIN RESULTS: Eighteen microRNAs including <g>let-7d</g> were significantly decreased in <d>IPF</d>. Transforming growth factor-beta down-regulated <g>let-7d</g> expression, and SMAD3 binding to the <g>let-7d</g> promoter was demonstrated. Inhibition of <g>let-7d</g> caused increases in mesenchymal markers N-cadherin-2, vimentin, and alpha-smooth muscle actin ACTA2 as well as HMGA2 in multiple epithelial cell lines. <g>let-7d</g> was significantly reduced in <d>IPF</d> lungs and the number of epithelial cells expressing <g>let-7d</g> correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of <d>IPF</d> lungs. <g>let-7d</g> inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC pulmonary-associated surfactant protein C expressing alveolar epithelial cells. CONCLUSIONS: Our results indicate a role for microRNAs in <d>IPF</d>. The down-regulation of <g>let-7d</g> in <d>IPF</d> and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis. Clinical trial registered with www.clinicaltrials.gov NCT 00258544.
20395557|a|RATIONALE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and usually lethal <d>fibrotic lung disease</d> characterized by profound changes in epithelial cell phenotype and fibroblast proliferation. OBJECTIVES: To determine changes in expression and role of microRNAs in <d>IPF</d>. METHODS: RNA from 10 control and 10 <d>IPF</d> tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. <g>SMAD3</g> binding to the <g>let-7d</g> promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of <g>let-7d</g> in response to transforming growth factor-beta. <g>HMGA2</g>, a <g>let-7d</g> target, was localized by immunohistochemistry. In mice, <g>let-7d</g> was inhibited by intratracheal administration of a <g>let-7d</g> antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry. MEASUREMENTS AND MAIN RESULTS: Eighteen microRNAs including <g>let-7d</g> were significantly decreased in <d>IPF</d>. Transforming growth factor-beta down-regulated <g>let-7d</g> expression, and <g>SMAD3</g> binding to the <g>let-7d</g> promoter was demonstrated. Inhibition of <g>let-7d</g> caused increases in mesenchymal markers N-cadherin-2, <g>vimentin</g>, and alpha-smooth muscle actin <g>ACTA2</g> as well as <g>HMGA2</g> in multiple epithelial cell lines. <g>let-7d</g> was significantly reduced in <d>IPF</d> lungs and the number of epithelial cells expressing <g>let-7d</g> correlated with pulmonary functions. <g>HMGA2</g> was increased in alveolar epithelial cells of <d>IPF</d> lungs. <g>let-7d</g> inhibition in vivo caused alveolar septal thickening and increases in collagen, <g>ACTA2</g>, and S100A4 expression in <g>SFTPC</g> pulmonary-associated surfactant protein C expressing alveolar epithelial cells. CONCLUSIONS: Our results indicate a role for microRNAs in <d>IPF</d>. The down-regulation of <g>let-7d</g> in <d>IPF</d> and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing <d>lung fibrosis</d>. Clinical trial registered with www.clinicaltrials.gov NCT 00258544.
20483575|a|BACKGROUND: Experimental data have provided evidence that progenitor cells of bone marrow BM origin may play a role in the fibrogenic process of the lung. OBJECTIVE: To probe the possible involvement of BM mesenchymal stem cells MSCs in the pathophysiology of <d>Idiopathic Pulmonary Fibrosis</d> IPF by investigating the molecular profile of these cells. DESIGN: BM MSCs were studied in 10 IPF patients and 10 healthy controls. MSCs were identified by their immunophenotypic characteristics and their potential to differentiate towards adipocytes/osteocytes/chondrocytes. We evaluated the mRNA expression of genes involved in the lung injury of IPF, namely the vascular endothelial growth factor VEGF, fibroblast growth factor FGF, transforming growth factor beta-1 TGF-beta1 and the axis stromal-cell-derived factor-1 SDF-1/CXCR4 in BM MSCs using quantitative RT-PCR. RESULTS: The BM MSCs of IPF patients displayed normal immunophenotypic characteristics and differentiation potential. No statistically significant difference was found between patients and controls in VEGF and FGF mRNA expression. TGF-beta1 was not expressed in either patients or controls. A significant increase in SDF-1-TR1 and CXCR4 mRNA expression was detected in IPF patients 1.6 x 1025 +/- 1.2 x 1025 and 3.1 x 107 +/- 3.1 x 107, respectively compared to controls 0.32 x 1025 +/- 0.07 x 1025 and 1.67 x 107 +/- 0.30 x 107, respectively p = 0.001 and p = 0.001, respectively whereas SDF-1 levels in MSC supernatants were similar in patients and controls. CONCLUSIONS: The increased CXCR4 expression by patient MSCs suggests that the BM is probably implicated in the pathophysiology of IPF by mobilizing MSCs in response to or preceding lung injury. The potential role of BM MSCs in IPF is another interesting field for further investigation.
20483575|a|BACKGROUND: Experimental data have provided evidence that progenitor cells of bone marrow BM origin may play a role in the fibrogenic process of the lung. OBJECTIVE: To probe the possible involvement of BM mesenchymal stem cells MSCs in the pathophysiology of <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> by investigating the molecular profile of these cells. DESIGN: BM MSCs were studied in 10 <d>IPF</d> patients and 10 healthy controls. MSCs were identified by their immunophenotypic characteristics and their potential to differentiate towards adipocytes/osteocytes/chondrocytes. We evaluated the mRNA expression of genes involved in the lung injury of <d>IPF</d>, namely the vascular endothelial growth factor VEGF, fibroblast growth factor FGF, transforming growth factor beta-1 TGF-beta1 and the axis stromal-cell-derived factor-1 SDF-1/CXCR4 in BM MSCs using quantitative RT-PCR. RESULTS: The BM MSCs of <d>IPF</d> patients displayed normal immunophenotypic characteristics and differentiation potential. No statistically significant difference was found between patients and controls in VEGF and FGF mRNA expression. TGF-beta1 was not expressed in either patients or controls. A significant increase in SDF-1-TR1 and CXCR4 mRNA expression was detected in <d>IPF</d> patients 1.6 x 1025 +/- 1.2 x 1025 and 3.1 x 107 +/- 3.1 x 107, respectively compared to controls 0.32 x 1025 +/- 0.07 x 1025 and 1.67 x 107 +/- 0.30 x 107, respectively p = 0.001 and p = 0.001, respectively whereas SDF-1 levels in MSC supernatants were similar in patients and controls. CONCLUSIONS: The increased CXCR4 expression by patient MSCs suggests that the BM is probably implicated in the pathophysiology of <d>IPF</d> by mobilizing MSCs in response to or preceding lung injury. The potential role of BM MSCs in <d>IPF</d> is another interesting field for further investigation.
20483575|a|BACKGROUND: Experimental data have provided evidence that progenitor cells of bone marrow BM origin may play a role in the fibrogenic process of the lung. OBJECTIVE: To probe the possible involvement of BM mesenchymal stem cells MSCs in the pathophysiology of <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> by investigating the molecular profile of these cells. DESIGN: BM MSCs were studied in 10 <d>IPF</d> patients and 10 healthy controls. MSCs were identified by their immunophenotypic characteristics and their potential to differentiate towards adipocytes/osteocytes/chondrocytes. We evaluated the mRNA expression of genes involved in the <d>lung injury</d> of <d>IPF</d>, namely the vascular endothelial growth factor VEGF, fibroblast growth factor FGF, transforming growth factor beta-1 TGF-beta1 and the axis stromal-cell-derived factor-1 SDF-1/CXCR4 in BM MSCs using quantitative RT-PCR. RESULTS: The BM MSCs of <d>IPF</d> patients displayed normal immunophenotypic characteristics and differentiation potential. No statistically significant difference was found between patients and controls in VEGF and FGF mRNA expression. TGF-beta1 was not expressed in either patients or controls. A significant increase in SDF-1-TR1 and CXCR4 mRNA expression was detected in <d>IPF</d> patients 1.6 x 1025 +/- 1.2 x 1025 and 3.1 x 107 +/- 3.1 x 107, respectively compared to controls 0.32 x 1025 +/- 0.07 x 1025 and 1.67 x 107 +/- 0.30 x 107, respectively p = 0.001 and p = 0.001, respectively whereas SDF-1 levels in MSC supernatants were similar in patients and controls. CONCLUSIONS: The increased CXCR4 expression by patient MSCs suggests that the BM is probably implicated in the pathophysiology of <d>IPF</d> by mobilizing MSCs in response to or preceding <d>lung injury</d>. The potential role of BM MSCs in <d>IPF</d> is another interesting field for further investigation.
20495078|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and lethal lung disease characterized by the expansion of the fibroblast/myofibroblast population and aberrant remodeling. However, the origin of mesenchymal cells in this disorder is still under debate. Recent evidence indicates that epithelial-mesenchymal transition EMT induced primarily by TGF-beta1 plays an important role; however, studies regarding the opposite process, mesenchymal-epithelial transition, are scanty. We have previously shown that fibroblast growth factor-1 <g>FGF-1</g> inhibits several profibrogenic effects of TGF-beta1. In this study, we examined the effects of <g>FGF-1</g> on TGF-beta1-induced EMT. A549 and RLE-6TN human and rat alveolar epithelial-like cell lines were stimulated with TGF-beta1 for 72 h, and then, in the presence of TGF-beta1, were cultured with <g>FGF-1</g> plus heparin for an additional 48 h. After TGF-beta1 treatment, epithelial cells acquired a spindle-like mesenchymal phenotype with a substantial reduction of E-cadherin and cytokeratins and concurrent induction of alpha-smooth muscle actin measured by real-time PCR, Western blotting, and immunocytochemistry. <g>FGF-1</g> plus heparin reversed these morphological changes and returned the epithelial and mesenchymal markers to control levels. Signaling pathways analyzed by selective pharmacological inhibitors showed that TGF-beta1 induces EMT through Smad pathway, while reversion by <g>FGF-1</g> occurs through MAPK/ERK kinase pathway, resulting in ERK-1 phosphorylation and Smad2 dephosphorylation. These findings indicate that TGF-beta1-induced EMT is reversed by <g>FGF-1</g> and suggest therapeutic approaches to target this process in IPF.
20495078|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and lethal lung disease characterized by the expansion of the fibroblast/myofibroblast population and aberrant remodeling. However, the origin of mesenchymal cells in this disorder is still under debate. Recent evidence indicates that epithelial-mesenchymal transition EMT induced primarily by TGF-beta1 plays an important role; however, studies regarding the opposite process, mesenchymal-epithelial transition, are scanty. We have previously shown that fibroblast growth factor-1 <g>FGF-1</g> inhibits several profibrogenic effects of TGF-beta1. In this study, we examined the effects of <g>FGF-1</g> on TGF-beta1-induced EMT. A549 and RLE-6TN human and rat alveolar epithelial-like cell lines were stimulated with TGF-beta1 for 72 h, and then, in the presence of TGF-beta1, were cultured with <g>FGF-1</g> plus heparin for an additional 48 h. After TGF-beta1 treatment, epithelial cells acquired a spindle-like mesenchymal phenotype with a substantial reduction of E-cadherin and cytokeratins and concurrent induction of alpha-smooth muscle actin measured by real-time PCR, Western blotting, and immunocytochemistry. <g>FGF-1</g> plus heparin reversed these morphological changes and returned the epithelial and mesenchymal markers to control levels. Signaling pathways analyzed by selective pharmacological inhibitors showed that TGF-beta1 induces EMT through Smad pathway, while reversion by <g>FGF-1</g> occurs through MAPK/ERK kinase pathway, resulting in ERK-1 phosphorylation and Smad2 dephosphorylation. These findings indicate that TGF-beta1-induced EMT is reversed by <g>FGF-1</g> and suggest therapeutic approaches to target this process in <d>IPF</d>.
20495078|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and <d>lethal lung disease</d> characterized by the expansion of the fibroblast/myofibroblast population and aberrant remodeling. However, the origin of mesenchymal cells in this disorder is still under debate. Recent evidence indicates that epithelial-mesenchymal transition EMT induced primarily by TGF-beta1 plays an important role; however, studies regarding the opposite process, mesenchymal-epithelial transition, are scanty. We have previously shown that fibroblast growth factor-1 <g>FGF-1</g> inhibits several profibrogenic effects of TGF-beta1. In this study, we examined the effects of <g>FGF-1</g> on TGF-beta1-induced EMT. A549 and RLE-6TN human and rat alveolar epithelial-like cell lines were stimulated with TGF-beta1 for 72 h, and then, in the presence of TGF-beta1, were cultured with <g>FGF-1</g> plus heparin for an additional 48 h. After TGF-beta1 treatment, epithelial cells acquired a spindle-like mesenchymal phenotype with a substantial reduction of E-cadherin and cytokeratins and concurrent induction of alpha-smooth muscle actin measured by real-time PCR, Western blotting, and immunocytochemistry. <g>FGF-1</g> plus heparin reversed these morphological changes and returned the epithelial and mesenchymal markers to control levels. Signaling pathways analyzed by selective pharmacological inhibitors showed that TGF-beta1 induces EMT through Smad pathway, while reversion by <g>FGF-1</g> occurs through MAPK/ERK kinase pathway, resulting in ERK-1 phosphorylation and Smad2 dephosphorylation. These findings indicate that TGF-beta1-induced EMT is reversed by <g>FGF-1</g> and suggest therapeutic approaches to target this process in <d>IPF</d>.
20550546|a|It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed <g>folate receptor beta</g> FRbeta while resident macrophages in normal tissues expressed no or low levels of FRbeta. In the present study, we examined the distribution of FRbeta-expressing macrophages in the lungs of patients with usual <d>idiopathic pulmonary fibrosis</d> UIP and mice with bleomycin-induced pulmonary fibrosis PF and tested whether the depletion of FRbeta-expressing macrophages could suppress bleomycin-induced PF in mice. Immunostaining with anti-human or -mouse FRbeta monoclonal antibody mAb revealed that FRbeta-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with UIP and mice with bleomycin-induced PF. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse FRbeta mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and fibrosis in bleomycin-induced PF. In immunohistochemical analysis, decreased numbers of tumour necrosis factor-alpha-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of FRbeta-expressing macrophages in IPF. Thus, targeting FRbeta-expressing macrophages may be a promising treatment of IPF.
20550546|a|It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed <g>folate receptor beta</g> FRbeta while resident macrophages in normal tissues expressed no or low levels of FRbeta. In the present study, we examined the distribution of FRbeta-expressing macrophages in the lungs of patients with usual <d>idiopathic pulmonary fibrosis</d> UIP and mice with bleomycin-induced pulmonary fibrosis PF and tested whether the depletion of FRbeta-expressing macrophages could suppress bleomycin-induced PF in mice. Immunostaining with anti-human or -mouse FRbeta monoclonal antibody mAb revealed that FRbeta-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with UIP and mice with bleomycin-induced PF. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse FRbeta mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and fibrosis in bleomycin-induced PF. In immunohistochemical analysis, decreased numbers of tumour necrosis factor-alpha-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of FRbeta-expressing macrophages in <d>IPF</d>. Thus, targeting FRbeta-expressing macrophages may be a promising treatment of <d>IPF</d>.
20550546|a|It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed <g>folate receptor beta</g> <g>FRbeta</g> while resident macrophages in normal tissues expressed no or low levels of <g>FRbeta</g>. In the present study, we examined the distribution of <g>FRbeta</g>-expressing macrophages in the lungs of patients with usual <d>idiopathic pulmonary fibrosis</d> <d>UIP</d> and mice with bleomycin-induced pulmonary fibrosis PF and tested whether the depletion of <g>FRbeta</g>-expressing macrophages could suppress bleomycin-induced PF in mice. Immunostaining with anti-human or -mouse <g>FRbeta</g> monoclonal antibody mAb revealed that <g>FRbeta</g>-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with <d>UIP</d> and mice with bleomycin-induced PF. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse <g>FRbeta</g> mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and fibrosis in bleomycin-induced PF. In immunohistochemical analysis, decreased numbers of tumour necrosis factor-alpha-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of <g>FRbeta</g>-expressing macrophages in <d>IPF</d>. Thus, targeting <g>FRbeta</g>-expressing macrophages may be a promising treatment of <d>IPF</d>.
20550546|a|It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed <g>folate receptor beta</g> <g>FRbeta</g> while resident macrophages in normal tissues expressed no or low levels of <g>FRbeta</g>. In the present study, we examined the distribution of <g>FRbeta</g>-expressing macrophages in the lungs of patients with usual <d>idiopathic <d>pulmonary fibrosis</d></d> <d>UIP</d> and mice with bleomycin-induced <d>pulmonary fibrosis</d> PF and tested whether the depletion of <g>FRbeta</g>-expressing macrophages could suppress bleomycin-induced PF in mice. Immunostaining with anti-human or -mouse <g>FRbeta</g> monoclonal antibody mAb revealed that <g>FRbeta</g>-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with <d>UIP</d> and mice with bleomycin-induced PF. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse <g>FRbeta</g> mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and fibrosis in bleomycin-induced PF. In immunohistochemical analysis, decreased numbers of tumour necrosis factor-alpha-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of <g>FRbeta</g>-expressing macrophages in <d>IPF</d>. Thus, targeting <g>FRbeta</g>-expressing macrophages may be a promising treatment of <d>IPF</d>.
20550546|a|It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>I<d>PF</d></d> by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed <g>folate receptor beta</g> <g>FRbeta</g> while resident macrophages in normal tissues expressed no or low levels of <g>FRbeta</g>. In the present study, we examined the distribution of <g>FRbeta</g>-expressing macrophages in the lungs of patients with usual <d>idiopathic <d>pulmonary fibrosis</d></d> <d>UIP</d> and mice with bleomycin-induced <d>pulmonary fibrosis</d> <d>PF</d> and tested whether the depletion of <g>FRbeta</g>-expressing macrophages could suppress bleomycin-induced <d>PF</d> in mice. Immunostaining with anti-human or -mouse <g>FRbeta</g> monoclonal antibody mAb revealed that <g>FRbeta</g>-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with <d>UIP</d> and mice with bleomycin-induced <d>PF</d>. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse <g>FRbeta</g> mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and fibrosis in bleomycin-induced <d>PF</d>. In immunohistochemical analysis, decreased numbers of tumour necrosis factor-alpha-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of <g>FRbeta</g>-expressing macrophages in <d>I<d>PF</d></d>. Thus, targeting <g>FRbeta</g>-expressing macrophages may be a promising treatment of <d>I<d>PF</d></d>.
20550546|a|It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>I<d>PF</d></d> by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed <g>folate receptor beta</g> <g>FRbeta</g> while resident macrophages in normal tissues expressed no or low levels of <g>FRbeta</g>. In the present study, we examined the distribution of <g>FRbeta</g>-expressing macrophages in the lungs of patients with usual <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>UIP</d> and mice with bleomycin-induced <d>pulmonary <d>fibrosis</d></d> <d>PF</d> and tested whether the depletion of <g>FRbeta</g>-expressing macrophages could suppress bleomycin-induced <d>PF</d> in mice. Immunostaining with anti-human or -mouse <g>FRbeta</g> monoclonal antibody mAb revealed that <g>FRbeta</g>-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with <d>UIP</d> and mice with bleomycin-induced <d>PF</d>. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse <g>FRbeta</g> mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and <d>fibrosis</d> in bleomycin-induced <d>PF</d>. In immunohistochemical analysis, decreased numbers of tumour necrosis factor-alpha-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of <g>FRbeta</g>-expressing macrophages in <d>I<d>PF</d></d>. Thus, targeting <g>FRbeta</g>-expressing macrophages may be a promising treatment of <d>I<d>PF</d></d>.
20550546|a|It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>I<d>PF</d></d> by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed <g>folate receptor beta</g> <g>FRbeta</g> while resident macrophages in normal tissues expressed no or low levels of <g>FRbeta</g>. In the present study, we examined the distribution of <g>FRbeta</g>-expressing macrophages in the lungs of patients with usual <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>UIP</d> and mice with bleomycin-induced <d>pulmonary <d>fibrosis</d></d> <d>PF</d> and tested whether the depletion of <g>FRbeta</g>-expressing macrophages could suppress bleomycin-induced <d>PF</d> in mice. Immunostaining with anti-human or -mouse <g>FRbeta</g> monoclonal antibody mAb revealed that <g>FRbeta</g>-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with <d>UIP</d> and mice with bleomycin-induced <d>PF</d>. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse <g>FRbeta</g> mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and <d>fibrosis</d> in bleomycin-induced <d>PF</d>. In immunohistochemical analysis, decreased numbers of <d>tumour</d> necrosis factor-alpha-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of <g>FRbeta</g>-expressing macrophages in <d>I<d>PF</d></d>. Thus, targeting <g>FRbeta</g>-expressing macrophages may be a promising treatment of <d>I<d>PF</d></d>.
20550546|a|It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>I<d>PF</d></d> by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed <g>folate receptor beta</g> <g>FRbeta</g> while resident macrophages in normal tissues expressed no or low levels of <g>FRbeta</g>. In the present study, we examined the distribution of <g>FRbeta</g>-expressing macrophages in the lungs of patients with usual <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>UIP</d> and mice with bleomycin-induced <d>pulmonary <d>fibrosis</d></d> <d>PF</d> and tested whether the depletion of <g>FRbeta</g>-expressing macrophages could suppress bleomycin-induced <d>PF</d> in mice. Immunostaining with anti-human or -mouse <g>FRbeta</g> monoclonal antibody mAb revealed that <g>FRbeta</g>-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with <d>UIP</d> and mice with bleomycin-induced <d>PF</d>. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse <g>FRbeta</g> mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and <d>fibrosis</d> in bleomycin-induced <d>PF</d>. In immunohistochemical analysis, decreased numbers of <d>tumour</d> <d>necrosis</d> factor-alpha-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of <g>FRbeta</g>-expressing macrophages in <d>I<d>PF</d></d>. Thus, targeting <g>FRbeta</g>-expressing macrophages may be a promising treatment of <d>I<d>PF</d></d>.
20560295|a|BACKGROUND: N-acetylcysteine NAC can act as an antioxidant. NAC slows the rate of decline of lung function in <d>idiopathic pulmonary fibrosis</d> IPF patients concurrently treated with prednisone and azathioprine. OBJECTIVE: In this study we investigated the effect of NAC on the production of tumor necrosis factor <g>TNF-alpha</g>, interleukin IL-1beta, IL-6, IL-8, IL-10, IL-12 p70, IL-18, transforming growth factor <g>TGF-beta1</g>, and the soluble TNF receptors sTNFR1 and sTNFR2 by alveolar macrophages AM in IPF patients. DESIGN: AMs were harvested by bronchoalveolar lavage BAL from 16 IPF patients and were cultured for 24 h with RPMI medium alone, or with lipopolysaccharide LPS 100 ng/ml, in the presence or absence of NAC at various concentrations. RESULTS: NAC suppressed the production of <g>TNF-alpha</g>, its soluble receptors, and <g>TGF-beta1</g> by AMs in a dose-dependent manner. At the highest concentration of NAC 10 mM, the spontaneous or LPS-stimulated production of<g>TNF-alpha</g>, sTNFR1, sTNFR2, and <g>TGF-beta1</g> were significantly reduced. The LPS-stimulated IL-1beta production was also suppressed by 10 mM NAC. CONCLUSIONS: NAC has the potential to down-regulate the production of <g>TNF-alpha</g> and their soluble receptors, as well as <g>TGF-beta1</g> and LPS-stimulated IL-1beta, by AM in IPF in vitro. NAC may have anti-inflammatory and anti-fibrotic effects.
20560295|a|BACKGROUND: N-acetylcysteine NAC can act as an antioxidant. NAC slows the rate of decline of lung function in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> patients concurrently treated with prednisone and azathioprine. OBJECTIVE: In this study we investigated the effect of NAC on the production of tumor necrosis factor <g>TNF-alpha</g>, interleukin IL-1beta, IL-6, IL-8, IL-10, IL-12 p70, IL-18, transforming growth factor <g>TGF-beta1</g>, and the soluble TNF receptors sTNFR1 and sTNFR2 by alveolar macrophages AM in <d>IPF</d> patients. DESIGN: AMs were harvested by bronchoalveolar lavage BAL from 16 <d>IPF</d> patients and were cultured for 24 h with RPMI medium alone, or with lipopolysaccharide LPS 100 ng/ml, in the presence or absence of NAC at various concentrations. RESULTS: NAC suppressed the production of <g>TNF-alpha</g>, its soluble receptors, and <g>TGF-beta1</g> by AMs in a dose-dependent manner. At the highest concentration of NAC 10 mM, the spontaneous or LPS-stimulated production of<g>TNF-alpha</g>, sTNFR1, sTNFR2, and <g>TGF-beta1</g> were significantly reduced. The LPS-stimulated IL-1beta production was also suppressed by 10 mM NAC. CONCLUSIONS: NAC has the potential to down-regulate the production of <g>TNF-alpha</g> and their soluble receptors, as well as <g>TGF-beta1</g> and LPS-stimulated IL-1beta, by AM in <d>IPF</d> in vitro. NAC may have anti-inflammatory and anti-fibrotic effects.
20566741|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a chronic progressive lung disorder of unknown etiology. Several studies have demonstrated an association between pulmonary infection with a herpesvirus and IPF. Based on those observations, we have developed a mouse model in which interferon IFNgammaR-/- mice infected intranasally with murine gammaherpesvirus 68 MHV68 develop lung fibrosis. We hypothesize that viral load was a critical factor for the development of fibrosis. Because nuclear factor NF-kappaB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNgammaR-/- mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-kappaB signaling pathway, called IkappaBalphaM. Striking differences were observed at the onset of the chronic infection, which correlated with a decreased virus load in mice infected with MHV68-IkappaBalphaM compared with mice infected with control MHV68 MHV68-MR. IFNgammaR-/- mice infected with MHV68-IkappaBalphaM lacked vasculitis and fibrosis 15 to 120 days post infection. Inhibition of NF-kappaB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 MCP-1 and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin alphavbeta6, which is implicated in the activation of the profibrotic factor TGF-beta. Thus, the inhibition of NF-kappaB signaling in the infected lung cells of IFNgammaR-/- mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated <d>pulmonary fibrosis</d>.
20566741|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive lung disorder of unknown etiology. Several studies have demonstrated an association between pulmonary infection with a herpesvirus and <d>IPF</d>. Based on those observations, we have developed a mouse model in which interferon IFNgammaR-/- mice infected intranasally with murine gammaherpesvirus 68 MHV68 develop lung fibrosis. We hypothesize that viral load was a critical factor for the development of fibrosis. Because nuclear factor NF-kappaB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNgammaR-/- mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-kappaB signaling pathway, called IkappaBalphaM. Striking differences were observed at the onset of the chronic infection, which correlated with a decreased virus load in mice infected with MHV68-IkappaBalphaM compared with mice infected with control MHV68 MHV68-MR. IFNgammaR-/- mice infected with MHV68-IkappaBalphaM lacked vasculitis and fibrosis 15 to 120 days post infection. Inhibition of NF-kappaB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 MCP-1 and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin alphavbeta6, which is implicated in the activation of the profibrotic factor TGF-beta. Thus, the inhibition of NF-kappaB signaling in the infected lung cells of IFNgammaR-/- mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated <d>pulmonary fibrosis</d>.
20566741|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic progressive lung disorder</d> of unknown etiology. Several studies have demonstrated an association between pulmonary infection with a herpesvirus and <d>IPF</d>. Based on those observations, we have developed a mouse model in which interferon IFNgammaR-/- mice infected intranasally with murine gammaherpesvirus 68 MHV68 develop lung fibrosis. We hypothesize that viral load was a critical factor for the development of fibrosis. Because nuclear factor NF-kappaB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNgammaR-/- mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-kappaB signaling pathway, called IkappaBalphaM. Striking differences were observed at the onset of the chronic infection, which correlated with a decreased virus load in mice infected with MHV68-IkappaBalphaM compared with mice infected with control MHV68 MHV68-MR. IFNgammaR-/- mice infected with MHV68-IkappaBalphaM lacked vasculitis and fibrosis 15 to 120 days post infection. Inhibition of NF-kappaB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 MCP-1 and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin alphavbeta6, which is implicated in the activation of the profibrotic factor TGF-beta. Thus, the inhibition of NF-kappaB signaling in the infected lung cells of IFNgammaR-/- mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated <d>pulmonary fibrosis</d>.
20566741|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic progressive lung disorder</d> of unknown etiology. Several studies have demonstrated an association between <d>pulmonary infection</d> with a herpesvirus and <d>IPF</d>. Based on those observations, we have developed a mouse model in which interferon IFNgammaR-/- mice infected intranasally with murine gammaherpesvirus 68 MHV68 develop lung fibrosis. We hypothesize that viral load was a critical factor for the development of fibrosis. Because nuclear factor NF-kappaB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNgammaR-/- mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-kappaB signaling pathway, called IkappaBalphaM. Striking differences were observed at the onset of the chronic infection, which correlated with a decreased virus load in mice infected with MHV68-IkappaBalphaM compared with mice infected with control MHV68 MHV68-MR. IFNgammaR-/- mice infected with MHV68-IkappaBalphaM lacked vasculitis and fibrosis 15 to 120 days post infection. Inhibition of NF-kappaB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 MCP-1 and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin alphavbeta6, which is implicated in the activation of the profibrotic factor TGF-beta. Thus, the inhibition of NF-kappaB signaling in the infected lung cells of IFNgammaR-/- mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated <d>pulmonary fibrosis</d>.
20566741|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>chronic progressive lung disorder</d> of unknown etiology. Several studies have demonstrated an association between <d>pulmonary infection</d> with a herpesvirus and <d>IPF</d>. Based on those observations, we have developed a mouse model in which interferon IFNgammaR-/- mice infected intranasally with murine gammaherpesvirus 68 MHV68 develop lung <d>fibrosis</d>. We hypothesize that viral load was a critical factor for the development of <d>fibrosis</d>. Because nuclear factor NF-kappaB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNgammaR-/- mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-kappaB signaling pathway, called IkappaBalphaM. Striking differences were observed at the onset of the chronic infection, which correlated with a decreased virus load in mice infected with MHV68-IkappaBalphaM compared with mice infected with control MHV68 MHV68-MR. IFNgammaR-/- mice infected with MHV68-IkappaBalphaM lacked vasculitis and <d>fibrosis</d> 15 to 120 days post infection. Inhibition of NF-kappaB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 MCP-1 and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin alphavbeta6, which is implicated in the activation of the profibrotic factor TGF-beta. Thus, the inhibition of NF-kappaB signaling in the infected lung cells of IFNgammaR-/- mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated <d>pulmonary <d>fibrosis</d></d>.
20566741|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>chronic progressive lung disorder</d> of unknown etiology. Several studies have demonstrated an association between <d>pulmonary infection</d> with a herpesvirus and <d>IPF</d>. Based on those observations, we have developed a mouse model in which interferon IFNgammaR-/- mice infected intranasally with murine gammaherpesvirus 68 MHV68 develop lung <d>fibrosis</d>. We hypothesize that viral load was a critical factor for the development of <d>fibrosis</d>. Because nuclear factor NF-kappaB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNgammaR-/- mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-kappaB signaling pathway, called IkappaBalphaM. Striking differences were observed at the onset of the <d>chronic infection</d>, which correlated with a decreased virus load in mice infected with MHV68-IkappaBalphaM compared with mice infected with control MHV68 MHV68-MR. IFNgammaR-/- mice infected with MHV68-IkappaBalphaM lacked vasculitis and <d>fibrosis</d> 15 to 120 days post infection. Inhibition of NF-kappaB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 MCP-1 and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin alphavbeta6, which is implicated in the activation of the profibrotic factor TGF-beta. Thus, the inhibition of NF-kappaB signaling in the infected lung cells of IFNgammaR-/- mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated <d>pulmonary <d>fibrosis</d></d>.
20566741|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>chronic progressive lung disorder</d> of unknown etiology. Several studies have demonstrated an association between <d>pulmonary infection</d> with a herpesvirus and <d>IPF</d>. Based on those observations, we have developed a mouse model in which interferon IFNgammaR-/- mice infected intranasally with murine gammaherpesvirus 68 MHV68 develop lung <d>fibrosis</d>. We hypothesize that viral load was a critical factor for the development of <d>fibrosis</d>. Because nuclear factor NF-kappaB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNgammaR-/- mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-kappaB signaling pathway, called IkappaBalphaM. Striking differences were observed at the onset of the <d>chronic infection</d>, which correlated with a decreased virus load in mice infected with MHV68-IkappaBalphaM compared with mice infected with control MHV68 MHV68-MR. IFNgammaR-/- mice infected with MHV68-IkappaBalphaM lacked <d>vasculitis</d> and <d>fibrosis</d> 15 to 120 days post infection. Inhibition of NF-kappaB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 MCP-1 and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin alphavbeta6, which is implicated in the activation of the profibrotic factor TGF-beta. Thus, the inhibition of NF-kappaB signaling in the infected lung cells of IFNgammaR-/- mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated <d>pulmonary <d>fibrosis</d></d>.
20566741|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>chronic progressive lung disorder</d> of unknown etiology. Several studies have demonstrated an association between <d>pulmonary <d>infection</d></d> with a herpesvirus and <d>IPF</d>. Based on those observations, we have developed a mouse model in which interferon IFNgammaR-/- mice infected intranasally with murine gammaherpesvirus 68 MHV68 develop lung <d>fibrosis</d>. We hypothesize that viral load was a critical factor for the development of <d>fibrosis</d>. Because nuclear factor NF-kappaB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNgammaR-/- mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-kappaB signaling pathway, called IkappaBalphaM. Striking differences were observed at the onset of the <d>chronic <d>infection</d></d>, which correlated with a decreased virus load in mice infected with MHV68-IkappaBalphaM compared with mice infected with control MHV68 MHV68-MR. IFNgammaR-/- mice infected with MHV68-IkappaBalphaM lacked <d>vasculitis</d> and <d>fibrosis</d> 15 to 120 days post <d>infection</d>. Inhibition of NF-kappaB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 MCP-1 and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin alphavbeta6, which is implicated in the activation of the profibrotic factor TGF-beta. Thus, the inhibition of NF-kappaB signaling in the infected lung cells of IFNgammaR-/- mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated <d>pulmonary <d>fibrosis</d></d>.
20643828|a|Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary <d>fibrosis</d> IPF, a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in fibrotic lung diseases is unclear. In this study, we found up-regulation of <g>miR-21</g> in the lungs of mice with bleomycin-induced <d>fibrosis</d> and also in the lungs of patients with IPF. Increased <g>miR-21</g> expression was primarily localized to myofibroblasts. Administration of <g>miR-21</g> antisense probes diminished the severity of experimental lung <d>fibrosis</d> in mice, even when treatment was started 5-7 d after initiation of pulmonary injury. TGF-beta1, a central pathological mediator of fibrotic diseases, enhanced <g>miR-21</g> expression in primary pulmonary fibroblasts. Increasing <g>miR-21</g> levels promoted, whereas knocking down <g>miR-21</g> attenuated, the pro-fibrogenic activity of TGF-beta1 in fibroblasts. A potential mechanism for the role of <g>miR-21</g> in <d>fibrosis</d> is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for <g>miR-21</g> in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory fibrotic diseases, such as IPF.
20643828|a|Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to <d>fibrotic diseases</d>, such as idiopathic pulmonary <d>fibrosis</d> IPF, a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in fibrotic lung diseases is unclear. In this study, we found up-regulation of <g>miR-21</g> in the lungs of mice with bleomycin-induced <d>fibrosis</d> and also in the lungs of patients with IPF. Increased <g>miR-21</g> expression was primarily localized to myofibroblasts. Administration of <g>miR-21</g> antisense probes diminished the severity of experimental lung <d>fibrosis</d> in mice, even when treatment was started 5-7 d after initiation of pulmonary injury. TGF-beta1, a central pathological mediator of <d>fibrotic diseases</d>, enhanced <g>miR-21</g> expression in primary pulmonary fibroblasts. Increasing <g>miR-21</g> levels promoted, whereas knocking down <g>miR-21</g> attenuated, the pro-fibrogenic activity of TGF-beta1 in fibroblasts. A potential mechanism for the role of <g>miR-21</g> in <d>fibrosis</d> is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for <g>miR-21</g> in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory <d>fibrotic diseases</d>, such as IPF.
20643828|a|Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to <d>fibrotic diseases</d>, such as idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in fibrotic lung diseases is unclear. In this study, we found up-regulation of <g>miR-21</g> in the lungs of mice with bleomycin-induced <d>fibrosis</d> and also in the lungs of patients with <d>IPF</d>. Increased <g>miR-21</g> expression was primarily localized to myofibroblasts. Administration of <g>miR-21</g> antisense probes diminished the severity of experimental lung <d>fibrosis</d> in mice, even when treatment was started 5-7 d after initiation of pulmonary injury. TGF-beta1, a central pathological mediator of <d>fibrotic diseases</d>, enhanced <g>miR-21</g> expression in primary pulmonary fibroblasts. Increasing <g>miR-21</g> levels promoted, whereas knocking down <g>miR-21</g> attenuated, the pro-fibrogenic activity of TGF-beta1 in fibroblasts. A potential mechanism for the role of <g>miR-21</g> in <d>fibrosis</d> is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for <g>miR-21</g> in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory <d>fibrotic diseases</d>, such as <d>IPF</d>.
20643828|a|Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to <d>fibrotic diseases</d>, such as idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in <d>fibrotic lung diseases</d> is unclear. In this study, we found up-regulation of <g>miR-21</g> in the lungs of mice with bleomycin-induced <d>fibrosis</d> and also in the lungs of patients with <d>IPF</d>. Increased <g>miR-21</g> expression was primarily localized to myofibroblasts. Administration of <g>miR-21</g> antisense probes diminished the severity of experimental lung <d>fibrosis</d> in mice, even when treatment was started 5-7 d after initiation of pulmonary injury. TGF-beta1, a central pathological mediator of <d>fibrotic diseases</d>, enhanced <g>miR-21</g> expression in primary pulmonary fibroblasts. Increasing <g>miR-21</g> levels promoted, whereas knocking down <g>miR-21</g> attenuated, the pro-fibrogenic activity of TGF-beta1 in fibroblasts. A potential mechanism for the role of <g>miR-21</g> in <d>fibrosis</d> is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for <g>miR-21</g> in <d>fibrotic lung diseases</d> and also suggest a novel approach using miRNA therapeutics in treating clinically refractory <d>fibrotic diseases</d>, such as <d>IPF</d>.
20643828|a|Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to <d>fibrotic diseases</d>, such as idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in <d>fibrotic lung diseases</d> is unclear. In this study, we found up-regulation of <g>miR-21</g> in the lungs of mice with bleomycin-induced <d>fibrosis</d> and also in the lungs of patients with <d>IPF</d>. Increased <g>miR-21</g> expression was primarily localized to myofibroblasts. Administration of <g>miR-21</g> antisense probes diminished the severity of experimental lung <d>fibrosis</d> in mice, even when treatment was started 5-7 d after initiation of <d>pulmonary injury</d>. TGF-beta1, a central pathological mediator of <d>fibrotic diseases</d>, enhanced <g>miR-21</g> expression in primary pulmonary fibroblasts. Increasing <g>miR-21</g> levels promoted, whereas knocking down <g>miR-21</g> attenuated, the pro-fibrogenic activity of TGF-beta1 in fibroblasts. A potential mechanism for the role of <g>miR-21</g> in <d>fibrosis</d> is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for <g>miR-21</g> in <d>fibrotic lung diseases</d> and also suggest a novel approach using miRNA therapeutics in treating clinically refractory <d>fibrotic diseases</d>, such as <d>IPF</d>.
20671305|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin 5-hydroxytryptamine; 5-HT induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on lung fibrosis in vivo and in vitro. METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of 5-HTR1A/B and 5-HTR2B was significantly increased in the lungs of patients with IPF n=12 and in those with non-specific interstitial pneumonia NSIP, n=6 compared with transplant donors n=12. The expression of 5-HTR2A was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR2A/B inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR2A/B antagonist terguride or vehicle in a therapeutic approach days 14-28 after bleomycin. Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor b1- or WNT3a-induced collagen production. CONCLUSION: The studies revealed an increased expression of 5-HTR2A specifically in IPF. Blockade of 5-HTR2A/B signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.
20671305|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin 5-hydroxytryptamine; 5-HT induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in <d>IPF</d> remains unclear. A study was undertaken to determine the expression of 5-HT receptors in <d>IPF</d> and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on lung fibrosis in vivo and in vitro. METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of 5-HTR1A/B and 5-HTR2B was significantly increased in the lungs of patients with <d>IPF</d> n=12 and in those with non-specific interstitial pneumonia NSIP, n=6 compared with transplant donors n=12. The expression of 5-HTR2A was increased specifically in <d>IPF</d> lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR2A/B inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR2A/B antagonist terguride or vehicle in a therapeutic approach days 14-28 after bleomycin. Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor b1- or WNT3a-induced collagen production. CONCLUSION: The studies revealed an increased expression of 5-HTR2A specifically in <d>IPF</d>. Blockade of 5-HTR2A/B signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for <d>IPF</d>.
20671305|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin 5-hydroxytryptamine; 5-HT induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in <d>IPF</d> remains unclear. A study was undertaken to determine the expression of 5-HT receptors in <d>IPF</d> and <d>experimental lung fibrosis</d> and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on lung fibrosis in vivo and in vitro. METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of 5-HTR1A/B and 5-HTR2B was significantly increased in the lungs of patients with <d>IPF</d> n=12 and in those with non-specific interstitial pneumonia NSIP, n=6 compared with transplant donors n=12. The expression of 5-HTR2A was increased specifically in <d>IPF</d> lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR2A/B inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR2A/B antagonist terguride or vehicle in a therapeutic approach days 14-28 after bleomycin. Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor b1- or WNT3a-induced collagen production. CONCLUSION: The studies revealed an increased expression of 5-HTR2A specifically in <d>IPF</d>. Blockade of 5-HTR2A/B signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for <d>IPF</d>.
20671305|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin 5-hydroxytryptamine; 5-HT induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in <d>IPF</d> remains unclear. A study was undertaken to determine the expression of 5-HT receptors in <d>IPF</d> and <d>experimental <d>lung fibrosis</d></d> and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on <d>lung fibrosis</d> in vivo and in vitro. METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of 5-HTR1A/B and 5-HTR2B was significantly increased in the lungs of patients with <d>IPF</d> n=12 and in those with non-specific interstitial pneumonia NSIP, n=6 compared with transplant donors n=12. The expression of 5-HTR2A was increased specifically in <d>IPF</d> lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR2A/B inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced <d>lung fibrosis</d> and treated with the 5-HTR2A/B antagonist terguride or vehicle in a therapeutic approach days 14-28 after bleomycin. Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor b1- or WNT3a-induced collagen production. CONCLUSION: The studies revealed an increased expression of 5-HTR2A specifically in <d>IPF</d>. Blockade of 5-HTR2A/B signalling by terguride reversed <d>lung fibrosis</d> and is thus a promising therapeutic approach for <d>IPF</d>.
20671305|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin 5-hydroxytryptamine; 5-HT induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in <d>IPF</d> remains unclear. A study was undertaken to determine the expression of 5-HT receptors in <d>IPF</d> and <d>experimental <d>lung fibrosis</d></d> and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on <d>lung fibrosis</d> in vivo and in vitro. METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of <g>5-HTR1A/B and 5-HTR2B</g> was significantly increased in the lungs of patients with <d>IPF</d> n=12 and in those with <d>non-specific interstitial pneumonia</d> NSIP, n=6 compared with transplant donors n=12. The expression of 5-HTR2A was increased specifically in <d>IPF</d> lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR2A/B inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced <d>lung fibrosis</d> and treated with the 5-HTR2A/B antagonist terguride or vehicle in a therapeutic approach days 14-28 after bleomycin. Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor b1- or WNT3a-induced collagen production. CONCLUSION: The studies revealed an increased expression of 5-HTR2A specifically in <d>IPF</d>. Blockade of 5-HTR2A/B signalling by terguride reversed <d>lung fibrosis</d> and is thus a promising therapeutic approach for <d>IPF</d>.
20671305|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin 5-hydroxytryptamine; 5-HT induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in <d>IPF</d> remains unclear. A study was undertaken to determine the expression of 5-HT receptors in <d>IPF</d> and <d>experimental <d>lung fibrosis</d></d> and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on <d>lung fibrosis</d> in vivo and in vitro. METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of <g>5-HTR1A/B and 5-HTR2B</g> was significantly increased in the lungs of patients with <d>IPF</d> n=12 and in those with <d>non-specific interstitial pneumonia</d> <d>NSIP</d>, n=6 compared with transplant donors n=12. The expression of 5-HTR2A was increased specifically in <d>IPF</d> lungs but not in <d>NSIP</d> lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR2A/B inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced <d>lung fibrosis</d> and treated with the 5-HTR2A/B antagonist terguride or vehicle in a therapeutic approach days 14-28 after bleomycin. Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor b1- or WNT3a-induced collagen production. CONCLUSION: The studies revealed an increased expression of 5-HTR2A specifically in <d>IPF</d>. Blockade of 5-HTR2A/B signalling by terguride reversed <d>lung fibrosis</d> and is thus a promising therapeutic approach for <d>IPF</d>.
20676040|a|Pulmonary fibrosis complicates a number of disease processes and leads to substantial morbidity and mortality. Idiopathic <d>pulmonary fibrosis</d> IPF is perhaps the most pernicious and enigmatic form of the greater problem of lung fibrogenesis with a median survival of three years from diagnosis in affected patients. In this review, we will focus on the pathology of IPF as a model of pulmonary fibrotic processes, review possible cellular mechanisms, review current treatment approaches and review two transgenic mouse models of lung fibrosis to provide insight into processes that cause lung fibrosis. We will also summarize the potential utility of signaling pathway inhibitors as a future treatment in <d>pulmonary fibrosis</d>. Finally, we will present data demonstrating a minimal contribution of epithelial-mesenchymal transition in the development of fibrotic lesions in the transforming growth factor-alpha transgenic model of lung fibrosis.
20676040|a|<d>Pulmonary fibrosis</d> complicates a number of disease processes and leads to substantial morbidity and mortality. Idiopathic <d>pulmonary fibrosis</d> IPF is perhaps the most pernicious and enigmatic form of the greater problem of lung fibrogenesis with a median survival of three years from diagnosis in affected patients. In this review, we will focus on the pathology of IPF as a model of pulmonary fibrotic processes, review possible cellular mechanisms, review current treatment approaches and review two transgenic mouse models of lung fibrosis to provide insight into processes that cause lung fibrosis. We will also summarize the potential utility of signaling pathway inhibitors as a future treatment in <d>pulmonary fibrosis</d>. Finally, we will present data demonstrating a minimal contribution of epithelial-mesenchymal transition in the development of fibrotic lesions in the transforming growth factor-alpha transgenic model of lung fibrosis.
20676040|a|<d>Pulmonary fibrosis</d> complicates a number of disease processes and leads to substantial morbidity and mortality. Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is perhaps the most pernicious and enigmatic form of the greater problem of lung fibrogenesis with a median survival of three years from diagnosis in affected patients. In this review, we will focus on the pathology of <d>IPF</d> as a model of pulmonary fibrotic processes, review possible cellular mechanisms, review current treatment approaches and review two transgenic mouse models of lung fibrosis to provide insight into processes that cause lung fibrosis. We will also summarize the potential utility of signaling pathway inhibitors as a future treatment in <d>pulmonary fibrosis</d>. Finally, we will present data demonstrating a minimal contribution of epithelial-mesenchymal transition in the development of fibrotic lesions in the transforming growth factor-alpha transgenic model of lung fibrosis.
20676040|a|<d>Pulmonary fibrosis</d> complicates a number of disease processes and leads to substantial morbidity and mortality. Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is perhaps the most pernicious and enigmatic form of the greater problem of lung fibrogenesis with a median survival of three years from diagnosis in affected patients. In this review, we will focus on the pathology of <d>IPF</d> as a model of pulmonary fibrotic processes, review possible cellular mechanisms, review current treatment approaches and review two transgenic mouse models of <d>lung fibrosis</d> to provide insight into processes that cause <d>lung fibrosis</d>. We will also summarize the potential utility of signaling pathway inhibitors as a future treatment in <d>pulmonary fibrosis</d>. Finally, we will present data demonstrating a minimal contribution of epithelial-mesenchymal transition in the development of fibrotic lesions in the transforming growth factor-alpha transgenic model of <d>lung fibrosis</d>.
20676040|a|<d>Pulmonary fibrosis</d> complicates a number of disease processes and leads to substantial morbidity and mortality. Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is perhaps the most pernicious and enigmatic form of the greater problem of lung fibrogenesis with a median survival of three years from diagnosis in affected patients. In this review, we will focus on the pathology of <d>IPF</d> as a model of pulmonary fibrotic processes, review possible cellular mechanisms, review current treatment approaches and review two transgenic mouse models of <d>lung fibrosis</d> to provide insight into processes that cause <d>lung fibrosis</d>. We will also summarize the potential utility of signaling pathway inhibitors as a future treatment in <d>pulmonary fibrosis</d>. Finally, we will present data demonstrating a minimal contribution of epithelial-mesenchymal transition in the development of <d>fibrotic lesions</d> in the transforming growth factor-alpha transgenic model of <d>lung fibrosis</d>.
20685750|a|BACKGROUND: Persistence of myofibroblasts is believed to contribute to the development of fibrosis in <d>idiopathic pulmonary fibrosis</d> IPF. Transforming growth factor beta1 TGFbeta1 irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin alpha-SMA and produce extracellular matrix proteins, such as procollagen I alpha1. Reactive oxygen species produced by NADPH oxidases NOXs have been shown to regulate cell differentiation. It was hypothesised that NOX could be expressed in parenchymal pulmonary fibroblasts and could mediate TGFbeta1-stimulated conversion of fibroblasts into myofibroblasts. METHODS: Fibroblasts were cultured from the lung of nine controls and eight patients with IPF. <g>NOX4</g>, alpha-SMA and procollagen I alpha1 mRNA and protein expression, reactive oxygen species production and Smad2/3 phosphorylation were quantified, in the absence and in the presence of incubation with TGFbeta1. Migration of platelet-derived growth factor PDGF-induced fibroblasts was also assessed. RESULTS: It was found that 1 <g>NOX4</g> mRNA and protein expression was upregulated in pulmonary fibroblasts from patients with IPF and correlated with mRNA expression of alpha-SMA and procollagen I alpha1 mRNA; 2 TGFbeta1 upregulated <g>NOX4</g>, alpha-SMA and procollagen I alpha1 expression in control and IPF fibroblasts; 3 the change in alpha-SMA and procollagen I alpha1 expression in response to TGFbeta1 was inhibited by antioxidants and by a <g>NOX4</g> small interfering RNA siRNA; 4 <g>NOX4</g> modulated alpha-SMA and procollagen I alpha1 expression by controlling activation of Smad2/3; and 5 <g>NOX4</g> modulated PDGF-induced fibroblast migration. CONCLUSION: <g>NOX4</g> is critical for modulation of the pulmonary myofibroblast phenotype in IPF, probably by modulating the response to TGFbeta1 and PDGF.
20685750|a|BACKGROUND: Persistence of myofibroblasts is believed to contribute to the development of <d>fibrosis</d> in <d>idiopathic pulmonary <d>fibrosis</d></d> IPF. Transforming growth factor beta1 <g>TGFbeta1</g> irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin alpha-SMA and produce extracellular matrix proteins, such as procollagen I alpha1. Reactive oxygen species produced by NADPH oxidases NOXs have been shown to regulate cell differentiation. It was hypothesised that NOX could be expressed in parenchymal pulmonary fibroblasts and could mediate <g>TGFbeta1</g>-stimulated conversion of fibroblasts into myofibroblasts. METHODS: Fibroblasts were cultured from the lung of nine controls and eight patients with IPF. <g>NOX4</g>, alpha-SMA and procollagen I alpha1 mRNA and protein expression, reactive oxygen species production and Smad2/3 phosphorylation were quantified, in the absence and in the presence of incubation with <g>TGFbeta1</g>. Migration of platelet-derived growth factor PDGF-induced fibroblasts was also assessed. RESULTS: It was found that 1 <g>NOX4</g> mRNA and protein expression was upregulated in pulmonary fibroblasts from patients with IPF and correlated with mRNA expression of alpha-SMA and procollagen I alpha1 mRNA; 2 <g>TGFbeta1</g> upregulated <g>NOX4</g>, alpha-SMA and procollagen I alpha1 expression in control and IPF fibroblasts; 3 the change in alpha-SMA and procollagen I alpha1 expression in response to <g>TGFbeta1</g> was inhibited by antioxidants and by a <g>NOX4</g> small interfering RNA siRNA; 4 <g>NOX4</g> modulated alpha-SMA and procollagen I alpha1 expression by controlling activation of Smad2/3; and 5 <g>NOX4</g> modulated PDGF-induced fibroblast migration. CONCLUSION: <g>NOX4</g> is critical for modulation of the pulmonary myofibroblast phenotype in IPF, probably by modulating the response to <g>TGFbeta1</g> and PDGF.
20685750|a|BACKGROUND: Persistence of myofibroblasts is believed to contribute to the development of <d>fibrosis</d> in <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. Transforming growth factor beta1 <g>TGFbeta1</g> irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin alpha-SMA and produce extracellular matrix proteins, such as procollagen I alpha1. Reactive oxygen species produced by NADPH oxidases NOXs have been shown to regulate cell differentiation. It was hypothesised that NOX could be expressed in parenchymal pulmonary fibroblasts and could mediate <g>TGFbeta1</g>-stimulated conversion of fibroblasts into myofibroblasts. METHODS: Fibroblasts were cultured from the lung of nine controls and eight patients with <d>IPF</d>. <g>NOX4</g>, alpha-SMA and procollagen I alpha1 mRNA and protein expression, reactive oxygen species production and Smad2/3 phosphorylation were quantified, in the absence and in the presence of incubation with <g>TGFbeta1</g>. Migration of platelet-derived growth factor PDGF-induced fibroblasts was also assessed. RESULTS: It was found that 1 <g>NOX4</g> mRNA and protein expression was upregulated in pulmonary fibroblasts from patients with <d>IPF</d> and correlated with mRNA expression of alpha-SMA and procollagen I alpha1 mRNA; 2 <g>TGFbeta1</g> upregulated <g>NOX4</g>, alpha-SMA and procollagen I alpha1 expression in control and <d>IPF</d> fibroblasts; 3 the change in alpha-SMA and procollagen I alpha1 expression in response to <g>TGFbeta1</g> was inhibited by antioxidants and by a <g>NOX4</g> small interfering RNA siRNA; 4 <g>NOX4</g> modulated alpha-SMA and procollagen I alpha1 expression by controlling activation of Smad2/3; and 5 <g>NOX4</g> modulated PDGF-induced fibroblast migration. CONCLUSION: <g>NOX4</g> is critical for modulation of the pulmonary myofibroblast phenotype in <d>IPF</d>, probably by modulating the response to <g>TGFbeta1</g> and PDGF.
20685750|a|BACKGROUND: Persistence of myofibroblasts is believed to contribute to the development of <d>fibrosis</d> in <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. <g>Transforming growth factor beta1</g> <g>TGFbeta1</g> irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin alpha-SMA and produce extracellular matrix proteins, such as procollagen I alpha1. Reactive oxygen species produced by NADPH oxidases NOXs have been shown to regulate cell differentiation. It was hypothesised that NOX could be expressed in parenchymal pulmonary fibroblasts and could mediate <g>TGFbeta1</g>-stimulated conversion of fibroblasts into myofibroblasts. METHODS: Fibroblasts were cultured from the lung of nine controls and eight patients with <d>IPF</d>. <g>NOX4</g>, alpha-SMA and procollagen I alpha1 mRNA and protein expression, reactive oxygen species production and <g>Smad2/3</g> phosphorylation were quantified, in the absence and in the presence of incubation with <g>TGFbeta1</g>. Migration of platelet-derived growth factor PDGF-induced fibroblasts was also assessed. RESULTS: It was found that 1 <g>NOX4</g> mRNA and protein expression was upregulated in pulmonary fibroblasts from patients with <d>IPF</d> and correlated with mRNA expression of alpha-SMA and procollagen I alpha1 mRNA; 2 <g>TGFbeta1</g> upregulated <g>NOX4</g>, alpha-SMA and procollagen I alpha1 expression in control and <d>IPF</d> fibroblasts; 3 the change in alpha-SMA and procollagen I alpha1 expression in response to <g>TGFbeta1</g> was inhibited by antioxidants and by a <g>NOX4</g> small interfering RNA siRNA; 4 <g>NOX4</g> modulated alpha-SMA and procollagen I alpha1 expression by controlling activation of <g>Smad2/3</g>; and 5 <g>NOX4</g> modulated PDGF-induced fibroblast migration. CONCLUSION: <g>NOX4</g> is critical for modulation of the <d>pulmonary myofibroblast</d> phenotype in <d>IPF</d>, probably by modulating the response to <g>TGFbeta1</g> and PDGF.
20693406|a|The histopathology of <d>idiopathic pulmonary fibrosis</d> IPF includes the presence of myofibroblasts within so-called fibroblastic foci, and studies suggest that lung myofibroblasts may be derived from epithelial cells through epithelial--mesenchymal transition EMT. Transforming growth factor TGF-b1 is expressed and/or activated in fibrogenesis, and induces EMT in lung epithelial cells in a dose-dependent manner. A higher occurrence of Epstein-Barr virus EBV has been reported in the lung tissue of patients with IPF. EBV expresses latent membrane protein LMP 1 during the latent phase of infection, and may play a role in the pathogenesis of pulmonary fibrosis inasmuch as LMP-1 may act as a constitutively active TNF-a receptor. Our data show a remarkable increase in mesenchymal cell markers, along with a concurrent reduction in the expression of epithelial cell markers in lung epithelial cells cotreated with LMP-1, and very low doses of TGF-b1. This effect was mirrored in lung epithelial cells infected with EBV expressing LMP1 and cotreated with TGF-b1. LMP1 pro-EMT signaling was identified, and occurs primarily through the nuclear factor-kB pathway and secondarily through the extracellular signal--regulated kinase ERK pathway. Activation of the ERK pathway was shown to be critical for aspects of TGF-b1-induced EMT. LMP1 accentuates the TGF-b1 activation of ERK. Together, these data demonstrate that the presence of EBV-LMP1 in lung epithelial cells synergizes with TGF-b1 to induce EMT. Our in vitro data may help to explain the observation that patients with IPF demonstrating positive staining for LMP1 in lung epithelial cells have a more rapid demise than patients in whom LMP1 is not detected.
20693406|a|The histopathology of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> includes the presence of myofibroblasts within so-called fibroblastic foci, and studies suggest that lung myofibroblasts may be derived from epithelial cells through epithelial--mesenchymal transition EMT. Transforming growth factor TGF-b1 is expressed and/or activated in fibrogenesis, and induces EMT in lung epithelial cells in a dose-dependent manner. A higher occurrence of Epstein-Barr virus EBV has been reported in the lung tissue of patients with <d>IPF</d>. EBV expresses latent membrane protein LMP 1 during the latent phase of infection, and may play a role in the pathogenesis of pulmonary fibrosis inasmuch as LMP-1 may act as a constitutively active TNF-a receptor. Our data show a remarkable increase in mesenchymal cell markers, along with a concurrent reduction in the expression of epithelial cell markers in lung epithelial cells cotreated with LMP-1, and very low doses of TGF-b1. This effect was mirrored in lung epithelial cells infected with EBV expressing LMP1 and cotreated with TGF-b1. LMP1 pro-EMT signaling was identified, and occurs primarily through the nuclear factor-kB pathway and secondarily through the extracellular signal--regulated kinase ERK pathway. Activation of the ERK pathway was shown to be critical for aspects of TGF-b1-induced EMT. LMP1 accentuates the TGF-b1 activation of ERK. Together, these data demonstrate that the presence of EBV-LMP1 in lung epithelial cells synergizes with TGF-b1 to induce EMT. Our in vitro data may help to explain the observation that patients with <d>IPF</d> demonstrating positive staining for LMP1 in lung epithelial cells have a more rapid demise than patients in whom LMP1 is not detected.
20693406|a|The histopathology of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> includes the presence of myofibroblasts within so-called fibroblastic foci, and studies suggest that lung myofibroblasts may be derived from epithelial cells through epithelial--mesenchymal transition EMT. <g>Transforming growth factor TGF-b1</g> is expressed and/or activated in fibrogenesis, and induces EMT in lung epithelial cells in a dose-dependent manner. A higher occurrence of Epstein-Barr virus <d>EBV</d> has been reported in the lung tissue of patients with <d>IPF</d>. <d>EBV</d> expresses latent membrane protein LMP 1 during the latent phase of infection, and may play a role in the pathogenesis of pulmonary fibrosis inasmuch as LMP-1 may act as a constitutively active TNF-a receptor. Our data show a remarkable increase in mesenchymal cell markers, along with a concurrent reduction in the expression of epithelial cell markers in lung epithelial cells cotreated with LMP-1, and very low doses of TGF-b1. This effect was mirrored in lung epithelial cells infected with <d>EBV</d> expressing LMP1 and cotreated with TGF-b1. LMP1 pro-EMT signaling was identified, and occurs primarily through the nuclear factor-kB pathway and secondarily through the extracellular signal--regulated kinase ERK pathway. Activation of the ERK pathway was shown to be critical for aspects of TGF-b1-induced EMT. LMP1 accentuates the TGF-b1 activation of ERK. Together, these data demonstrate that the presence of <d>EBV</d>-LMP1 in lung epithelial cells synergizes with TGF-b1 to induce EMT. Our in vitro data may help to explain the observation that patients with <d>IPF</d> demonstrating positive staining for LMP1 in lung epithelial cells have a more rapid demise than patients in whom LMP1 is not detected.
20693406|a|The histopathology of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> includes the presence of myofibroblasts within so-called fibroblastic foci, and studies suggest that lung myofibroblasts may be derived from epithelial cells through epithelial--mesenchymal transition EMT. <g>Transforming growth factor TGF-b1</g> is expressed and/or activated in fibrogenesis, and induces EMT in lung epithelial cells in a dose-dependent manner. A higher occurrence of Epstein-Barr virus <d>EBV</d> has been reported in the lung tissue of patients with <d>IPF</d>. <d>EBV</d> expresses <g>latent membrane protein LMP 1</g> during the latent phase of infection, and may play a role in the pathogenesis of <d>pulmonary fibrosis</d> inasmuch as LMP-1 may act as a constitutively active TNF-a receptor. Our data show a remarkable increase in mesenchymal cell markers, along with a concurrent reduction in the expression of epithelial cell markers in lung epithelial cells cotreated with LMP-1, and very low doses of TGF-b1. This effect was mirrored in lung epithelial cells infected with <d>EBV</d> expressing LMP1 and cotreated with TGF-b1. LMP1 pro-EMT signaling was identified, and occurs primarily through the nuclear factor-kB pathway and secondarily through the extracellular signal--regulated kinase ERK pathway. Activation of the ERK pathway was shown to be critical for aspects of TGF-b1-induced EMT. LMP1 accentuates the TGF-b1 activation of ERK. Together, these data demonstrate that the presence of <d>EBV</d>-LMP1 in lung epithelial cells synergizes with TGF-b1 to induce EMT. Our in vitro data may help to explain the observation that patients with <d>IPF</d> demonstrating positive staining for LMP1 in lung epithelial cells have a more rapid demise than patients in whom LMP1 is not detected.
20715983|a|alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of <d>lung diseases</d>, including idiopathic pulmonary fibrosis IPF, cystic fibrosis CF, and diffuse panbronchiolitis DPB. In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in IPF and around the airways in CF and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to IPF, CF, and DPB. alpha-Defensins are known to induce interleukin IL-8 in airway epithelial cells, but the effects of alpha-defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide HNP-1 a subtype of alpha-defensin on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of IPF, CF, and DPB according to the location in the lung where the alpha-defensins are mainly produced.
20715983|a|alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of <d>lung diseases</d>, including <d>idiopathic pulmonary fibrosis</d> IPF, cystic fibrosis CF, and diffuse panbronchiolitis DPB. In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in IPF and around the airways in CF and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to IPF, CF, and DPB. alpha-Defensins are known to induce interleukin IL-8 in airway epithelial cells, but the effects of alpha-defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide HNP-1 a subtype of alpha-defensin on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of IPF, CF, and DPB according to the location in the lung where the alpha-defensins are mainly produced.
20715983|a|alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of <d>lung diseases</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, cystic fibrosis CF, and diffuse panbronchiolitis DPB. In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in <d>IPF</d> and around the airways in CF and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to <d>IPF</d>, CF, and DPB. alpha-Defensins are known to induce interleukin IL-8 in airway epithelial cells, but the effects of alpha-defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide HNP-1 a subtype of alpha-defensin on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of <d>IPF</d>, CF, and DPB according to the location in the lung where the alpha-defensins are mainly produced.
20715983|a|alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of <d>lung diseases</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>cystic fibrosis</d> CF, and diffuse panbronchiolitis DPB. In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in <d>IPF</d> and around the airways in CF and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to <d>IPF</d>, CF, and DPB. alpha-Defensins are known to induce interleukin IL-8 in airway epithelial cells, but the effects of alpha-defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide HNP-1 a subtype of alpha-defensin on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of <d>IPF</d>, CF, and DPB according to the location in the lung where the alpha-defensins are mainly produced.
20715983|a|alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of <d>lung diseases</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>cystic fibrosis</d> <d>CF</d>, and diffuse panbronchiolitis DPB. In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in <d>IPF</d> and around the airways in <d>CF</d> and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to <d>IPF</d>, <d>CF</d>, and DPB. alpha-Defensins are known to induce interleukin IL-8 in airway epithelial cells, but the effects of alpha-defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide HNP-1 a subtype of alpha-defensin on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of <d>IPF</d>, <d>CF</d>, and DPB according to the location in the lung where the alpha-defensins are mainly produced.
20715983|a|alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of <d>lung diseases</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>cystic fibrosis</d> <d>CF</d>, and <d>diffuse panbronchiolitis</d> DPB. In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in <d>IPF</d> and around the airways in <d>CF</d> and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to <d>IPF</d>, <d>CF</d>, and DPB. alpha-Defensins are known to induce interleukin IL-8 in airway epithelial cells, but the effects of alpha-defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide HNP-1 a subtype of alpha-defensin on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of <d>IPF</d>, <d>CF</d>, and DPB according to the location in the lung where the alpha-defensins are mainly produced.
20952439|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive fibrotic lung disease with an appalling prognosis. The failure of anti-inflammatory therapies coupled with the observation that deranged epithelium overlies proliferative myofibroblasts to form the fibroblastic focus has lead to the emerging concept that IPF is a disease of deregulated epithelial-mesenchymal crosstalk. IPF is triggered by an as yet unidentified alveolar injury that leads to activation of transforming growth factor-b TGF-b and alveolar basement membrane disruption. In the presence of persisting injurious pathways, or disrupted repair pathways, activated TGF-b can lead to enhanced epithelial apoptosis and epithelial-to-mesenchymal transition EMT as well as fibroblast, and fibrocyte, transformation into myofibroblasts which are resistant to apoptosis. The resulting deposition of excess disrupted matrix by these myofibroblasts leads to the development of IPF.
20952439|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive fibrotic lung disease with an appalling prognosis. The failure of anti-inflammatory therapies coupled with the observation that deranged epithelium overlies proliferative myofibroblasts to form the fibroblastic focus has lead to the emerging concept that <d>IPF</d> is a disease of deregulated epithelial-mesenchymal crosstalk. <d>IPF</d> is triggered by an as yet unidentified alveolar injury that leads to activation of transforming growth factor-b TGF-b and alveolar basement membrane disruption. In the presence of persisting injurious pathways, or disrupted repair pathways, activated TGF-b can lead to enhanced epithelial apoptosis and epithelial-to-mesenchymal transition EMT as well as fibroblast, and fibrocyte, transformation into myofibroblasts which are resistant to apoptosis. The resulting deposition of excess disrupted matrix by these myofibroblasts leads to the development of <d>IPF</d>.
20952439|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> with an appalling prognosis. The failure of anti-inflammatory therapies coupled with the observation that deranged epithelium overlies proliferative myofibroblasts to form the fibroblastic focus has lead to the emerging concept that <d>IPF</d> is a disease of deregulated epithelial-mesenchymal crosstalk. <d>IPF</d> is triggered by an as yet unidentified alveolar injury that leads to activation of transforming growth factor-b TGF-b and alveolar basement membrane disruption. In the presence of persisting injurious pathways, or disrupted repair pathways, activated TGF-b can lead to enhanced epithelial apoptosis and epithelial-to-mesenchymal transition EMT as well as fibroblast, and fibrocyte, transformation into myofibroblasts which are resistant to apoptosis. The resulting deposition of excess disrupted matrix by these myofibroblasts leads to the development of <d>IPF</d>.
20952439|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> with an appalling prognosis. The failure of anti-inflammatory therapies coupled with the observation that deranged epithelium overlies proliferative myofibroblasts to form the fibroblastic focus has lead to the emerging concept that <d>IPF</d> is a disease of deregulated epithelial-mesenchymal crosstalk. <d>IPF</d> is triggered by an as yet unidentified <d>alveolar injury</d> that leads to activation of transforming growth factor-b TGF-b and alveolar basement membrane disruption. In the presence of persisting injurious pathways, or disrupted repair pathways, activated TGF-b can lead to enhanced epithelial apoptosis and epithelial-to-mesenchymal transition EMT as well as fibroblast, and fibrocyte, transformation into myofibroblasts which are resistant to apoptosis. The resulting deposition of excess disrupted matrix by these myofibroblasts leads to the development of <d>IPF</d>.
21044893|a|The pleiotropic growth factor TGFb1 promotes many of the pathogenic mechanisms observed in lung <d>fibrosis</d> and airway remodeling, such as aberrant extracellular matrix deposition due to both fibroblast activation and fibroblast to myofibroblast differentiation. Serum amyloid P SAP, a member of the pentraxin family of proteins inhibits bleomycin-induced lung <d>fibrosis</d> through an inhibition of pulmonary fibrocyte and pro-fibrotic alternative M2 macrophage accumulation. It is unknown if SAP has effects downstream of TGFb1, a major mediator of pulmonary <d>fibrosis</d>. Using the lung specific TGFb1 transgenic mouse model, we determined that SAP inhibits all of the pathologies driven by TGFb1 including apoptosis, airway inflammation, pulmonary fibrocyte accumulation and collagen deposition, without affecting levels of TGFb1. To explore the role of monocyte derived cells in this model we used liposomal clodronate to deplete pulmonary macrophages. This led to pronounced anti-fibrotic effects that were independent of fibrocyte accumulation. Administration of SAP mirrored these effects and reduced both pulmonary M2 macrophages and increased chemokine IP10/CXCL10 expression in a SMAD 3-independent manner. Interestingly, SAP concentrations were reduced in the circulation of IPF patients and correlated with disease severity. Last, SAP directly inhibited M2 macrophage differentiation of monocytes obtained from these patients. These data suggest that the beneficial anti-fibrotic effects of SAP in TGFb1-induced lung disease are via modulating monocyte responses.
21044893|a|The pleiotropic growth factor <g>TGFb1</g> promotes many of the pathogenic mechanisms observed in lung <d>fibrosis</d> and airway remodeling, such as aberrant extracellular matrix deposition due to both fibroblast activation and fibroblast to myofibroblast differentiation. Serum amyloid P SAP, a member of the pentraxin family of proteins inhibits bleomycin-induced lung <d>fibrosis</d> through an inhibition of pulmonary fibrocyte and pro-fibrotic alternative M2 macrophage accumulation. It is unknown if SAP has effects downstream of <g>TGFb1</g>, a major mediator of pulmonary <d>fibrosis</d>. Using the lung specific <g>TGFb1</g> transgenic mouse model, we determined that SAP inhibits all of the pathologies driven by <g>TGFb1</g> including apoptosis, <d>airway inflammation</d>, pulmonary fibrocyte accumulation and collagen deposition, without affecting levels of <g>TGFb1</g>. To explore the role of monocyte derived cells in this model we used liposomal clodronate to deplete pulmonary macrophages. This led to pronounced anti-fibrotic effects that were independent of fibrocyte accumulation. Administration of SAP mirrored these effects and reduced both pulmonary M2 macrophages and increased chemokine IP10/CXCL10 expression in a SMAD 3-independent manner. Interestingly, SAP concentrations were reduced in the circulation of IPF patients and correlated with disease severity. Last, SAP directly inhibited M2 macrophage differentiation of monocytes obtained from these patients. These data suggest that the beneficial anti-fibrotic effects of SAP in <g>TGFb1</g>-induced lung disease are via modulating monocyte responses.
21044893|a|The pleiotropic growth factor <g>TGFb1</g> promotes many of the pathogenic mechanisms observed in lung <d>fibrosis</d> and airway remodeling, such as aberrant extracellular matrix deposition due to both fibroblast activation and fibroblast to myofibroblast differentiation. Serum amyloid P SAP, a member of the pentraxin family of proteins inhibits bleomycin-induced lung <d>fibrosis</d> through an inhibition of pulmonary fibrocyte and pro-fibrotic alternative M2 macrophage accumulation. It is unknown if SAP has effects downstream of <g>TGFb1</g>, a major mediator of pulmonary <d>fibrosis</d>. Using the lung specific <g>TGFb1</g> transgenic mouse model, we determined that SAP inhibits all of the pathologies driven by <g>TGFb1</g> including apoptosis, <d>airway inflammation</d>, pulmonary fibrocyte accumulation and collagen deposition, without affecting levels of <g>TGFb1</g>. To explore the role of monocyte derived cells in this model we used liposomal clodronate to deplete pulmonary macrophages. This led to pronounced anti-fibrotic effects that were independent of fibrocyte accumulation. Administration of SAP mirrored these effects and reduced both pulmonary M2 macrophages and increased chemokine <g>IP10</g>/<g>CXCL10</g> expression in a <g>SMAD 3</g>-independent manner. Interestingly, SAP concentrations were reduced in the circulation of <d>IPF</d> patients and correlated with disease severity. Last, SAP directly inhibited M2 macrophage differentiation of monocytes obtained from these patients. These data suggest that the beneficial anti-fibrotic effects of SAP in <g>TGFb1</g>-induced lung disease are via modulating monocyte responses.
21044893|a|The pleiotropic growth factor <g>TGFb1</g> promotes many of the pathogenic mechanisms observed in lung <d>fibrosis</d> and airway remodeling, such as aberrant extracellular matrix deposition due to both fibroblast activation and fibroblast to myofibroblast differentiation. Serum amyloid P SAP, a member of the pentraxin family of proteins inhibits bleomycin-induced lung <d>fibrosis</d> through an inhibition of pulmonary fibrocyte and pro-fibrotic alternative M2 macrophage accumulation. It is unknown if SAP has effects downstream of <g>TGFb1</g>, a major mediator of pulmonary <d>fibrosis</d>. Using the lung specific <g>TGFb1</g> transgenic mouse model, we determined that SAP inhibits all of the pathologies driven by <g>TGFb1</g> including apoptosis, <d>airway inflammation</d>, pulmonary fibrocyte accumulation and collagen deposition, without affecting levels of <g>TGFb1</g>. To explore the role of monocyte derived cells in this model we used liposomal clodronate to deplete pulmonary macrophages. This led to pronounced anti-fibrotic effects that were independent of fibrocyte accumulation. Administration of SAP mirrored these effects and reduced both pulmonary M2 macrophages and increased chemokine <g>IP10</g>/<g>CXCL10</g> expression in a <g>SMAD 3</g>-independent manner. Interestingly, SAP concentrations were reduced in the circulation of <d>IPF</d> patients and correlated with disease severity. Last, SAP directly inhibited M2 macrophage differentiation of monocytes obtained from these patients. These data suggest that the beneficial anti-fibrotic effects of SAP in <g>TGFb1</g>-induced <d>lung disease</d> are via modulating monocyte responses.
21056957|a|Pulmonary fibrosis PF is characterized by increased deposition of proteoglycans PGs, in particular core proteins. Glycosaminoglycans GAGs are key players in tissue repair and fibrosis, and we investigated whether PF is associated with changes in the expression and structure of GAGs as well as in the expression of b1,3-glucuronosyltransferase I GlcAT-I, a rate-limiting enzyme in GAG synthesis. Lung biopsies from idiopathic <d>pulmonary fibrosis</d> IPF patients and lung tissue from a rat model of bleomycin BLM-induced PF were immunostained for chondroitin sulfated-GAGs and GlcAT-I expression. Alterations in disaccharide composition and sulfation of chondroitin/dermatan sulfate CS/DS were evaluated by fluorophore-assisted carbohydrate electrophoresis FACE in BLM rats. Lung fibroblasts isolated from control saline-instilled or BLM rat lungs were assessed for GAG structure and GlcAT-I expression. Disaccharide analysis showed that 4- and 6-sulfated disaccharides were increased in the lungs and lung fibroblasts obtained from fibrotic rats compared with controls. Fibrotic lung fibroblasts and transforming growth factor-b1 TGF-b1-treated normal lung fibroblasts expressed increased amounts of hyaluronan and 4- and 6-sulfated chondroitin, and neutralizing anti-TGF-b1 antibody diminished the same. TGF-b1 upregulated GlcAT-I and versican expression in lung fibroblasts, and signaling through TGF-b type I receptor/p38 MAPK was required for TGF-b1-mediated GlcAT-I and CS-GAG expression in fibroblasts. Our data show for the first time increased expression of CS-GAGs and GlcAT-I in IPF, fibrotic rat lungs, and fibrotic lung fibroblasts. These data suggest that alterations of sulfation isomers of CS/DS and upregulation of GlcAT-I contribute to the pathological PG-GAG accumulation in PF.
21056957|a|<d>Pulmonary fibrosis</d> PF is characterized by increased deposition of proteoglycans PGs, in particular core proteins. Glycosaminoglycans GAGs are key players in tissue repair and fibrosis, and we investigated whether PF is associated with changes in the expression and structure of GAGs as well as in the expression of b1,3-glucuronosyltransferase I GlcAT-I, a rate-limiting enzyme in GAG synthesis. Lung biopsies from idiopathic <d>pulmonary fibrosis</d> IPF patients and lung tissue from a rat model of bleomycin BLM-induced PF were immunostained for chondroitin sulfated-GAGs and GlcAT-I expression. Alterations in disaccharide composition and sulfation of chondroitin/dermatan sulfate CS/DS were evaluated by fluorophore-assisted carbohydrate electrophoresis FACE in BLM rats. Lung fibroblasts isolated from control saline-instilled or BLM rat lungs were assessed for GAG structure and GlcAT-I expression. Disaccharide analysis showed that 4- and 6-sulfated disaccharides were increased in the lungs and lung fibroblasts obtained from fibrotic rats compared with controls. Fibrotic lung fibroblasts and transforming growth factor-b1 TGF-b1-treated normal lung fibroblasts expressed increased amounts of hyaluronan and 4- and 6-sulfated chondroitin, and neutralizing anti-TGF-b1 antibody diminished the same. TGF-b1 upregulated GlcAT-I and versican expression in lung fibroblasts, and signaling through TGF-b type I receptor/p38 MAPK was required for TGF-b1-mediated GlcAT-I and CS-GAG expression in fibroblasts. Our data show for the first time increased expression of CS-GAGs and GlcAT-I in IPF, fibrotic rat lungs, and fibrotic lung fibroblasts. These data suggest that alterations of sulfation isomers of CS/DS and upregulation of GlcAT-I contribute to the pathological PG-GAG accumulation in PF.
21056957|a|<d>Pulmonary fibrosis</d> <d>PF</d> is characterized by increased deposition of proteoglycans PGs, in particular core proteins. Glycosaminoglycans GAGs are key players in tissue repair and fibrosis, and we investigated whether <d>PF</d> is associated with changes in the expression and structure of GAGs as well as in the expression of b1,3-glucuronosyltransferase I GlcAT-I, a rate-limiting enzyme in GAG synthesis. Lung biopsies from idiopathic <d>pulmonary fibrosis</d> I<d>PF</d> patients and lung tissue from a rat model of bleomycin BLM-induced <d>PF</d> were immunostained for chondroitin sulfated-GAGs and GlcAT-I expression. Alterations in disaccharide composition and sulfation of chondroitin/dermatan sulfate CS/DS were evaluated by fluorophore-assisted carbohydrate electrophoresis FACE in BLM rats. Lung fibroblasts isolated from control saline-instilled or BLM rat lungs were assessed for GAG structure and GlcAT-I expression. Disaccharide analysis showed that 4- and 6-sulfated disaccharides were increased in the lungs and lung fibroblasts obtained from fibrotic rats compared with controls. Fibrotic lung fibroblasts and transforming growth factor-b1 TGF-b1-treated normal lung fibroblasts expressed increased amounts of hyaluronan and 4- and 6-sulfated chondroitin, and neutralizing anti-TGF-b1 antibody diminished the same. TGF-b1 upregulated GlcAT-I and versican expression in lung fibroblasts, and signaling through TGF-b type I receptor/p38 MAPK was required for TGF-b1-mediated GlcAT-I and CS-GAG expression in fibroblasts. Our data show for the first time increased expression of CS-GAGs and GlcAT-I in I<d>PF</d>, fibrotic rat lungs, and fibrotic lung fibroblasts. These data suggest that alterations of sulfation isomers of CS/DS and upregulation of GlcAT-I contribute to the pathological PG-GAG accumulation in <d>PF</d>.
21056957|a|<d>Pulmonary <d>fibrosis</d></d> <d>PF</d> is characterized by increased deposition of proteoglycans PGs, in particular core proteins. Glycosaminoglycans GAGs are key players in tissue repair and <d>fibrosis</d>, and we investigated whether <d>PF</d> is associated with changes in the expression and structure of GAGs as well as in the expression of b1,3-glucuronosyltransferase I GlcAT-I, a rate-limiting enzyme in GAG synthesis. Lung biopsies from idiopathic <d>pulmonary <d>fibrosis</d></d> I<d>PF</d> patients and lung tissue from a rat model of bleomycin BLM-induced <d>PF</d> were immunostained for chondroitin sulfated-GAGs and GlcAT-I expression. Alterations in disaccharide composition and sulfation of chondroitin/dermatan sulfate CS/DS were evaluated by fluorophore-assisted carbohydrate electrophoresis FACE in BLM rats. Lung fibroblasts isolated from control saline-instilled or BLM rat lungs were assessed for GAG structure and GlcAT-I expression. Disaccharide analysis showed that 4- and 6-sulfated disaccharides were increased in the lungs and lung fibroblasts obtained from fibrotic rats compared with controls. Fibrotic lung fibroblasts and transforming growth factor-b1 TGF-b1-treated normal lung fibroblasts expressed increased amounts of hyaluronan and 4- and 6-sulfated chondroitin, and neutralizing anti-TGF-b1 antibody diminished the same. TGF-b1 upregulated GlcAT-I and versican expression in lung fibroblasts, and signaling through TGF-b type I receptor/p38 MAPK was required for TGF-b1-mediated GlcAT-I and CS-GAG expression in fibroblasts. Our data show for the first time increased expression of CS-GAGs and GlcAT-I in I<d>PF</d>, fibrotic rat lungs, and fibrotic lung fibroblasts. These data suggest that alterations of sulfation isomers of CS/DS and upregulation of GlcAT-I contribute to the pathological PG-GAG accumulation in <d>PF</d>.
21086900|a|New paradigms have been recently proposed in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF, evidencing that in IPF the cumulative action of an accelerated parenchymal senescence determined by either telomere dysfunction or genetic defects, together with the concurrent noxious activity of tobacco smoking, are able to severely compromise the regenerative potential of parenchymal epithelial stem cells, triggering a cascade of molecular signals and events scarring, bronchiolar proliferation, abnormal remodelling eventually leading to severe and irreversible functional impairment. New pathogenic schemes focus on the complex molecular mechanisms driving in a vicious circle the different signalling pathways e.g. Wnt/ -catenin, TGF-beta, caveolin-1, etc. potentially involved in epithelial-mesenchymal transition and irreversible lung remodelling.
21086900|a|New paradigms have been recently proposed in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, evidencing that in <d>IPF</d> the cumulative action of an accelerated parenchymal senescence determined by either telomere dysfunction or genetic defects, together with the concurrent noxious activity of tobacco smoking, are able to severely compromise the regenerative potential of parenchymal epithelial stem cells, triggering a cascade of molecular signals and events scarring, bronchiolar proliferation, abnormal remodelling eventually leading to severe and irreversible functional impairment. New pathogenic schemes focus on the complex molecular mechanisms driving in a vicious circle the different signalling pathways e.g. Wnt/ -catenin, TGF-beta, caveolin-1, etc. potentially involved in epithelial-mesenchymal transition and irreversible lung remodelling.
21086900|a|New paradigms have been recently proposed in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, evidencing that in <d>IPF</d> the cumulative action of an accelerated parenchymal senescence determined by either <d>telomere dysfunction</d> or genetic defects, together with the concurrent noxious activity of tobacco smoking, are able to severely compromise the regenerative potential of parenchymal epithelial stem cells, triggering a cascade of molecular signals and events scarring, bronchiolar proliferation, abnormal remodelling eventually leading to severe and irreversible functional impairment. New pathogenic schemes focus on the complex molecular mechanisms driving in a vicious circle the different signalling pathways e.g. Wnt/ -catenin, TGF-beta, caveolin-1, etc. potentially involved in epithelial-mesenchymal transition and irreversible lung remodelling.
21086900|a|New paradigms have been recently proposed in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, evidencing that in <d>IPF</d> the cumulative action of an accelerated parenchymal senescence determined by either <d>telomere dysfunction</d> or genetic defects, together with the concurrent noxious activity of tobacco smoking, are able to severely compromise the regenerative potential of parenchymal epithelial stem cells, triggering a cascade of molecular signals and events <d>scarring</d>, bronchiolar proliferation, abnormal remodelling eventually leading to severe and irreversible functional impairment. New pathogenic schemes focus on the complex molecular mechanisms driving in a vicious circle the different signalling pathways e.g. Wnt/ -catenin, TGF-beta, caveolin-1, etc. potentially involved in epithelial-mesenchymal transition and irreversible lung remodelling.
21103368|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and fatal illness whose pathogenesis remains poorly understood. Recent evidence suggests oxidative stress as a key player in the establishment/progression of lung fibrosis in animal models and possibly in human IPF. The aim of the present study was to characterize the cellular phenotype of fibroblasts derived from IPF patients and identify underlying molecular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We first analyzed the baseline differentiation features and growth ability of primary lung fibroblasts derived from 7 histology proven IPF patients and 4 control subjects at different culture passages. Then, we focused on the redox state and related molecular pathways of IPF fibroblasts and investigated the impact of oxidative stress in the establishment of the IPF phenotype. IPF fibroblasts were differentiated into alpha-smooth muscle actin SMA-positive myofibroblasts, displayed a pro-fibrotic phenotype as expressing type-I collagen, and proliferated lower than controls cells. The IPF phenotype was inducible upon oxidative stress in control cells and was sensitive to ROS scavenging. IPF fibroblasts also contained large excess of reactive oxygen species ROS due to the activation of an NADPH oxidase-like system, displayed higher levels of tyrosine phosphorylated proteins and were more resistant to oxidative-stress induced cell death. Interestingly, the IPF traits disappeared with time in culture, indicating a transient effect of the initial trigger. CONCLUSIONS/SIGNIFICANCE: Robust expression of a-SMA and type-I collagen, high and uniformly-distributed ROS levels, resistance to oxidative-stress induced cell death and constitutive activation of tyrosine kinases signalling are distinctive features of the IPF phenotype. We suggest that this phenotype can be used as a model to identify the initial trigger of IPF.
21103368|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal illness whose pathogenesis remains poorly understood. Recent evidence suggests oxidative stress as a key player in the establishment/progression of lung fibrosis in animal models and possibly in human <d>IPF</d>. The aim of the present study was to characterize the cellular phenotype of fibroblasts derived from <d>IPF</d> patients and identify underlying molecular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We first analyzed the baseline differentiation features and growth ability of primary lung fibroblasts derived from 7 histology proven <d>IPF</d> patients and 4 control subjects at different culture passages. Then, we focused on the redox state and related molecular pathways of <d>IPF</d> fibroblasts and investigated the impact of oxidative stress in the establishment of the <d>IPF</d> phenotype. <d>IPF</d> fibroblasts were differentiated into alpha-smooth muscle actin SMA-positive myofibroblasts, displayed a pro-fibrotic phenotype as expressing type-I collagen, and proliferated lower than controls cells. The <d>IPF</d> phenotype was inducible upon oxidative stress in control cells and was sensitive to ROS scavenging. <d>IPF</d> fibroblasts also contained large excess of reactive oxygen species ROS due to the activation of an NADPH oxidase-like system, displayed higher levels of tyrosine phosphorylated proteins and were more resistant to oxidative-stress induced cell death. Interestingly, the <d>IPF</d> traits disappeared with time in culture, indicating a transient effect of the initial trigger. CONCLUSIONS/SIGNIFICANCE: Robust expression of a-SMA and type-I collagen, high and uniformly-distributed ROS levels, resistance to oxidative-stress induced cell death and constitutive activation of tyrosine kinases signalling are distinctive features of the <d>IPF</d> phenotype. We suggest that this phenotype can be used as a model to identify the initial trigger of <d>IPF</d>.
21103368|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal illness whose pathogenesis remains poorly understood. Recent evidence suggests oxidative stress as a key player in the establishment/progression of <d>lung fibrosis</d> in animal models and possibly in human <d>IPF</d>. The aim of the present study was to characterize the cellular phenotype of fibroblasts derived from <d>IPF</d> patients and identify underlying molecular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We first analyzed the baseline differentiation features and growth ability of primary lung fibroblasts derived from 7 histology proven <d>IPF</d> patients and 4 control subjects at different culture passages. Then, we focused on the redox state and related molecular pathways of <d>IPF</d> fibroblasts and investigated the impact of oxidative stress in the establishment of the <d>IPF</d> phenotype. <d>IPF</d> fibroblasts were differentiated into alpha-smooth muscle actin SMA-positive myofibroblasts, displayed a pro-fibrotic phenotype as expressing type-I collagen, and proliferated lower than controls cells. The <d>IPF</d> phenotype was inducible upon oxidative stress in control cells and was sensitive to ROS scavenging. <d>IPF</d> fibroblasts also contained large excess of reactive oxygen species ROS due to the activation of an NADPH oxidase-like system, displayed higher levels of tyrosine phosphorylated proteins and were more resistant to oxidative-stress induced cell death. Interestingly, the <d>IPF</d> traits disappeared with time in culture, indicating a transient effect of the initial trigger. CONCLUSIONS/SIGNIFICANCE: Robust expression of a-SMA and type-I collagen, high and uniformly-distributed ROS levels, resistance to oxidative-stress induced cell death and constitutive activation of tyrosine kinases signalling are distinctive features of the <d>IPF</d> phenotype. We suggest that this phenotype can be used as a model to identify the initial trigger of <d>IPF</d>.
21103368|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal illness whose pathogenesis remains poorly understood. Recent evidence suggests oxidative stress as a key player in the establishment/progression of <d>lung fibrosis</d> in animal models and possibly in human <d>IPF</d>. The aim of the present study was to characterize the cellular phenotype of fibroblasts derived from <d>IPF</d> patients and identify underlying molecular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We first analyzed the baseline differentiation features and growth ability of primary lung fibroblasts derived from 7 histology proven <d>IPF</d> patients and 4 control subjects at different culture passages. Then, we focused on the redox state and related molecular pathways of <d>IPF</d> fibroblasts and investigated the impact of oxidative stress in the establishment of the <d>IPF</d> phenotype. <d>IPF</d> fibroblasts were differentiated into <d>alpha-smooth muscle actin</d> SMA-positive myofibroblasts, displayed a pro-fibrotic phenotype as expressing type-I collagen, and proliferated lower than controls cells. The <d>IPF</d> phenotype was inducible upon oxidative stress in control cells and was sensitive to ROS scavenging. <d>IPF</d> fibroblasts also contained large excess of reactive oxygen species ROS due to the activation of an NADPH oxidase-like system, displayed higher levels of tyrosine phosphorylated proteins and were more resistant to oxidative-stress induced cell death. Interestingly, the <d>IPF</d> traits disappeared with time in culture, indicating a transient effect of the initial trigger. CONCLUSIONS/SIGNIFICANCE: Robust expression of a-SMA and type-I collagen, high and uniformly-distributed ROS levels, resistance to oxidative-stress induced cell death and constitutive activation of tyrosine kinases signalling are distinctive features of the <d>IPF</d> phenotype. We suggest that this phenotype can be used as a model to identify the initial trigger of <d>IPF</d>.
21103368|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal illness whose pathogenesis remains poorly understood. Recent evidence suggests oxidative stress as a key player in the establishment/progression of <d>lung fibrosis</d> in animal models and possibly in human <d>IPF</d>. The aim of the present study was to characterize the cellular phenotype of fibroblasts derived from <d>IPF</d> patients and identify underlying molecular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We first analyzed the baseline differentiation features and growth ability of primary lung fibroblasts derived from 7 histology proven <d>IPF</d> patients and 4 control subjects at different culture passages. Then, we focused on the redox state and related molecular pathways of <d>IPF</d> fibroblasts and investigated the impact of oxidative stress in the establishment of the <d>IPF</d> phenotype. <d>IPF</d> fibroblasts were differentiated into <d>alpha-smooth muscle actin</d> <d>SMA</d>-positive myofibroblasts, displayed a pro-fibrotic phenotype as expressing type-I collagen, and proliferated lower than controls cells. The <d>IPF</d> phenotype was inducible upon oxidative stress in control cells and was sensitive to ROS scavenging. <d>IPF</d> fibroblasts also contained large excess of reactive oxygen species ROS due to the activation of an NADPH oxidase-like system, displayed higher levels of tyrosine phosphorylated proteins and were more resistant to oxidative-stress induced cell death. Interestingly, the <d>IPF</d> traits disappeared with time in culture, indicating a transient effect of the initial trigger. CONCLUSIONS/SIGNIFICANCE: Robust expression of a-<d>SMA</d> and type-I collagen, high and uniformly-distributed ROS levels, resistance to oxidative-stress induced cell death and constitutive activation of tyrosine kinases signalling are distinctive features of the <d>IPF</d> phenotype. We suggest that this phenotype can be used as a model to identify the initial trigger of <d>IPF</d>.
21135509|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments. Although the etiology of IPF is unknown, dysregulated <g>TGF-b</g> signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial <g>TGF-b</g> signaling via <g>TGF-b</g> receptor II TbRII and its contribution to fibrosis by generating mice in which TbRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TbRIINkx2.1-cre mice, were used to determine the impact of TbRII inactivation on a embryonic lung morphogenesis in vivo; and b the epithelial cell response to <g>TGF-b</g> signaling in vitro and in a bleomycin-induced, <g>TGF-b</g>-mediated mouse model of <d>pulmonary fibrosis</d>. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TbRIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TbRII in alveolar homeostasis. Absence of TbRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic <g>TGF-b</g>. However, TbRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced <d>pulmonary fibrosis</d>. To our knowledge, these findings are the first to demonstrate a specific role for <g>TGF-b</g> signaling in the lung epithelium in the pathogenesis of <d>pulmonary fibrosis</d>.
21135509|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments. Although the etiology of <d>IPF</d> is unknown, dysregulated <g>TGF-b</g> signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial <g>TGF-b</g> signaling via <g>TGF-b</g> receptor II TbRII and its contribution to fibrosis by generating mice in which TbRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TbRIINkx2.1-cre mice, were used to determine the impact of TbRII inactivation on a embryonic lung morphogenesis in vivo; and b the epithelial cell response to <g>TGF-b</g> signaling in vitro and in a bleomycin-induced, <g>TGF-b</g>-mediated mouse model of <d>pulmonary fibrosis</d>. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TbRIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TbRII in alveolar homeostasis. Absence of TbRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic <g>TGF-b</g>. However, TbRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced <d>pulmonary fibrosis</d>. To our knowledge, these findings are the first to demonstrate a specific role for <g>TGF-b</g> signaling in the lung epithelium in the pathogenesis of <d>pulmonary fibrosis</d>.
21135509|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic <d>fibroproliferative pulmonary disorder</d> for which there are currently no treatments. Although the etiology of <d>IPF</d> is unknown, dysregulated <g>TGF-b</g> signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial <g>TGF-b</g> signaling via <g>TGF-b</g> receptor II TbRII and its contribution to fibrosis by generating mice in which TbRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TbRIINkx2.1-cre mice, were used to determine the impact of TbRII inactivation on a embryonic lung morphogenesis in vivo; and b the epithelial cell response to <g>TGF-b</g> signaling in vitro and in a bleomycin-induced, <g>TGF-b</g>-mediated mouse model of <d>pulmonary fibrosis</d>. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TbRIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TbRII in alveolar homeostasis. Absence of TbRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic <g>TGF-b</g>. However, TbRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced <d>pulmonary fibrosis</d>. To our knowledge, these findings are the first to demonstrate a specific role for <g>TGF-b</g> signaling in the lung epithelium in the pathogenesis of <d>pulmonary fibrosis</d>.
21135509|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic <d>fibroproliferative pulmonary disorder</d> for which there are currently no treatments. Although the etiology of <d>IPF</d> is unknown, dysregulated <g>TGF-b</g> signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial <g>TGF-b</g> signaling via <g>TGF-b</g> receptor II <g>TbRII</g> and its contribution to <d>fibrosis</d> by generating mice in which <g>TbRII</g> was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as <g>TbRII</g>Nkx2.1-cre mice, were used to determine the impact of <g>TbRII</g> inactivation on a embryonic lung morphogenesis in vivo; and b the epithelial cell response to <g>TGF-b</g> signaling in vitro and in a bleomycin-induced, <g>TGF-b</g>-mediated mouse model of <d>pulmonary <d>fibrosis</d></d>. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, <g>TbRII</g>Nkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial <g>TbRII</g> in alveolar homeostasis. Absence of <g>TbRII</g> increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic <g>TGF-b</g>. However, <g>TbRII</g>Nkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. To our knowledge, these findings are the first to demonstrate a specific role for <g>TGF-b</g> signaling in the lung epithelium in the pathogenesis of <d>pulmonary <d>fibrosis</d></d>.
21135509|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic <d>fibroproliferative pulmonary disorder</d> for which there are currently no treatments. Although the etiology of <d>IPF</d> is unknown, dysregulated <g>TGF-b</g> signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial <g>TGF-b</g> signaling via <g>TGF-b</g> receptor II <g>TbRII</g> and its contribution to <d>fibrosis</d> by generating mice in which <g>TbRII</g> was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as <g>TbRII</g>Nkx2.1-cre mice, were used to determine the impact of <g>TbRII</g> inactivation on a embryonic lung morphogenesis in vivo; and b the epithelial cell response to <g>TGF-b</g> signaling in vitro and in a bleomycin-induced, <g>TGF-b</g>-mediated mouse model of <d>pulmonary <d>fibrosis</d></d>. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, <g>TbRII</g>Nkx2.1-cre mice developed <d>emphysema</d>, suggesting a requirement for epithelial <g>TbRII</g> in alveolar homeostasis. Absence of <g>TbRII</g> increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic <g>TGF-b</g>. However, <g>TbRII</g>Nkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. To our knowledge, these findings are the first to demonstrate a specific role for <g>TGF-b</g> signaling in the lung epithelium in the pathogenesis of <d>pulmonary <d>fibrosis</d></d>.
21166126|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic, progressive and lethal process of unknown etiology. The sub-pleural localization of fibrosis is a hallmark of early IPF but no link between the pleura and IPF has been established yet. We developed an experimental model of pleural fibrosis induced by adenovirus-mediated gene transfer of transforming growth factor TGF-beta1 to mesothelial cells and observed collagen accumulation within the pleura but also in the sub-pleural parenchyma. This sub-pleural fibrosis was associated, in vivo, with a mesothelial--to--myofibroblast transformation mesothelio-fibroblastoid transformation, a process similar to the epithelial-mesenchymal transition. This phenotypic modification was also observed in vitro in mesothelial cells treated with recombinant TGF-beta1. These results suggest that mesothelial cells may have a central role not only in pleural fibrosis but also in the onset and progression of IPF.
21166126|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and lethal process of unknown etiology. The sub-pleural localization of fibrosis is a hallmark of early <d>IPF</d> but no link between the pleura and <d>IPF</d> has been established yet. We developed an experimental model of pleural fibrosis induced by adenovirus-mediated gene transfer of transforming growth factor TGF-beta1 to mesothelial cells and observed collagen accumulation within the pleura but also in the sub-pleural parenchyma. This sub-pleural fibrosis was associated, in vivo, with a mesothelial--to--myofibroblast transformation mesothelio-fibroblastoid transformation, a process similar to the epithelial-mesenchymal transition. This phenotypic modification was also observed in vitro in mesothelial cells treated with recombinant TGF-beta1. These results suggest that mesothelial cells may have a central role not only in pleural fibrosis but also in the onset and progression of <d>IPF</d>.
21166126|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic, progressive and lethal process of unknown etiology. The sub-pleural localization of <d>fibrosis</d> is a hallmark of early <d>IPF</d> but no link between the pleura and <d>IPF</d> has been established yet. We developed an experimental model of pleural <d>fibrosis</d> induced by adenovirus-mediated gene transfer of transforming growth factor TGF-beta1 to mesothelial cells and observed collagen accumulation within the pleura but also in the sub-pleural parenchyma. This sub-pleural <d>fibrosis</d> was associated, in vivo, with a mesothelial--to--myofibroblast transformation mesothelio-fibroblastoid transformation, a process similar to the epithelial-mesenchymal transition. This phenotypic modification was also observed in vitro in mesothelial cells treated with recombinant TGF-beta1. These results suggest that mesothelial cells may have a central role not only in pleural <d>fibrosis</d> but also in the onset and progression of <d>IPF</d>.
21166126|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic, progressive and lethal process of unknown etiology. The sub-pleural localization of <d>fibrosis</d> is a hallmark of early <d>IPF</d> but no link between the pleura and <d>IPF</d> has been established yet. We developed an experimental model of pleural <d>fibrosis</d> induced by adenovirus-mediated gene transfer of transforming growth factor TGF-beta1 to mesothelial cells and observed collagen accumulation within the pleura but also in the <d>sub-pleural parenchyma</d>. This sub-pleural <d>fibrosis</d> was associated, in vivo, with a mesothelial--to--myofibroblast transformation mesothelio-fibroblastoid transformation, a process similar to the epithelial-mesenchymal transition. This phenotypic modification was also observed in vitro in mesothelial cells treated with recombinant TGF-beta1. These results suggest that mesothelial cells may have a central role not only in pleural <d>fibrosis</d> but also in the onset and progression of <d>IPF</d>.
21169469|a|RATIONALE: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic <d>pulmonary fibrosis</d> IPF. The transcription factor Yin Yang 1 YY1 plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known. OBJECTIVES: To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. METHODS: Lung fibroblasts were cultured with transforming growth factor TGF-b or tumor necrosis factor-a. Nuclear factor NF-kB, YY1, and a-smooth muscle actin SMA were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1f/f conditional knockout mouse after being exposed to silica or bleomycin. MEASUREMENTS AND MAIN RESULTS: TGF-b and tumor necrosis factor-a up-regulated YY1 expression in lung fibroblasts. TGF-b-induced YY1 expression was dramatically decreased by an inhibitor of NF-kB, which blocked I-kB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate a-SMA expression in pulmonary fibroblasts. YY1-deficient YY1+/- mice were significantly protected from lung fibrosis, which was associated with attenuated a-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1f/f mice reduced lung fibrosis. CONCLUSIONS: YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-kB-dependent manner, and YY1 regulates fibrogenesis at least in part by increasing a-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for <d>pulmonary fibrosis</d>.
21169469|a|RATIONALE: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. The transcription factor Yin Yang 1 YY1 plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known. OBJECTIVES: To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. METHODS: Lung fibroblasts were cultured with transforming growth factor TGF-b or tumor necrosis factor-a. Nuclear factor NF-kB, YY1, and a-smooth muscle actin SMA were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1f/f conditional knockout mouse after being exposed to silica or bleomycin. MEASUREMENTS AND MAIN RESULTS: TGF-b and tumor necrosis factor-a up-regulated YY1 expression in lung fibroblasts. TGF-b-induced YY1 expression was dramatically decreased by an inhibitor of NF-kB, which blocked I-kB degradation. YY1 is significantly overexpressed in both human <d>IPF</d> and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate a-SMA expression in pulmonary fibroblasts. YY1-deficient YY1+/- mice were significantly protected from lung fibrosis, which was associated with attenuated a-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1f/f mice reduced lung fibrosis. CONCLUSIONS: YY1 is overexpressed in fibroblasts in both human <d>IPF</d> and murine models in a NF-kB-dependent manner, and YY1 regulates fibrogenesis at least in part by increasing a-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for <d>pulmonary fibrosis</d>.
21169469|a|RATIONALE: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. The transcription factor <g>Yin Yang 1</g> <g>YY1</g> plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic <d>lung diseases</d> is not known. OBJECTIVES: To elucidate the mechanism by which <g>YY1</g> regulates fibroblast differentiation and lung fibrosis. METHODS: Lung fibroblasts were cultured with transforming growth factor TGF-b or tumor necrosis factor-a. Nuclear factor NF-kB, <g>YY1</g>, and a-smooth muscle actin SMA were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial <g>YY1</g>-deficient mouse and a <g>YY1</g>f/f conditional knockout mouse after being exposed to silica or bleomycin. MEASUREMENTS AND MAIN RESULTS: TGF-b and tumor necrosis factor-a up-regulated <g>YY1</g> expression in lung fibroblasts. TGF-b-induced <g>YY1</g> expression was dramatically decreased by an inhibitor of NF-kB, which blocked I-kB degradation. <g>YY1</g> is significantly overexpressed in both human <d>IPF</d> and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that <g>YY1</g> can up-regulate a-SMA expression in pulmonary fibroblasts. <g>YY1</g>-deficient <g>YY1</g>+/- mice were significantly protected from lung fibrosis, which was associated with attenuated a-SMA and collagen expression. Finally, decreasing <g>YY1</g> expression through instilled adenovirus-cre in floxed-<g>YY1</g>f/f mice reduced lung fibrosis. CONCLUSIONS: <g>YY1</g> is overexpressed in fibroblasts in both human <d>IPF</d> and murine models in a NF-kB-dependent manner, and <g>YY1</g> regulates fibrogenesis at least in part by increasing a-SMA and collagen expression. Decreasing <g>YY1</g> expression may provide a new therapeutic strategy for <d>pulmonary fibrosis</d>.
21169469|a|RATIONALE: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. The transcription factor <g>Yin Yang 1</g> <g>YY1</g> plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic <d>lung diseases</d> is not known. OBJECTIVES: To elucidate the mechanism by which <g>YY1</g> regulates fibroblast differentiation and <d>lung fibrosis</d>. METHODS: Lung fibroblasts were cultured with transforming growth factor TGF-b or tumor necrosis factor-a. Nuclear factor NF-kB, <g>YY1</g>, and a-smooth muscle actin SMA were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and <d>lung fibrosis</d> were assessed in a partial <g>YY1</g>-deficient mouse and a <g>YY1</g>f/f conditional knockout mouse after being exposed to silica or bleomycin. MEASUREMENTS AND MAIN RESULTS: TGF-b and tumor necrosis factor-a up-regulated <g>YY1</g> expression in lung fibroblasts. TGF-b-induced <g>YY1</g> expression was dramatically decreased by an inhibitor of NF-kB, which blocked I-kB degradation. <g>YY1</g> is significantly overexpressed in both human <d>IPF</d> and murine models of <d>lung fibrosis</d>, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that <g>YY1</g> can up-regulate a-SMA expression in pulmonary fibroblasts. <g>YY1</g>-deficient <g>YY1</g>+/- mice were significantly protected from <d>lung fibrosis</d>, which was associated with attenuated a-SMA and collagen expression. Finally, decreasing <g>YY1</g> expression through instilled adenovirus-cre in floxed-<g>YY1</g>f/f mice reduced <d>lung fibrosis</d>. CONCLUSIONS: <g>YY1</g> is overexpressed in fibroblasts in both human <d>IPF</d> and murine models in a NF-kB-dependent manner, and <g>YY1</g> regulates fibrogenesis at least in part by increasing a-SMA and collagen expression. Decreasing <g>YY1</g> expression may provide a new therapeutic strategy for <d>pulmonary fibrosis</d>.
21169469|a|RATIONALE: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. The transcription factor <g>Yin Yang 1</g> <g>YY1</g> plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic <d>lung diseases</d> is not known. OBJECTIVES: To elucidate the mechanism by which <g>YY1</g> regulates fibroblast differentiation and <d>lung fibrosis</d>. METHODS: Lung fibroblasts were cultured with transforming growth factor TGF-b or <d>tumor</d> necrosis factor-a. Nuclear factor NF-kB, <g>YY1</g>, and a-smooth muscle actin SMA were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and <d>lung fibrosis</d> were assessed in a partial <g>YY1</g>-deficient mouse and a <g>YY1</g>f/f conditional knockout mouse after being exposed to silica or bleomycin. MEASUREMENTS AND MAIN RESULTS: TGF-b and <d>tumor</d> necrosis factor-a up-regulated <g>YY1</g> expression in lung fibroblasts. TGF-b-induced <g>YY1</g> expression was dramatically decreased by an inhibitor of NF-kB, which blocked I-kB degradation. <g>YY1</g> is significantly overexpressed in both human <d>IPF</d> and murine models of <d>lung fibrosis</d>, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that <g>YY1</g> can up-regulate a-SMA expression in pulmonary fibroblasts. <g>YY1</g>-deficient <g>YY1</g>+/- mice were significantly protected from <d>lung fibrosis</d>, which was associated with attenuated a-SMA and collagen expression. Finally, decreasing <g>YY1</g> expression through instilled adenovirus-cre in floxed-<g>YY1</g>f/f mice reduced <d>lung fibrosis</d>. CONCLUSIONS: <g>YY1</g> is overexpressed in fibroblasts in both human <d>IPF</d> and murine models in a NF-kB-dependent manner, and <g>YY1</g> regulates fibrogenesis at least in part by increasing a-SMA and collagen expression. Decreasing <g>YY1</g> expression may provide a new therapeutic strategy for <d>pulmonary fibrosis</d>.
21212602|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive fibrotic lung disease and characterized by abnormal growth of fibroblasts and lung scarring. While the pathogenesis of IPF is not clearly understood, activation of transforming growth factor-b TGF-b and disruption of alveolar basement membrane seem to play important roles in leading to excess disruption of the matrix, which is associated with activated matrix metalloproteinase MMP and aberrant proliferation of myofibroblasts. The Wnt/b-catenin pathway is an important regulator of cellular proliferation and differentiation and abnormal activation of Wnt/b-catenin signal was observed in IPF. We examined whether inhibition of the Wnt/b-catenin pathway could attenuate <d>pulmonary fibrosis</d> in a bleomycin-induced murine model of <d>pulmonary fibrosis</d>. Pulmonary fibrosis was induced in C57BL/6N mice by intratracheal instillation of bleomycin. To inhibit the Wnt/b-catenin pathway, small interfering RNA siRNA for b-catenin was administered into trachea 2 h before bleomycin instillation and every 48 h afterward until sacrifice on day 14. The level of b-catenin expression was increased in the epithelial cells of bleomycin-administered mice. Intratracheal treatment with b-catenin siRNA significantly reduced b-catenin expression, <d>pulmonary fibrosis</d> and collagen synthesis in bleomycin-administered mice compared with controls, with no significant effect on the inflammatory response. The b-catenin-targeted siRNA also significantly decreased the levels of MMP-2 P<0.01 and TGF-b P<0.01 expression in the lung tissue. Blockade of the Wnt/b-catenin pathway by b-catenin siRNA decreased bleomycin-induced <d>pulmonary fibrosis</d> in the murine model. These findings suggest that targeting Wnt/b-catenin signaling may be an effective therapeutic approach in the treatment of IPF.
21212602|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive fibrotic lung disease and characterized by abnormal growth of fibroblasts and lung scarring. While the pathogenesis of <d>IPF</d> is not clearly understood, activation of transforming growth factor-b TGF-b and disruption of alveolar basement membrane seem to play important roles in leading to excess disruption of the matrix, which is associated with activated matrix metalloproteinase MMP and aberrant proliferation of myofibroblasts. The Wnt/b-catenin pathway is an important regulator of cellular proliferation and differentiation and abnormal activation of Wnt/b-catenin signal was observed in <d>IPF</d>. We examined whether inhibition of the Wnt/b-catenin pathway could attenuate <d>pulmonary fibrosis</d> in a bleomycin-induced murine model of <d>pulmonary fibrosis</d>. Pulmonary fibrosis was induced in C57BL/6N mice by intratracheal instillation of bleomycin. To inhibit the Wnt/b-catenin pathway, small interfering RNA siRNA for b-catenin was administered into trachea 2 h before bleomycin instillation and every 48 h afterward until sacrifice on day 14. The level of b-catenin expression was increased in the epithelial cells of bleomycin-administered mice. Intratracheal treatment with b-catenin siRNA significantly reduced b-catenin expression, <d>pulmonary fibrosis</d> and collagen synthesis in bleomycin-administered mice compared with controls, with no significant effect on the inflammatory response. The b-catenin-targeted siRNA also significantly decreased the levels of MMP-2 P<0.01 and TGF-b P<0.01 expression in the lung tissue. Blockade of the Wnt/b-catenin pathway by b-catenin siRNA decreased bleomycin-induced <d>pulmonary fibrosis</d> in the murine model. These findings suggest that targeting Wnt/b-catenin signaling may be an effective therapeutic approach in the treatment of <d>IPF</d>.
21212602|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> and characterized by abnormal growth of fibroblasts and lung scarring. While the pathogenesis of <d>IPF</d> is not clearly understood, activation of transforming growth factor-b TGF-b and disruption of alveolar basement membrane seem to play important roles in leading to excess disruption of the matrix, which is associated with activated matrix metalloproteinase MMP and aberrant proliferation of myofibroblasts. The Wnt/b-catenin pathway is an important regulator of cellular proliferation and differentiation and abnormal activation of Wnt/b-catenin signal was observed in <d>IPF</d>. We examined whether inhibition of the Wnt/b-catenin pathway could attenuate <d>pulmonary fibrosis</d> in a bleomycin-induced murine model of <d>pulmonary fibrosis</d>. Pulmonary fibrosis was induced in C57BL/6N mice by intratracheal instillation of bleomycin. To inhibit the Wnt/b-catenin pathway, small interfering RNA siRNA for b-catenin was administered into trachea 2 h before bleomycin instillation and every 48 h afterward until sacrifice on day 14. The level of b-catenin expression was increased in the epithelial cells of bleomycin-administered mice. Intratracheal treatment with b-catenin siRNA significantly reduced b-catenin expression, <d>pulmonary fibrosis</d> and collagen synthesis in bleomycin-administered mice compared with controls, with no significant effect on the inflammatory response. The b-catenin-targeted siRNA also significantly decreased the levels of MMP-2 P<0.01 and TGF-b P<0.01 expression in the lung tissue. Blockade of the Wnt/b-catenin pathway by b-catenin siRNA decreased bleomycin-induced <d>pulmonary fibrosis</d> in the murine model. These findings suggest that targeting Wnt/b-catenin signaling may be an effective therapeutic approach in the treatment of <d>IPF</d>.
21212602|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> and characterized by abnormal growth of fibroblasts and lung scarring. While the pathogenesis of <d>IPF</d> is not clearly understood, activation of <g>transforming growth factor-b</g> <g>TGF-b</g> and disruption of <d>alveolar basement</d> membrane seem to play important roles in leading to excess disruption of the matrix, which is associated with activated matrix metalloproteinase MMP and aberrant proliferation of myofibroblasts. The Wnt/b-catenin pathway is an important regulator of cellular proliferation and differentiation and abnormal activation of Wnt/b-catenin signal was observed in <d>IPF</d>. We examined whether inhibition of the Wnt/b-catenin pathway could attenuate <d>pulmonary fibrosis</d> in a bleomycin-induced murine model of <d>pulmonary fibrosis</d>. Pulmonary fibrosis was induced in C57BL/6N mice by intratracheal instillation of bleomycin. To inhibit the Wnt/b-catenin pathway, small interfering RNA siRNA for b-catenin was administered into trachea 2 h before bleomycin instillation and every 48 h afterward until sacrifice on day 14. The level of b-catenin expression was increased in the epithelial cells of bleomycin-administered mice. Intratracheal treatment with b-catenin siRNA significantly reduced b-catenin expression, <d>pulmonary fibrosis</d> and collagen synthesis in bleomycin-administered mice compared with controls, with no significant effect on the inflammatory response. The b-catenin-targeted siRNA also significantly decreased the levels of MMP-2 P<0.01 and <g>TGF-b</g> P<0.01 expression in the lung tissue. Blockade of the Wnt/b-catenin pathway by b-catenin siRNA decreased bleomycin-induced <d>pulmonary fibrosis</d> in the murine model. These findings suggest that targeting Wnt/b-catenin signaling may be an effective therapeutic approach in the treatment of <d>IPF</d>.
21212602|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> and characterized by abnormal growth of fibroblasts and lung scarring. While the pathogenesis of <d>IPF</d> is not clearly understood, activation of <g>transforming growth factor-b</g> <g>TGF-b</g> and disruption of <d>alveolar basement</d> membrane seem to play important roles in leading to excess disruption of the matrix, which is associated with activated matrix metalloproteinase MMP and aberrant proliferation of myofibroblasts. The Wnt/b-catenin pathway is an important regulator of cellular proliferation and differentiation and abnormal activation of Wnt/b-catenin signal was observed in <d>IPF</d>. We examined whether inhibition of the Wnt/b-catenin pathway could attenuate <d>pulmonary fibrosis</d> in a bleomycin-induced murine model of <d>pulmonary fibrosis</d>. <d>Pulmonary fibrosis</d> was induced in C57BL/6N mice by intratracheal instillation of bleomycin. To inhibit the Wnt/b-catenin pathway, small interfering RNA siRNA for b-catenin was administered into trachea 2 h before bleomycin instillation and every 48 h afterward until sacrifice on day 14. The level of b-catenin expression was increased in the epithelial cells of bleomycin-administered mice. Intratracheal treatment with b-catenin siRNA significantly reduced b-catenin expression, <d>pulmonary fibrosis</d> and collagen synthesis in bleomycin-administered mice compared with controls, with no significant effect on the inflammatory response. The b-catenin-targeted siRNA also significantly decreased the levels of MMP-2 P<0.01 and <g>TGF-b</g> P<0.01 expression in the lung tissue. Blockade of the Wnt/b-catenin pathway by b-catenin siRNA decreased bleomycin-induced <d>pulmonary fibrosis</d> in the murine model. These findings suggest that targeting Wnt/b-catenin signaling may be an effective therapeutic approach in the treatment of <d>IPF</d>.
21212602|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> and characterized by abnormal growth of fibroblasts and lung scarring. While the pathogenesis of <d>IPF</d> is not clearly understood, activation of <g>transforming growth factor-b</g> <g>TGF-b</g> and disruption of <d>alveolar basement</d> membrane seem to play important roles in leading to excess disruption of the matrix, which is associated with activated matrix metalloproteinase MMP and aberrant proliferation of myofibroblasts. The Wnt/b-catenin pathway is an important regulator of cellular proliferation and differentiation and abnormal activation of Wnt/b-catenin signal was observed in <d>IPF</d>. We examined whether inhibition of the Wnt/b-catenin pathway could attenuate <d>pulmonary fibrosis</d> in a bleomycin-induced murine model of <d>pulmonary fibrosis</d>. <d>Pulmonary fibrosis</d> was induced in C57BL/6N mice by intra<d>trachea</d>l instillation of bleomycin. To inhibit the Wnt/b-catenin pathway, small interfering RNA siRNA for b-catenin was administered into <d>trachea</d> 2 h before bleomycin instillation and every 48 h afterward until sacrifice on day 14. The level of b-catenin expression was increased in the epithelial cells of bleomycin-administered mice. Intra<d>trachea</d>l treatment with b-catenin siRNA significantly reduced b-catenin expression, <d>pulmonary fibrosis</d> and collagen synthesis in bleomycin-administered mice compared with controls, with no significant effect on the inflammatory response. The b-catenin-targeted siRNA also significantly decreased the levels of MMP-2 P<0.01 and <g>TGF-b</g> P<0.01 expression in the lung tissue. Blockade of the Wnt/b-catenin pathway by b-catenin siRNA decreased bleomycin-induced <d>pulmonary fibrosis</d> in the murine model. These findings suggest that targeting Wnt/b-catenin signaling may be an effective therapeutic approach in the treatment of <d>IPF</d>.
21224216|a|Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis <d>IPF</d> and is implicated in <d>IPF</d> pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of <d>IPF</d>, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin SIRT family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in <d>IPF</d> lung. Senescence-associated b-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor TGF-b-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells HBEC. The changes of SIRT6, p21, and interleukin IL-1b expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In <d>IPF</d> lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-b induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-b also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-b-induced senescence via proteasomal degradation of p21. TGF-b-induced senescent HBEC secreted increased amounts of IL-1b, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in <d>IPF</d> pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6.
21224216|a|Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and is implicated in <d>IPF</d> pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of <d>IPF</d>, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin SIRT family, <g>SIRT6</g>, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with <g>SIRT6</g> expression in <d>IPF</d> lung. Senescence-associated b-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor <g>TGF-b</g>-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells HBEC. The changes of <g>SIRT6</g>, p21, and interleukin IL-1b expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In <d>IPF</d> lung samples, an increase in markers of senescence and <g>SIRT6</g> expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that <g>TGF-b</g> induced senescence in primary HBEC by increasing p21 expression, and, whereas <g>TGF-b</g> also induced <g>SIRT6</g>, it was not sufficient to inhibit cellular senescence. However, overexpression of <g>SIRT6</g> efficiently inhibited <g>TGF-b</g>-induced senescence via proteasomal degradation of p21. <g>TGF-b</g>-induced senescent HBEC secreted increased amounts of IL-1b, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in <d>IPF</d> pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by <g>SIRT6</g>.
21253589|a|Transforming growth factor beta <g>TGFb</g> induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary <d>fibrosis</d>. Although the typical <g>TGFb</g> signaling pathway involves the Smad family of transcription factors, we have previously reported that peroxisome proliferator-activated receptor-y <g>PPAR</g>-y ligands inhibit <g>TGFb</g>-mediated differentiation of human lung fibroblasts to myofibroblasts via a Smad-independent pathway. <g>TGFb</g> also activates the phosphatidylinositol 3 kinase/protein kinase B <g>PI3K</g>/<g>Akt</g> pathway leading to phosphorylation of <g>Akt</g>S473. Here, we report that <g>PPAR</g>-y ligands, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid CDDO and 15-deoxy-12,14-15d-prostaglandin J2 15d-PGJ2, inhibit human myofibroblast differentiation of normal and idiopathic pulmonary fibrotic IPF fibroblasts, by blocking <g>Akt</g> phosphorylation at Ser473 by a <g>PPAR</g>-y-independent mechanism. The <g>PI3K</g> inhibitor LY294002 and a dominant-negative inactive kinase-domain mutant of <g>Akt</g> both inhibited <g>TGFb</g>-stimulated myofibroblast differentiation, as determined by Western blotting for a-smooth muscle actin and calponin. Prostaglandin A1 PGA1, a structural analogue of 15d-PGJ2 with an electrophilic center, also reduced <g>TGFb</g>-driven phosphorylation of <g>Akt</g>, while CAY10410, another analogue that lacks an electrophilic center, did not; implying that the activity of 15d-PGJ2 and CDDO is dependent on their electrophilic properties. <g>PPAR</g>-y ligands inhibited <g>TGFb</g>-induced <g>Akt</g> phosphorylation via both post-translational and post-transcriptional mechanisms. This inhibition is independent of MAPK-p38 and PTEN but is dependent on <g>TGFb</g>-induced phosphorylation of FAK, a kinase that acts upstream of <g>Akt</g>. Thus, <g>PPAR</g>-y ligands inhibit <g>TGFb</g> signaling by affecting two pro-survival pathways that culminate in myofibroblast differentiation. Further studies of <g>PPAR</g>-y ligands and small electrophilic molecules may lead to a new generation of anti-fibrotic therapeutics.
21253589|a|<g>Transforming growth factor beta</g> <g>TGFb</g> induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary <d>fibrosis</d>. Although the typical <g>TGFb</g> signaling pathway involves the Smad family of transcription factors, we have previously reported that <g>peroxisome proliferator-activated receptor-y</g> <g>PPAR</g>-y ligands inhibit <g>TGFb</g>-mediated differentiation of human lung fibroblasts to myofibroblasts via a Smad-independent pathway. <g>TGFb</g> also activates the phosphatidylinositol 3 kinase/<g>protein kinase B</g> <g>PI3K</g>/<g>Akt</g> pathway leading to phosphorylation of <g>Akt</g>S473. Here, we report that <g>PPAR</g>-y ligands, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid CDDO and 15-deoxy-12,14-15d-prostaglandin J2 15d-PGJ2, inhibit human myofibroblast differentiation of normal and <d>idiopathic pulmonary fibrotic</d> IPF fibroblasts, by blocking <g>Akt</g> phosphorylation at Ser473 by a <g>PPAR</g>-y-independent mechanism. The <g>PI3K</g> inhibitor LY294002 and a dominant-negative inactive kinase-domain mutant of <g>Akt</g> both inhibited <g>TGFb</g>-stimulated myofibroblast differentiation, as determined by Western blotting for a-smooth muscle actin and calponin. Prostaglandin A1 PGA1, a structural analogue of 15d-PGJ2 with an electrophilic center, also reduced <g>TGFb</g>-driven phosphorylation of <g>Akt</g>, while CAY10410, another analogue that lacks an electrophilic center, did not; implying that the activity of 15d-PGJ2 and CDDO is dependent on their electrophilic properties. <g>PPAR</g>-y ligands inhibited <g>TGFb</g>-induced <g>Akt</g> phosphorylation via both post-translational and post-transcriptional mechanisms. This inhibition is independent of MAPK-p38 and PTEN but is dependent on <g>TGFb</g>-induced phosphorylation of FAK, a kinase that acts upstream of <g>Akt</g>. Thus, <g>PPAR</g>-y ligands inhibit <g>TGFb</g> signaling by affecting two pro-survival pathways that culminate in myofibroblast differentiation. Further studies of <g>PPAR</g>-y ligands and small electrophilic molecules may lead to a new generation of anti-fibrotic therapeutics.
21253589|a|<g>Transforming growth factor beta</g> <g>TGFb</g> induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary <d>fibrosis</d>. Although the typical <g>TGFb</g> signaling pathway involves the Smad family of transcription factors, we have previously reported that <g>peroxisome proliferator-activated receptor-y</g> <g>PPAR</g>-y ligands inhibit <g>TGFb</g>-mediated differentiation of human lung fibroblasts to myofibroblasts via a Smad-independent pathway. <g>TGFb</g> also activates the phosphatidylinositol 3 kinase/<g>protein kinase B</g> <g>PI3K</g>/<g>Akt</g> pathway leading to phosphorylation of <g>Akt</g>S473. Here, we report that <g>PPAR</g>-y ligands, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid CDDO and 15-deoxy-12,14-15d-prostaglandin J2 15d-PGJ2, inhibit human myofibroblast differentiation of normal and <d>idiopathic pulmonary fibrotic</d> <d>IPF</d> fibroblasts, by blocking <g>Akt</g> phosphorylation at Ser473 by a <g>PPAR</g>-y-independent mechanism. The <g>PI3K</g> inhibitor LY294002 and a dominant-negative inactive kinase-domain mutant of <g>Akt</g> both inhibited <g>TGFb</g>-stimulated myofibroblast differentiation, as determined by Western blotting for a-smooth muscle actin and calponin. Prostaglandin A1 PGA1, a structural analogue of 15d-PGJ2 with an electrophilic center, also reduced <g>TGFb</g>-driven phosphorylation of <g>Akt</g>, while CAY10410, another analogue that lacks an electrophilic center, did not; implying that the activity of 15d-PGJ2 and CDDO is dependent on their electrophilic properties. <g>PPAR</g>-y ligands inhibited <g>TGFb</g>-induced <g>Akt</g> phosphorylation via both post-translational and post-transcriptional mechanisms. This inhibition is independent of MAPK-p38 and PTEN but is dependent on <g>TGFb</g>-induced phosphorylation of FAK, a kinase that acts upstream of <g>Akt</g>. Thus, <g>PPAR</g>-y ligands inhibit <g>TGFb</g> signaling by affecting two pro-survival pathways that culminate in myofibroblast differentiation. Further studies of <g>PPAR</g>-y ligands and small electrophilic molecules may lead to a new generation of anti-fibrotic therapeutics.
21269063|a|The authors investigated the role of resveratrol RV, a natural poliphenolic molecule with several biological activities, in transforming growth factor-b <g>TGF-b</g>-induced proliferation and differentiation of ex vivo human pulmonary fibroblasts into myofibroblasts. The effects of RV treatment were evaluated by analyzing <g>TGF-b</g>-induced a-smooth muscle actin <g>a-SMA</g> expression and collagen production, as well as cell proliferation of both normal and <d>idiopathic pulmonary fibrosis</d> IPF lung fibroblasts. Results demonstrate that RV inhibits <g>TGF-b</g>-induced cell proliferation of both normal and pathological lung fibroblasts, attenuates <g>a-SMA</g> expression at both the mRNA and protein levels, and also inhibits intracellular collagen deposition. In order to understand the molecular mechanisms, the authors also investigated the effects of RV treatment on signaling pathways involved in <g>TGF-b</g>-induced fibrosis. The authors show that RV inhibited <g>TGF-b</g>-induced phosphorylation of both extracellular signal-regulated kinases <g>ERK</g>1/2 and the serine/threonine kinase, <g>Akt</g>. Moreover, RV treatment blocked the <g>TGF-b</g>-induced decrease in phosphatase and tensin homolog <g>PTEN</g> expression levels.
21269063|a|The authors investigated the role of resveratrol RV, a natural poliphenolic molecule with several biological activities, in transforming growth factor-b <g>TGF-b</g>-induced proliferation and differentiation of ex vivo human pulmonary fibroblasts into myofibroblasts. The effects of RV treatment were evaluated by analyzing <g>TGF-b</g>-induced a-smooth muscle actin <g>a-SMA</g> expression and collagen production, as well as cell proliferation of both normal and <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> lung fibroblasts. Results demonstrate that RV inhibits <g>TGF-b</g>-induced cell proliferation of both normal and pathological lung fibroblasts, attenuates <g>a-SMA</g> expression at both the mRNA and protein levels, and also inhibits intracellular collagen deposition. In order to understand the molecular mechanisms, the authors also investigated the effects of RV treatment on signaling pathways involved in <g>TGF-b</g>-induced fibrosis. The authors show that RV inhibited <g>TGF-b</g>-induced phosphorylation of both extracellular signal-regulated kinases <g>ERK</g>1/2 and the serine/threonine kinase, <g>Akt</g>. Moreover, RV treatment blocked the <g>TGF-b</g>-induced decrease in phosphatase and tensin homolog <g>PTEN</g> expression levels.
21269063|a|The authors investigated the role of resveratrol RV, a natural poliphenolic molecule with several biological activities, in transforming growth factor-b <g>TGF-b</g>-induced proliferation and differentiation of ex vivo human pulmonary fibroblasts into myofibroblasts. The effects of RV treatment were evaluated by analyzing <g>TGF-b</g>-induced a-smooth muscle actin <g>a-SMA</g> expression and collagen production, as well as cell proliferation of both normal and <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> lung fibroblasts. Results demonstrate that RV inhibits <g>TGF-b</g>-induced cell proliferation of both normal and pathological lung fibroblasts, attenuates <g>a-SMA</g> expression at both the mRNA and protein levels, and also inhibits intracellular collagen deposition. In order to understand the molecular mechanisms, the authors also investigated the effects of RV treatment on signaling pathways involved in <g>TGF-b</g>-induced <d>fibrosis</d>. The authors show that RV inhibited <g>TGF-b</g>-induced phosphorylation of both extracellular signal-regulated kinases <g>ERK</g>1/2 and the serine/threonine kinase, <g>Akt</g>. Moreover, RV treatment blocked the <g>TGF-b</g>-induced decrease in phosphatase and tensin homolog <g>PTEN</g> expression levels.
21278261|a|<d>Fibrosis</d> of the lung is characterized by the accumulation of myofibroblasts, a key mediator in the fibrogenic reaction. Cumulative evidence indicates that epithelial-mesenchymal transition EMT, a process whereby epithelial cells become mesenchyme-like, is an important contributing source for the myofibroblast population. Underlying this phenotypical change is a dramatic alteration in cellular structure. The receptor for advanced glycation end-products <g>RAGE</g> has been suggested to maintain lung homeostasis by mediating cell adhesion, while the family of ezrin/radixin/moesin ERM proteins, on the other hand, serve as an important cross-linker between the plasma membrane and cytoskeleton. In the present investigation, we tested the hypothesis that <g>RAGE</g> and ERM interact and play a key role in regulating EMT-associated structural changes in alveolar epithelial cells. Exposure of A549 cells to inflammatory cytokines resulted in phosphorylation and redistribution of ERM to the cell periphery and localization with EMT-related actin stress fibers. Simultaneously, blockade of Rho kinase ROCK signaling attenuated these cytokine-induced structural changes. Additionally, <g>RAGE</g> expression was diminished after cytokine stimulation, with release of its soluble isoform via a matrix metalloproteinase MMP-9-dependent mechanism. Immunofluorescence microscopy and coimmunoprecipitation revealed association between ERM and <g>RAGE</g> under basal conditions, which was disrupted when challenged with inflammatory cytokines, as ERM in its activated state complexed with membrane-linked <g>CD44</g>. Dual-fluorescence immunohistochemistry of patient idiopathic pulmonary fibrosis IPF tissues highlighted marked diminution of <g>RAGE</g> in fibrotic samples, together with enhanced levels of <g>CD44</g> and double-positive cells for <g>CD44</g> and phospho pERM. These data suggest that dysregulation of the ERM-<g>RAGE</g> complex might be an important step in rearrangement of the actin cytoskeleton during proinflammatory cytokine-induced EMT of human alveolar epithelial cells.
21278261|a|<d>Fibrosis</d> of the lung is characterized by the accumulation of myofibroblasts, a key mediator in the fibrogenic reaction. Cumulative evidence indicates that epithelial-mesenchymal transition EMT, a process whereby epithelial cells become mesenchyme-like, is an important contributing source for the myofibroblast population. Underlying this phenotypical change is a dramatic alteration in cellular structure. The receptor for advanced glycation end-products <g>RAGE</g> has been suggested to maintain lung homeostasis by mediating cell adhesion, while the family of ezrin/radixin/moesin ERM proteins, on the other hand, serve as an important cross-linker between the plasma membrane and cytoskeleton. In the present investigation, we tested the hypothesis that <g>RAGE</g> and ERM interact and play a key role in regulating EMT-associated structural changes in alveolar epithelial cells. Exposure of A549 cells to inflammatory cytokines resulted in phosphorylation and redistribution of ERM to the cell periphery and localization with EMT-related actin stress fibers. Simultaneously, blockade of Rho kinase ROCK signaling attenuated these cytokine-induced structural changes. Additionally, <g>RAGE</g> expression was diminished after cytokine stimulation, with release of its soluble isoform via a <g>matrix metalloproteinase MMP-9</g>-dependent mechanism. Immunofluorescence microscopy and coimmunoprecipitation revealed association between ERM and <g>RAGE</g> under basal conditions, which was disrupted when challenged with inflammatory cytokines, as ERM in its activated state complexed with membrane-linked <g>CD44</g>. Dual-fluorescence immunohistochemistry of patient <d>idiopathic pulmonary fibrosis</d> IPF tissues highlighted marked diminution of <g>RAGE</g> in fibrotic samples, together with enhanced levels of <g>CD44</g> and double-positive cells for <g>CD44</g> and phospho pERM. These data suggest that dysregulation of the ERM-<g>RAGE</g> complex might be an important step in rearrangement of the actin cytoskeleton during proinflammatory cytokine-induced EMT of human alveolar epithelial cells.
21278261|a|<d>Fibrosis</d> of the lung is characterized by the accumulation of myofibroblasts, a key mediator in the fibrogenic reaction. Cumulative evidence indicates that epithelial-mesenchymal transition EMT, a process whereby epithelial cells become mesenchyme-like, is an important contributing source for the myofibroblast population. Underlying this phenotypical change is a dramatic alteration in cellular structure. The receptor for advanced glycation end-products <g>RAGE</g> has been suggested to maintain lung homeostasis by mediating cell adhesion, while the family of ezrin/radixin/moesin ERM proteins, on the other hand, serve as an important cross-linker between the plasma membrane and cytoskeleton. In the present investigation, we tested the hypothesis that <g>RAGE</g> and ERM interact and play a key role in regulating EMT-associated structural changes in alveolar epithelial cells. Exposure of A549 cells to inflammatory cytokines resulted in phosphorylation and redistribution of ERM to the cell periphery and localization with EMT-related actin stress fibers. Simultaneously, blockade of Rho kinase ROCK signaling attenuated these cytokine-induced structural changes. Additionally, <g>RAGE</g> expression was diminished after cytokine stimulation, with release of its soluble isoform via a <g>matrix metalloproteinase MMP-9</g>-dependent mechanism. Immunofluorescence microscopy and coimmunoprecipitation revealed association between ERM and <g>RAGE</g> under basal conditions, which was disrupted when challenged with inflammatory cytokines, as ERM in its activated state complexed with membrane-linked <g>CD44</g>. Dual-fluorescence immunohistochemistry of patient <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> tissues highlighted marked diminution of <g>RAGE</g> in fibrotic samples, together with enhanced levels of <g>CD44</g> and double-positive cells for <g>CD44</g> and phospho pERM. These data suggest that dysregulation of the ERM-<g>RAGE</g> complex might be an important step in rearrangement of the actin cytoskeleton during proinflammatory cytokine-induced EMT of human alveolar epithelial cells.
21420029|a|In this review, we describe the recent advances in the understanding of the role of microRNAs in <d>idiopathic pulmonary fibrosis</d> IPF, a chronic progressive and lethal fibrotic lung disease. Approximately 10% of the microRNAs are significantly changed in IPF lungs. Among the significantly downregulated microRNAs are members of let-7, mir-29, and mir-30 families as well as miR-17   92 cluster among the upregulated mir-155 and mir-21. Downregulation of let-7 family members leads to changes consistent with epithelial mesenchymal transition in lung epithelial cells both in vitro and in vivo, whereas inhibition of mir-21 modulates fibrosis in the bleomycin model of lung fibrosis. Perturbations of mir-155 and mir-29 have profibrotic effects in vitro but have not yet been assessed in vivo in the context of lung fibrosis. A recurrent global theme is that many microRNAs studied in IPF are both regulated by transforming growth factor b1 TGFb1 and regulate TGFb1 signaling pathway by their target genes. As a result, their aberrant expression leads to a release of inhibitions on the TGFb1 pathway and to the creation of feed-forward loops. Coanalysis of published microRNA and gene expression microarray data in IPF reveals enrichment of the TGFb1, Wnt, sonic hedgehog, p53, and vascular endothelial growth factor pathways and complex regulatory networks. The changes in microRNA expression in the IPF lung and the evidence for their role in the fibrosis suggest that microRNAs should be evaluated as therapeutic targets in IPF.
21420029|a|In this review, we describe the recent advances in the understanding of the role of microRNAs in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a chronic progressive and lethal fibrotic lung disease. Approximately 10% of the microRNAs are significantly changed in <d>IPF</d> lungs. Among the significantly downregulated microRNAs are members of let-7, mir-29, and mir-30 families as well as miR-17   92 cluster among the upregulated mir-155 and mir-21. Downregulation of let-7 family members leads to changes consistent with epithelial mesenchymal transition in lung epithelial cells both in vitro and in vivo, whereas inhibition of mir-21 modulates fibrosis in the bleomycin model of lung fibrosis. Perturbations of mir-155 and mir-29 have profibrotic effects in vitro but have not yet been assessed in vivo in the context of lung fibrosis. A recurrent global theme is that many microRNAs studied in <d>IPF</d> are both regulated by transforming growth factor b1 TGFb1 and regulate TGFb1 signaling pathway by their target genes. As a result, their aberrant expression leads to a release of inhibitions on the TGFb1 pathway and to the creation of feed-forward loops. Coanalysis of published microRNA and gene expression microarray data in <d>IPF</d> reveals enrichment of the TGFb1, Wnt, sonic hedgehog, p53, and vascular endothelial growth factor pathways and complex regulatory networks. The changes in microRNA expression in the <d>IPF</d> lung and the evidence for their role in the fibrosis suggest that microRNAs should be evaluated as therapeutic targets in <d>IPF</d>.
21420029|a|In this review, we describe the recent advances in the understanding of the role of microRNAs in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a chronic progressive and lethal <d>fibrotic lung disease</d>. Approximately 10% of the microRNAs are significantly changed in <d>IPF</d> lungs. Among the significantly downregulated microRNAs are members of let-7, mir-29, and mir-30 families as well as miR-17   92 cluster among the upregulated mir-155 and mir-21. Downregulation of let-7 family members leads to changes consistent with epithelial mesenchymal transition in lung epithelial cells both in vitro and in vivo, whereas inhibition of mir-21 modulates fibrosis in the bleomycin model of lung fibrosis. Perturbations of mir-155 and mir-29 have profibrotic effects in vitro but have not yet been assessed in vivo in the context of lung fibrosis. A recurrent global theme is that many microRNAs studied in <d>IPF</d> are both regulated by transforming growth factor b1 TGFb1 and regulate TGFb1 signaling pathway by their target genes. As a result, their aberrant expression leads to a release of inhibitions on the TGFb1 pathway and to the creation of feed-forward loops. Coanalysis of published microRNA and gene expression microarray data in <d>IPF</d> reveals enrichment of the TGFb1, Wnt, sonic hedgehog, p53, and vascular endothelial growth factor pathways and complex regulatory networks. The changes in microRNA expression in the <d>IPF</d> lung and the evidence for their role in the fibrosis suggest that microRNAs should be evaluated as therapeutic targets in <d>IPF</d>.
21420029|a|In this review, we describe the recent advances in the understanding of the role of microRNAs in <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, a chronic progressive and lethal <d>fibrotic lung disease</d>. Approximately 10% of the microRNAs are significantly changed in <d>IPF</d> lungs. Among the significantly downregulated microRNAs are members of let-7, mir-29, and mir-30 families as well as <g>miR-17   92</g> cluster among the upregulated <g>mir-155</g> and <g>mir-21</g>. Downregulation of let-7 family members leads to changes consistent with epithelial mesenchymal transition in lung epithelial cells both in vitro and in vivo, whereas inhibition of <g>mir-21</g> modulates <d>fibrosis</d> in the bleomycin model of lung <d>fibrosis</d>. Perturbations of <g>mir-155</g> and mir-29 have profibrotic effects in vitro but have not yet been assessed in vivo in the context of lung <d>fibrosis</d>. A recurrent global theme is that many microRNAs studied in <d>IPF</d> are both regulated by transforming growth factor b1 TGFb1 and regulate TGFb1 signaling pathway by their target genes. As a result, their aberrant expression leads to a release of inhibitions on the TGFb1 pathway and to the creation of feed-forward loops. Coanalysis of published microRNA and gene expression microarray data in <d>IPF</d> reveals enrichment of the TGFb1, Wnt, sonic hedgehog, p53, and vascular endothelial growth factor pathways and complex regulatory networks. The changes in microRNA expression in the <d>IPF</d> lung and the evidence for their role in the <d>fibrosis</d> suggest that microRNAs should be evaluated as therapeutic targets in <d>IPF</d>.
21471103|a|RATIONALE: Activation of the coagulation cascade has been demonstrated in pulmonary fibrosis. In addition to its procoagulant function, various coagulation proteases exhibit cellular effects that may also contribute to fibrotic processes in the lung. OBJECTIVE: To investigate the importance of protease-activated receptor PAR-2 and its activators, coagulation factor VIIa FVIIa/tissue factor TF, in the development of <d>idiopathic pulmonary fibrosis</d> IPF. METHODS: Expression and localization of PAR-2 and its activators were examined in IPF lung tissue. The ability of PAR-2 to mediate various cellular processes was studied in vitro. MEASUREMENTS AND MAIN RESULTS: Expression of PAR-2 was strongly elevated in IPF lungs and was attributable to alveolar type II cells and fibroblasts/myofibroblasts. Transforming growth factor-b1, a key profibrotic cytokine, considerably enhanced PAR-2 expression in human lung fibroblasts. FVIIa stimulated proliferation of human lung fibroblasts and extracellular matrix production in a PAR-2-dependent manner, but did not initiate differentiation of fibroblasts into myofibroblasts. PAR-2/FVIIa-driven mitogenic activities were mediated via the p44/42 mitogen-activated protein kinase pathway and were independent of factor Xa and thrombin production. Proproliferative properties of FVIIa were markedly potentiated in the presence of TF and abrogated by TF antisense oligonucleotides. Hyperplastic alveolar type II cells overlying fibroblastic foci were found to be the source of FVII in IPF lungs. Moreover, TF colocalized with PAR-2 on fibroblasts/myofibroblasts in IPF lungs. CONCLUSIONS: The PAR-2/TF/FVIIa axis may contribute to the development of pulmonary fibrosis; thus, interference with this pathway confers novel therapeutic potential for the treatment of IPF.
21471103|a|RATIONALE: Activation of the coagulation cascade has been demonstrated in <d>pulmonary fibrosis</d>. In addition to its procoagulant function, various coagulation proteases exhibit cellular effects that may also contribute to fibrotic processes in the lung. OBJECTIVE: To investigate the importance of protease-activated receptor PAR-2 and its activators, coagulation factor VIIa FVIIa/tissue factor TF, in the development of <d>idiopathic <d>pulmonary fibrosis</d></d> IPF. METHODS: Expression and localization of PAR-2 and its activators were examined in IPF lung tissue. The ability of PAR-2 to mediate various cellular processes was studied in vitro. MEASUREMENTS AND MAIN RESULTS: Expression of PAR-2 was strongly elevated in IPF lungs and was attributable to alveolar type II cells and fibroblasts/myofibroblasts. Transforming growth factor-b1, a key profibrotic cytokine, considerably enhanced PAR-2 expression in human lung fibroblasts. FVIIa stimulated proliferation of human lung fibroblasts and extracellular matrix production in a PAR-2-dependent manner, but did not initiate differentiation of fibroblasts into myofibroblasts. PAR-2/FVIIa-driven mitogenic activities were mediated via the p44/42 mitogen-activated protein kinase pathway and were independent of factor Xa and thrombin production. Proproliferative properties of FVIIa were markedly potentiated in the presence of TF and abrogated by TF antisense oligonucleotides. Hyperplastic alveolar type II cells overlying fibroblastic foci were found to be the source of FVII in IPF lungs. Moreover, TF colocalized with PAR-2 on fibroblasts/myofibroblasts in IPF lungs. CONCLUSIONS: The PAR-2/TF/FVIIa axis may contribute to the development of <d>pulmonary fibrosis</d>; thus, interference with this pathway confers novel therapeutic potential for the treatment of IPF.
21471103|a|RATIONALE: Activation of the coagulation cascade has been demonstrated in <d>pulmonary fibrosis</d>. In addition to its procoagulant function, various coagulation proteases exhibit cellular effects that may also contribute to fibrotic processes in the lung. OBJECTIVE: To investigate the importance of <g>protease-activated receptor PAR-2</g> and its activators, coagulation factor VIIa FVIIa/<g>tissue factor</g> TF, in the development of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. METHODS: Expression and localization of PAR-2 and its activators were examined in <d>IPF</d> lung tissue. The ability of PAR-2 to mediate various cellular processes was studied in vitro. MEASUREMENTS AND MAIN RESULTS: Expression of PAR-2 was strongly elevated in <d>IPF</d> lungs and was attributable to alveolar type II cells and fibroblasts/myofibroblasts. Transforming growth factor-b1, a key profibrotic cytokine, considerably enhanced PAR-2 expression in human lung fibroblasts. FVIIa stimulated proliferation of human lung fibroblasts and extracellular matrix production in a PAR-2-dependent manner, but did not initiate differentiation of fibroblasts into myofibroblasts. PAR-2/FVIIa-driven mitogenic activities were mediated via the p44/42 mitogen-activated protein kinase pathway and were independent of factor Xa and thrombin production. Proproliferative properties of FVIIa were markedly potentiated in the presence of TF and abrogated by TF antisense oligonucleotides. Hyperplastic alveolar type II cells overlying fibroblastic foci were found to be the source of FVII in <d>IPF</d> lungs. Moreover, TF colocalized with PAR-2 on fibroblasts/myofibroblasts in <d>IPF</d> lungs. CONCLUSIONS: The PAR-2/TF/FVIIa axis may contribute to the development of <d>pulmonary fibrosis</d>; thus, interference with this pathway confers novel therapeutic potential for the treatment of <d>IPF</d>.
21471103|a|RATIONALE: Activation of the coagulation cascade has been demonstrated in <d>pulmonary fibrosis</d>. In addition to its procoagulant function, various coagulation proteases exhibit cellular effects that may also contribute to fibrotic processes in the lung. OBJECTIVE: To investigate the importance of <g>protease-activated receptor <g>PAR-2</g></g> and its activators, coagulation factor VIIa FVIIa/<g>tissue factor</g> TF, in the development of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. METHODS: Expression and localization of <g>PAR-2</g> and its activators were examined in <d>IPF</d> lung tissue. The ability of <g>PAR-2</g> to mediate various cellular processes was studied in vitro. MEASUREMENTS AND MAIN RESULTS: Expression of <g>PAR-2</g> was strongly elevated in <d>IPF</d> lungs and was attributable to alveolar type II cells and fibroblasts/myofibroblasts. <g>Transforming growth factor-b1</g>, a key profibrotic cytokine, considerably enhanced <g>PAR-2</g> expression in human lung fibroblasts. FVIIa stimulated proliferation of human lung fibroblasts and extracellular matrix production in a <g>PAR-2</g>-dependent manner, but did not initiate differentiation of fibroblasts into myofibroblasts. <g>PAR-2</g>/FVIIa-driven mitogenic activities were mediated via the p44/42 mitogen-activated protein kinase pathway and were independent of factor Xa and thrombin production. Proproliferative properties of FVIIa were markedly potentiated in the presence of TF and abrogated by TF antisense oligonucleotides. <d>Hyperplastic</d> alveolar type II cells overlying fibroblastic foci were found to be the source of FVII in <d>IPF</d> lungs. Moreover, TF colocalized with <g>PAR-2</g> on fibroblasts/myofibroblasts in <d>IPF</d> lungs. CONCLUSIONS: The <g>PAR-2</g>/TF/FVIIa axis may contribute to the development of <d>pulmonary fibrosis</d>; thus, interference with this pathway confers novel therapeutic potential for the treatment of <d>IPF</d>.
21498628|a|Prior work has shown that transforming growth factor-b TGF-b can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with <d>idiopathic pulmonary fibrosis</d> IPF, we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, a-smooth muscle actin a-SMA, and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C SPC and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and a-SMA; markers of mesenchymal cells. Addition of a TGF-b receptor kinase inhibitor SB431542 to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-b can mediate this process.
21498628|a|Prior work has shown that <g>transforming growth factor-b</g> <g>TGF-b</g> can mediate transition of <d>alveolar type II</d> cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with <d>idiopathic pulmonary fibrosis</d> IPF, we studied <d>alveolar type II</d> cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, a-smooth muscle actin a-SMA, and calponin. When cultured on Matrigel/collagen, human <d>alveolar type II</d> cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C SPC and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and a-SMA; markers of mesenchymal cells. Addition of a <g>TGF-b</g> receptor kinase inhibitor SB431542 to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that <d>alveolar type II</d> cells can acquire features of mesenchymal cells in IPF lungs and that <g>TGF-b</g> can mediate this process.
21498628|a|Prior work has shown that <g>transforming growth factor-b</g> <g>TGF-b</g> can mediate transition of <d>alveolar type II</d> cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, we studied <d>alveolar type II</d> cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with <d>IPF</d> express higher levels of mRNA for the mesenchymal proteins type I collagen, a-smooth muscle actin a-SMA, and calponin. When cultured on Matrigel/collagen, human <d>alveolar type II</d> cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C SPC and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and a-SMA; markers of mesenchymal cells. Addition of a <g>TGF-b</g> receptor kinase inhibitor SB431542 to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that <d>alveolar type II</d> cells can acquire features of mesenchymal cells in <d>IPF</d> lungs and that <g>TGF-b</g> can mediate this process.
21502778|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> IPF is characterized by progressive fibrosis and a poor prognosis. Alveolar epithelial cells AECs are considered to play important roles by releasing growth factors and matrix metalloproteinases MMPs and by being involved in epithelial mesenchymal transition in IPF. Doxycycline hydrochloride DOXY, an inhibitor of MMPs, attenuates <d>pulmonary fibrosis</d> in models and in patients with IPF; however, the mechanism of this action remains obscure. OBJECTIVES: The present study investigated the effect of DOXY on growth factors and MMP production in AECs. METHODS: Bleomycin BL-induced murine <d>pulmonary fibrosis</d> was treated with DOXY and examined by pathological and immunohistochemical staining. The human alveolar epithelial cell line A549 was stimulated with transforming growth factor TGF-b1 and incubated with DOXY, and then the expression of growth factors, MMPs, and collagen type I was evaluated at the mRNA and protein levels. We also evaluated the effects of DOXY on the TGF-b1-induced Smad signaling pathway. RESULTS: DOXY reduced fibrosis scores and the production of collagen type I, connective tissue growth factor CTGF, and TGF-b1 in BL models. DOXY inhibited the mRNA expression of MMP-2, MPP-9, CTGF, and collagen type I as well as the production of MMP-2 and platelet-derived growth factor-AA protein induced in A549 cells by TGF-b1 but not by Smad2 and Smad3 phosphorylation. We did not find a similar effect of DOXY in normal lung fibroblasts. CONCLUSIONS: Our results suggest that DOXY could be useful for attenuating <d>pulmonary fibrosis</d> through the inhibition of growth factors and MMP production in AECs.
21502778|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is characterized by progressive fibrosis and a poor prognosis. Alveolar epithelial cells AECs are considered to play important roles by releasing growth factors and matrix metalloproteinases MMPs and by being involved in epithelial mesenchymal transition in <d>IPF</d>. Doxycycline hydrochloride DOXY, an inhibitor of MMPs, attenuates <d>pulmonary fibrosis</d> in models and in patients with <d>IPF</d>; however, the mechanism of this action remains obscure. OBJECTIVES: The present study investigated the effect of DOXY on growth factors and MMP production in AECs. METHODS: Bleomycin BL-induced murine <d>pulmonary fibrosis</d> was treated with DOXY and examined by pathological and immunohistochemical staining. The human alveolar epithelial cell line A549 was stimulated with transforming growth factor TGF-b1 and incubated with DOXY, and then the expression of growth factors, MMPs, and collagen type I was evaluated at the mRNA and protein levels. We also evaluated the effects of DOXY on the TGF-b1-induced Smad signaling pathway. RESULTS: DOXY reduced fibrosis scores and the production of collagen type I, connective tissue growth factor CTGF, and TGF-b1 in BL models. DOXY inhibited the mRNA expression of MMP-2, MPP-9, CTGF, and collagen type I as well as the production of MMP-2 and platelet-derived growth factor-AA protein induced in A549 cells by TGF-b1 but not by Smad2 and Smad3 phosphorylation. We did not find a similar effect of DOXY in normal lung fibroblasts. CONCLUSIONS: Our results suggest that DOXY could be useful for attenuating <d>pulmonary fibrosis</d> through the inhibition of growth factors and MMP production in AECs.
21502778|a|BACKGROUND: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characterized by progressive <d>fibrosis</d> and a poor prognosis. Alveolar epithelial cells AECs are considered to play important roles by releasing growth factors and matrix metalloproteinases MMPs and by being involved in epithelial mesenchymal transition in <d>IPF</d>. Doxycycline hydrochloride DOXY, an inhibitor of MMPs, attenuates <d>pulmonary <d>fibrosis</d></d> in models and in patients with <d>IPF</d>; however, the mechanism of this action remains obscure. OBJECTIVES: The present study investigated the effect of DOXY on growth factors and MMP production in AECs. METHODS: Bleomycin BL-induced murine <d>pulmonary <d>fibrosis</d></d> was treated with DOXY and examined by pathological and immunohistochemical staining. The human alveolar epithelial cell line A549 was stimulated with transforming growth factor TGF-b1 and incubated with DOXY, and then the expression of growth factors, MMPs, and collagen type I was evaluated at the mRNA and protein levels. We also evaluated the effects of DOXY on the TGF-b1-induced Smad signaling pathway. RESULTS: DOXY reduced <d>fibrosis</d> scores and the production of collagen type I, connective tissue growth factor CTGF, and TGF-b1 in BL models. DOXY inhibited the mRNA expression of MMP-2, MPP-9, CTGF, and collagen type I as well as the production of MMP-2 and platelet-derived growth factor-AA protein induced in A549 cells by TGF-b1 but not by Smad2 and Smad3 phosphorylation. We did not find a similar effect of DOXY in normal lung fibroblasts. CONCLUSIONS: Our results suggest that DOXY could be useful for attenuating <d>pulmonary <d>fibrosis</d></d> through the inhibition of growth factors and MMP production in AECs.
21511034|a|Fibrosis is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as obesity and aging. The pathogenesis of <d>fibrosis</d> involves multiple cell types and extracellular signals, of which transforming growth factor-   TGF-   is pre-eminent. The prevalence of <d>fibrosis</d> is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor Egr-1 in the pathogenesis of <d>fibrosis</d>. Egr-1 couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to injury and stress. In contrast to other ligand-activated transcription factors such as NF-kB, c-jun and Smad2/3 that undergo post-translational modification such as phosphorylation and nuclear translocation, Egr-1 activity is regulated via its biosynthesis. Aberrant Egr-1 expression or activity is implicated in cancer, inflammation, atherosclerosis, and ischemic injury and recent studies now indicate an important role for Egr-1 in TGF-  -dependent profibrotic responses. Fibrosis in various animal models and human diseases such as scleroderma SSc and idiopathic pulmonary <d>fibrosis</d> IPF is accompanied by aberrant Egr-1 expression. Moreover Egr-1 appears to be required for physiologic and pathological connective tissue remodeling, and Egr-1-null mice are protected from <d>fibrosis</d>. As a novel profibrotic mediator, Egr-1 thus appears to be a promising potential target for the development of anti-fibrotic therapies.
21511034|a|<d>Fibrosis</d> is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as obesity and aging. The pathogenesis of <d>fibrosis</d> involves multiple cell types and extracellular signals, of which transforming growth factor-   TGF-   is pre-eminent. The prevalence of <d>fibrosis</d> is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor Egr-1 in the pathogenesis of <d>fibrosis</d>. Egr-1 couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to injury and stress. In contrast to other ligand-activated transcription factors such as NF-kB, c-jun and Smad2/3 that undergo post-translational modification such as phosphorylation and nuclear translocation, Egr-1 activity is regulated via its biosynthesis. Aberrant Egr-1 expression or activity is implicated in cancer, inflammation, atherosclerosis, and ischemic injury and recent studies now indicate an important role for Egr-1 in TGF-  -dependent profibrotic responses. <d>Fibrosis</d> in various animal models and human diseases such as scleroderma SSc and idiopathic pulmonary <d>fibrosis</d> IPF is accompanied by aberrant Egr-1 expression. Moreover Egr-1 appears to be required for physiologic and pathological connective tissue remodeling, and Egr-1-null mice are protected from <d>fibrosis</d>. As a novel profibrotic mediator, Egr-1 thus appears to be a promising potential target for the development of anti-fibrotic therapies.
21511034|a|<d>Fibrosis</d> is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as <d>obesity</d> and aging. The pathogenesis of <d>fibrosis</d> involves multiple cell types and extracellular signals, of which transforming growth factor-   TGF-   is pre-eminent. The prevalence of <d>fibrosis</d> is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor Egr-1 in the pathogenesis of <d>fibrosis</d>. Egr-1 couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to injury and stress. In contrast to other ligand-activated transcription factors such as NF-kB, c-jun and Smad2/3 that undergo post-translational modification such as phosphorylation and nuclear translocation, Egr-1 activity is regulated via its biosynthesis. Aberrant Egr-1 expression or activity is implicated in cancer, inflammation, atherosclerosis, and ischemic injury and recent studies now indicate an important role for Egr-1 in TGF-  -dependent profibrotic responses. <d>Fibrosis</d> in various animal models and human diseases such as scleroderma SSc and idiopathic pulmonary <d>fibrosis</d> IPF is accompanied by aberrant Egr-1 expression. Moreover Egr-1 appears to be required for physiologic and pathological connective tissue remodeling, and Egr-1-null mice are protected from <d>fibrosis</d>. As a novel profibrotic mediator, Egr-1 thus appears to be a promising potential target for the development of anti-fibrotic therapies.
21511034|a|<d>Fibrosis</d> is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as <d>obesity</d> and aging. The pathogenesis of <d>fibrosis</d> involves multiple cell types and extracellular signals, of which transforming growth factor-   TGF-   is pre-eminent. The prevalence of <d>fibrosis</d> is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor <g>Egr-1</g> in the pathogenesis of <d>fibrosis</d>. <g>Egr-1</g> couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to <d>injury</d> and stress. In contrast to other ligand-activated transcription factors such as NF-kB, c-jun and Smad2/3 that undergo post-translational modification such as phosphorylation and nuclear translocation, <g>Egr-1</g> activity is regulated via its biosynthesis. Aberrant <g>Egr-1</g> expression or activity is implicated in cancer, inflammation, atherosclerosis, and ischemic <d>injury</d> and recent studies now indicate an important role for <g>Egr-1</g> in TGF-  -dependent profibrotic responses. <d>Fibrosis</d> in various animal models and human diseases such as scleroderma SSc and idiopathic pulmonary <d>fibrosis</d> IPF is accompanied by aberrant <g>Egr-1</g> expression. Moreover <g>Egr-1</g> appears to be required for physiologic and pathological connective tissue remodeling, and <g>Egr-1</g>-null mice are protected from <d>fibrosis</d>. As a novel profibrotic mediator, <g>Egr-1</g> thus appears to be a promising potential target for the development of anti-fibrotic therapies.
21511034|a|<d>Fibrosis</d> is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as <d>obesity</d> and aging. The pathogenesis of <d>fibrosis</d> involves multiple cell types and extracellular signals, of which transforming growth factor-   TGF-   is pre-eminent. The prevalence of <d>fibrosis</d> is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor <g>Egr-1</g> in the pathogenesis of <d>fibrosis</d>. <g>Egr-1</g> couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to <d>injury</d> and stress. In contrast to other ligand-activated transcription factors such as NF-kB, <g>c-jun</g> and <g>Smad2/3</g> that undergo post-translational modification such as phosphorylation and nuclear translocation, <g>Egr-1</g> activity is regulated via its biosynthesis. Aberrant <g>Egr-1</g> expression or activity is implicated in <d>cancer</d>, inflammation, atherosclerosis, and ischemic <d>injury</d> and recent studies now indicate an important role for <g>Egr-1</g> in TGF-  -dependent profibrotic responses. <d>Fibrosis</d> in various animal models and human diseases such as scleroderma SSc and idiopathic pulmonary <d>fibrosis</d> IPF is accompanied by aberrant <g>Egr-1</g> expression. Moreover <g>Egr-1</g> appears to be required for physiologic and pathological connective tissue remodeling, and <g>Egr-1</g>-null mice are protected from <d>fibrosis</d>. As a novel profibrotic mediator, <g>Egr-1</g> thus appears to be a promising potential target for the development of anti-fibrotic therapies.
21511034|a|<d>Fibrosis</d> is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as <d>obesity</d> and aging. The pathogenesis of <d>fibrosis</d> involves multiple cell types and extracellular signals, of which transforming growth factor-   TGF-   is pre-eminent. The prevalence of <d>fibrosis</d> is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor <g>Egr-1</g> in the pathogenesis of <d>fibrosis</d>. <g>Egr-1</g> couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to <d>injury</d> and stress. In contrast to other ligand-activated transcription factors such as NF-kB, <g>c-jun</g> and <g>Smad2/3</g> that undergo post-translational modification such as phosphorylation and nuclear translocation, <g>Egr-1</g> activity is regulated via its biosynthesis. Aberrant <g>Egr-1</g> expression or activity is implicated in <d>cancer</d>, <d>inflammation</d>, atherosclerosis, and ischemic <d>injury</d> and recent studies now indicate an important role for <g>Egr-1</g> in TGF-  -dependent profibrotic responses. <d>Fibrosis</d> in various animal models and human diseases such as scleroderma SSc and idiopathic pulmonary <d>fibrosis</d> IPF is accompanied by aberrant <g>Egr-1</g> expression. Moreover <g>Egr-1</g> appears to be required for physiologic and pathological connective tissue remodeling, and <g>Egr-1</g>-null mice are protected from <d>fibrosis</d>. As a novel profibrotic mediator, <g>Egr-1</g> thus appears to be a promising potential target for the development of anti-fibrotic therapies.
21511034|a|<d>Fibrosis</d> is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as <d>obesity</d> and aging. The pathogenesis of <d>fibrosis</d> involves multiple cell types and extracellular signals, of which transforming growth factor-   TGF-   is pre-eminent. The prevalence of <d>fibrosis</d> is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor <g>Egr-1</g> in the pathogenesis of <d>fibrosis</d>. <g>Egr-1</g> couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to <d>injury</d> and stress. In contrast to other ligand-activated transcription factors such as NF-kB, <g>c-jun</g> and <g>Smad2/3</g> that undergo post-translational modification such as phosphorylation and nuclear translocation, <g>Egr-1</g> activity is regulated via its biosynthesis. Aberrant <g>Egr-1</g> expression or activity is implicated in <d>cancer</d>, <d>inflammation</d>, <d>atherosclerosis</d>, and ischemic <d>injury</d> and recent studies now indicate an important role for <g>Egr-1</g> in TGF-  -dependent profibrotic responses. <d>Fibrosis</d> in various animal models and human diseases such as scleroderma SSc and idiopathic pulmonary <d>fibrosis</d> IPF is accompanied by aberrant <g>Egr-1</g> expression. Moreover <g>Egr-1</g> appears to be required for physiologic and pathological connective tissue remodeling, and <g>Egr-1</g>-null mice are protected from <d>fibrosis</d>. As a novel profibrotic mediator, <g>Egr-1</g> thus appears to be a promising potential target for the development of anti-fibrotic therapies.
21511034|a|<d>Fibrosis</d> is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as <d>obesity</d> and aging. The pathogenesis of <d>fibrosis</d> involves multiple cell types and extracellular signals, of which transforming growth factor-   TGF-   is pre-eminent. The prevalence of <d>fibrosis</d> is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor <g>Egr-1</g> in the pathogenesis of <d>fibrosis</d>. <g>Egr-1</g> couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to <d>injury</d> and stress. In contrast to other ligand-activated transcription factors such as NF-kB, <g>c-jun</g> and <g>Smad2/3</g> that undergo post-translational modification such as phosphorylation and nuclear translocation, <g>Egr-1</g> activity is regulated via its biosynthesis. Aberrant <g>Egr-1</g> expression or activity is implicated in <d>cancer</d>, <d>inflammation</d>, <d>atherosclerosis</d>, and ischemic <d>injury</d> and recent studies now indicate an important role for <g>Egr-1</g> in TGF-  -dependent profibrotic responses. <d>Fibrosis</d> in various animal models and human diseases such as <d>scleroderma</d> SSc and idiopathic pulmonary <d>fibrosis</d> IPF is accompanied by aberrant <g>Egr-1</g> expression. Moreover <g>Egr-1</g> appears to be required for physiologic and pathological connective tissue remodeling, and <g>Egr-1</g>-null mice are protected from <d>fibrosis</d>. As a novel profibrotic mediator, <g>Egr-1</g> thus appears to be a promising potential target for the development of anti-fibrotic therapies.
21513813|a|This review focuses on the roles of NADPH oxidase/NOX proteins in <d>idiopathic pulmonary fibrosis</d> IPF pathophysiology and in the signalling pathways involved in IPF. NOX proteins are membrane-associated multi-unit enzymes that catalyze the reduction of oxygen using NADPH as an electron donor. Recent studies indicate that NOX4 is induced in pulmonary fibroblasts in response to TGF-b. TGF-b or PDGF induce myofibroblast proliferation, differentiation, migration, contractility and extracellular matrix production, through NOX4 and reactive oxygen species dependent SMAD2/3 phosphorylation. NOX4 is increased in pulmonary fibroblasts from IPF patients and deletion of Nox4 in mice prevents bleomycin-induced pulmonary fibrosis. These data strongly suggest that targeting of NOX4 could be a step forward in the treatment of fibrotic lung diseases, by specifically targeting myofibroblasts, a major player in this disease.
21513813|a|This review focuses on the roles of NADPH oxidase/NOX proteins in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> pathophysiology and in the signalling pathways involved in <d>IPF</d>. NOX proteins are membrane-associated multi-unit enzymes that catalyze the reduction of oxygen using NADPH as an electron donor. Recent studies indicate that NOX4 is induced in pulmonary fibroblasts in response to TGF-b. TGF-b or PDGF induce myofibroblast proliferation, differentiation, migration, contractility and extracellular matrix production, through NOX4 and reactive oxygen species dependent SMAD2/3 phosphorylation. NOX4 is increased in pulmonary fibroblasts from <d>IPF</d> patients and deletion of Nox4 in mice prevents bleomycin-induced pulmonary fibrosis. These data strongly suggest that targeting of NOX4 could be a step forward in the treatment of fibrotic lung diseases, by specifically targeting myofibroblasts, a major player in this disease.
21513813|a|This review focuses on the roles of NADPH oxidase/NOX proteins in <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> pathophysiology and in the signalling pathways involved in <d>IPF</d>. NOX proteins are membrane-associated multi-unit enzymes that catalyze the reduction of oxygen using NADPH as an electron donor. Recent studies indicate that <g>NOX4</g> is induced in pulmonary fibroblasts in response to <g>TGF-b</g>. <g>TGF-b</g> or PDGF induce myofibroblast proliferation, differentiation, migration, contractility and extracellular matrix production, through <g>NOX4</g> and reactive oxygen species dependent <g>SMAD2/3</g> phosphorylation. <g>NOX4</g> is increased in pulmonary fibroblasts from <d>IPF</d> patients and deletion of <g>Nox4</g> in mice prevents bleomycin-induced <d>pulmonary fibrosis</d>. These data strongly suggest that targeting of <g>NOX4</g> could be a step forward in the treatment of fibrotic lung diseases, by specifically targeting myofibroblasts, a major player in this disease.
21513813|a|This review focuses on the roles of NADPH oxidase/NOX proteins in <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> pathophysiology and in the signalling pathways involved in <d>IPF</d>. NOX proteins are membrane-associated multi-unit enzymes that catalyze the reduction of oxygen using NADPH as an electron donor. Recent studies indicate that <g>NOX4</g> is induced in pulmonary fibroblasts in response to <g>TGF-b</g>. <g>TGF-b</g> or PDGF induce myofibroblast proliferation, differentiation, migration, contractility and extracellular matrix production, through <g>NOX4</g> and reactive oxygen species dependent <g>SMAD2/3</g> phosphorylation. <g>NOX4</g> is increased in pulmonary fibroblasts from <d>IPF</d> patients and deletion of <g>Nox4</g> in mice prevents bleomycin-induced <d>pulmonary fibrosis</d>. These data strongly suggest that targeting of <g>NOX4</g> could be a step forward in the treatment of <d>fibrotic lung diseases</d>, by specifically targeting myofibroblasts, a major player in this disease.
21577212|a|Fibroblasts differ in a variety of phenotypic features, including the expression of <g>Thy-1</g> a glycophosphatidylinositol-linked glycoprotein. Fibroblasts in <d>idiopathic pulmonary fibrosis</d> IPF are <g>Thy-1</g> negative, whereas most fibroblasts from normal lungs are <g>Thy-1</g> positive. However, the functional consequences of the absence of <g>Thy-1</g> are not fully understood. We analyzed the expression of <g>Thy-1</g> in several primary fibroblasts lines derived from IPF, hypersensitivity pneumonitis HP, and normal human lungs. We found that a high proportion, independently of their origin, expressed <g>Thy-1</g> in vitro. We identified a primary culture of HP fibroblasts, which did not express <g>Thy-1</g>, and compared several functional activities between <g>Thy-1</g> - and <g>Thy-1</g> + fibroblasts. <g>Thy-1</g> - fibroblasts were smaller length: 41.3  20.8     versus 83.1  40  , showed increased proliferative capacity and enhanced PDGF-induced transmigration through collagen I 59.9% versus 42.2% over control under basal conditions, P<0.01. Likewise, <g>Thy-1</g> - fibroblasts either spontaneously or after <g>TGF-b</g> stimulation demonstrated stronger contraction of collagen matrices eg, 0.17  0.03 versus 0.6  0.05 cm   after <g>TGF-b</g> stimulation at 24 h; P<0.01. <g>Thy-1</g> - lung fibroblasts stimulated with <g>TGF-b</g>1 expressed <g>MMP-9</g>, an enzyme that is usually not produced by lung fibroblasts. TGFb-induced <g>MMP-9</g> expression was reversible upon re-expression of <g>Thy-1</g> after transfection with full-length <g>Thy-1</g>. b-glycan, a <g>TGF-b</g> receptor antagonist abolished <g>MMP-9</g> expression. <g>TGF-b</g>1-induced <g>MMP-9</g> in <g>Thy-1</g> - fibroblasts depended on the activation of ERK1/2 signaling pathway. Finally, we demonstrated that fibroblasts from IPF fibroblastic foci, which do not express <g>Thy-1</g> exhibit strong staining for immunoreactive <g>MMP-9</g> protein in vivo. These findings indicate that loss of <g>Thy-1</g> in human lung fibroblasts induces a fibrogenic phenotype.
21577212|a|Fibroblasts differ in a variety of phenotypic features, including the expression of <g>Thy-1</g> a glycophosphatidylinositol-linked glycoprotein. Fibroblasts in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> are <g>Thy-1</g> negative, whereas most fibroblasts from normal lungs are <g>Thy-1</g> positive. However, the functional consequences of the absence of <g>Thy-1</g> are not fully understood. We analyzed the expression of <g>Thy-1</g> in several primary fibroblasts lines derived from <d>IPF</d>, hypersensitivity pneumonitis HP, and normal human lungs. We found that a high proportion, independently of their origin, expressed <g>Thy-1</g> in vitro. We identified a primary culture of HP fibroblasts, which did not express <g>Thy-1</g>, and compared several functional activities between <g>Thy-1</g> - and <g>Thy-1</g> + fibroblasts. <g>Thy-1</g> - fibroblasts were smaller length: 41.3  20.8     versus 83.1  40  , showed increased proliferative capacity and enhanced PDGF-induced transmigration through collagen I 59.9% versus 42.2% over control under basal conditions, P<0.01. Likewise, <g>Thy-1</g> - fibroblasts either spontaneously or after <g>TGF-b</g> stimulation demonstrated stronger contraction of collagen matrices eg, 0.17  0.03 versus 0.6  0.05 cm   after <g>TGF-b</g> stimulation at 24 h; P<0.01. <g>Thy-1</g> - lung fibroblasts stimulated with <g>TGF-b</g>1 expressed <g>MMP-9</g>, an enzyme that is usually not produced by lung fibroblasts. TGFb-induced <g>MMP-9</g> expression was reversible upon re-expression of <g>Thy-1</g> after transfection with full-length <g>Thy-1</g>. b-glycan, a <g>TGF-b</g> receptor antagonist abolished <g>MMP-9</g> expression. <g>TGF-b</g>1-induced <g>MMP-9</g> in <g>Thy-1</g> - fibroblasts depended on the activation of ERK1/2 signaling pathway. Finally, we demonstrated that fibroblasts from <d>IPF</d> fibroblastic foci, which do not express <g>Thy-1</g> exhibit strong staining for immunoreactive <g>MMP-9</g> protein in vivo. These findings indicate that loss of <g>Thy-1</g> in human lung fibroblasts induces a fibrogenic phenotype.
21577212|a|Fibroblasts differ in a variety of phenotypic features, including the expression of <g>Thy-1</g> a glycophosphatidylinositol-linked glycoprotein. Fibroblasts in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> are <g>Thy-1</g> negative, whereas most fibroblasts from normal lungs are <g>Thy-1</g> positive. However, the functional consequences of the absence of <g>Thy-1</g> are not fully understood. We analyzed the expression of <g>Thy-1</g> in several primary fibroblasts lines derived from <d>IPF</d>, <d>hypersensitivity pneumonitis</d> HP, and normal human lungs. We found that a high proportion, independently of their origin, expressed <g>Thy-1</g> in vitro. We identified a primary culture of HP fibroblasts, which did not express <g>Thy-1</g>, and compared several functional activities between <g>Thy-1</g> - and <g>Thy-1</g> + fibroblasts. <g>Thy-1</g> - fibroblasts were smaller length: 41.3  20.8     versus 83.1  40  , showed increased proliferative capacity and enhanced PDGF-induced transmigration through collagen I 59.9% versus 42.2% over control under basal conditions, P<0.01. Likewise, <g>Thy-1</g> - fibroblasts either spontaneously or after <g>TGF-b</g> stimulation demonstrated stronger contraction of collagen matrices eg, 0.17  0.03 versus 0.6  0.05 cm   after <g>TGF-b</g> stimulation at 24 h; P<0.01. <g>Thy-1</g> - lung fibroblasts stimulated with <g>TGF-b</g>1 expressed <g>MMP-9</g>, an enzyme that is usually not produced by lung fibroblasts. TGFb-induced <g>MMP-9</g> expression was reversible upon re-expression of <g>Thy-1</g> after transfection with full-length <g>Thy-1</g>. b-glycan, a <g>TGF-b</g> receptor antagonist abolished <g>MMP-9</g> expression. <g>TGF-b</g>1-induced <g>MMP-9</g> in <g>Thy-1</g> - fibroblasts depended on the activation of ERK1/2 signaling pathway. Finally, we demonstrated that fibroblasts from <d>IPF</d> fibroblastic foci, which do not express <g>Thy-1</g> exhibit strong staining for immunoreactive <g>MMP-9</g> protein in vivo. These findings indicate that loss of <g>Thy-1</g> in human lung fibroblasts induces a fibrogenic phenotype.
21577212|a|Fibroblasts differ in a variety of phenotypic features, including the expression of <g>Thy-1</g> a glycophosphatidylinositol-linked glycoprotein. Fibroblasts in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> are <g>Thy-1</g> negative, whereas most fibroblasts from normal lungs are <g>Thy-1</g> positive. However, the functional consequences of the absence of <g>Thy-1</g> are not fully understood. We analyzed the expression of <g>Thy-1</g> in several primary fibroblasts lines derived from <d>IPF</d>, <d>hypersensitivity pneumonitis</d> <d>HP</d>, and normal human lungs. We found that a high proportion, independently of their origin, expressed <g>Thy-1</g> in vitro. We identified a primary culture of <d>HP</d> fibroblasts, which did not express <g>Thy-1</g>, and compared several functional activities between <g>Thy-1</g> - and <g>Thy-1</g> + fibroblasts. <g>Thy-1</g> - fibroblasts were smaller length: 41.3  20.8     versus 83.1  40  , showed increased proliferative capacity and enhanced PDGF-induced transmigration through collagen I 59.9% versus 42.2% over control under basal conditions, P<0.01. Likewise, <g>Thy-1</g> - fibroblasts either spontaneously or after <g>TGF-b</g> stimulation demonstrated stronger contraction of collagen matrices eg, 0.17  0.03 versus 0.6  0.05 cm   after <g>TGF-b</g> stimulation at 24 h; P<0.01. <g>Thy-1</g> - lung fibroblasts stimulated with <g>TGF-b</g>1 expressed <g>MMP-9</g>, an enzyme that is usually not produced by lung fibroblasts. TGFb-induced <g>MMP-9</g> expression was reversible upon re-expression of <g>Thy-1</g> after transfection with full-length <g>Thy-1</g>. b-glycan, a <g>TGF-b</g> receptor antagonist abolished <g>MMP-9</g> expression. <g>TGF-b</g>1-induced <g>MMP-9</g> in <g>Thy-1</g> - fibroblasts depended on the activation of ERK1/2 signaling pathway. Finally, we demonstrated that fibroblasts from <d>IPF</d> fibroblastic foci, which do not express <g>Thy-1</g> exhibit strong staining for immunoreactive <g>MMP-9</g> protein in vivo. These findings indicate that loss of <g>Thy-1</g> in human lung fibroblasts induces a fibrogenic phenotype.
21642472|a|Idiopathic pulmonary fibrosis IPF is characterized by exaggerated fibroblast proliferation and accumulation of collagens and fibronectin. The extracellular fibronectin and collagen network is regulated by <d>von Hippel-Lindau</d> protein pVHL. However, it is unknown whether pVHL contributes to pulmonary fibrosis. We found that lungs from patients with IPF expressed increased levels of pVHL in fibroblastic foci. Bleomycin treatment also induced pVHL in lung fibroblasts, but not in alveolar type II cells. Overexpression of pVHL increased lung fibroblast proliferation, protein abundance of fibronectin and collagen, and extracellular fibronectin. In addition, overexpression of pVHL induced expression of the a5 integrin subunit. Overexpression of pVHL did not alter hypoxia-inducible factor luciferase reporter activity and mRNA expression of vascular endothelial growth factor. Fibroblasts overexpressing pVHL were more sensitive to RGD peptide-mediated reduction in proliferation. Activating a5 and b1 integrin increased proliferation of fibroblasts overexpressing pVHL and those cells were more resistant to the inhibition of a5 integrin. Overexpression of pVHL also increased activation of focal adhesion kinase FAK. Moreover, suppression of pVHL prevented TGF-b1-induced proliferation of mouse embryonic fibroblasts. Taken together, our results indicate that elevated expression of pVHL results in the aberrant fibronectin expression, activation of integrin/FAK signaling, fibroblast proliferation, and fibrosis.
21642472|a|Idiopathic pulmonary <d>fibrosis</d> IPF is characterized by exaggerated fibroblast proliferation and accumulation of collagens and fibronectin. The extracellular fibronectin and collagen network is regulated by <d>von Hippel-Lindau</d> protein pVHL. However, it is unknown whether pVHL contributes to pulmonary <d>fibrosis</d>. We found that lungs from patients with IPF expressed increased levels of pVHL in fibroblastic foci. Bleomycin treatment also induced pVHL in lung fibroblasts, but not in alveolar type II cells. Overexpression of pVHL increased lung fibroblast proliferation, protein abundance of fibronectin and collagen, and extracellular fibronectin. In addition, overexpression of pVHL induced expression of the a5 integrin subunit. Overexpression of pVHL did not alter hypoxia-inducible factor luciferase reporter activity and mRNA expression of vascular endothelial growth factor. Fibroblasts overexpressing pVHL were more sensitive to RGD peptide-mediated reduction in proliferation. Activating a5 and b1 integrin increased proliferation of fibroblasts overexpressing pVHL and those cells were more resistant to the inhibition of a5 integrin. Overexpression of pVHL also increased activation of focal adhesion kinase FAK. Moreover, suppression of pVHL prevented TGF-b1-induced proliferation of mouse embryonic fibroblasts. Taken together, our results indicate that elevated expression of pVHL results in the aberrant fibronectin expression, activation of integrin/FAK signaling, fibroblast proliferation, and <d>fibrosis</d>.
21642472|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is characterized by exaggerated fibroblast proliferation and accumulation of collagens and fibronectin. The extracellular fibronectin and collagen network is regulated by <d>von Hippel-Lindau</d> protein pVHL. However, it is unknown whether pVHL contributes to pulmonary <d>fibrosis</d>. We found that lungs from patients with <d>IPF</d> expressed increased levels of pVHL in fibroblastic foci. Bleomycin treatment also induced pVHL in lung fibroblasts, but not in alveolar type II cells. Overexpression of pVHL increased lung fibroblast proliferation, protein abundance of fibronectin and collagen, and extracellular fibronectin. In addition, overexpression of pVHL induced expression of the a5 integrin subunit. Overexpression of pVHL did not alter hypoxia-inducible factor luciferase reporter activity and mRNA expression of vascular endothelial growth factor. Fibroblasts overexpressing pVHL were more sensitive to RGD peptide-mediated reduction in proliferation. Activating a5 and b1 integrin increased proliferation of fibroblasts overexpressing pVHL and those cells were more resistant to the inhibition of a5 integrin. Overexpression of pVHL also increased activation of focal adhesion kinase FAK. Moreover, suppression of pVHL prevented TGF-b1-induced proliferation of mouse embryonic fibroblasts. Taken together, our results indicate that elevated expression of pVHL results in the aberrant fibronectin expression, activation of integrin/FAK signaling, fibroblast proliferation, and <d>fibrosis</d>.
21642472|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is characterized by exaggerated fibroblast proliferation and accumulation of collagens and <g>fibronectin</g>. The extracellular <g>fibronectin</g> and collagen network is regulated by <d>von Hippel-Lindau</d> protein <g>pVHL</g>. However, it is unknown whether <g>pVHL</g> contributes to pulmonary <d>fibrosis</d>. We found that lungs from patients with <d>IPF</d> expressed increased levels of <g>pVHL</g> in fibroblastic foci. Bleomycin treatment also induced <g>pVHL</g> in lung fibroblasts, but not in alveolar type II cells. Overexpression of <g>pVHL</g> increased lung fibroblast proliferation, protein abundance of <g>fibronectin</g> and collagen, and extracellular <g>fibronectin</g>. In addition, overexpression of <g>pVHL</g> induced expression of the a5 integrin subunit. Overexpression of <g>pVHL</g> did not alter <d>hypoxia</d>-inducible factor luciferase reporter activity and mRNA expression of vascular endothelial growth factor. Fibroblasts overexpressing <g>pVHL</g> were more sensitive to RGD peptide-mediated reduction in proliferation. Activating a5 and b1 integrin increased proliferation of fibroblasts overexpressing <g>pVHL</g> and those cells were more resistant to the inhibition of a5 integrin. Overexpression of <g>pVHL</g> also increased activation of focal adhesion kinase FAK. Moreover, suppression of <g>pVHL</g> prevented TGF-b1-induced proliferation of mouse embryonic fibroblasts. Taken together, our results indicate that elevated expression of <g>pVHL</g> results in the aberrant <g>fibronectin</g> expression, activation of integrin/FAK signaling, fibroblast proliferation, and <d>fibrosis</d>.
21659414|a|The pathogenesis of idiopathic <d>pulmonary fibrosis</d> IPF is probably the result of interplay between cytokines/chemokines and growth factors. The renin-angiotensin Ang system is involved, although its profibrotic effect is attributed to Ang II. However, recent studies suggest that renin, through a specific receptor, is implicated in fibrogenesis. In this study, the expression of renin and renin receptor was examined in normal and IPF lungs and fibroblasts. Normal human lung fibroblasts were stimulated with renin or transfected with renin small interfering RNA siRNA, and the expression of transforming growth factor TGF-b1 and a-1-type I collagen was analysed. Normal lungs and lung fibroblasts expressed renin, which was strongly upregulated in IPF lungs and fibroblasts    10-fold increase; p<0.05. Immunocytochemistry showed intense renin staining in IPF fibroblasts. <g>Renin</g>-stimulated lung fibroblasts displayed an increase in the expression of TGF-b1 mean    sd 1.8   103    0.2   103 versus 1.2   103   0.3   103 mRNA copies per 18S ribosomal RNA; p<0.01 and collagen 5.93   102   0.66   102 versus 3.28   102    0.5   102; p<0.01, while knocking down renin expression using siRNA provoked a strong decrease of both molecules. These effects were independent of Ang II, since neither losartan nor captopril decreased these effects. <g>Renin</g> also decreased matrix metalloprotease-1 expression and induced TGF-b1 activation 163    34 versus 110    15 pg active TGF-b1 per mg total protein. These findings highlight the possible role of renin as an Ang II-independent profibrotic factor in lung fibrosis.
21659414|a|The pathogenesis of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is probably the result of interplay between cytokines/chemokines and growth factors. The renin-angiotensin Ang system is involved, although its profibrotic effect is attributed to Ang II. However, recent studies suggest that renin, through a specific receptor, is implicated in fibrogenesis. In this study, the expression of renin and renin receptor was examined in normal and <d>IPF</d> lungs and fibroblasts. Normal human lung fibroblasts were stimulated with renin or transfected with renin small interfering RNA siRNA, and the expression of transforming growth factor TGF-b1 and a-1-type I collagen was analysed. Normal lungs and lung fibroblasts expressed renin, which was strongly upregulated in <d>IPF</d> lungs and fibroblasts    10-fold increase; p<0.05. Immunocytochemistry showed intense renin staining in <d>IPF</d> fibroblasts. <g>Renin</g>-stimulated lung fibroblasts displayed an increase in the expression of TGF-b1 mean    sd 1.8   103    0.2   103 versus 1.2   103   0.3   103 mRNA copies per 18S ribosomal RNA; p<0.01 and collagen 5.93   102   0.66   102 versus 3.28   102    0.5   102; p<0.01, while knocking down renin expression using siRNA provoked a strong decrease of both molecules. These effects were independent of Ang II, since neither losartan nor captopril decreased these effects. <g>Renin</g> also decreased matrix metalloprotease-1 expression and induced TGF-b1 activation 163    34 versus 110    15 pg active TGF-b1 per mg total protein. These findings highlight the possible role of renin as an Ang II-independent profibrotic factor in lung fibrosis.
21659414|a|The pathogenesis of idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is probably the result of interplay between cytokines/chemokines and growth factors. The <g>renin</g>-angiotensin Ang system is involved, although its profibrotic effect is attributed to Ang II. However, recent studies suggest that <g>renin</g>, through a specific receptor, is implicated in fibrogenesis. In this study, the expression of <g>renin</g> and <g>renin</g> receptor was examined in normal and <d>IPF</d> lungs and fibroblasts. Normal human lung fibroblasts were stimulated with <g>renin</g> or transfected with <g>renin</g> small interfering RNA siRNA, and the expression of transforming growth factor <g>TGF-b1</g> and a-1-type I collagen was analysed. Normal lungs and lung fibroblasts expressed <g>renin</g>, which was strongly upregulated in <d>IPF</d> lungs and fibroblasts    10-fold increase; p<0.05. Immunocytochemistry showed intense <g>renin</g> staining in <d>IPF</d> fibroblasts. <g>Renin</g>-stimulated lung fibroblasts displayed an increase in the expression of <g>TGF-b1</g> mean    sd 1.8   103    0.2   103 versus 1.2   103   0.3   103 mRNA copies per 18S ribosomal RNA; p<0.01 and collagen 5.93   102   0.66   102 versus 3.28   102    0.5   102; p<0.01, while knocking down <g>renin</g> expression using siRNA provoked a strong decrease of both molecules. These effects were independent of Ang II, since neither losartan nor captopril decreased these effects. <g>Renin</g> also decreased <g>matrix metalloprotease-1</g> expression and induced <g>TGF-b1</g> activation 163    34 versus 110    15 pg active <g>TGF-b1</g> per mg total protein. These findings highlight the possible role of <g>renin</g> as an Ang II-independent profibrotic factor in lung <d>fibrosis</d>.
21700912|a|RATIONALE: Idiopathic <d>pulmonary fibrosis</d> IPF is a deadly progressive disease with few treatment options. <g>Transglutaminase 2</g> TG2 is a multifunctional protein, but its function in <d>pulmonary fibrosis</d> is unknown. OBJECTIVES: To determine the role of TG2 in <d>pulmonary fibrosis</d>. METHODS: The fibrotic response to bleomycin was compared between wild-type and TG2 knockout mice. Transglutaminase and transglutaminase-catalyzed isopeptide bond expression was examined in formalin-fixed human lung biopsy sections by immunohistochemistry from patients with IPF. In addition, primary human lung fibroblasts were used to study TG2 function in vitro. MEASUREMENTS AND MAIN RESULTS: TG2 knockout mice developed significantly reduced fibrosis compared with wild-type mice as determined by hydroxyproline content and histologic fibrosis score P < 0.05. TG2 expression and activity are increased in lung biopsy sections in humans with IPF compared with normal control subjects. In vitro overexpression of TG2 led to increased fibronectin deposition, whereas transglutaminase knockdown led to defects in contraction and adhesion. The profibrotic cytokine transforming growth factor-b causes an increase in membrane-localized TG2, increasing its enzymatic activity. CONCLUSIONS: TG2 is involved in <d>pulmonary fibrosis</d> in a mouse model and in human disease and is important in normal fibroblast function. With continued research on TG2, it may offer a new therapeutic target.
21700912|a|RATIONALE: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a deadly progressive disease with few treatment options. <g>Transglutaminase 2</g> TG2 is a multifunctional protein, but its function in <d>pulmonary fibrosis</d> is unknown. OBJECTIVES: To determine the role of TG2 in <d>pulmonary fibrosis</d>. METHODS: The fibrotic response to bleomycin was compared between wild-type and TG2 knockout mice. Transglutaminase and transglutaminase-catalyzed isopeptide bond expression was examined in formalin-fixed human lung biopsy sections by immunohistochemistry from patients with <d>IPF</d>. In addition, primary human lung fibroblasts were used to study TG2 function in vitro. MEASUREMENTS AND MAIN RESULTS: TG2 knockout mice developed significantly reduced fibrosis compared with wild-type mice as determined by hydroxyproline content and histologic fibrosis score P < 0.05. TG2 expression and activity are increased in lung biopsy sections in humans with <d>IPF</d> compared with normal control subjects. In vitro overexpression of TG2 led to increased fibronectin deposition, whereas transglutaminase knockdown led to defects in contraction and adhesion. The profibrotic cytokine transforming growth factor-b causes an increase in membrane-localized TG2, increasing its enzymatic activity. CONCLUSIONS: TG2 is involved in <d>pulmonary fibrosis</d> in a mouse model and in human disease and is important in normal fibroblast function. With continued research on TG2, it may offer a new therapeutic target.
21700912|a|RATIONALE: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a deadly progressive disease with few treatment options. <g>Transglutaminase 2</g> <g>TG2</g> is a multifunctional protein, but its function in <d>pulmonary <d>fibrosis</d></d> is unknown. OBJECTIVES: To determine the role of <g>TG2</g> in <d>pulmonary <d>fibrosis</d></d>. METHODS: The fibrotic response to bleomycin was compared between wild-type and <g>TG2</g> knockout mice. Transglutaminase and transglutaminase-catalyzed isopeptide bond expression was examined in formalin-fixed human lung biopsy sections by immunohistochemistry from patients with <d>IPF</d>. In addition, primary human lung fibroblasts were used to study <g>TG2</g> function in vitro. MEASUREMENTS AND MAIN RESULTS: <g>TG2</g> knockout mice developed significantly reduced <d>fibrosis</d> compared with wild-type mice as determined by hydroxyproline content and histologic <d>fibrosis</d> score P < 0.05. <g>TG2</g> expression and activity are increased in lung biopsy sections in humans with <d>IPF</d> compared with normal control subjects. In vitro overexpression of <g>TG2</g> led to increased fibronectin deposition, whereas transglutaminase knockdown led to defects in contraction and adhesion. The profibrotic cytokine transforming growth factor-b causes an increase in membrane-localized <g>TG2</g>, increasing its enzymatic activity. CONCLUSIONS: <g>TG2</g> is involved in <d>pulmonary <d>fibrosis</d></d> in a mouse model and in human disease and is important in normal fibroblast function. With continued research on <g>TG2</g>, it may offer a new therapeutic target.
21743278|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a lethal parenchymal lung disease characterized by myofibroblast proliferation. Alveolar epithelial cells AECs are thought to produce myofibroblasts through the epithelial to mesenchymal transition EMT. Receptor for advanced glycation end products <g>RAGE</g> is a member of the immunoglobulin superfamily of cell surface receptors whose activation is associated with renal fibrosis during diabetes and liver fibrosis. <g>RAGE</g> is expressed at low basal levels in most adult tissues except the lung. In this study, we evaluated the interaction of ligand advanced glycation end products AGE with <g>RAGE</g> during the epithelial to myofibroblast transition in rat AECs. Our results indicate that AGE inhibited the <g>TGF-b</g>-dependent alveolar EMT by increasing Smad7 expression, and that the effect was abolished by <g>RAGE</g> siRNA treatment. Thus, the induction of Smad7 by the AGE-<g>RAGE</g> interaction limits the development of pulmonary fibrosis by inhibiting <g>TGF-b</g>-dependent signaling in AECs.
21743278|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal parenchymal lung disease characterized by myofibroblast proliferation. Alveolar epithelial cells AECs are thought to produce myofibroblasts through the epithelial to mesenchymal transition EMT. Receptor for advanced glycation end products <g>RAGE</g> is a member of the immunoglobulin superfamily of cell surface receptors whose activation is associated with renal fibrosis during diabetes and liver fibrosis. <g>RAGE</g> is expressed at low basal levels in most adult tissues except the lung. In this study, we evaluated the interaction of ligand advanced glycation end products AGE with <g>RAGE</g> during the epithelial to myofibroblast transition in rat AECs. Our results indicate that AGE inhibited the <g>TGF-b</g>-dependent alveolar EMT by increasing Smad7 expression, and that the effect was abolished by <g>RAGE</g> siRNA treatment. Thus, the induction of Smad7 by the AGE-<g>RAGE</g> interaction limits the development of pulmonary fibrosis by inhibiting <g>TGF-b</g>-dependent signaling in AECs.
21743278|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal <d>parenchymal lung disease</d> characterized by myofibroblast proliferation. Alveolar epithelial cells AECs are thought to produce myofibroblasts through the epithelial to mesenchymal transition EMT. Receptor for advanced glycation end products <g>RAGE</g> is a member of the immunoglobulin superfamily of cell surface receptors whose activation is associated with renal fibrosis during diabetes and liver fibrosis. <g>RAGE</g> is expressed at low basal levels in most adult tissues except the lung. In this study, we evaluated the interaction of ligand advanced glycation end products AGE with <g>RAGE</g> during the epithelial to myofibroblast transition in rat AECs. Our results indicate that AGE inhibited the <g>TGF-b</g>-dependent alveolar EMT by increasing Smad7 expression, and that the effect was abolished by <g>RAGE</g> siRNA treatment. Thus, the induction of Smad7 by the AGE-<g>RAGE</g> interaction limits the development of pulmonary fibrosis by inhibiting <g>TGF-b</g>-dependent signaling in AECs.
21743278|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a lethal <d>parenchymal lung disease</d> characterized by myofibroblast proliferation. Alveolar epithelial cells AECs are thought to produce myofibroblasts through the epithelial to mesenchymal transition EMT. <g>Receptor for advanced glycation end products</g> <g>RAGE</g> is a member of the immunoglobulin superfamily of cell surface receptors whose activation is associated with renal <d>fibrosis</d> during diabetes and liver <d>fibrosis</d>. <g>RAGE</g> is expressed at low basal levels in most adult tissues except the lung. In this study, we evaluated the interaction of ligand advanced glycation end products AGE with <g>RAGE</g> during the epithelial to myofibroblast transition in rat AECs. Our results indicate that AGE inhibited the <g>TGF-b</g>-dependent alveolar EMT by increasing Smad7 expression, and that the effect was abolished by <g>RAGE</g> siRNA treatment. Thus, the induction of Smad7 by the AGE-<g>RAGE</g> interaction limits the development of pulmonary <d>fibrosis</d> by inhibiting <g>TGF-b</g>-dependent signaling in AECs.
21743278|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a lethal <d>parenchymal lung disease</d> characterized by myofibroblast proliferation. Alveolar epithelial cells AECs are thought to produce myofibroblasts through the epithelial to mesenchymal transition EMT. <g>Receptor for advanced glycation end products</g> <g>RAGE</g> is a member of the immunoglobulin superfamily of cell surface receptors whose activation is associated with renal <d>fibrosis</d> during diabetes and liver <d>fibrosis</d>. <g>RAGE</g> is expressed at low basal levels in most adult tissues except the lung. In this study, we evaluated the interaction of ligand advanced glycation end products AGE with <g>RAGE</g> during the epithelial to myofibroblast transition in rat AECs. Our results indicate that AGE inhibited the <g>TGF-b</g>-dependent <d>alveolar EMT</d> by increasing Smad7 expression, and that the effect was abolished by <g>RAGE</g> siRNA treatment. Thus, the induction of Smad7 by the AGE-<g>RAGE</g> interaction limits the development of pulmonary <d>fibrosis</d> by inhibiting <g>TGF-b</g>-dependent signaling in AECs.
21864521|a|BACKGROUND: Idiopathic pulmonary fibrosis <d>IPF</d> is a chronic, progressive and fatal pulmonary fibrotic disease and useful biomarkers are required to diagnose and predict disease activity. <g>CCN2</g> connective tissue growth factor; <g>CTGF</g> has been reported as one of the key profibrotic factors associated with transforming growth factor-b TGF-b, and its assay has potential as a non-invasive measure in various fibrotic diseases. Recently, we developed a new subtraction method for determination of plasma <g>CCN2</g> levels. We examined the utility of plasma <g>CCN2</g> levels as a surrogate marker in <d>IPF</d>. METHODS: Plasma <g>CCN2</g> levels were calculated in 33 patients with <d>IPF</d>, 14 patients with non-<d>IPF</d> idiopathic interstitial pneumonias IIPs and 101 healthy volunteers by sandwich enzyme-linked immunosorbent assay ELISA using specific monoclonal antibodies for two distinct epitopes of human <g>CCN2</g>. We evaluated the utility of plasma <g>CCN2</g> levels by comparison with clinical parameters. RESULTS: Plasma <g>CCN2</g> levels were significantly higher in patients with <d>IPF</d> than in those with non-<d>IPF</d> IIPs and healthy volunteers. Importantly, plasma <g>CCN2</g> levels showed significantly negative correlation with 6-month change of forced vital capacity FVC in patients with <d>IPF</d>. CONCLUSIONS: Plasma <g>CCN2</g> is a potential biomarker for <d>IPF</d>.
21864521|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and fatal pulmonary fibrotic disease and useful biomarkers are required to diagnose and predict disease activity. <g>CCN2</g> connective tissue growth factor; <g>CTGF</g> has been reported as one of the key profibrotic factors associated with transforming growth factor-b TGF-b, and its assay has potential as a non-invasive measure in various fibrotic diseases. Recently, we developed a new subtraction method for determination of plasma <g>CCN2</g> levels. We examined the utility of plasma <g>CCN2</g> levels as a surrogate marker in <d>IPF</d>. METHODS: Plasma <g>CCN2</g> levels were calculated in 33 patients with <d>IPF</d>, 14 patients with non-<d>IPF</d> idiopathic interstitial pneumonias IIPs and 101 healthy volunteers by sandwich enzyme-linked immunosorbent assay ELISA using specific monoclonal antibodies for two distinct epitopes of human <g>CCN2</g>. We evaluated the utility of plasma <g>CCN2</g> levels by comparison with clinical parameters. RESULTS: Plasma <g>CCN2</g> levels were significantly higher in patients with <d>IPF</d> than in those with non-<d>IPF</d> IIPs and healthy volunteers. Importantly, plasma <g>CCN2</g> levels showed significantly negative correlation with 6-month change of forced vital capacity FVC in patients with <d>IPF</d>. CONCLUSIONS: Plasma <g>CCN2</g> is a potential biomarker for <d>IPF</d>.
21864521|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and <d>fatal pulmonary fibrotic disease</d> and useful biomarkers are required to diagnose and predict disease activity. <g>CCN2</g> connective tissue growth factor; <g>CTGF</g> has been reported as one of the key profibrotic factors associated with transforming growth factor-b TGF-b, and its assay has potential as a non-invasive measure in various fibrotic diseases. Recently, we developed a new subtraction method for determination of plasma <g>CCN2</g> levels. We examined the utility of plasma <g>CCN2</g> levels as a surrogate marker in <d>IPF</d>. METHODS: Plasma <g>CCN2</g> levels were calculated in 33 patients with <d>IPF</d>, 14 patients with non-<d>IPF</d> idiopathic interstitial pneumonias IIPs and 101 healthy volunteers by sandwich enzyme-linked immunosorbent assay ELISA using specific monoclonal antibodies for two distinct epitopes of human <g>CCN2</g>. We evaluated the utility of plasma <g>CCN2</g> levels by comparison with clinical parameters. RESULTS: Plasma <g>CCN2</g> levels were significantly higher in patients with <d>IPF</d> than in those with non-<d>IPF</d> IIPs and healthy volunteers. Importantly, plasma <g>CCN2</g> levels showed significantly negative correlation with 6-month change of forced vital capacity FVC in patients with <d>IPF</d>. CONCLUSIONS: Plasma <g>CCN2</g> is a potential biomarker for <d>IPF</d>.
21864521|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and <d>fatal pulmonary fibrotic disease</d> and useful biomarkers are required to diagnose and predict disease activity. <g>CCN2</g> connective tissue growth factor; <g>CTGF</g> has been reported as one of the key profibrotic factors associated with <g>transforming growth factor-b</g> <g>TGF-b</g>, and its assay has potential as a non-invasive measure in various <d>fibrotic diseases</d>. Recently, we developed a new subtraction method for determination of plasma <g>CCN2</g> levels. We examined the utility of plasma <g>CCN2</g> levels as a surrogate marker in <d>IPF</d>. METHODS: Plasma <g>CCN2</g> levels were calculated in 33 patients with <d>IPF</d>, 14 patients with non-<d>IPF</d> idiopathic interstitial pneumonias IIPs and 101 healthy volunteers by sandwich enzyme-linked immunosorbent assay ELISA using specific monoclonal antibodies for two distinct epitopes of human <g>CCN2</g>. We evaluated the utility of plasma <g>CCN2</g> levels by comparison with clinical parameters. RESULTS: Plasma <g>CCN2</g> levels were significantly higher in patients with <d>IPF</d> than in those with non-<d>IPF</d> IIPs and healthy volunteers. Importantly, plasma <g>CCN2</g> levels showed significantly negative correlation with 6-month change of forced vital capacity FVC in patients with <d>IPF</d>. CONCLUSIONS: Plasma <g>CCN2</g> is a potential biomarker for <d>IPF</d>.
21864521|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and <d>fatal pulmonary fibrotic disease</d> and useful biomarkers are required to diagnose and predict disease activity. <g>CCN2</g> connective tissue growth factor; <g>CTGF</g> has been reported as one of the key profibrotic factors associated with <g>transforming growth factor-b</g> <g>TGF-b</g>, and its assay has potential as a non-invasive measure in various <d>fibrotic diseases</d>. Recently, we developed a new subtraction method for determination of plasma <g>CCN2</g> levels. We examined the utility of plasma <g>CCN2</g> levels as a surrogate marker in <d>IPF</d>. METHODS: Plasma <g>CCN2</g> levels were calculated in 33 patients with <d>IPF</d>, 14 patients with non-<d>IPF</d> <d>idiopathic interstitial pneumonias</d> IIPs and 101 healthy volunteers by sandwich enzyme-linked immunosorbent assay ELISA using specific monoclonal antibodies for two distinct epitopes of human <g>CCN2</g>. We evaluated the utility of plasma <g>CCN2</g> levels by comparison with clinical parameters. RESULTS: Plasma <g>CCN2</g> levels were significantly higher in patients with <d>IPF</d> than in those with non-<d>IPF</d> IIPs and healthy volunteers. Importantly, plasma <g>CCN2</g> levels showed significantly negative correlation with 6-month change of forced vital capacity FVC in patients with <d>IPF</d>. CONCLUSIONS: Plasma <g>CCN2</g> is a potential biomarker for <d>IPF</d>.
21864521|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and <d>fatal pulmonary fibrotic disease</d> and useful biomarkers are required to diagnose and predict disease activity. <g>CCN2</g> connective tissue growth factor; <g>CTGF</g> has been reported as one of the key profibrotic factors associated with <g>transforming growth factor-b</g> <g>TGF-b</g>, and its assay has potential as a non-invasive measure in various <d>fibrotic diseases</d>. Recently, we developed a new subtraction method for determination of plasma <g>CCN2</g> levels. We examined the utility of plasma <g>CCN2</g> levels as a surrogate marker in <d>IPF</d>. METHODS: Plasma <g>CCN2</g> levels were calculated in 33 patients with <d>IPF</d>, 14 patients with non-<d>IPF</d> <d>idiopathic interstitial pneumonias</d> <d>IIPs</d> and 101 healthy volunteers by sandwich enzyme-linked immunosorbent assay ELISA using specific monoclonal antibodies for two distinct epitopes of human <g>CCN2</g>. We evaluated the utility of plasma <g>CCN2</g> levels by comparison with clinical parameters. RESULTS: Plasma <g>CCN2</g> levels were significantly higher in patients with <d>IPF</d> than in those with non-<d>IPF</d> <d>IIPs</d> and healthy volunteers. Importantly, plasma <g>CCN2</g> levels showed significantly negative correlation with 6-month change of forced vital capacity FVC in patients with <d>IPF</d>. CONCLUSIONS: Plasma <g>CCN2</g> is a potential biomarker for <d>IPF</d>.
21871427|a|Idiopathic <d>pulmonary fibrosis</d> IPF may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 MMP-3 in the pathogenesis of IPF through i determination of MMP-3 expression in patients with IPF, ii in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in IPF, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and <d>pulmonary fibrosis</d>. Conversely, MMP-3-null mice were protected against bleomycin-induced <d>pulmonary fibrosis</d>. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the b-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of b-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of b-catenin signaling and induction of epithelial-mesenchymal transition.
21871427|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 MMP-3 in the pathogenesis of <d>IPF</d> through i determination of MMP-3 expression in patients with <d>IPF</d>, ii in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in <d>IPF</d>, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and <d>pulmonary fibrosis</d>. Conversely, MMP-3-null mice were protected against bleomycin-induced <d>pulmonary fibrosis</d>. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the b-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of b-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of <d>IPF</d>, through activation of b-catenin signaling and induction of epithelial-mesenchymal transition.
21871427|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of <g>matrix metalloproteinase-3</g> <g>MMP-3</g> in the pathogenesis of <d>IPF</d> through i determination of <g>MMP-3</g> expression in patients with <d>IPF</d>, ii in vivo experiments examining the relevance of <g>MMP-3</g> in experimental models of <d>fibrosis</d>, and iii in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of <g>MMP-3</g> in <d>IPF</d>, compared with control. Transient adenoviral vector-mediated expression of recombinant <g>MMP-3</g> in rat lung resulted in accumulation of myofibroblasts and <d>pulmonary <d>fibrosis</d></d>. Conversely, <g>MMP-3</g>-null mice were protected against bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. In vitro treatment of cultured lung epithelial cells with purified <g>MMP-3</g> resulted in activation of the b-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated <g>MMP-3</g>-null mice, as assessed by cytosolic translocation of b-catenin and cyclin D1 expression. These observations support a novel role for <g>MMP-3</g> in the pathogenesis of <d>IPF</d>, through activation of b-catenin signaling and induction of epithelial-mesenchymal transition.
21882188|a|Transforming growth factor-b TGF-b is a diverse cytokine regulating growth, apoptosis, differentiation, adhesion, invasion, and extracellular matrix production. Dysregulation of TGF-b is associated with fibrotic disorders and epithelial-mesenchymal transition, and has been linked with idiopathic pulmonary <d>fibrosis</d> IPF. <g>Cysteine-rich protein 1</g> CRP1 is a small LIM-domain containing protein involved in smooth muscle differentiation. Here, we show that TGF-b1 increases the expression of CRP1 protein and that CRP1 levels increase in a biphasic fashion. A rapid transient 15-45   min increase in CRP1 is followed by a subsequent, sustained increase in CRP1 a few hours afterwards that lasts several days. We find that TGF-b1 regulates the expression of CRP1 through Smad and non-conventional p38 MAPK signaling pathways in a transcription-independent manner and that the induction occurs concomitant with an increase in myofibroblast differentiation. Using CRP1 silencing by shRNA, we identify CRP1 as a novel factor mediating cell contractility. Furthermore, we localize CRP1 to fibroblastic foci in IPF lungs and find that CRP1 is significantly more expressed in IPF as compared to control lung tissue. The results show that CRP1 is a novel TGF-b1 regulated protein that is expressed in fibrotic lesions and may be relevant in the IPF disease.
21882188|a|<g>Transforming growth factor-b</g> <g>TGF-b</g> is a diverse cytokine regulating growth, apoptosis, differentiation, adhesion, invasion, and extracellular matrix production. Dysregulation of <g>TGF-b</g> is associated with <d>fibrotic disorders</d> and epithelial-mesenchymal transition, and has been linked with idiopathic pulmonary <d>fibrosis</d> IPF. <g>Cysteine-rich protein 1</g> CRP1 is a small LIM-domain containing protein involved in smooth muscle differentiation. Here, we show that <g>TGF-b</g>1 increases the expression of CRP1 protein and that CRP1 levels increase in a biphasic fashion. A rapid transient 15-45   min increase in CRP1 is followed by a subsequent, sustained increase in CRP1 a few hours afterwards that lasts several days. We find that <g>TGF-b</g>1 regulates the expression of CRP1 through Smad and non-conventional p38 MAPK signaling pathways in a transcription-independent manner and that the induction occurs concomitant with an increase in myofibroblast differentiation. Using CRP1 silencing by shRNA, we identify CRP1 as a novel factor mediating cell contractility. Furthermore, we localize CRP1 to fibroblastic foci in IPF lungs and find that CRP1 is significantly more expressed in IPF as compared to control lung tissue. The results show that CRP1 is a novel <g>TGF-b</g>1 regulated protein that is expressed in fibrotic lesions and may be relevant in the IPF disease.
21882188|a|<g>Transforming growth factor-b</g> <g>TGF-b</g> is a diverse cytokine regulating growth, apoptosis, differentiation, adhesion, invasion, and extracellular matrix production. Dysregulation of <g>TGF-b</g> is associated with <d>fibrotic disorders</d> and epithelial-mesenchymal transition, and has been linked with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. <g>Cysteine-rich protein 1</g> CRP1 is a small LIM-domain containing protein involved in smooth muscle differentiation. Here, we show that <g>TGF-b</g>1 increases the expression of CRP1 protein and that CRP1 levels increase in a biphasic fashion. A rapid transient 15-45   min increase in CRP1 is followed by a subsequent, sustained increase in CRP1 a few hours afterwards that lasts several days. We find that <g>TGF-b</g>1 regulates the expression of CRP1 through Smad and non-conventional p38 MAPK signaling pathways in a transcription-independent manner and that the induction occurs concomitant with an increase in myofibroblast differentiation. Using CRP1 silencing by shRNA, we identify CRP1 as a novel factor mediating cell contractility. Furthermore, we localize CRP1 to fibroblastic foci in <d>IPF</d> lungs and find that CRP1 is significantly more expressed in <d>IPF</d> as compared to control lung tissue. The results show that CRP1 is a novel <g>TGF-b</g>1 regulated protein that is expressed in fibrotic lesions and may be relevant in the <d>IPF</d> disease.
21882188|a|<g>Transforming growth factor-b</g> <g>TGF-b</g> is a diverse cytokine regulating growth, apoptosis, differentiation, adhesion, invasion, and extracellular matrix production. Dysregulation of <g>TGF-b</g> is associated with <d>fibrotic disorders</d> and epithelial-mesenchymal transition, and has been linked with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. <g>Cysteine-rich protein 1</g> <g>CRP1</g> is a small LIM-domain containing protein involved in smooth muscle differentiation. Here, we show that <g>TGF-b</g>1 increases the expression of <g>CRP1</g> protein and that <g>CRP1</g> levels increase in a biphasic fashion. A rapid transient 15-45   min increase in <g>CRP1</g> is followed by a subsequent, sustained increase in <g>CRP1</g> a few hours afterwards that lasts several days. We find that <g>TGF-b</g>1 regulates the expression of <g>CRP1</g> through Smad and non-conventional <g>p38</g> MAPK signaling pathways in a transcription-independent manner and that the induction occurs concomitant with an increase in myofibroblast differentiation. Using <g>CRP1</g> silencing by shRNA, we identify <g>CRP1</g> as a novel factor mediating cell contractility. Furthermore, we localize <g>CRP1</g> to fibroblastic foci in <d>IPF</d> lungs and find that <g>CRP1</g> is significantly more expressed in <d>IPF</d> as compared to control lung tissue. The results show that <g>CRP1</g> is a novel <g>TGF-b</g>1 regulated protein that is expressed in <d>fibrotic lesions</d> and may be relevant in the <d>IPF</d> disease.
21984893|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive fibroproliferative disease characterized by an accumulation of fibroblasts and myofibroblasts in the alveolar wall. Even though the pathogenesis of this fatal disorder remains unclear, transforming growth factor-b TGF-b-induced differentiation and proliferation of myofibroblasts is recognized as a primary event. The molecular pathways involved in TGF-b signalling are generally Smad-dependent yet Smad-independent pathways, including phosphatidylinositol-3-kinase/protein kinase B <g>PI3K</g>/Akt, have been recently proposed. In this research we established ex-vivo cultures of human lung fibroblasts and we investigated the role of the <g>PI3K</g>/Akt pathway in two critical stages of the fibrotic process induced by TGF-b: fibroblast proliferation and differentiation into myofibroblasts. Here we show that the pan-inhibitor of <g>PI3K</g>s LY294002 is able to abrogate the TGF-b-induced increase in cell proliferation, in a- smooth muscle actin expression and in collagen production besides inhibiting Akt phosphorylation, thus demonstrating the centrality of the <g>PI3K</g>/Akt pathway in lung fibroblast proliferation and differentiation. Moreover, for the first time we show that <g>PI3K</g> p110   and p110y are functionally expressed in human lung fibroblasts, in addition to the ubiquitously expressed p110a and b. Finally, results obtained with both selective inhibitors and gene knocking-down experiments demonstrate a major role of p110y and p110a in both TGF-b-induced fibroblast proliferation and differentiation. This finding suggests that specific <g>PI3K</g> isoforms can be pharmacological targets in IPF.
21984893|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive fibroproliferative disease characterized by an accumulation of fibroblasts and myofibroblasts in the alveolar wall. Even though the pathogenesis of this fatal disorder remains unclear, transforming growth factor-b TGF-b-induced differentiation and proliferation of myofibroblasts is recognized as a primary event. The molecular pathways involved in TGF-b signalling are generally Smad-dependent yet Smad-independent pathways, including phosphatidylinositol-3-kinase/protein kinase B <g>PI3K</g>/Akt, have been recently proposed. In this research we established ex-vivo cultures of human lung fibroblasts and we investigated the role of the <g>PI3K</g>/Akt pathway in two critical stages of the fibrotic process induced by TGF-b: fibroblast proliferation and differentiation into myofibroblasts. Here we show that the pan-inhibitor of <g>PI3K</g>s LY294002 is able to abrogate the TGF-b-induced increase in cell proliferation, in a- smooth muscle actin expression and in collagen production besides inhibiting Akt phosphorylation, thus demonstrating the centrality of the <g>PI3K</g>/Akt pathway in lung fibroblast proliferation and differentiation. Moreover, for the first time we show that <g>PI3K</g> p110   and p110y are functionally expressed in human lung fibroblasts, in addition to the ubiquitously expressed p110a and b. Finally, results obtained with both selective inhibitors and gene knocking-down experiments demonstrate a major role of p110y and p110a in both TGF-b-induced fibroblast proliferation and differentiation. This finding suggests that specific <g>PI3K</g> isoforms can be pharmacological targets in <d>IPF</d>.
21984893|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibroproliferative disease</d> characterized by an accumulation of fibroblasts and myofibroblasts in the alveolar wall. Even though the pathogenesis of this fatal disorder remains unclear, transforming growth factor-b TGF-b-induced differentiation and proliferation of myofibroblasts is recognized as a primary event. The molecular pathways involved in TGF-b signalling are generally Smad-dependent yet Smad-independent pathways, including phosphatidylinositol-3-kinase/protein kinase B <g>PI3K</g>/Akt, have been recently proposed. In this research we established ex-vivo cultures of human lung fibroblasts and we investigated the role of the <g>PI3K</g>/Akt pathway in two critical stages of the fibrotic process induced by TGF-b: fibroblast proliferation and differentiation into myofibroblasts. Here we show that the pan-inhibitor of <g>PI3K</g>s LY294002 is able to abrogate the TGF-b-induced increase in cell proliferation, in a- smooth muscle actin expression and in collagen production besides inhibiting Akt phosphorylation, thus demonstrating the centrality of the <g>PI3K</g>/Akt pathway in lung fibroblast proliferation and differentiation. Moreover, for the first time we show that <g>PI3K</g> p110   and p110y are functionally expressed in human lung fibroblasts, in addition to the ubiquitously expressed p110a and b. Finally, results obtained with both selective inhibitors and gene knocking-down experiments demonstrate a major role of p110y and p110a in both TGF-b-induced fibroblast proliferation and differentiation. This finding suggests that specific <g>PI3K</g> isoforms can be pharmacological targets in <d>IPF</d>.
21984893|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibroproliferative disease</d> characterized by an accumulation of fibroblasts and myofibroblasts in the alveolar wall. Even though the pathogenesis of this <d>fatal disorder</d> remains unclear, transforming growth factor-b TGF-b-induced differentiation and proliferation of myofibroblasts is recognized as a primary event. The molecular pathways involved in TGF-b signalling are generally Smad-dependent yet Smad-independent pathways, including phosphatidylinositol-3-kinase/protein kinase B <g>PI3K</g>/Akt, have been recently proposed. In this research we established ex-vivo cultures of human lung fibroblasts and we investigated the role of the <g>PI3K</g>/Akt pathway in two critical stages of the fibrotic process induced by TGF-b: fibroblast proliferation and differentiation into myofibroblasts. Here we show that the pan-inhibitor of <g>PI3K</g>s LY294002 is able to abrogate the TGF-b-induced increase in cell proliferation, in a- smooth muscle actin expression and in collagen production besides inhibiting Akt phosphorylation, thus demonstrating the centrality of the <g>PI3K</g>/Akt pathway in lung fibroblast proliferation and differentiation. Moreover, for the first time we show that <g>PI3K</g> p110   and p110y are functionally expressed in human lung fibroblasts, in addition to the ubiquitously expressed p110a and b. Finally, results obtained with both selective inhibitors and gene knocking-down experiments demonstrate a major role of p110y and p110a in both TGF-b-induced fibroblast proliferation and differentiation. This finding suggests that specific <g>PI3K</g> isoforms can be pharmacological targets in <d>IPF</d>.
22014187|a|BACKGROUND: Although mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in <d>cystic fibrosis</d> CF and idiopathic pulmonary fibrosis IPF has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls. METHODS: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF 20 lung regions; 5 patients, IPF 21 regions; 7 patients and controls 16 regions; 8 subjects. In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-b. RESULTS: In the alveolar parenchyma in lungs from patients with CF, MCTC numbers increased in areas showing cellular inflammation or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-b. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-b, correlated negatively with patient lung function. CONCLUSIONS: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
22014187|a|BACKGROUND: Although mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in <d>cystic fibrosis</d> CF and <d>idiopathic pulmonary fibrosis</d> IPF has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls. METHODS: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF 20 lung regions; 5 patients, IPF 21 regions; 7 patients and controls 16 regions; 8 subjects. In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-b. RESULTS: In the alveolar parenchyma in lungs from patients with CF, MCTC numbers increased in areas showing cellular inflammation or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-b. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-b, correlated negatively with patient lung function. CONCLUSIONS: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
22014187|a|BACKGROUND: Although mast cells are regarded as important regulators of <d>inflammation</d> and tissue remodelling, their role in <d>cystic fibrosis</d> CF and <d>idiopathic pulmonary fibrosis</d> IPF has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls. METHODS: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF 20 lung regions; 5 patients, IPF 21 regions; 7 patients and controls 16 regions; 8 subjects. In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-b. RESULTS: In the alveolar parenchyma in lungs from patients with CF, MCTC numbers increased in areas showing cellular <d>inflammation</d> or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-b. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-b, correlated negatively with patient lung function. CONCLUSIONS: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
22014187|a|BACKGROUND: Although mast cells are regarded as important regulators of <d>inflammation</d> and tissue remodelling, their role in <d>cystic fibrosis</d> <d>CF</d> and <d>idiopathic pulmonary fibrosis</d> IPF has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with <d>CF</d>, IPF and never smoking controls. METHODS: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with <d>CF</d> 20 lung regions; 5 patients, IPF 21 regions; 7 patients and controls 16 regions; 8 subjects. In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-b. RESULTS: In the alveolar parenchyma in lungs from patients with <d>CF</d>, MCTC numbers increased in areas showing cellular <d>inflammation</d> or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in <d>CF</d> lungs showed elevated expression of IL-6. In <d>CF</d>, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-b. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-b, correlated negatively with patient lung function. CONCLUSIONS: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in <d>CF</d> and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
22014187|a|BACKGROUND: Although mast cells are regarded as important regulators of <d>inflammation</d> and tissue remodelling, their role in <d>cystic fibrosis</d> <d>CF</d> and <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with <d>CF</d>, <d>IPF</d> and never smoking controls. METHODS: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with <d>CF</d> 20 lung regions; 5 patients, <d>IPF</d> 21 regions; 7 patients and controls 16 regions; 8 subjects. In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-b. RESULTS: In the alveolar parenchyma in lungs from patients with <d>CF</d>, MCTC numbers increased in areas showing cellular <d>inflammation</d> or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in <d>CF</d> lungs showed elevated expression of IL-6. In <d>CF</d>, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with <d>IPF</d>, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-b. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in <d>IPF</d>. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-b, correlated negatively with patient lung function. CONCLUSIONS: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in <d>CF</d> and <d>IPF</d>. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
22014187|a|BACKGROUND: Although mast cells are regarded as important regulators of <d>inflammation</d> and tissue remodelling, their role in <d>cystic fibrosis</d> <d>CF</d> and <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with <d>CF</d>, <d>IPF</d> and never smoking controls. METHODS: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with <d>CF</d> 20 lung regions; 5 patients, <d>IPF</d> 21 regions; 7 patients and controls 16 regions; 8 subjects. In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of <g>IL-6</g> and <g>TGF-b</g>. RESULTS: In the <d>alveolar parenchyma</d> in lungs from patients with <d>CF</d>, MCTC numbers increased in areas showing cellular <d>inflammation</d> or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in <d>CF</d> lungs showed elevated expression of <g>IL-6</g>. In <d>CF</d>, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with <d>IPF</d>, a significantly elevated MCTC density was present in fibrotic areas of the <d>alveolar parenchyma</d> with increased mast cell expression of <g>TGF-b</g>. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in <d>IPF</d>. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of <g>TGF-b</g>, correlated negatively with patient lung function. CONCLUSIONS: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased <d>alveolar parenchyma</d>, represents a significant component of the histopathology in <d>CF</d> and <d>IPF</d>. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
22014187|a|BACKGROUND: Although mast cells are regarded as important regulators of <d>inflammation</d> and tissue remodelling, their role in <d>cystic <d>fibrosis</d></d> <d>CF</d> and <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with <d>CF</d>, <d>IPF</d> and never smoking controls. METHODS: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with <d>CF</d> 20 lung regions; 5 patients, <d>IPF</d> 21 regions; 7 patients and controls 16 regions; 8 subjects. In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of <g>IL-6</g> and <g>TGF-b</g>. RESULTS: In the <d>alveolar parenchyma</d> in lungs from patients with <d>CF</d>, MCTC numbers increased in areas showing cellular <d>inflammation</d> or <d>fibrosis</d> compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in <d>CF</d> lungs showed elevated expression of <g>IL-6</g>. In <d>CF</d>, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with <d>IPF</d>, a significantly elevated MCTC density was present in fibrotic areas of the <d>alveolar parenchyma</d> with increased mast cell expression of <g>TGF-b</g>. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in <d>IPF</d>. Both the density, as well as the percentage, of MCTC correlated positively with the degree of <d>fibrosis</d>. The increased density of MCTC, as well as MCTC expression of <g>TGF-b</g>, correlated negatively with patient lung function. CONCLUSIONS: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased <d>alveolar parenchyma</d>, represents a significant component of the histopathology in <d>CF</d> and <d>IPF</d>. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
22088447|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and lethal fibrotic lung disease of unknown etiology. Host susceptibility or genetic factors may be important for the predisposition to it. Transforming growth factor-b1 TGF-b1, a potent profibrotic cytokine and plasminogen activator inhibitor 1 PAI-1 play important roles in the development of pulmonary fibrosis. The objective of the study was to investigate the association between the gene polymorphisms of TGF-b1 869 T > C and PAI-1 4G/5G and the susceptibility to IPF in Han ethnicity. METHODS: Polymerase chain reaction PCR and restriction fragment length polymorphism were performed to analyse the gene polymorphisms of TGF-b1 in 869T > C and PAI-1 4G/5G in 85 IPF patients and 85 healthy controls matched in age, gender, race and smoker status. RESULTS: There was a significant difference in 869T > C genotype distribution of TGF-b1 between IPF cases and controls, a significant negative association between TC genotype and the development of IPF OR = 0.508, 95%CI: 0.275 - 0.941 and a positive association between CC genotype and the development of IPF OR = 1.967, 95%CI: 1.063 - 3.641. There was a significant positive association between PAI-1 5G/5G genotype and the development of IPF OR = 0.418, 95%CI: 0.193 - 0.904. CONCLUSIONS: Gene polymorphisms of TGF-b1 in 869T > C and PAI-1 4G/5G may affect the susceptibility to IPF in Han ethnicity. Further investigations are needed to confirm these findings and assess their biological significance in the development of the disease in this ethnic population.
22088447|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and lethal fibrotic lung disease of unknown etiology. Host susceptibility or genetic factors may be important for the predisposition to it. Transforming growth factor-b1 TGF-b1, a potent profibrotic cytokine and <g>plasminogen activator inhibitor 1</g> PAI-1 play important roles in the development of pulmonary fibrosis. The objective of the study was to investigate the association between the gene polymorphisms of TGF-b1 869 T > C and PAI-1 4G/5G and the susceptibility to <d>IPF</d> in Han ethnicity. METHODS: Polymerase chain reaction PCR and restriction fragment length polymorphism were performed to analyse the gene polymorphisms of TGF-b1 in 869T > C and PAI-1 4G/5G in 85 <d>IPF</d> patients and 85 healthy controls matched in age, gender, race and smoker status. RESULTS: There was a significant difference in 869T > C genotype distribution of TGF-b1 between <d>IPF</d> cases and controls, a significant negative association between TC genotype and the development of <d>IPF</d> OR = 0.508, 95%CI: 0.275 - 0.941 and a positive association between CC genotype and the development of <d>IPF</d> OR = 1.967, 95%CI: 1.063 - 3.641. There was a significant positive association between PAI-1 5G/5G genotype and the development of <d>IPF</d> OR = 0.418, 95%CI: 0.193 - 0.904. CONCLUSIONS: Gene polymorphisms of TGF-b1 in 869T > C and PAI-1 4G/5G may affect the susceptibility to <d>IPF</d> in Han ethnicity. Further investigations are needed to confirm these findings and assess their biological significance in the development of the disease in this ethnic population.
22088447|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and lethal <d>fibrotic lung disease</d> of unknown etiology. Host susceptibility or genetic factors may be important for the predisposition to it. Transforming growth factor-b1 TGF-b1, a potent profibrotic cytokine and <g>plasminogen activator inhibitor 1</g> PAI-1 play important roles in the development of pulmonary fibrosis. The objective of the study was to investigate the association between the gene polymorphisms of TGF-b1 869 T > C and PAI-1 4G/5G and the susceptibility to <d>IPF</d> in Han ethnicity. METHODS: Polymerase chain reaction PCR and restriction fragment length polymorphism were performed to analyse the gene polymorphisms of TGF-b1 in 869T > C and PAI-1 4G/5G in 85 <d>IPF</d> patients and 85 healthy controls matched in age, gender, race and smoker status. RESULTS: There was a significant difference in 869T > C genotype distribution of TGF-b1 between <d>IPF</d> cases and controls, a significant negative association between TC genotype and the development of <d>IPF</d> OR = 0.508, 95%CI: 0.275 - 0.941 and a positive association between CC genotype and the development of <d>IPF</d> OR = 1.967, 95%CI: 1.063 - 3.641. There was a significant positive association between PAI-1 5G/5G genotype and the development of <d>IPF</d> OR = 0.418, 95%CI: 0.193 - 0.904. CONCLUSIONS: Gene polymorphisms of TGF-b1 in 869T > C and PAI-1 4G/5G may affect the susceptibility to <d>IPF</d> in Han ethnicity. Further investigations are needed to confirm these findings and assess their biological significance in the development of the disease in this ethnic population.
22088447|a|BACKGROUND: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive and lethal <d>fibrotic lung disease</d> of unknown etiology. Host susceptibility or genetic factors may be important for the predisposition to it. <g>Transforming growth factor-b1</g> <g>TGF-b1</g>, a potent profibrotic cytokine and <g>plasminogen activator inhibitor 1</g> <g>PAI-1</g> play important roles in the development of <d>pulmonary fibrosis</d>. The objective of the study was to investigate the association between the gene polymorphisms of <g>TGF-b1</g> 869 T > C and <g>PAI-1</g> 4G/5G and the susceptibility to <d>IPF</d> in Han ethnicity. METHODS: Polymerase chain reaction PCR and restriction fragment length polymorphism were performed to analyse the gene polymorphisms of <g>TGF-b1</g> in 869T > C and <g>PAI-1</g> 4G/5G in 85 <d>IPF</d> patients and 85 healthy controls matched in age, gender, race and smoker status. RESULTS: There was a significant difference in 869T > C genotype distribution of <g>TGF-b1</g> between <d>IPF</d> cases and controls, a significant negative association between TC genotype and the development of <d>IPF</d> OR = 0.508, 95%CI: 0.275 - 0.941 and a positive association between CC genotype and the development of <d>IPF</d> OR = 1.967, 95%CI: 1.063 - 3.641. There was a significant positive association between <g>PAI-1</g> 5G/5G genotype and the development of <d>IPF</d> OR = 0.418, 95%CI: 0.193 - 0.904. CONCLUSIONS: Gene polymorphisms of <g>TGF-b1</g> in 869T > C and <g>PAI-1</g> 4G/5G may affect the susceptibility to <d>IPF</d> in Han ethnicity. Further investigations are needed to confirm these findings and assess their biological significance in the development of the disease in this ethnic population.
22095546|a|RATIONALE: Idiopathic pulmonary <d>fibrosis</d> IPF is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a b-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. OBJECTIVES: To examine the role of galectin-3 in pulmonary <d>fibrosis</d>. METHODS: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung <d>fibrosis</d>. Further mechanistic studies were performed in vitro and on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: Transforming growth factor TGF-b and bleomycin-induced lung <d>fibrosis</d> was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-b1-induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of b-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin-3, TD139, blocked TGF-b-induced b-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung <d>fibrosis</d> after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that galectin-3 may be a marker of active <d>fibrosis</d> in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF. CONCLUSIONS: This study identifies galectin-3 as an important regulator of lung <d>fibrosis</d> and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF.
22095546|a|RATIONALE: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a b-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. OBJECTIVES: To examine the role of <g>galectin-3</g> in pulmonary <d>fibrosis</d>. METHODS: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung <d>fibrosis</d>. Further mechanistic studies were performed in vitro and on samples from patients with <d>IPF</d>. MEASUREMENTS AND MAIN RESULTS: Transforming growth factor TGF-b and bleomycin-induced lung <d>fibrosis</d> was dramatically reduced in mice deficient in <g>galectin-3</g>, manifest by reduced TGF-b1-induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of b-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of <g>galectin-3</g>, TD139, blocked TGF-b-induced b-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung <d>fibrosis</d> after bleomycin. There was increased expression of <g>galectin-3</g> in the bronchoalveolar lavage fluid and serum from patients with stable <d>IPF</d> compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that <g>galectin-3</g> may be a marker of active <d>fibrosis</d> in <d>IPF</d> and that strategies that block <g>galectin-3</g> may be effective in treating acute fibrotic exacerbations of <d>IPF</d>. CONCLUSIONS: This study identifies <g>galectin-3</g> as an important regulator of lung <d>fibrosis</d> and provides a proof of principle for <g>galectin-3</g> inhibition as a potential novel therapeutic strategy for <d>IPF</d>.
22095546|a|RATIONALE: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic dysregulated response to <d>alveolar epithelial injury</d> with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a b-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. OBJECTIVES: To examine the role of <g>galectin-3</g> in pulmonary <d>fibrosis</d>. METHODS: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung <d>fibrosis</d>. Further mechanistic studies were performed in vitro and on samples from patients with <d>IPF</d>. MEASUREMENTS AND MAIN RESULTS: Transforming growth factor TGF-b and bleomycin-induced lung <d>fibrosis</d> was dramatically reduced in mice deficient in <g>galectin-3</g>, manifest by reduced TGF-b1-induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of b-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of <g>galectin-3</g>, TD139, blocked TGF-b-induced b-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung <d>fibrosis</d> after bleomycin. There was increased expression of <g>galectin-3</g> in the bronchoalveolar lavage fluid and serum from patients with stable <d>IPF</d> compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that <g>galectin-3</g> may be a marker of active <d>fibrosis</d> in <d>IPF</d> and that strategies that block <g>galectin-3</g> may be effective in treating acute fibrotic exacerbations of <d>IPF</d>. CONCLUSIONS: This study identifies <g>galectin-3</g> as an important regulator of lung <d>fibrosis</d> and provides a proof of principle for <g>galectin-3</g> inhibition as a potential novel therapeutic strategy for <d>IPF</d>.
22095546|a|RATIONALE: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic dysregulated response to <d>alveolar epithelial injury</d> with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. <g>Galectin-3</g> is a b-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. OBJECTIVES: To examine the role of <g>galectin-3</g> in pulmonary <d>fibrosis</d>. METHODS: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung <d>fibrosis</d>. Further mechanistic studies were performed in vitro and on samples from patients with <d>IPF</d>. MEASUREMENTS AND MAIN RESULTS: <g>Transforming growth factor <g>TGF-b</g></g> and bleomycin-induced lung <d>fibrosis</d> was dramatically reduced in mice deficient in <g>galectin-3</g>, manifest by reduced <g><g>TGF-b</g>1</g>-induced EMT and myofibroblast activation and collagen production. <g>Galectin-3</g> reduced phosphorylation and nuclear translocation of <g>b-catenin</g> but had no effect on <g>Smad2/3</g> phosphorylation. A novel inhibitor of <g>galectin-3</g>, TD139, blocked <g>TGF-b</g>-induced <g>b-catenin</g> activation in vitro and in vivo and attenuated the late-stage progression of lung <d>fibrosis</d> after bleomycin. There was increased expression of <g>galectin-3</g> in the bronchoalveolar lavage fluid and serum from patients with stable <d>IPF</d> compared with nonspecific <d>interstitial pneumonitis</d> and controls, which rose sharply during an acute exacerbation suggesting that <g>galectin-3</g> may be a marker of active <d>fibrosis</d> in <d>IPF</d> and that strategies that block <g>galectin-3</g> may be effective in treating acute fibrotic exacerbations of <d>IPF</d>. CONCLUSIONS: This study identifies <g>galectin-3</g> as an important regulator of lung <d>fibrosis</d> and provides a proof of principle for <g>galectin-3</g> inhibition as a potential novel therapeutic strategy for <d>IPF</d>.
22106015|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is characterised by the aberrant epithelial to mesenchymal transition EMT and myofibroblast accumulation. Sphingosine-1-phosphate S1P and sphingosine kinase 1 SPHK1 have been implicated in lung myofibroblast transition, but their role in EMT and their expression in patients with IPF is unknown. METHODS AND RESULTS: S1P levels were measured in serum n=27 and bronchoalveolar lavage BAL; n=15 from patients with IPF and controls n=30 for serum and n=15 for BAL studies. SPHK1 expression was measured in lung tissue from patients with IPF n=12 and controls n=15. Alveolar type II transformation into mesenchymal cells was studied in response to S1P 10-9-10-5 M. The median IQR of S1P serum levels was increased in patients with IPF 1.4 0.4  M versus controls 1 0.26  M; p<0.0001. BAL S1P levels were increased in patients with IPF 1.12 0.53  M versus controls 0.2 0.5; p<0.0001 and correlated with diffusion capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and forced vital capacity Spearman's r=-0.87, -0.72 and -0.68, respectively in patients with IPF. SPHK1 was upregulated in lung tissue from patients with IPF and correlated with a-smooth muscle actin, vimentin and collagen type I Spearman's r=0.82, 0.85 and 0.72, respectively. S1P induced EMT in alveolar type II cells by interacting with S1P2 and S1P3, as well as by the activation of p-Smad3, RhoA-GTP, oxidative stress and transforming growth factor-b1 TGF-b1 release. Furthermore, TGF-b1-induced EMT was partially conducted by the S1P/SPHK1 activation, suggesting crosstalk between TGF-b1 and the S1P/SPHK1 axis. CONCLUSIONS: S1P is elevated in patients with IPF, correlates with the lung function and mediates EMT.
22106015|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterised by the aberrant epithelial to mesenchymal transition EMT and myofibroblast accumulation. Sphingosine-1-phosphate S1P and sphingosine kinase 1 SPHK1 have been implicated in lung myofibroblast transition, but their role in EMT and their expression in patients with <d>IPF</d> is unknown. METHODS AND RESULTS: S1P levels were measured in serum n=27 and bronchoalveolar lavage BAL; n=15 from patients with <d>IPF</d> and controls n=30 for serum and n=15 for BAL studies. SPHK1 expression was measured in lung tissue from patients with <d>IPF</d> n=12 and controls n=15. Alveolar type II transformation into mesenchymal cells was studied in response to S1P 10-9-10-5 M. The median IQR of S1P serum levels was increased in patients with <d>IPF</d> 1.4 0.4  M versus controls 1 0.26  M; p<0.0001. BAL S1P levels were increased in patients with <d>IPF</d> 1.12 0.53  M versus controls 0.2 0.5; p<0.0001 and correlated with diffusion capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and forced vital capacity Spearman's r=-0.87, -0.72 and -0.68, respectively in patients with <d>IPF</d>. SPHK1 was upregulated in lung tissue from patients with <d>IPF</d> and correlated with a-smooth muscle actin, vimentin and collagen type I Spearman's r=0.82, 0.85 and 0.72, respectively. S1P induced EMT in alveolar type II cells by interacting with S1P2 and S1P3, as well as by the activation of p-Smad3, RhoA-GTP, oxidative stress and transforming growth factor-b1 TGF-b1 release. Furthermore, TGF-b1-induced EMT was partially conducted by the S1P/SPHK1 activation, suggesting crosstalk between TGF-b1 and the S1P/SPHK1 axis. CONCLUSIONS: S1P is elevated in patients with <d>IPF</d>, correlates with the lung function and mediates EMT.
22117501|a|BACKGROUND: Previous studies identified clinical and physiologic factors of <d>idiopathic pulmonary fibrosis</d> IPF that are related to an increased risk of mortality. But there are few studies about histologic and molecular approach. OBJECTIVE: We investigated whether the C-reactive protein CRP, fibroblastic foci, phosphorylated Smad2/3 p-Smad2/3, tumor growth factor-beta TGF-beta, TGF-beta receptor II TbetaRII, and the polymorphism of the TGF-beta1 codon 10 are associated with the progression of IPF patients. DESIGN: Eighty-six IPF patients who underwent surgical lung biopsies were examined. For each patient, clinical and physiologic parameters were investigated, and we performed immunohistochemical staining for p-Smad2/3 and TbetaRII, and genotyping of the TGF-beta1 codon 10 polymorphism. RESULTS: Age at diagnosis, gender, symptom duration, and smoking status did not show a significant association. However, the amount of smoking p = 0.002, severe reduction in the percentages of predicted forced vital capacity p = 0.013 and diffusion lung capacity of carbon monoxide p = 0.023, CRP p = 0.009 at diagnosis, and fibroblastic foci p = 0.026 were associated with a poor prognosis. Cellularity, fibrosis, expression level of p-Smad2/3 and TbetaRII, and genotype of the TGF-beta1 codon 10 polymorphism did not have a statistically significant association with the prognosis. CONCLUSION: This study confirmed the amount of smoking, abrupt decrease in follow-up pulmonary function parameters, fibroblastic foci, and increased levels of CRP concentration at diagnosis were significantly associated with poor survival. Larger studies are required to confirm all prognostic factors including CRP.
22117501|a|BACKGROUND: Previous studies identified clinical and physiologic factors of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> that are related to an increased risk of mortality. But there are few studies about histologic and molecular approach. OBJECTIVE: We investigated whether the C-reactive protein CRP, fibroblastic foci, phosphorylated Smad2/3 p-Smad2/3, tumor growth factor-beta TGF-beta, TGF-beta receptor II TbetaRII, and the polymorphism of the TGF-beta1 codon 10 are associated with the progression of <d>IPF</d> patients. DESIGN: Eighty-six <d>IPF</d> patients who underwent surgical lung biopsies were examined. For each patient, clinical and physiologic parameters were investigated, and we performed immunohistochemical staining for p-Smad2/3 and TbetaRII, and genotyping of the TGF-beta1 codon 10 polymorphism. RESULTS: Age at diagnosis, gender, symptom duration, and smoking status did not show a significant association. However, the amount of smoking p = 0.002, severe reduction in the percentages of predicted forced vital capacity p = 0.013 and diffusion lung capacity of carbon monoxide p = 0.023, CRP p = 0.009 at diagnosis, and fibroblastic foci p = 0.026 were associated with a poor prognosis. Cellularity, fibrosis, expression level of p-Smad2/3 and TbetaRII, and genotype of the TGF-beta1 codon 10 polymorphism did not have a statistically significant association with the prognosis. CONCLUSION: This study confirmed the amount of smoking, abrupt decrease in follow-up pulmonary function parameters, fibroblastic foci, and increased levels of CRP concentration at diagnosis were significantly associated with poor survival. Larger studies are required to confirm all prognostic factors including CRP.
22117501|a|BACKGROUND: Previous studies identified clinical and physiologic factors of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> that are related to an increased risk of mortality. But there are few studies about histologic and molecular approach. OBJECTIVE: We investigated whether the C-reactive protein CRP, fibroblastic foci, phosphorylated <g>Smad2/3</g> p-<g>Smad2/3</g>, <d>tumor</d> growth factor-beta TGF-beta, TGF-beta receptor II TbetaRII, and the polymorphism of the TGF-beta1 codon 10 are associated with the progression of <d>IPF</d> patients. DESIGN: Eighty-six <d>IPF</d> patients who underwent surgical lung biopsies were examined. For each patient, clinical and physiologic parameters were investigated, and we performed immunohistochemical staining for p-<g>Smad2/3</g> and TbetaRII, and genotyping of the TGF-beta1 codon 10 polymorphism. RESULTS: Age at diagnosis, gender, symptom duration, and smoking status did not show a significant association. However, the amount of smoking p = 0.002, severe reduction in the percentages of predicted forced vital capacity p = 0.013 and diffusion lung capacity of carbon monoxide p = 0.023, CRP p = 0.009 at diagnosis, and fibroblastic foci p = 0.026 were associated with a poor prognosis. Cellularity, fibrosis, expression level of p-<g>Smad2/3</g> and TbetaRII, and genotype of the TGF-beta1 codon 10 polymorphism did not have a statistically significant association with the prognosis. CONCLUSION: This study confirmed the amount of smoking, abrupt decrease in follow-up pulmonary function parameters, fibroblastic foci, and increased levels of CRP concentration at diagnosis were significantly associated with poor survival. Larger studies are required to confirm all prognostic factors including CRP.
22117501|a|BACKGROUND: Previous studies identified clinical and physiologic factors of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> that are related to an increased risk of mortality. But there are few studies about histologic and molecular approach. OBJECTIVE: We investigated whether the C-reactive protein CRP, fibroblastic foci, phosphorylated <g>Smad2/3</g> p-<g>Smad2/3</g>, <d>tumor</d> growth factor-beta <g>TGF-beta</g>, <g>TGF-beta</g> receptor II <g>TbetaRII</g>, and the polymorphism of the <g>TGF-beta</g>1 codon 10 are associated with the progression of <d>IPF</d> patients. DESIGN: Eighty-six <d>IPF</d> patients who underwent surgical lung biopsies were examined. For each patient, clinical and physiologic parameters were investigated, and we performed immunohistochemical staining for p-<g>Smad2/3</g> and <g>TbetaRII</g>, and genotyping of the <g>TGF-beta</g>1 codon 10 polymorphism. RESULTS: Age at diagnosis, gender, symptom duration, and smoking status did not show a significant association. However, the amount of smoking p = 0.002, severe reduction in the percentages of predicted forced vital capacity p = 0.013 and diffusion lung capacity of carbon monoxide p = 0.023, CRP p = 0.009 at diagnosis, and fibroblastic foci p = 0.026 were associated with a poor prognosis. Cellularity, <d>fibrosis</d>, expression level of p-<g>Smad2/3</g> and <g>TbetaRII</g>, and genotype of the <g>TGF-beta</g>1 codon 10 polymorphism did not have a statistically significant association with the prognosis. CONCLUSION: This study confirmed the amount of smoking, abrupt decrease in follow-up pulmonary function parameters, fibroblastic foci, and increased levels of CRP concentration at diagnosis were significantly associated with poor survival. Larger studies are required to confirm all prognostic factors including CRP.
22173045|a|INTRODUCTION: <d>Idiopathic pulmonary fibrosis</d> IPF is a devastating progressive lung disease with an average survival of only 3 to 5 years. The mechanisms underlying the initiation and progression of IPF are poorly understood, and treatments available have only modest effect on disease progression. Interestingly, the incidence of IPF is approximately 60 times more common in individuals aged 75 years and older, but the mechanism by which aging promotes fibrosis is unclear. The authors hypothesized that aged lungs have a profibrotic phenotype that render it susceptible to disrepair after injury. METHODS: Young and old mice were treated with bleomycin to examine disrepair in the aged lung. In addition, uninjured young and old mouse lungs were analyzed for transforming growth factor-beta 1 TGF-b1 production, extracellular matrix composition and lung fibroblast phenotype. Lung fibroblasts were treated with a DNA methyltransferase inhibitor to examine the potential epigenetic mechanisms involved in age-associated phenotypic alterations. RESULTS: The lungs of old mice showed worse fibrosis after bleomycin-induced injury compared with the lungs from young mice. At baseline, aged lungs expressed a profibrotic phenotype characterized by increased mRNA expression for fibronectin extracellular domain A Fn-EDA and the matrix metalloproteinases MMPs MMP-2 and MMP-9. Old lungs also expressed higher levels of TGF-b receptor 1 and TGF-b1 mRNA, protein and activity as determined by increased Smad3 expression, protein phosphorylation and DNA binding. Lung fibroblasts harvested from aged lungs showed reduced expression of the surface molecule Thy-1, a finding also implicated in lung fibrosis; the latter did not seem related to Thy-1 gene methylation. CONCLUSION: Altogether, aged lungs manifest a profibrotic phenotype characterized by enhanced fibronectin extracellular domain A and MMP expression and increased TGF-b1 expression and signaling and are populated by Thy-1-negative fibroblasts, all implicated in the pathogenesis of lung fibrosis.
22173045|a|INTRODUCTION: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating progressive lung disease with an average survival of only 3 to 5 years. The mechanisms underlying the initiation and progression of <d>IPF</d> are poorly understood, and treatments available have only modest effect on disease progression. Interestingly, the incidence of <d>IPF</d> is approximately 60 times more common in individuals aged 75 years and older, but the mechanism by which aging promotes fibrosis is unclear. The authors hypothesized that aged lungs have a profibrotic phenotype that render it susceptible to disrepair after injury. METHODS: Young and old mice were treated with bleomycin to examine disrepair in the aged lung. In addition, uninjured young and old mouse lungs were analyzed for transforming growth factor-beta 1 TGF-b1 production, extracellular matrix composition and lung fibroblast phenotype. Lung fibroblasts were treated with a DNA methyltransferase inhibitor to examine the potential epigenetic mechanisms involved in age-associated phenotypic alterations. RESULTS: The lungs of old mice showed worse fibrosis after bleomycin-induced injury compared with the lungs from young mice. At baseline, aged lungs expressed a profibrotic phenotype characterized by increased mRNA expression for fibronectin extracellular domain A Fn-EDA and the matrix metalloproteinases MMPs MMP-2 and MMP-9. Old lungs also expressed higher levels of TGF-b receptor 1 and TGF-b1 mRNA, protein and activity as determined by increased Smad3 expression, protein phosphorylation and DNA binding. Lung fibroblasts harvested from aged lungs showed reduced expression of the surface molecule Thy-1, a finding also implicated in lung fibrosis; the latter did not seem related to Thy-1 gene methylation. CONCLUSION: Altogether, aged lungs manifest a profibrotic phenotype characterized by enhanced fibronectin extracellular domain A and MMP expression and increased TGF-b1 expression and signaling and are populated by Thy-1-negative fibroblasts, all implicated in the pathogenesis of lung fibrosis.
22173045|a|INTRODUCTION: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating progressive <d>lung disease</d> with an average survival of only 3 to 5 years. The mechanisms underlying the initiation and progression of <d>IPF</d> are poorly understood, and treatments available have only modest effect on disease progression. Interestingly, the incidence of <d>IPF</d> is approximately 60 times more common in individuals aged 75 years and older, but the mechanism by which aging promotes fibrosis is unclear. The authors hypothesized that aged lungs have a profibrotic phenotype that render it susceptible to disrepair after injury. METHODS: Young and old mice were treated with bleomycin to examine disrepair in the aged lung. In addition, uninjured young and old mouse lungs were analyzed for transforming growth factor-beta 1 TGF-b1 production, extracellular matrix composition and lung fibroblast phenotype. Lung fibroblasts were treated with a DNA methyltransferase inhibitor to examine the potential epigenetic mechanisms involved in age-associated phenotypic alterations. RESULTS: The lungs of old mice showed worse fibrosis after bleomycin-induced injury compared with the lungs from young mice. At baseline, aged lungs expressed a profibrotic phenotype characterized by increased mRNA expression for fibronectin extracellular domain A Fn-EDA and the matrix metalloproteinases MMPs MMP-2 and MMP-9. Old lungs also expressed higher levels of TGF-b receptor 1 and TGF-b1 mRNA, protein and activity as determined by increased Smad3 expression, protein phosphorylation and DNA binding. Lung fibroblasts harvested from aged lungs showed reduced expression of the surface molecule Thy-1, a finding also implicated in lung fibrosis; the latter did not seem related to Thy-1 gene methylation. CONCLUSION: Altogether, aged lungs manifest a profibrotic phenotype characterized by enhanced fibronectin extracellular domain A and MMP expression and increased TGF-b1 expression and signaling and are populated by Thy-1-negative fibroblasts, all implicated in the pathogenesis of lung fibrosis.
22173045|a|INTRODUCTION: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating progressive <d>lung disease</d> with an average survival of only 3 to 5 years. The mechanisms underlying the initiation and progression of <d>IPF</d> are poorly understood, and treatments available have only modest effect on disease progression. Interestingly, the incidence of <d>IPF</d> is approximately 60 times more common in individuals aged 75 years and older, but the mechanism by which aging promotes <d>fibrosis</d> is unclear. The authors hypothesized that aged lungs have a profibrotic phenotype that render it susceptible to disrepair after injury. METHODS: Young and old mice were treated with bleomycin to examine disrepair in the aged lung. In addition, uninjured young and old mouse lungs were analyzed for transforming growth factor-beta 1 TGF-b1 production, extracellular matrix composition and lung fibroblast phenotype. Lung fibroblasts were treated with a DNA methyltransferase inhibitor to examine the potential epigenetic mechanisms involved in age-associated phenotypic alterations. RESULTS: The lungs of old mice showed worse <d>fibrosis</d> after bleomycin-induced injury compared with the lungs from young mice. At baseline, aged lungs expressed a profibrotic phenotype characterized by increased mRNA expression for fibronectin extracellular domain A Fn-EDA and the matrix metalloproteinases MMPs MMP-2 and MMP-9. Old lungs also expressed higher levels of TGF-b receptor 1 and TGF-b1 mRNA, protein and activity as determined by increased Smad3 expression, protein phosphorylation and DNA binding. Lung fibroblasts harvested from aged lungs showed reduced expression of the surface molecule Thy-1, a finding also implicated in lung <d>fibrosis</d>; the latter did not seem related to Thy-1 gene methylation. CONCLUSION: Altogether, aged lungs manifest a profibrotic phenotype characterized by enhanced fibronectin extracellular domain A and MMP expression and increased TGF-b1 expression and signaling and are populated by Thy-1-negative fibroblasts, all implicated in the pathogenesis of lung <d>fibrosis</d>.
22173045|a|INTRODUCTION: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating progressive <d>lung disease</d> with an average survival of only 3 to 5 years. The mechanisms underlying the initiation and progression of <d>IPF</d> are poorly understood, and treatments available have only modest effect on disease progression. Interestingly, the incidence of <d>IPF</d> is approximately 60 times more common in individuals aged 75 years and older, but the mechanism by which aging promotes <d>fibrosis</d> is unclear. The authors hypothesized that aged lungs have a profibrotic phenotype that render it susceptible to disrepair after <d>injury</d>. METHODS: Young and old mice were treated with bleomycin to examine disrepair in the aged lung. In addition, uninjured young and old mouse lungs were analyzed for transforming growth factor-beta 1 TGF-b1 production, extracellular matrix composition and lung fibroblast phenotype. Lung fibroblasts were treated with a DNA methyltransferase inhibitor to examine the potential epigenetic mechanisms involved in age-associated phenotypic alterations. RESULTS: The lungs of old mice showed worse <d>fibrosis</d> after bleomycin-induced <d>injury</d> compared with the lungs from young mice. At baseline, aged lungs expressed a profibrotic phenotype characterized by increased mRNA expression for fibronectin extracellular domain A Fn-EDA and the matrix metalloproteinases MMPs MMP-2 and MMP-9. Old lungs also expressed higher levels of TGF-b receptor 1 and TGF-b1 mRNA, protein and activity as determined by increased Smad3 expression, protein phosphorylation and DNA binding. Lung fibroblasts harvested from aged lungs showed reduced expression of the surface molecule Thy-1, a finding also implicated in lung <d>fibrosis</d>; the latter did not seem related to Thy-1 gene methylation. CONCLUSION: Altogether, aged lungs manifest a profibrotic phenotype characterized by enhanced fibronectin extracellular domain A and MMP expression and increased TGF-b1 expression and signaling and are populated by Thy-1-negative fibroblasts, all implicated in the pathogenesis of lung <d>fibrosis</d>.
22189082|a|Excessive extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic <d>pulmonary fibrosis</d> IPF. Epithelial-mesenchymal transition, involving transition of alveolar epithelial cells AECs to pulmonary fibroblasts, appears to be an important contributory process to lung fibrosis. Although aberrant expression of microRNAs miRs is involved in a variety of pathophysiologic processes, the role of miRs in fibrotic lung diseases is less well understood. In the present study, we found that miR-200a, miR-200b, and miR-200c are significantly down-regulated in the lungs of mice with experimental lung fibrosis. Levels of miR-200a and miR-200c were reduced in the lungs of patients with IPF. miR-200 had greater expression in AECs than in lung fibroblasts, and AECs from mice with experimental <d>pulmonary fibrosis</d> had diminished expression of miR-200. We found that the miR-200 family members inhibit transforming growth factor-b1-induced epithelial-mesenchymal transition of AECs. miR-200 family members can reverse the fibrogenic activity of pulmonary fibroblasts from mice with experimental <d>pulmonary fibrosis</d> and from patients with IPF. Indeed, the introduction of miR-200c diminishes experimental <d>pulmonary fibrosis</d> in mice. Thus, the miR-200 family members participate importantly in fibrotic lung diseases and suggest that restoring miR-200 expression in the lungs may represent a novel therapeutic approach in treating pulmonary fibrotic diseases.
22189082|a|Excessive extracellular matrix production by fibroblasts in response to tissue injury contributes to <d>fibrotic diseases</d>, such as idiopathic <d>pulmonary fibrosis</d> IPF. Epithelial-mesenchymal transition, involving transition of alveolar epithelial cells AECs to pulmonary fibroblasts, appears to be an important contributory process to lung fibrosis. Although aberrant expression of microRNAs miRs is involved in a variety of pathophysiologic processes, the role of miRs in fibrotic lung diseases is less well understood. In the present study, we found that miR-200a, miR-200b, and miR-200c are significantly down-regulated in the lungs of mice with experimental lung fibrosis. Levels of miR-200a and miR-200c were reduced in the lungs of patients with IPF. miR-200 had greater expression in AECs than in lung fibroblasts, and AECs from mice with experimental <d>pulmonary fibrosis</d> had diminished expression of miR-200. We found that the miR-200 family members inhibit transforming growth factor-b1-induced epithelial-mesenchymal transition of AECs. miR-200 family members can reverse the fibrogenic activity of pulmonary fibroblasts from mice with experimental <d>pulmonary fibrosis</d> and from patients with IPF. Indeed, the introduction of miR-200c diminishes experimental <d>pulmonary fibrosis</d> in mice. Thus, the miR-200 family members participate importantly in fibrotic lung diseases and suggest that restoring miR-200 expression in the lungs may represent a novel therapeutic approach in treating pulmonary <d>fibrotic diseases</d>.
22189082|a|Excessive extracellular matrix production by fibroblasts in response to tissue injury contributes to <d>fibrotic diseases</d>, such as idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. Epithelial-mesenchymal transition, involving transition of alveolar epithelial cells AECs to pulmonary fibroblasts, appears to be an important contributory process to lung fibrosis. Although aberrant expression of microRNAs miRs is involved in a variety of pathophysiologic processes, the role of miRs in fibrotic lung diseases is less well understood. In the present study, we found that miR-200a, miR-200b, and miR-200c are significantly down-regulated in the lungs of mice with experimental lung fibrosis. Levels of miR-200a and miR-200c were reduced in the lungs of patients with <d>IPF</d>. miR-200 had greater expression in AECs than in lung fibroblasts, and AECs from mice with experimental <d>pulmonary fibrosis</d> had diminished expression of miR-200. We found that the miR-200 family members inhibit transforming growth factor-b1-induced epithelial-mesenchymal transition of AECs. miR-200 family members can reverse the fibrogenic activity of pulmonary fibroblasts from mice with experimental <d>pulmonary fibrosis</d> and from patients with <d>IPF</d>. Indeed, the introduction of miR-200c diminishes experimental <d>pulmonary fibrosis</d> in mice. Thus, the miR-200 family members participate importantly in fibrotic lung diseases and suggest that restoring miR-200 expression in the lungs may represent a novel therapeutic approach in treating pulmonary <d>fibrotic diseases</d>.
22189082|a|Excessive extracellular matrix production by fibroblasts in response to tissue injury contributes to <d>fibrotic diseases</d>, such as idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Epithelial-mesenchymal transition, involving transition of alveolar epithelial cells AECs to pulmonary fibroblasts, appears to be an important contributory process to lung <d>fibrosis</d>. Although aberrant expression of microRNAs miRs is involved in a variety of pathophysiologic processes, the role of miRs in fibrotic lung diseases is less well understood. In the present study, we found that miR-200a, miR-200b, and miR-200c are significantly down-regulated in the lungs of mice with experimental lung <d>fibrosis</d>. Levels of miR-200a and miR-200c were reduced in the lungs of patients with <d>IPF</d>. miR-200 had greater expression in AECs than in lung fibroblasts, and AECs from mice with experimental <d>pulmonary <d>fibrosis</d></d> had diminished expression of miR-200. We found that the miR-200 family members inhibit transforming growth factor-b1-induced epithelial-mesenchymal transition of AECs. miR-200 family members can reverse the fibrogenic activity of pulmonary fibroblasts from mice with experimental <d>pulmonary <d>fibrosis</d></d> and from patients with <d>IPF</d>. Indeed, the introduction of miR-200c diminishes experimental <d>pulmonary <d>fibrosis</d></d> in mice. Thus, the miR-200 family members participate importantly in fibrotic lung diseases and suggest that restoring miR-200 expression in the lungs may represent a novel therapeutic approach in treating pulmonary <d>fibrotic diseases</d>.
22189082|a|Excessive extracellular matrix production by fibroblasts in response to tissue injury contributes to <d>fibrotic diseases</d>, such as idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Epithelial-mesenchymal transition, involving transition of alveolar epithelial cells AECs to pulmonary fibroblasts, appears to be an important contributory process to lung <d>fibrosis</d>. Although aberrant expression of microRNAs miRs is involved in a variety of pathophysiologic processes, the role of miRs in <d>fibrotic lung diseases</d> is less well understood. In the present study, we found that miR-200a, miR-200b, and miR-200c are significantly down-regulated in the lungs of mice with experimental lung <d>fibrosis</d>. Levels of miR-200a and miR-200c were reduced in the lungs of patients with <d>IPF</d>. miR-200 had greater expression in AECs than in lung fibroblasts, and AECs from mice with experimental <d>pulmonary <d>fibrosis</d></d> had diminished expression of miR-200. We found that the miR-200 family members inhibit transforming growth factor-b1-induced epithelial-mesenchymal transition of AECs. miR-200 family members can reverse the fibrogenic activity of pulmonary fibroblasts from mice with experimental <d>pulmonary <d>fibrosis</d></d> and from patients with <d>IPF</d>. Indeed, the introduction of miR-200c diminishes experimental <d>pulmonary <d>fibrosis</d></d> in mice. Thus, the miR-200 family members participate importantly in <d>fibrotic lung diseases</d> and suggest that restoring miR-200 expression in the lungs may represent a novel therapeutic approach in treating pulmonary <d>fibrotic diseases</d>.
23896962|a|Chronic <d>hypersensitivity pneumonitis</d> HP causes progressive and irreversible pulmonary fibrosis, a disease also observed in conjunction with idiopathic pulmonary fibrosis IPF. Previous studies have demonstrated that the myofibroblast, a cell type whose origins involve the epithelial-mesenchymal transition EMT, may play a role in the pathogenesis of IPF. The goal of this study was to determine whether EMT has a role in the pathogenesis of chronic HP. Lung specimens from a chronic HP model and from patients with chronic HP were analyzed. Cellular co-localization of epithelial and mesenchymal markers on the same alveolar epithelial cells AECs were examined using immunohistochemistry and cadherin switching by western blotting as indicators of EMT. EMT cells in the AECs were significantly more prevalent in lung specimens from Th2-prone A/J mice than in specimens from Th1-prone C57BL/6 mice. The percentage of EMT cells was correlated with the mRNA expressions of IL-13 and TGF-b1, the fibrosis score, and the collagen content in the A/J mice. In human, EMT cells in the AECs were significantly more prevalent in lungs specimens from patients with usual interstitial pneumonia pattern than in specimens from patients with nonspecific interstitial pneumonia pattern at the moderate stage of fibrosis. In conclusion, EMT may play an important role in the fibrotic process of chronic HP under the Th2-biased environment.
23896962|a|Chronic <d>hypersensitivity pneumonitis</d> <d>HP</d> causes progressive and irreversible pulmonary fibrosis, a disease also observed in conjunction with idiopathic pulmonary fibrosis IPF. Previous studies have demonstrated that the myofibroblast, a cell type whose origins involve the epithelial-mesenchymal transition EMT, may play a role in the pathogenesis of IPF. The goal of this study was to determine whether EMT has a role in the pathogenesis of chronic <d>HP</d>. Lung specimens from a chronic <d>HP</d> model and from patients with chronic <d>HP</d> were analyzed. Cellular co-localization of epithelial and mesenchymal markers on the same alveolar epithelial cells AECs were examined using immunohistochemistry and cadherin switching by western blotting as indicators of EMT. EMT cells in the AECs were significantly more prevalent in lung specimens from Th2-prone A/J mice than in specimens from Th1-prone C57BL/6 mice. The percentage of EMT cells was correlated with the mRNA expressions of IL-13 and TGF-b1, the fibrosis score, and the collagen content in the A/J mice. In human, EMT cells in the AECs were significantly more prevalent in lungs specimens from patients with usual interstitial pneumonia pattern than in specimens from patients with nonspecific interstitial pneumonia pattern at the moderate stage of fibrosis. In conclusion, EMT may play an important role in the fibrotic process of chronic <d>HP</d> under the Th2-biased environment.
23896962|a|Chronic <d>hypersensitivity pneumonitis</d> <d>HP</d> causes progressive and irreversible <d>pulmonary fibrosis</d>, a disease also observed in conjunction with idiopathic <d>pulmonary fibrosis</d> IPF. Previous studies have demonstrated that the myofibroblast, a cell type whose origins involve the epithelial-mesenchymal transition EMT, may play a role in the pathogenesis of IPF. The goal of this study was to determine whether EMT has a role in the pathogenesis of chronic <d>HP</d>. Lung specimens from a chronic <d>HP</d> model and from patients with chronic <d>HP</d> were analyzed. Cellular co-localization of epithelial and mesenchymal markers on the same alveolar epithelial cells AECs were examined using immunohistochemistry and cadherin switching by western blotting as indicators of EMT. EMT cells in the AECs were significantly more prevalent in lung specimens from Th2-prone A/J mice than in specimens from Th1-prone C57BL/6 mice. The percentage of EMT cells was correlated with the mRNA expressions of IL-13 and TGF-b1, the fibrosis score, and the collagen content in the A/J mice. In human, EMT cells in the AECs were significantly more prevalent in lungs specimens from patients with usual interstitial pneumonia pattern than in specimens from patients with nonspecific interstitial pneumonia pattern at the moderate stage of fibrosis. In conclusion, EMT may play an important role in the fibrotic process of chronic <d>HP</d> under the Th2-biased environment.
23896962|a|Chronic <d>hypersensitivity pneumonitis</d> <d>HP</d> causes progressive and irreversible <d>pulmonary fibrosis</d>, a disease also observed in conjunction with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. Previous studies have demonstrated that the myofibroblast, a cell type whose origins involve the epithelial-mesenchymal transition EMT, may play a role in the pathogenesis of <d>IPF</d>. The goal of this study was to determine whether EMT has a role in the pathogenesis of chronic <d>HP</d>. Lung specimens from a chronic <d>HP</d> model and from patients with chronic <d>HP</d> were analyzed. Cellular co-localization of epithelial and mesenchymal markers on the same alveolar epithelial cells AECs were examined using immunohistochemistry and cadherin switching by western blotting as indicators of EMT. EMT cells in the AECs were significantly more prevalent in lung specimens from Th2-prone A/J mice than in specimens from Th1-prone C57BL/6 mice. The percentage of EMT cells was correlated with the mRNA expressions of IL-13 and TGF-b1, the fibrosis score, and the collagen content in the A/J mice. In human, EMT cells in the AECs were significantly more prevalent in lungs specimens from patients with usual interstitial pneumonia pattern than in specimens from patients with nonspecific interstitial pneumonia pattern at the moderate stage of fibrosis. In conclusion, EMT may play an important role in the fibrotic process of chronic <d>HP</d> under the Th2-biased environment.
23896962|a|Chronic <d>hypersensitivity pneumonitis</d> <d>HP</d> causes progressive and irreversible <d>pulmonary <d>fibrosis</d></d>, a disease also observed in conjunction with idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Previous studies have demonstrated that the myofibroblast, a cell type whose origins involve the epithelial-mesenchymal transition EMT, may play a role in the pathogenesis of <d>IPF</d>. The goal of this study was to determine whether EMT has a role in the pathogenesis of chronic <d>HP</d>. Lung specimens from a chronic <d>HP</d> model and from patients with chronic <d>HP</d> were analyzed. Cellular co-localization of epithelial and mesenchymal markers on the same alveolar epithelial cells AECs were examined using immunohistochemistry and cadherin switching by western blotting as indicators of EMT. EMT cells in the AECs were significantly more prevalent in lung specimens from Th2-prone A/J mice than in specimens from Th1-prone C57BL/6 mice. The percentage of EMT cells was correlated with the mRNA expressions of <g>IL-13</g> and <g>TGF-b1</g>, the <d>fibrosis</d> score, and the collagen content in the A/J mice. In human, EMT cells in the AECs were significantly more prevalent in lungs specimens from patients with usual interstitial pneumonia pattern than in specimens from patients with nonspecific interstitial pneumonia pattern at the moderate stage of <d>fibrosis</d>. In conclusion, EMT may play an important role in the fibrotic process of chronic <d>HP</d> under the Th2-biased environment.
23896962|a|Chronic <d>hypersensitivity pneumonitis</d> <d>HP</d> causes progressive and irreversible <d>pulmonary <d>fibrosis</d></d>, a disease also observed in conjunction with idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Previous studies have demonstrated that the myofibroblast, a cell type whose origins involve the epithelial-mesenchymal transition EMT, may play a role in the pathogenesis of <d>IPF</d>. The goal of this study was to determine whether EMT has a role in the pathogenesis of chronic <d>HP</d>. Lung specimens from a chronic <d>HP</d> model and from patients with chronic <d>HP</d> were analyzed. Cellular co-localization of epithelial and mesenchymal markers on the same alveolar epithelial cells AECs were examined using immunohistochemistry and cadherin switching by western blotting as indicators of EMT. EMT cells in the AECs were significantly more prevalent in lung specimens from Th2-prone A/J mice than in specimens from Th1-prone C57BL/6 mice. The percentage of EMT cells was correlated with the mRNA expressions of <g>IL-13</g> and <g>TGF-b1</g>, the <d>fibrosis</d> score, and the collagen content in the A/J mice. In human, EMT cells in the AECs were significantly more prevalent in lungs specimens from patients with <d>usual interstitial pneumonia</d> pattern than in specimens from patients with nonspecific interstitial pneumonia pattern at the moderate stage of <d>fibrosis</d>. In conclusion, EMT may play an important role in the fibrotic process of chronic <d>HP</d> under the Th2-biased environment.
23896962|a|Chronic <d>hypersensitivity pneumonitis</d> <d>HP</d> causes progressive and irreversible <d>pulmonary <d>fibrosis</d></d>, a disease also observed in conjunction with idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Previous studies have demonstrated that the myofibroblast, a cell type whose origins involve the epithelial-mesenchymal transition EMT, may play a role in the pathogenesis of <d>IPF</d>. The goal of this study was to determine whether EMT has a role in the pathogenesis of chronic <d>HP</d>. Lung specimens from a chronic <d>HP</d> model and from patients with chronic <d>HP</d> were analyzed. Cellular co-localization of epithelial and mesenchymal markers on the same alveolar epithelial cells AECs were examined using immunohistochemistry and cadherin switching by western blotting as indicators of EMT. EMT cells in the AECs were significantly more prevalent in lung specimens from Th2-prone A/J mice than in specimens from Th1-prone C57BL/6 mice. The percentage of EMT cells was correlated with the mRNA expressions of <g>IL-13</g> and <g>TGF-b1</g>, the <d>fibrosis</d> score, and the collagen content in the A/J mice. In human, EMT cells in the AECs were significantly more prevalent in lungs specimens from patients with <d>usual <d>interstitial pneumonia</d></d> pattern than in specimens from patients with nonspecific <d>interstitial pneumonia</d> pattern at the moderate stage of <d>fibrosis</d>. In conclusion, EMT may play an important role in the fibrotic process of chronic <d>HP</d> under the Th2-biased environment.
22227563|a|The incidence of idiopathic pulmonary <d>fibrosis</d> IPF increases with age. The mechanisms that underlie the age-dependent risk for IPF are unknown. Based on studies that suggest an association of IPF and yherpesvirus infection, we infected young 2-3 mo and old >= 18 mo C57BL/6 mice with the murine yherpesvirus 68. Acute murine yherpesvirus 68 infection in aging mice resulted in severe pneumonitis and <d>fibrosis</d> compared with young animals. Progressive clinical deterioration and lung <d>fibrosis</d> in the late chronic phase of infection was observed exclusively in old mice with diminution of tidal volume. Infected aging mice showed higher expression of transforming growth factor-b during the acute phase of infection. In addition, aging, infected mice showed elevation of proinflammatory cytokines and the fibrocyte recruitment chemokine, CXCL12, in bronchoalveolar lavage. Analyses of lytic virus infection and virus reactivation indicate that old mice were able to control chronic infection and elicit antivirus immune responses. However, old, infected mice showed a significant increase in apoptotic responses determined by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay, levels of caspase-3, and expression of the proapoptotitc molecule, Bcl-2 interacting mediator. Apoptosis of type II lung epithelial cells in aging lungs was accompanied by up-regulation of endoplasmic reticulum stress marker, binding immunoglobulin protein, and splicing of X-box-binding protein 1. These results indicate that the aging lung is more susceptible to injury and <d>fibrosis</d> associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways.
22227563|a|The incidence of idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> increases with age. The mechanisms that underlie the age-dependent risk for <d>IPF</d> are unknown. Based on studies that suggest an association of <d>IPF</d> and yherpesvirus infection, we infected young 2-3 mo and old >= 18 mo C57BL/6 mice with the murine yherpesvirus 68. Acute murine yherpesvirus 68 infection in aging mice resulted in severe pneumonitis and <d>fibrosis</d> compared with young animals. Progressive clinical deterioration and lung <d>fibrosis</d> in the late chronic phase of infection was observed exclusively in old mice with diminution of tidal volume. Infected aging mice showed higher expression of transforming growth factor-b during the acute phase of infection. In addition, aging, infected mice showed elevation of proinflammatory cytokines and the fibrocyte recruitment chemokine, CXCL12, in bronchoalveolar lavage. Analyses of lytic virus infection and virus reactivation indicate that old mice were able to control chronic infection and elicit antivirus immune responses. However, old, infected mice showed a significant increase in apoptotic responses determined by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay, levels of caspase-3, and expression of the proapoptotitc molecule, Bcl-2 interacting mediator. Apoptosis of type II lung epithelial cells in aging lungs was accompanied by up-regulation of endoplasmic reticulum stress marker, binding immunoglobulin protein, and splicing of X-box-binding protein 1. These results indicate that the aging lung is more susceptible to injury and <d>fibrosis</d> associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways.
22227563|a|The incidence of idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> increases with age. The mechanisms that underlie the age-dependent risk for <d>IPF</d> are unknown. Based on studies that suggest an association of <d>IPF</d> and yherpesvirus infection, we infected young 2-3 mo and old >= 18 mo C57BL/6 mice with the murine yherpesvirus 68. Acute murine yherpesvirus 68 infection in aging mice resulted in severe <d>pneumonitis</d> and <d>fibrosis</d> compared with young animals. Progressive clinical deterioration and lung <d>fibrosis</d> in the late chronic phase of infection was observed exclusively in old mice with diminution of tidal volume. Infected aging mice showed higher expression of transforming growth factor-b during the acute phase of infection. In addition, aging, infected mice showed elevation of proinflammatory cytokines and the fibrocyte recruitment chemokine, CXCL12, in bronchoalveolar lavage. Analyses of lytic virus infection and virus reactivation indicate that old mice were able to control chronic infection and elicit antivirus immune responses. However, old, infected mice showed a significant increase in apoptotic responses determined by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay, levels of caspase-3, and expression of the proapoptotitc molecule, Bcl-2 interacting mediator. Apoptosis of type II lung epithelial cells in aging lungs was accompanied by up-regulation of endoplasmic reticulum stress marker, binding immunoglobulin protein, and splicing of X-box-binding protein 1. These results indicate that the aging lung is more susceptible to injury and <d>fibrosis</d> associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways.
22227563|a|The incidence of idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> increases with age. The mechanisms that underlie the age-dependent risk for <d>IPF</d> are unknown. Based on studies that suggest an association of <d>IPF</d> and yherpesvirus infection, we infected young 2-3 mo and old >= 18 mo C57BL/6 mice with the murine yherpesvirus 68. Acute murine yherpesvirus 68 infection in aging mice resulted in severe <d>pneumonitis</d> and <d>fibrosis</d> compared with young animals. Progressive clinical deterioration and lung <d>fibrosis</d> in the late chronic phase of infection was observed exclusively in old mice with diminution of tidal volume. Infected aging mice showed higher expression of transforming growth factor-b during the acute phase of infection. In addition, aging, infected mice showed elevation of proinflammatory cytokines and the fibrocyte recruitment chemokine, <g>CXCL12</g>, in bronchoalveolar lavage. <d>Analyses of lytic virus infection</d> and virus reactivation indicate that old mice were able to control chronic infection and elicit antivirus immune responses. However, old, infected mice showed a significant increase in apoptotic responses determined by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay, levels of caspase-3, and expression of the proapoptotitc molecule, Bcl-2 interacting mediator. Apoptosis of type II lung epithelial cells in aging lungs was accompanied by up-regulation of endoplasmic reticulum stress marker, binding immunoglobulin protein, and splicing of X-box-binding protein 1. These results indicate that the aging lung is more susceptible to injury and <d>fibrosis</d> associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways.
22227563|a|The incidence of idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> increases with age. The mechanisms that underlie the age-dependent risk for <d>IPF</d> are unknown. Based on studies that suggest an association of <d>IPF</d> and yherpesvirus infection, we infected young 2-3 mo and old >= 18 mo C57BL/6 mice with the murine yherpesvirus 68. Acute murine yherpesvirus 68 infection in aging mice resulted in severe <d>pneumonitis</d> and <d>fibrosis</d> compared with young animals. Progressive clinical deterioration and lung <d>fibrosis</d> in the late chronic phase of infection was observed exclusively in old mice with diminution of tidal volume. Infected aging mice showed higher expression of transforming growth factor-b during the acute phase of infection. In addition, aging, infected mice showed elevation of proinflammatory cytokines and the fibrocyte recruitment chemokine, <g>CXCL12</g>, in bronchoalveolar lavage. <d>Analyses of lytic virus infection</d> and virus reactivation indicate that old mice were able to control <d>chronic infection</d> and elicit antivirus immune responses. However, old, infected mice showed a significant increase in apoptotic responses determined by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay, levels of caspase-3, and expression of the proapoptotitc molecule, Bcl-2 interacting mediator. Apoptosis of type II lung epithelial cells in aging lungs was accompanied by up-regulation of endoplasmic reticulum stress marker, binding immunoglobulin protein, and splicing of X-box-binding protein 1. These results indicate that the aging lung is more susceptible to injury and <d>fibrosis</d> associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways.
22240154|a|<d>Fibrotic remodelling of lung parenchymal</d> and airway compartments is the major contributor to life-threatening organ dysfunction in chronic lung diseases such as idiopathic pulmonary fibrosis IPF and Chronic Obstructive Pulmonary Disease COPD. Since transforming growth factor-b1 <g>TGF-b1</g> is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in bronchoalveolar lavage BAL from such patients we sought to investigate whether both factors might be interrelated. Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition EMT via the augmentation of <g>TGF-b1</g>. We show that in response to 400 M hydrogen peroxide H2O2 A549 cells, used a model for alveolar epithelium, and human primary bronchial epithelial cells PBECs undergo EMT displaying morphology changes, decreased expression of epithelial markers E-cadherin and ZO-1, increased expression of mesenchymal markers vimentin and a-smooth muscle actin as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of <g>TGF-b1</g>. Inhibition of <g>TGF-b1</g> signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone PBN and superoxide dismutase 3 SOD3 prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes. This study identifies a link between oxidative stress, <g>TGF-b1</g> and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease.
22240154|a|<d>Fibrotic remodelling of lung parenchymal</d> and airway compartments is the major contributor to life-threatening organ dysfunction in chronic <d>lung diseases</d> such as idiopathic pulmonary fibrosis IPF and Chronic Obstructive Pulmonary Disease COPD. Since transforming growth factor-b1 <g>TGF-b1</g> is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in bronchoalveolar lavage BAL from such patients we sought to investigate whether both factors might be interrelated. Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition EMT via the augmentation of <g>TGF-b1</g>. We show that in response to 400 M hydrogen peroxide H2O2 A549 cells, used a model for alveolar epithelium, and human primary bronchial epithelial cells PBECs undergo EMT displaying morphology changes, decreased expression of epithelial markers E-cadherin and ZO-1, increased expression of mesenchymal markers vimentin and a-smooth muscle actin as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of <g>TGF-b1</g>. Inhibition of <g>TGF-b1</g> signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone PBN and superoxide dismutase 3 SOD3 prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes. This study identifies a link between oxidative stress, <g>TGF-b1</g> and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease.
22240154|a|<d>Fibrotic remodelling of lung parenchymal</d> and airway compartments is the major contributor to life-threatening organ dysfunction in chronic <d>lung diseases</d> such as <d>idiopathic pulmonary fibrosis</d> IPF and Chronic Obstructive Pulmonary Disease COPD. Since transforming growth factor-b1 <g>TGF-b1</g> is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in bronchoalveolar lavage BAL from such patients we sought to investigate whether both factors might be interrelated. Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition EMT via the augmentation of <g>TGF-b1</g>. We show that in response to 400 M hydrogen peroxide H2O2 A549 cells, used a model for alveolar epithelium, and human primary bronchial epithelial cells PBECs undergo EMT displaying morphology changes, decreased expression of epithelial markers E-cadherin and ZO-1, increased expression of mesenchymal markers vimentin and a-smooth muscle actin as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of <g>TGF-b1</g>. Inhibition of <g>TGF-b1</g> signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone PBN and superoxide dismutase 3 SOD3 prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes. This study identifies a link between oxidative stress, <g>TGF-b1</g> and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease.
22240154|a|<d>Fibrotic remodelling of lung parenchymal</d> and airway compartments is the major contributor to life-threatening organ dysfunction in chronic <d>lung diseases</d> such as <d>idiopathic pulmonary fibrosis</d> IPF and <d>Chronic Obstructive Pulmonary Disease</d> COPD. Since transforming growth factor-b1 <g>TGF-b1</g> is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in bronchoalveolar lavage BAL from such patients we sought to investigate whether both factors might be interrelated. Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition EMT via the augmentation of <g>TGF-b1</g>. We show that in response to 400 M hydrogen peroxide H2O2 A549 cells, used a model for alveolar epithelium, and human primary bronchial epithelial cells PBECs undergo EMT displaying morphology changes, decreased expression of epithelial markers E-cadherin and ZO-1, increased expression of mesenchymal markers vimentin and a-smooth muscle actin as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of <g>TGF-b1</g>. Inhibition of <g>TGF-b1</g> signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone PBN and superoxide dismutase 3 SOD3 prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes. This study identifies a link between oxidative stress, <g>TGF-b1</g> and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease.
22240154|a|<d>Fibrotic remodelling of lung parenchymal</d> and airway compartments is the major contributor to life-threatening organ dysfunction in chronic <d>lung diseases</d> such as <d>idiopathic pulmonary fibrosis</d> IPF and <d>Chronic Obstructive Pulmonary Disease</d> <d>COPD</d>. Since transforming growth factor-b1 <g>TGF-b1</g> is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in bronchoalveolar lavage BAL from such patients we sought to investigate whether both factors might be interrelated. Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition EMT via the augmentation of <g>TGF-b1</g>. We show that in response to 400 M hydrogen peroxide H2O2 A549 cells, used a model for alveolar epithelium, and human primary bronchial epithelial cells PBECs undergo EMT displaying morphology changes, decreased expression of epithelial markers E-cadherin and ZO-1, increased expression of mesenchymal markers vimentin and a-smooth muscle actin as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of <g>TGF-b1</g>. Inhibition of <g>TGF-b1</g> signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone PBN and superoxide dismutase 3 SOD3 prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes. This study identifies a link between oxidative stress, <g>TGF-b1</g> and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease.
22240154|a|<d>Fibrotic remodelling of lung parenchymal</d> and airway compartments is the major contributor to life-threatening organ dysfunction in chronic <d>lung diseases</d> such as <d>idiopathic pulmonary fibrosis</d> IPF and <d>Chronic Obstructive Pulmonary Disease</d> <d>COPD</d>. Since <g>transforming growth factor-b1</g> <g>TGF-b1</g> is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in broncho<d>alveolar</d> lavage BAL from such patients we sought to investigate whether both factors might be interrelated. Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition EMT via the augmentation of <g>TGF-b1</g>. We show that in response to 400 M hydrogen peroxide H2O2 A549 cells, used a model for <d>alveolar</d> epithelium, and human primary bronchial epithelial cells PBECs undergo EMT displaying morphology changes, decreased expression of epithelial markers E-cadherin and ZO-1, increased expression of mesenchymal markers vimentin and a-smooth muscle actin as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of <g>TGF-b1</g>. Inhibition of <g>TGF-b1</g> signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone PBN and superoxide dismutase 3 SOD3 prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes. This study identifies a link between oxidative stress, <g>TGF-b1</g> and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease.
22240154|a|<d>Fibrotic remodelling of lung parenchymal</d> and airway compartments is the major contributor to life-threatening organ dysfunction in chronic <d>lung diseases</d> such as <d>idiopathic pulmonary fibrosis</d> IPF and <d>Chronic Obstructive Pulmonary Disease</d> <d>COPD</d>. Since <g>transforming growth factor-b1</g> <g>TGF-b1</g> is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in broncho<d>alveolar</d> lavage BAL from such patients we sought to investigate whether both factors might be interrelated. Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition EMT via the augmentation of <g>TGF-b1</g>. We show that in response to 400 M hydrogen peroxide H2O2 A549 cells, used a model for <d>alveolar</d> epithelium, and human primary bronchial epithelial cells PBECs undergo EMT displaying morphology changes, decreased expression of epithelial markers <g>E-cadherin</g> and <g>ZO-1</g>, increased expression of mesenchymal markers vimentin and a-smooth muscle actin as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of <g>TGF-b1</g>. Inhibition of <g>TGF-b1</g> signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone PBN and <g>superoxide dismutase 3</g> <g>SOD3</g> prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes. This study identifies a link between oxidative stress, <g>TGF-b1</g> and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to <d>chronic lung disease</d>.
22241478|a|Interactions between <g>transforming growth factor-b</g> <g>TGF-b</g> and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition EMT and precise mechanisms in many cases remain unknown. We investigated <g>b-catenin</g>-dependent and <g>transforming growth factor-b</g>1 <g>TGF-b</g>1 interactions in <d>pulmonary alveolar epithelial</d> cells AEC in the context of EMT and pulmonary fibrosis. We previously demonstrated that ICG-001, a small molecule specific inhibitor of the <g>b-catenin</g>/<g>CBP</g> but not <g>b-catenin</g>/p300 interaction, ameliorates and reverses pulmonary fibrosis and inhibits <g>TGF-b</g>1-mediated a-smooth muscle actin a-SMA and collagen induction in AEC. We now demonstrate that <g>TGF-b</g>1 induces LEF/TCF TOPFLASH reporter activation and nuclear <g>b-catenin</g> accumulation, while LiCl augments <g>TGF-b</g>-induced a-SMA expression, further confirming co-operation between <g>b-catenin</g>- and <g>TGF-b</g>-dependent signaling pathways. Inhibition and knockdown of Smad3, knockdown of <g>b-catenin</g> and overexpression of ICAT abrogated effects of <g>TGF-b</g>1 on a-SMA transcription/expression, indicating a requirement for <g>b-catenin</g> in these Smad3-dependent effects. Following <g>TGF-b</g> treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and <g>b-catenin</g>, while chromatin immunoprecipitation ChIP-re-ChIP identified spatial and temporal regulation of a-SMA via complex formation among Smad3, <g>b-catenin</g>, and <g>CBP</g>. ICG-001 inhibited a-SMA expression/transcription in response to <g>TGF-b</g> as well as a-SMA promoter occupancy by <g>b-catenin</g> and <g>CBP</g>, demonstrating a previously unknown requisite <g>TGF-b</g>1/<g>b-catenin</g>/<g>CBP</g>-mediated pro-EMT signaling pathway. Clinical relevance was shown by <g>b-catenin</g>/Smad3 co-localization and <g>CBP</g> expression in AEC of IPF patients. These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling <g>CBP</g>/catenin-dependent signaling downstream of <g>TGF-b</g>.
22241478|a|Interactions between <g>transforming growth factor-b</g> <g>TGF-b</g> and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition EMT and precise mechanisms in many cases remain unknown. We investigated <g>b-catenin</g>-dependent and <g>transforming growth factor-b</g>1 <g>TGF-b</g>1 interactions in <d>pulmonary alveolar epithelial</d> cells AEC in the context of EMT and <d>pulmonary fibrosis</d>. We previously demonstrated that ICG-001, a small molecule specific inhibitor of the <g>b-catenin</g>/<g>CBP</g> but not <g>b-catenin</g>/p300 interaction, ameliorates and reverses <d>pulmonary fibrosis</d> and inhibits <g>TGF-b</g>1-mediated a-smooth muscle actin a-SMA and collagen induction in AEC. We now demonstrate that <g>TGF-b</g>1 induces LEF/TCF TOPFLASH reporter activation and nuclear <g>b-catenin</g> accumulation, while LiCl augments <g>TGF-b</g>-induced a-SMA expression, further confirming co-operation between <g>b-catenin</g>- and <g>TGF-b</g>-dependent signaling pathways. Inhibition and knockdown of Smad3, knockdown of <g>b-catenin</g> and overexpression of ICAT abrogated effects of <g>TGF-b</g>1 on a-SMA transcription/expression, indicating a requirement for <g>b-catenin</g> in these Smad3-dependent effects. Following <g>TGF-b</g> treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and <g>b-catenin</g>, while chromatin immunoprecipitation ChIP-re-ChIP identified spatial and temporal regulation of a-SMA via complex formation among Smad3, <g>b-catenin</g>, and <g>CBP</g>. ICG-001 inhibited a-SMA expression/transcription in response to <g>TGF-b</g> as well as a-SMA promoter occupancy by <g>b-catenin</g> and <g>CBP</g>, demonstrating a previously unknown requisite <g>TGF-b</g>1/<g>b-catenin</g>/<g>CBP</g>-mediated pro-EMT signaling pathway. Clinical relevance was shown by <g>b-catenin</g>/Smad3 co-localization and <g>CBP</g> expression in AEC of IPF patients. These findings suggest a new therapeutic approach to <d>pulmonary fibrosis</d> by specifically uncoupling <g>CBP</g>/catenin-dependent signaling downstream of <g>TGF-b</g>.
22241478|a|Interactions between <g>transforming growth factor-b</g> <g>TGF-b</g> and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition EMT and precise mechanisms in many cases remain unknown. We investigated <g>b-catenin</g>-dependent and <g>transforming growth factor-b</g>1 <g>TGF-b</g>1 interactions in <d>pulmonary alveolar epithelial</d> cells AEC in the context of EMT and <d>pulmonary fibrosis</d>. We previously demonstrated that ICG-001, a small molecule specific inhibitor of the <g>b-catenin</g>/<g>CBP</g> but not <g>b-catenin</g>/<g>p300</g> interaction, ameliorates and reverses <d>pulmonary fibrosis</d> and inhibits <g>TGF-b</g>1-mediated a-smooth muscle actin <g>a-SMA</g> and collagen induction in AEC. We now demonstrate that <g>TGF-b</g>1 induces <g>LEF/TCF</g> TOPFLASH reporter activation and nuclear <g>b-catenin</g> accumulation, while LiCl augments <g>TGF-b</g>-induced <g>a-SMA</g> expression, further confirming co-operation between <g>b-catenin</g>- and <g>TGF-b</g>-dependent signaling pathways. Inhibition and knockdown of <g>Smad3</g>, knockdown of <g>b-catenin</g> and overexpression of <g>ICAT</g> abrogated effects of <g>TGF-b</g>1 on <g>a-SMA</g> transcription/expression, indicating a requirement for <g>b-catenin</g> in these <g>Smad3</g>-dependent effects. Following <g>TGF-b</g> treatment, co-immunoprecipitation demonstrated direct interaction between endogenous <g>Smad3</g> and <g>b-catenin</g>, while chromatin immunoprecipitation ChIP-re-ChIP identified spatial and temporal regulation of <g>a-SMA</g> via complex formation among <g>Smad3</g>, <g>b-catenin</g>, and <g>CBP</g>. ICG-001 inhibited <g>a-SMA</g> expression/transcription in response to <g>TGF-b</g> as well as <g>a-SMA</g> promoter occupancy by <g>b-catenin</g> and <g>CBP</g>, demonstrating a previously unknown requisite <g>TGF-b</g>1/<g>b-catenin</g>/<g>CBP</g>-mediated pro-EMT signaling pathway. Clinical relevance was shown by <g>b-catenin</g>/<g>Smad3</g> co-localization and <g>CBP</g> expression in AEC of <d>IPF</d> patients. These findings suggest a new therapeutic approach to <d>pulmonary fibrosis</d> by specifically uncoupling <g>CBP</g>/catenin-dependent signaling downstream of <g>TGF-b</g>.
22246864|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive scarring disorder characterized by the proliferation of interstitial fibroblasts and the deposition of extracellular matrix causing impaired gas exchange. <g>Spiruchostatin A</g> SpA is a histone deacetylase inhibitor HDI with selectivity toward Class I enzymes, which distinguishes it from other nonspecific HDIs that are reported to inhibit myofibroblast proliferation and differentiation. Because the selectivity of HDIs may be important clinically, we postulated that SpA inhibits the proliferation and differentiation of IPF fibroblasts. Primary fibroblasts were grown from lung biopsy explants obtained from patients with IPF or from normal control subjects, using two-dimensional or three-dimensional culture models. The effect of SpA on fibroproliferation in serum-containing medium    transforming growth factor TGF-b1 was quantified by methylene blue binding. The acetylation of histone H3, the expression of the cell-cycle inhibitor p21waf1, and the myofibroblast markers a-smooth muscle actin a-SMA and collagens I and III were determined by Western blotting, quantitative RT-PCR, immunofluorescent staining, or colorimetry. SpA inhibited the proliferation of IPF or normal fibroblasts in a time-dependent and concentration-dependent manner concentration required to achieve 50% inhibition = 3.8    0.4 nM versus 7.8    0.2 nM, respectively; P < 0.05, with little cytotoxicity. Western blot analyses revealed that SpA caused a concentration-dependent increase in histone H3 acetylation, paralleling its antiproliferative effect. SpA also increased p21waf1 expression, suggesting that direct cell-cycle regulation was the mechanism of inhibiting proliferation. Although treatment with TGF-b1 induced myofibroblast differentiation associated with increased expression of a-SMA, collagen I and collagen III and soluble collagen release, these responses were potently inhibited by SpA. These data support the concept that bicyclic tetrapeptide HDIs merit further investigation as potential treatments for IPF.
22246864|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive scarring disorder characterized by the proliferation of interstitial fibroblasts and the deposition of extracellular matrix causing impaired gas exchange. <g>Spiruchostatin A</g> SpA is a histone deacetylase inhibitor HDI with selectivity toward Class I enzymes, which distinguishes it from other nonspecific HDIs that are reported to inhibit myofibroblast proliferation and differentiation. Because the selectivity of HDIs may be important clinically, we postulated that SpA inhibits the proliferation and differentiation of <d>IPF</d> fibroblasts. Primary fibroblasts were grown from lung biopsy explants obtained from patients with <d>IPF</d> or from normal control subjects, using two-dimensional or three-dimensional culture models. The effect of SpA on fibroproliferation in serum-containing medium    transforming growth factor TGF-b1 was quantified by methylene blue binding. The acetylation of histone H3, the expression of the cell-cycle inhibitor p21waf1, and the myofibroblast markers a-smooth muscle actin a-SMA and collagens I and III were determined by Western blotting, quantitative RT-PCR, immunofluorescent staining, or colorimetry. SpA inhibited the proliferation of <d>IPF</d> or normal fibroblasts in a time-dependent and concentration-dependent manner concentration required to achieve 50% inhibition = 3.8    0.4 nM versus 7.8    0.2 nM, respectively; P < 0.05, with little cytotoxicity. Western blot analyses revealed that SpA caused a concentration-dependent increase in histone H3 acetylation, paralleling its antiproliferative effect. SpA also increased p21waf1 expression, suggesting that direct cell-cycle regulation was the mechanism of inhibiting proliferation. Although treatment with TGF-b1 induced myofibroblast differentiation associated with increased expression of a-SMA, collagen I and collagen III and soluble collagen release, these responses were potently inhibited by SpA. These data support the concept that bicyclic tetrapeptide HDIs merit further investigation as potential treatments for <d>IPF</d>.
22246864|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>scarring disorder</d> characterized by the proliferation of interstitial fibroblasts and the deposition of extracellular matrix causing impaired gas exchange. <g>Spiruchostatin A</g> SpA is a histone deacetylase inhibitor HDI with selectivity toward Class I enzymes, which distinguishes it from other nonspecific HDIs that are reported to inhibit myofibroblast proliferation and differentiation. Because the selectivity of HDIs may be important clinically, we postulated that SpA inhibits the proliferation and differentiation of <d>IPF</d> fibroblasts. Primary fibroblasts were grown from lung biopsy explants obtained from patients with <d>IPF</d> or from normal control subjects, using two-dimensional or three-dimensional culture models. The effect of SpA on fibroproliferation in serum-containing medium    transforming growth factor TGF-b1 was quantified by methylene blue binding. The acetylation of histone H3, the expression of the cell-cycle inhibitor p21waf1, and the myofibroblast markers a-smooth muscle actin a-SMA and collagens I and III were determined by Western blotting, quantitative RT-PCR, immunofluorescent staining, or colorimetry. SpA inhibited the proliferation of <d>IPF</d> or normal fibroblasts in a time-dependent and concentration-dependent manner concentration required to achieve 50% inhibition = 3.8    0.4 nM versus 7.8    0.2 nM, respectively; P < 0.05, with little cytotoxicity. Western blot analyses revealed that SpA caused a concentration-dependent increase in histone H3 acetylation, paralleling its antiproliferative effect. SpA also increased p21waf1 expression, suggesting that direct cell-cycle regulation was the mechanism of inhibiting proliferation. Although treatment with TGF-b1 induced myofibroblast differentiation associated with increased expression of a-SMA, collagen I and collagen III and soluble collagen release, these responses were potently inhibited by SpA. These data support the concept that bicyclic tetrapeptide HDIs merit further investigation as potential treatments for <d>IPF</d>.
22246864|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>scarring disorder</d> characterized by the proliferation of interstitial fibroblasts and the deposition of extracellular matrix causing impaired gas exchange. <g>Spiruchostatin A</g> <g>SpA</g> is a histone deacetylase inhibitor HDI with selectivity toward Class I enzymes, which distinguishes it from other nonspecific HDIs that are reported to inhibit myofibroblast proliferation and differentiation. Because the selectivity of HDIs may be important clinically, we postulated that <g>SpA</g> inhibits the proliferation and differentiation of <d>IPF</d> fibroblasts. Primary fibroblasts were grown from lung biopsy explants obtained from patients with <d>IPF</d> or from normal control subjects, using two-dimensional or three-dimensional culture models. The effect of <g>SpA</g> on fibroproliferation in serum-containing medium    transforming growth factor TGF-b1 was quantified by methylene blue binding. The acetylation of histone H3, the expression of the cell-cycle inhibitor <g>p21waf1</g>, and the myofibroblast markers a-smooth muscle actin <g>a-SMA</g> and collagens I and III were determined by Western blotting, quantitative RT-PCR, immunofluorescent staining, or colorimetry. <g>SpA</g> inhibited the proliferation of <d>IPF</d> or normal fibroblasts in a time-dependent and concentration-dependent manner concentration required to achieve 50% inhibition = 3.8    0.4 nM versus 7.8    0.2 nM, respectively; P < 0.05, with little <d>cytotoxicity</d>. Western blot analyses revealed that <g>SpA</g> caused a concentration-dependent increase in histone H3 acetylation, paralleling its antiproliferative effect. <g>SpA</g> also increased <g>p21waf1</g> expression, suggesting that direct cell-cycle regulation was the mechanism of inhibiting proliferation. Although treatment with TGF-b1 induced myofibroblast differentiation associated with increased expression of <g>a-SMA</g>, collagen I and collagen III and soluble collagen release, these responses were potently inhibited by <g>SpA</g>. These data support the concept that bicyclic tetrapeptide HDIs merit further investigation as potential treatments for <d>IPF</d>.
22284809|a|BACKGROUND: <g>Transforming growth factor-b1</g> <g>TGF-b1</g> is a profibrotic cytokine that plays a major role in vascular biology, and is known to regulate the phenotype and activity of various vascular cell populations. Because most <d>fibrotic diseases</d>, such as idiopathic pulmonary fibrosis IPF, are associated with vascular remodeling, and as endothelial progenitor cells EPCs may be involved in this process, we investigated the impact of <g>TGF-b1</g> modulation of EPC angiogenic properties. METHODS: <g>TGF-b1</g> plasma levels were determined in 64 patients with IPF and compared with those in controls. The effect of <g>TGF-b1</g> on angiogenesis was studied in vivo in a Matrigel plug model and in vitro on endothelial colony-forming cells ECFCs. We studied the effects of inhibiting the expression of the three main receptors of <g>TGF-b1</g> in ECFCs by using short interfering RNA. RESULTS: Total <g>TGF-b1</g> plasma levels were significantly increased in patients with IPF as compared with controls P < 0.0001. <g>TGF-b1</g> had proangiogenic effects in vivo by increasing hemoglobin content and blood vessel formation in Matrigel plugs implanted in C57/Bl6 mice, and in vitro by enhancing ECFC viability and migration. The effects were abolished by silencing the three main <g>TGF-b1</g> receptors. CONCLUSIONS: <g>TGF-b1</g> is proangiogenic in vivo and induces ECFC angiogenic properties in vitro, suggesting that <g>TGF-b1</g> may play a role during vascular remodeling in fibrotic disease states via EPCs.
22284809|a|BACKGROUND: <g>Transforming growth factor-b1</g> <g>TGF-b1</g> is a profibrotic cytokine that plays a major role in vascular biology, and is known to regulate the phenotype and activity of various vascular cell populations. Because most <d>fibrotic diseases</d>, such as <d>idiopathic pulmonary fibrosis</d> IPF, are associated with vascular remodeling, and as endothelial progenitor cells EPCs may be involved in this process, we investigated the impact of <g>TGF-b1</g> modulation of EPC angiogenic properties. METHODS: <g>TGF-b1</g> plasma levels were determined in 64 patients with IPF and compared with those in controls. The effect of <g>TGF-b1</g> on angiogenesis was studied in vivo in a Matrigel plug model and in vitro on endothelial colony-forming cells ECFCs. We studied the effects of inhibiting the expression of the three main receptors of <g>TGF-b1</g> in ECFCs by using short interfering RNA. RESULTS: Total <g>TGF-b1</g> plasma levels were significantly increased in patients with IPF as compared with controls P < 0.0001. <g>TGF-b1</g> had proangiogenic effects in vivo by increasing hemoglobin content and blood vessel formation in Matrigel plugs implanted in C57/Bl6 mice, and in vitro by enhancing ECFC viability and migration. The effects were abolished by silencing the three main <g>TGF-b1</g> receptors. CONCLUSIONS: <g>TGF-b1</g> is proangiogenic in vivo and induces ECFC angiogenic properties in vitro, suggesting that <g>TGF-b1</g> may play a role during vascular remodeling in fibrotic disease states via EPCs.
22284809|a|BACKGROUND: <g>Transforming growth factor-b1</g> <g>TGF-b1</g> is a profibrotic cytokine that plays a major role in vascular biology, and is known to regulate the phenotype and activity of various vascular cell populations. Because most <d>fibrotic diseases</d>, such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, are associated with vascular remodeling, and as endothelial progenitor cells EPCs may be involved in this process, we investigated the impact of <g>TGF-b1</g> modulation of EPC angiogenic properties. METHODS: <g>TGF-b1</g> plasma levels were determined in 64 patients with <d>IPF</d> and compared with those in controls. The effect of <g>TGF-b1</g> on angiogenesis was studied in vivo in a Matrigel plug model and in vitro on endothelial colony-forming cells ECFCs. We studied the effects of inhibiting the expression of the three main receptors of <g>TGF-b1</g> in ECFCs by using short interfering RNA. RESULTS: Total <g>TGF-b1</g> plasma levels were significantly increased in patients with <d>IPF</d> as compared with controls P < 0.0001. <g>TGF-b1</g> had proangiogenic effects in vivo by increasing hemoglobin content and blood vessel formation in Matrigel plugs implanted in C57/Bl6 mice, and in vitro by enhancing ECFC viability and migration. The effects were abolished by silencing the three main <g>TGF-b1</g> receptors. CONCLUSIONS: <g>TGF-b1</g> is proangiogenic in vivo and induces ECFC angiogenic properties in vitro, suggesting that <g>TGF-b1</g> may play a role during vascular remodeling in fibrotic disease states via EPCs.
22284809|a|BACKGROUND: <g>Transforming growth factor-b1</g> <g>TGF-b1</g> is a profibrotic cytokine that plays a major role in vascular biology, and is known to regulate the phenotype and activity of various vascular cell populations. Because most <d><d>fibrotic disease</d>s</d>, such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, are associated with vascular remodeling, and as endothelial progenitor cells EPCs may be involved in this process, we investigated the impact of <g>TGF-b1</g> modulation of EPC angiogenic properties. METHODS: <g>TGF-b1</g> plasma levels were determined in 64 patients with <d>IPF</d> and compared with those in controls. The effect of <g>TGF-b1</g> on angiogenesis was studied in vivo in a Matrigel plug model and in vitro on endothelial colony-forming cells ECFCs. We studied the effects of inhibiting the expression of the three main receptors of <g>TGF-b1</g> in ECFCs by using short interfering RNA. RESULTS: Total <g>TGF-b1</g> plasma levels were significantly increased in patients with <d>IPF</d> as compared with controls P < 0.0001. <g>TGF-b1</g> had proangiogenic effects in vivo by increasing hemoglobin content and blood vessel formation in Matrigel plugs implanted in C57/Bl6 mice, and in vitro by enhancing ECFC viability and migration. The effects were abolished by silencing the three main <g>TGF-b1</g> receptors. CONCLUSIONS: <g>TGF-b1</g> is proangiogenic in vivo and induces ECFC angiogenic properties in vitro, suggesting that <g>TGF-b1</g> may play a role during vascular remodeling in <d>fibrotic disease</d> states via EPCs.
22295148|a|AIM: This study explored the cellular and biological interrelationships involved in <d>Idiopathic Pulmonary Fibrosis</d> IPF lung tissue remodelling using immunohistochemical analysis. METHODS AND RESULTS: IPF and control lung tissues were examined for localisation of Epithelial Mesenchymal Transition EMT, proliferation and growth factor markers assessing their relationship to key histological aberrations. E-cadherin was expressed in IPF and control Alveolar type II ATII cells >75%. In IPF, mean expression of N-cadherin was scanty <10%: however 4 cases demonstrated augmented expression in ATII cells correlating to histological disease status Pearson correlation score 0.557. Twist was expressed within fibroblastic foci but not in ATII cells. Transforming Growth Factor- b TGF-b protein expression was significantly increased in IPF ATII cells with variable expression within fibroblastic foci. Antigen Ki-67 was observed within hyperplastic ATII cells but not in cells overlying foci. Collagen I and a-smooth muscle actin a-SMA were strongly expressed within fibroblastic foci >75%; cytoplasmic collagen I in ATII cells was present in 3 IPF cases. IPF ATII cells demonstrated variable Surfactant Protein-C SP-C. CONCLUSIONS: The pathogenesis of IPF is complex and involves multiple factors, possibly including EMT. Histological analysis suggests TGF-b-stimulated myofib rob lasts initiate a contractile response within established fibroblastic foci while proliferating ATII cells attempt to instigate alveolar epithelium repair. Marker expression N-cadherin and Ki-67 correlation with histological disease activity as reflected by fibroblastic foci extent may emerge as future prognostic indicators for IPF.
22295148|a|AIM: This study explored the cellular and biological interrelationships involved in <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> lung tissue remodelling using immunohistochemical analysis. METHODS AND RESULTS: <d>IPF</d> and control lung tissues were examined for localisation of Epithelial Mesenchymal Transition EMT, proliferation and growth factor markers assessing their relationship to key histological aberrations. E-cadherin was expressed in <d>IPF</d> and control Alveolar type II ATII cells >75%. In <d>IPF</d>, mean expression of N-cadherin was scanty <10%: however 4 cases demonstrated augmented expression in ATII cells correlating to histological disease status Pearson correlation score 0.557. Twist was expressed within fibroblastic foci but not in ATII cells. Transforming Growth Factor- b TGF-b protein expression was significantly increased in <d>IPF</d> ATII cells with variable expression within fibroblastic foci. Antigen Ki-67 was observed within hyperplastic ATII cells but not in cells overlying foci. Collagen I and a-smooth muscle actin a-SMA were strongly expressed within fibroblastic foci >75%; cytoplasmic collagen I in ATII cells was present in 3 <d>IPF</d> cases. <d>IPF</d> ATII cells demonstrated variable Surfactant Protein-C SP-C. CONCLUSIONS: The pathogenesis of <d>IPF</d> is complex and involves multiple factors, possibly including EMT. Histological analysis suggests TGF-b-stimulated myofib rob lasts initiate a contractile response within established fibroblastic foci while proliferating ATII cells attempt to instigate alveolar epithelium repair. Marker expression N-cadherin and Ki-67 correlation with histological disease activity as reflected by fibroblastic foci extent may emerge as future prognostic indicators for <d>IPF</d>.
22295148|a|AIM: This study explored the cellular and biological interrelationships involved in <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> lung tissue remodelling using immunohistochemical analysis. METHODS AND RESULTS: <d>IPF</d> and control lung tissues were examined for localisation of Epithelial Mesenchymal Transition EMT, proliferation and growth factor markers assessing their relationship to key histological aberrations. <g>E-cadherin</g> was expressed in <d>IPF</d> and control <d>Alveolar type II</d> ATII cells >75%. In <d>IPF</d>, mean expression of N-cadherin was scanty <10%: however 4 cases demonstrated augmented expression in ATII cells correlating to histological disease status Pearson correlation score 0.557. Twist was expressed within fibroblastic foci but not in ATII cells. Transforming Growth Factor- b TGF-b protein expression was significantly increased in <d>IPF</d> ATII cells with variable expression within fibroblastic foci. Antigen Ki-67 was observed within hyperplastic ATII cells but not in cells overlying foci. Collagen I and a-smooth muscle actin a-SMA were strongly expressed within fibroblastic foci >75%; cytoplasmic collagen I in ATII cells was present in 3 <d>IPF</d> cases. <d>IPF</d> ATII cells demonstrated variable Surfactant Protein-C SP-C. CONCLUSIONS: The pathogenesis of <d>IPF</d> is complex and involves multiple factors, possibly including EMT. Histological analysis suggests TGF-b-stimulated myofib rob lasts initiate a contractile response within established fibroblastic foci while proliferating ATII cells attempt to instigate alveolar epithelium repair. Marker expression N-cadherin and Ki-67 correlation with histological disease activity as reflected by fibroblastic foci extent may emerge as future prognostic indicators for <d>IPF</d>.
22322297|a|<g>STAT3</g> is a latent transcription factor that plays a role in regulating fibroblast function in <d>fibrotic lung diseases</d>. To further understand the role of <g>STAT3</g> in the phenotypic divergence and function of human lung fibroblasts LFs, we investigated the effect of basal and cytokine-induced <g>STAT3</g> activity on indices of LF differentiation and activation, including expression of a-smooth muscle actin a-SMA, collagen, and adhesion molecules Thy-1/CD90 and av b3 and b5 integrins. We identified a population of fibroblasts from usual interstitial pneumonia UIP/idiopathic pulmonary fibrosis IPF lungs characterized by constitutively phosphorylated <g>STAT3</g>, lower proliferation rates, and diminished expression of a-SMA, Thy-1/CD90, and b3 integrins compared with control LFs. Staining of UIP lung biopsy specimens demonstrated that phosphorylated <g>STAT3</g> was not present in a-SMA-positive fibroblastic foci but was observed in the nuclei of cells located in the areas of dense fibrosis. <g>STAT3</g> activation in LFs did not significantly influence basal or transforming growth factor b1-induced collagen I expression but inhibited expression of a-SMA, Thy-1/CD90, and av b3 integrins. Suppression of <g>STAT3</g> signaling diminished resistance of IPF LFs to staurosporine-induced apoptosis and responsiveness to transforming growth factor b1 but increased basal a-SMA and restored b3 integrin expression in LFs via an ALK-5-dependent, SMAD3/7-independent mechanism. These data suggest that <g>STAT3</g> activation regulates several pathways in human LFs associated with normal wound healing, whereas aberrant <g>STAT3</g> signaling plays a critical role in UIP/IPF pathogenesis.
22322297|a|<g>STAT3</g> is a latent transcription factor that plays a role in regulating fibroblast function in <d>fibrotic lung diseases</d>. To further understand the role of <g>STAT3</g> in the phenotypic divergence and function of human lung fibroblasts LFs, we investigated the effect of basal and cytokine-induced <g>STAT3</g> activity on indices of LF differentiation and activation, including expression of <g>a-smooth muscle actin</g> <g>a-SMA</g>, collagen, and adhesion molecules <g>Thy-1</g>/<g>CD90</g> and av b3 and b5 integrins. We identified a population of fibroblasts from usual <d>interstitial pneumonia</d> UIP/idiopathic pulmonary fibrosis IPF lungs characterized by constitutively phosphorylated <g>STAT3</g>, lower proliferation rates, and diminished expression of <g>a-SMA</g>, <g>Thy-1</g>/<g>CD90</g>, and b3 integrins compared with control LFs. Staining of UIP lung biopsy specimens demonstrated that phosphorylated <g>STAT3</g> was not present in <g>a-SMA</g>-positive fibroblastic foci but was observed in the nuclei of cells located in the areas of dense fibrosis. <g>STAT3</g> activation in LFs did not significantly influence basal or transforming growth factor b1-induced collagen I expression but inhibited expression of <g>a-SMA</g>, <g>Thy-1</g>/<g>CD90</g>, and av b3 integrins. Suppression of <g>STAT3</g> signaling diminished resistance of IPF LFs to staurosporine-induced apoptosis and responsiveness to transforming growth factor b1 but increased basal <g>a-SMA</g> and restored b3 integrin expression in LFs via an ALK-5-dependent, SMAD3/7-independent mechanism. These data suggest that <g>STAT3</g> activation regulates several pathways in human LFs associated with normal wound healing, whereas aberrant <g>STAT3</g> signaling plays a critical role in UIP/IPF pathogenesis.
22322297|a|<g>STAT3</g> is a latent transcription factor that plays a role in regulating fibroblast function in <d>fibrotic lung diseases</d>. To further understand the role of <g>STAT3</g> in the phenotypic divergence and function of human lung fibroblasts LFs, we investigated the effect of basal and cytokine-induced <g>STAT3</g> activity on indices of LF differentiation and activation, including expression of <g>a-smooth muscle actin</g> <g>a-SMA</g>, collagen, and adhesion molecules <g>Thy-1</g>/<g>CD90</g> and av b3 and b5 integrins. We identified a population of fibroblasts from usual <d>interstitial pneumonia</d> UIP/<d>idiopathic pulmonary fibrosis</d> IPF lungs characterized by constitutively phosphorylated <g>STAT3</g>, lower proliferation rates, and diminished expression of <g>a-SMA</g>, <g>Thy-1</g>/<g>CD90</g>, and b3 integrins compared with control LFs. Staining of UIP lung biopsy specimens demonstrated that phosphorylated <g>STAT3</g> was not present in <g>a-SMA</g>-positive fibroblastic foci but was observed in the nuclei of cells located in the areas of dense fibrosis. <g>STAT3</g> activation in LFs did not significantly influence basal or transforming growth factor b1-induced collagen I expression but inhibited expression of <g>a-SMA</g>, <g>Thy-1</g>/<g>CD90</g>, and av b3 integrins. Suppression of <g>STAT3</g> signaling diminished resistance of IPF LFs to staurosporine-induced apoptosis and responsiveness to transforming growth factor b1 but increased basal <g>a-SMA</g> and restored b3 integrin expression in LFs via an ALK-5-dependent, SMAD3/7-independent mechanism. These data suggest that <g>STAT3</g> activation regulates several pathways in human LFs associated with normal wound healing, whereas aberrant <g>STAT3</g> signaling plays a critical role in UIP/IPF pathogenesis.
22322297|a|<g>STAT3</g> is a latent transcription factor that plays a role in regulating fibroblast function in <d>fibrotic lung diseases</d>. To further understand the role of <g>STAT3</g> in the phenotypic divergence and function of human lung fibroblasts LFs, we investigated the effect of basal and cytokine-induced <g>STAT3</g> activity on indices of LF differentiation and activation, including expression of <g>a-smooth muscle actin</g> <g>a-SMA</g>, collagen, and adhesion molecules <g>Thy-1</g>/<g>CD90</g> and av b3 and b5 integrins. We identified a population of fibroblasts from usual <d>interstitial pneumonia</d> UIP/<d>idiopathic pulmonary <d>fibrosis</d></d> IPF lungs characterized by constitutively phosphorylated <g>STAT3</g>, lower proliferation rates, and diminished expression of <g>a-SMA</g>, <g>Thy-1</g>/<g>CD90</g>, and b3 integrins compared with control LFs. Staining of UIP lung biopsy specimens demonstrated that phosphorylated <g>STAT3</g> was not present in <g>a-SMA</g>-positive fibroblastic foci but was observed in the nuclei of cells located in the areas of dense <d>fibrosis</d>. <g>STAT3</g> activation in LFs did not significantly influence basal or transforming growth factor b1-induced collagen I expression but inhibited expression of <g>a-SMA</g>, <g>Thy-1</g>/<g>CD90</g>, and av b3 integrins. Suppression of <g>STAT3</g> signaling diminished resistance of IPF LFs to staurosporine-induced apoptosis and responsiveness to transforming growth factor b1 but increased basal <g>a-SMA</g> and restored b3 integrin expression in LFs via an ALK-5-dependent, SMAD3/7-independent mechanism. These data suggest that <g>STAT3</g> activation regulates several pathways in human LFs associated with normal wound healing, whereas aberrant <g>STAT3</g> signaling plays a critical role in UIP/IPF pathogenesis.
22365247|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive disease of unknown cause that conveys a dismal prognosis. In the United States there are currently no licensed therapies for treatment of IPF. The development of effective IPF clinical trials networks across the United States and Europe, however, has led to key developments in the treatment of IPF. Advances in understanding of the pathogenetic processes involved in the development of pulmonary fibrosis have led to novel therapeutic targets. These developments offer hope that there may, in the near future, be therapeutic options available for treatment of this devastating disease.
22365247|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive disease of unknown cause that conveys a dismal prognosis. In the United States there are currently no licensed therapies for treatment of <d>IPF</d>. The development of effective <d>IPF</d> clinical trials networks across the United States and Europe, however, has led to key developments in the treatment of <d>IPF</d>. Advances in understanding of the pathogenetic processes involved in the development of pulmonary fibrosis have led to novel therapeutic targets. These developments offer hope that there may, in the near future, be therapeutic options available for treatment of this devastating disease.
22365247|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive disease of unknown cause that conveys a dismal prognosis. In the United States there are currently no licensed therapies for treatment of <d>IPF</d>. The development of effective <d>IPF</d> clinical trials networks across the United States and Europe, however, has led to key developments in the treatment of <d>IPF</d>. Advances in understanding of the pathogenetic processes involved in the development of <d>pulmonary fibrosis</d> have led to novel therapeutic targets. These developments offer hope that there may, in the near future, be therapeutic options available for treatment of this devastating disease.
22394287|a|In addition to parenchymal <d>fibrosis</d>, fibrotic remodeling of the distal airways has been reported in interstitial lung diseases. Mechanisms of airway wall remodeling, which occurs in a variety of chronic lung diseases, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary <d>fibrosis</d> IPF and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for <d>fibrosis</d> and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and immunohistochemistry for transforming growth factor b1 TGFb1, TGFb2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and <d>fibrosis</d> and greater airflow resistance after high-dose bleomycin. Increased TUNEL+ bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFb1 and TGFb2 and accumulation of S100A4+ fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. IPF is characterized by small airway remodeling in addition to parenchymal <d>fibrosis</d>, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial <d>fibrosis</d>. Thus, this model can be utilized to investigate mechanisms of airway remodeling.
22394287|a|In addition to parenchymal <d>fibrosis</d>, fibrotic remodeling of the distal airways has been reported in <d>interstitial lung diseases</d>. Mechanisms of airway wall remodeling, which occurs in a variety of chronic lung diseases, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary <d>fibrosis</d> IPF and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for <d>fibrosis</d> and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and immunohistochemistry for transforming growth factor b1 TGFb1, TGFb2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and <d>fibrosis</d> and greater airflow resistance after high-dose bleomycin. Increased TUNEL+ bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFb1 and TGFb2 and accumulation of S100A4+ fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. IPF is characterized by small airway remodeling in addition to parenchymal <d>fibrosis</d>, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial <d>fibrosis</d>. Thus, this model can be utilized to investigate mechanisms of airway remodeling.
22394287|a|In addition to parenchymal <d>fibrosis</d>, fibrotic remodeling of the distal airways has been reported in <d>interstitial <d>lung diseases</d></d>. Mechanisms of airway wall remodeling, which occurs in a variety of chronic <d>lung diseases</d>, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary <d>fibrosis</d> IPF and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for <d>fibrosis</d> and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and immunohistochemistry for transforming growth factor b1 TGFb1, TGFb2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and <d>fibrosis</d> and greater airflow resistance after high-dose bleomycin. Increased TUNEL+ bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFb1 and TGFb2 and accumulation of S100A4+ fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. IPF is characterized by small airway remodeling in addition to parenchymal <d>fibrosis</d>, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial <d>fibrosis</d>. Thus, this model can be utilized to investigate mechanisms of airway remodeling.
22394287|a|In addition to parenchymal <d>fibrosis</d>, fibrotic remodeling of the distal airways has been reported in <d>interstitial <d>lung diseases</d></d>. Mechanisms of airway wall remodeling, which occurs in a variety of chronic <d>lung diseases</d>, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for <d>fibrosis</d> and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and immunohistochemistry for transforming growth factor b1 TGFb1, TGFb2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. <d>IPF</d> lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and <d>fibrosis</d> and greater airflow resistance after high-dose bleomycin. Increased TUNEL+ bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFb1 and TGFb2 and accumulation of S100A4+ fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. <d>IPF</d> is characterized by small airway remodeling in addition to parenchymal <d>fibrosis</d>, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial <d>fibrosis</d>. Thus, this model can be utilized to investigate mechanisms of airway remodeling.
22394287|a|In addition to parenchymal <d>fibrosis</d>, fibrotic remodeling of the distal airways has been reported in <d>interstitial <d>lung diseases</d></d>. Mechanisms of airway wall remodeling, which occurs in a variety of chronic <d>lung diseases</d>, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for <d>fibrosis</d> and <d>peribronchial inflammation</d>, morphometric evaluation of subepithelial connective tissue volume density, TUNEL terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and immunohistochemistry for transforming growth factor b1 TGFb1, TGFb2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. <d>IPF</d> lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and <d>fibrosis</d> and greater airflow resistance after high-dose bleomycin. Increased TUNEL+ bronchial epithelial cells and <d>peribronchial inflammation</d> were noted by 1 week, and expression of TGFb1 and TGFb2 and accumulation of S100A4+ fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. <d>IPF</d> is characterized by small airway remodeling in addition to parenchymal <d>fibrosis</d>, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial <d>fibrosis</d>. Thus, this model can be utilized to investigate mechanisms of airway remodeling.
22394287|a|In addition to parenchymal <d>fibrosis</d>, fibrotic remodeling of the distal airways has been reported in <d>interstitial <d>lung diseases</d></d>. Mechanisms of airway wall remodeling, which occurs in a variety of chronic <d>lung diseases</d>, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for <d>fibrosis</d> and <d>peribronchial <d>inflammation</d></d>, morphometric evaluation of subepithelial connective tissue volume density, TUNEL terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and immunohistochemistry for <g>transforming growth factor b1</g> <g>TGFb1</g>, <g>TGFb2</g>, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. <d>IPF</d> lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall <d>inflammation</d> and <d>fibrosis</d> and greater airflow resistance after high-dose bleomycin. Increased TUNEL+ bronchial epithelial cells and <d>peribronchial <d>inflammation</d></d> were noted by 1 week, and expression of <g>TGFb1</g> and <g>TGFb2</g> and accumulation of S100A4+ fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. <d>IPF</d> is characterized by small airway remodeling in addition to parenchymal <d>fibrosis</d>, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway <d>inflammation</d>, profibrotic cytokine expression, fibroblast accumulation, and peribronchial <d>fibrosis</d>. Thus, this model can be utilized to investigate mechanisms of airway remodeling.
22406480|a|AIMS: The aim of the study was to evaluate the role of Serpin B3/B4 in advanced idiopathic pulmonary fibrosis IPF patients, mainly focusing on epithelial proliferation. METHODS: Lungs from 48 IPF patients including cases with cancer or high-grade epithelial dysplasia were studied and compared with other diffuse parenchymal diseases and normal lungs. Immunohistochemistry for Serpin B3/B4 and Ki-67 was quantified in all cases, distinguishing stained metaplastic cells. In IPF patients correlations between Serpin expression and several clinicopathological data, including fibrotic remodelling [fibrosis extension and transforming growth factor b expression TGF-b] were performed. Molecular analysis was used for Serpin isoform characterisation. RESULTS: In IPF patients Serpin B3/B4 and Ki-67 were significantly overexpressed in many metaplastic cells mainly squamous type compared to control cases. Higher Serpin B3/B4 was found in older patients and cases with more impaired respiratory function. Serpin B3/B4 expression was related to both TGF-b and Ki-67 and was higher in patients with cancer/high-grade dysplasia. Serpin B3 was expressed in all cases, whereas <g>Serpin B4</g> was expressed only in IPF. CONCLUSIONS: Serpin B3/B4, particularly <g>Serpin B4</g>, appears to play an important role in aberrant epithelial proliferation. Evaluation of Serpin B3/B4 could have prognostic value in predicting disease progression, especially in patients with increased susceptibility to <d>lung cancer</d>.
22406480|a|AIMS: The aim of the study was to evaluate the role of Serpin B3/B4 in advanced <d>idiopathic pulmonary fibrosis</d> IPF patients, mainly focusing on epithelial proliferation. METHODS: Lungs from 48 IPF patients including cases with cancer or high-grade epithelial dysplasia were studied and compared with other diffuse parenchymal diseases and normal lungs. Immunohistochemistry for Serpin B3/B4 and Ki-67 was quantified in all cases, distinguishing stained metaplastic cells. In IPF patients correlations between Serpin expression and several clinicopathological data, including fibrotic remodelling [fibrosis extension and transforming growth factor b expression TGF-b] were performed. Molecular analysis was used for Serpin isoform characterisation. RESULTS: In IPF patients Serpin B3/B4 and Ki-67 were significantly overexpressed in many metaplastic cells mainly squamous type compared to control cases. Higher Serpin B3/B4 was found in older patients and cases with more impaired respiratory function. Serpin B3/B4 expression was related to both TGF-b and Ki-67 and was higher in patients with cancer/high-grade dysplasia. Serpin B3 was expressed in all cases, whereas <g>Serpin B4</g> was expressed only in IPF. CONCLUSIONS: Serpin B3/B4, particularly <g>Serpin B4</g>, appears to play an important role in aberrant epithelial proliferation. Evaluation of Serpin B3/B4 could have prognostic value in predicting disease progression, especially in patients with increased susceptibility to <d>lung cancer</d>.
22406480|a|AIMS: The aim of the study was to evaluate the role of <g>Serpin B3/B4</g> in advanced <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> patients, mainly focusing on epithelial proliferation. METHODS: Lungs from 48 <d>IPF</d> patients including cases with cancer or high-grade epithelial dysplasia were studied and compared with other diffuse parenchymal diseases and normal lungs. Immunohistochemistry for <g>Serpin B3/B4</g> and Ki-67 was quantified in all cases, distinguishing stained metaplastic cells. In <d>IPF</d> patients correlations between Serpin expression and several clinicopathological data, including fibrotic remodelling [fibrosis extension and transforming growth factor b expression TGF-b] were performed. Molecular analysis was used for Serpin isoform characterisation. RESULTS: In <d>IPF</d> patients <g>Serpin B3/B4</g> and Ki-67 were significantly overexpressed in many metaplastic cells mainly squamous type compared to control cases. Higher <g>Serpin B3/B4</g> was found in older patients and cases with more impaired respiratory function. <g>Serpin B3/B4</g> expression was related to both TGF-b and Ki-67 and was higher in patients with cancer/high-grade dysplasia. Serpin B3 was expressed in all cases, whereas <g>Serpin B4</g> was expressed only in <d>IPF</d>. CONCLUSIONS: <g>Serpin B3/B4</g>, particularly <g>Serpin B4</g>, appears to play an important role in aberrant epithelial proliferation. Evaluation of <g>Serpin B3/B4</g> could have prognostic value in predicting disease progression, especially in patients with increased susceptibility to <d>lung cancer</d>.
22406480|a|AIMS: The aim of the study was to evaluate the role of <g>Serpin B3/B4</g> in advanced <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> patients, mainly focusing on epithelial proliferation. METHODS: Lungs from 48 <d>IPF</d> patients including cases with <d>cancer</d> or high-grade epithelial dysplasia were studied and compared with other diffuse parenchymal diseases and normal lungs. Immunohistochemistry for <g>Serpin B3/B4</g> and Ki-67 was quantified in all cases, distinguishing stained metaplastic cells. In <d>IPF</d> patients correlations between Serpin expression and several clinicopathological data, including fibrotic remodelling [fibrosis extension and transforming growth factor b expression TGF-b] were performed. Molecular analysis was used for Serpin isoform characterisation. RESULTS: In <d>IPF</d> patients <g>Serpin B3/B4</g> and Ki-67 were significantly overexpressed in many metaplastic cells mainly squamous type compared to control cases. Higher <g>Serpin B3/B4</g> was found in older patients and cases with more impaired respiratory function. <g>Serpin B3/B4</g> expression was related to both TGF-b and Ki-67 and was higher in patients with <d>cancer</d>/high-grade dysplasia. Serpin B3 was expressed in all cases, whereas <g>Serpin B4</g> was expressed only in <d>IPF</d>. CONCLUSIONS: <g>Serpin B3/B4</g>, particularly <g>Serpin B4</g>, appears to play an important role in aberrant epithelial proliferation. Evaluation of <g>Serpin B3/B4</g> could have prognostic value in predicting disease progression, especially in patients with increased susceptibility to <d>lung <d>cancer</d></d>.
22406480|a|AIMS: The aim of the study was to evaluate the role of <g>Serpin B3/B4</g> in advanced <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> patients, mainly focusing on epithelial proliferation. METHODS: Lungs from 48 <d>IPF</d> patients including cases with <d>cancer</d> or high-grade <d>epithelial dysplasia</d> were studied and compared with other diffuse parenchymal diseases and normal lungs. Immunohistochemistry for <g>Serpin B3/B4</g> and Ki-67 was quantified in all cases, distinguishing stained metaplastic cells. In <d>IPF</d> patients correlations between Serpin expression and several clinicopathological data, including fibrotic remodelling [fibrosis extension and transforming growth factor b expression TGF-b] were performed. Molecular analysis was used for Serpin isoform characterisation. RESULTS: In <d>IPF</d> patients <g>Serpin B3/B4</g> and Ki-67 were significantly overexpressed in many metaplastic cells mainly squamous type compared to control cases. Higher <g>Serpin B3/B4</g> was found in older patients and cases with more impaired respiratory function. <g>Serpin B3/B4</g> expression was related to both TGF-b and Ki-67 and was higher in patients with <d>cancer</d>/high-grade dysplasia. Serpin B3 was expressed in all cases, whereas <g>Serpin B4</g> was expressed only in <d>IPF</d>. CONCLUSIONS: <g>Serpin B3/B4</g>, particularly <g>Serpin B4</g>, appears to play an important role in aberrant epithelial proliferation. Evaluation of <g>Serpin B3/B4</g> could have prognostic value in predicting disease progression, especially in patients with increased susceptibility to <d>lung <d>cancer</d></d>.
22406480|a|AIMS: The aim of the study was to evaluate the role of <g>Serpin B3/B4</g> in advanced <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> patients, mainly focusing on epithelial proliferation. METHODS: Lungs from 48 <d>IPF</d> patients including cases with <d>cancer</d> or high-grade <d>epithelial dysplasia</d> were studied and compared with other diffuse parenchymal diseases and normal lungs. Immunohistochemistry for <g>Serpin B3/B4</g> and Ki-67 was quantified in all cases, distinguishing stained metaplastic cells. In <d>IPF</d> patients correlations between Serpin expression and several clinicopathological data, including <d>fibrotic remodelling</d> [fibrosis extension and transforming growth factor b expression TGF-b] were performed. Molecular analysis was used for Serpin isoform characterisation. RESULTS: In <d>IPF</d> patients <g>Serpin B3/B4</g> and Ki-67 were significantly overexpressed in many metaplastic cells mainly squamous type compared to control cases. Higher <g>Serpin B3/B4</g> was found in older patients and cases with more impaired respiratory function. <g>Serpin B3/B4</g> expression was related to both TGF-b and Ki-67 and was higher in patients with <d>cancer</d>/high-grade dysplasia. Serpin B3 was expressed in all cases, whereas <g>Serpin B4</g> was expressed only in <d>IPF</d>. CONCLUSIONS: <g>Serpin B3/B4</g>, particularly <g>Serpin B4</g>, appears to play an important role in aberrant epithelial proliferation. Evaluation of <g>Serpin B3/B4</g> could have prognostic value in predicting disease progression, especially in patients with increased susceptibility to <d>lung <d>cancer</d></d>.
22406480|a|AIMS: The aim of the study was to evaluate the role of <g>Serpin B3/B4</g> in advanced <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> patients, mainly focusing on epithelial proliferation. METHODS: Lungs from 48 <d>IPF</d> patients including cases with <d>cancer</d> or high-grade <d>epithelial dysplasia</d> were studied and compared with other diffuse parenchymal diseases and normal lungs. Immunohistochemistry for <g>Serpin B3/B4</g> and Ki-67 was quantified in all cases, distinguishing stained metaplastic cells. In <d>IPF</d> patients correlations between Serpin expression and several clinicopathological data, including <d>fibrotic remodelling</d> [<d>fibrosis</d> extension and transforming growth factor b expression TGF-b] were performed. Molecular analysis was used for Serpin isoform characterisation. RESULTS: In <d>IPF</d> patients <g>Serpin B3/B4</g> and Ki-67 were significantly overexpressed in many metaplastic cells mainly squamous type compared to control cases. Higher <g>Serpin B3/B4</g> was found in older patients and cases with more impaired respiratory function. <g>Serpin B3/B4</g> expression was related to both TGF-b and Ki-67 and was higher in patients with <d>cancer</d>/high-grade dysplasia. Serpin B3 was expressed in all cases, whereas <g>Serpin B4</g> was expressed only in <d>IPF</d>. CONCLUSIONS: <g>Serpin B3/B4</g>, particularly <g>Serpin B4</g>, appears to play an important role in aberrant epithelial proliferation. Evaluation of <g>Serpin B3/B4</g> could have prognostic value in predicting disease progression, especially in patients with increased susceptibility to <d>lung <d>cancer</d></d>.
22406480|a|AIMS: The aim of the study was to evaluate the role of <g><g>Serpin B3</g>/B4</g> in advanced <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> patients, mainly focusing on epithelial proliferation. METHODS: Lungs from 48 <d>IPF</d> patients including cases with <d>cancer</d> or high-grade <d>epithelial <d>dysplasia</d></d> were studied and compared with other diffuse parenchymal diseases and normal lungs. Immunohistochemistry for <g><g>Serpin B3</g>/B4</g> and Ki-67 was quantified in all cases, distinguishing stained metaplastic cells. In <d>IPF</d> patients correlations between Serpin expression and several clinicopathological data, including <d>fibrotic remodelling</d> [<d>fibrosis</d> extension and <g>transforming growth factor b expression</g> <g>TGF-b</g>] were performed. Molecular analysis was used for Serpin isoform characterisation. RESULTS: In <d>IPF</d> patients <g><g>Serpin B3</g>/B4</g> and Ki-67 were significantly overexpressed in many metaplastic cells mainly squamous type compared to control cases. Higher <g><g>Serpin B3</g>/B4</g> was found in older patients and cases with more impaired respiratory function. <g><g>Serpin B3</g>/B4</g> expression was related to both <g>TGF-b</g> and Ki-67 and was higher in patients with <d>cancer</d>/high-grade <d>dysplasia</d>. <g>Serpin B3</g> was expressed in all cases, whereas <g>Serpin B4</g> was expressed only in <d>IPF</d>. CONCLUSIONS: <g><g>Serpin B3</g>/B4</g>, particularly <g>Serpin B4</g>, appears to play an important role in aberrant epithelial proliferation. Evaluation of <g><g>Serpin B3</g>/B4</g> could have prognostic value in predicting disease progression, especially in patients with increased susceptibility to <d>lung <d>cancer</d></d>.
22434388|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive disease of unknown cause. The pathogenesis of the disease is characterized by fibroblast accumulation and excessive transforming growth factor-b <g>TGF-b</g> activation. Although <g>TGF-b</g> activation is a complex process involving various protein interactions, little is known of the specific routes of <g>TGF-b</g> storage and activation in human lung. Here, we have systematically analyzed the expression of specific proteins involved in extracellular matrix targeting and activation of <g>TGF-b</g>. Latent <g>TGF-b</g>-binding protein LTBP-1 was found to be significantly upregulated in IPF patient lungs. LTBP-1 expression was especially high in the fibroblastic foci, in which P-Smad2 immunoreactivity, indicative of <g>TGF-b</g> signaling activity, was less prominent. In cultured primary lung fibroblasts and epithelial cells, short-interfering-RNA-mediated downregulation of LTBP-1 resulted in either increased or decreased <g>TGF-b</g> signaling activity, respectively, suggesting that LTBP-1-mediated <g>TGF-b</g> activation is dependent on the cellular context in the lung. Furthermore, LTBP-1 was shown to colocalize with fibronectin, fibrillin-1 and fibrillin-2 proteins in the IPF lung. Fibrillin-2, a developmental gene expressed only in blood vessels in normal adult lung, was found specifically upregulated in IPF fibroblastic foci. The <g>TGF-b</g>-activating integrin b8 subunit was expressed at low levels in both control and IPF lungs. Alterations in extracellular matrix composition, such as high levels of the <g>TGF-b</g> storage protein LTBP-1 and the re-appearance of fibrillin-2, probably modulate <g>TGF-b</g> availability and activation in different pulmonary compartments in the fibrotic lung.
22434388|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive disease of unknown cause. The pathogenesis of the disease is characterized by fibroblast accumulation and excessive transforming growth factor-b <g>TGF-b</g> activation. Although <g>TGF-b</g> activation is a complex process involving various protein interactions, little is known of the specific routes of <g>TGF-b</g> storage and activation in human lung. Here, we have systematically analyzed the expression of specific proteins involved in extracellular matrix targeting and activation of <g>TGF-b</g>. Latent <g>TGF-b</g>-binding protein LTBP-1 was found to be significantly upregulated in <d>IPF</d> patient lungs. LTBP-1 expression was especially high in the fibroblastic foci, in which P-Smad2 immunoreactivity, indicative of <g>TGF-b</g> signaling activity, was less prominent. In cultured primary lung fibroblasts and epithelial cells, short-interfering-RNA-mediated downregulation of LTBP-1 resulted in either increased or decreased <g>TGF-b</g> signaling activity, respectively, suggesting that LTBP-1-mediated <g>TGF-b</g> activation is dependent on the cellular context in the lung. Furthermore, LTBP-1 was shown to colocalize with fibronectin, fibrillin-1 and fibrillin-2 proteins in the <d>IPF</d> lung. Fibrillin-2, a developmental gene expressed only in blood vessels in normal adult lung, was found specifically upregulated in <d>IPF</d> fibroblastic foci. The <g>TGF-b</g>-activating integrin b8 subunit was expressed at low levels in both control and <d>IPF</d> lungs. Alterations in extracellular matrix composition, such as high levels of the <g>TGF-b</g> storage protein LTBP-1 and the re-appearance of fibrillin-2, probably modulate <g>TGF-b</g> availability and activation in different pulmonary compartments in the fibrotic lung.
22446029|a|Peptide crosslinkers containing the sequence C-X-CG X represents various adhesive peptides were incorporated into polyethylene glycol PEG hydrogel networks with different mechanical properties. Pulmonary fibroblasts PFs exhibit increased adhesion to rigid hydrogels modified with X=RGDS, DGEA and IKVAV 0.5 and/or 5 mM compared with a scrambled control X=HRPNS. PFs exhibit increased adhesion to softer hydrogels when X=DGEA at low 0.5 mM peptide concentration. PFs seeded onto hydrogels modified with X=RGDS produce <g>alpha-smooth muscle actin</g> <g>a-SMA</g>, a myofibroblast marker, and form an extensive cytoskeleton with focal adhesions. Decreasing substrate stiffness achieved through <d>hydrolytic degradation</d> results in down-regulation of <g>a-SMA</g> expression by PFs. Substrate stiffness increases the sensitivity of PFs to exogenously applied transforming growth factor beta <g>TGF-b</g>1; PFs on the most rigid gels E=900 kPa express <g>a-SMA</g> when treated with low concentrations of <g>TGF-b</g>1 1 ng ml-1, while those on less rigid gels E=20-60 kPa do not. These results demonstrate the importance of both mechanical and chemical cues in studying pulmonary fibroblast activation, and establish PEG hydrogels as a viable material for further study of IPF etiology.
22446029|a|Peptide crosslinkers containing the sequence C-X-CG X represents various adhesive peptides were incorporated into polyethylene glycol PEG hydrogel networks with different mechanical properties. Pulmonary fibroblasts PFs exhibit increased adhesion to rigid hydrogels modified with X=RGDS, DGEA and IKVAV 0.5 and/or 5 mM compared with a scrambled control X=HRPNS. PFs exhibit increased adhesion to softer hydrogels when X=DGEA at low 0.5 mM peptide concentration. PFs seeded onto hydrogels modified with X=RGDS produce <g>alpha-smooth muscle actin</g> <g>a-SMA</g>, a myofibroblast marker, and form an extensive cytoskeleton with focal adhesions. Decreasing substrate stiffness achieved through <d>hydrolytic degradation</d> results in down-regulation of <g>a-SMA</g> expression by PFs. Substrate stiffness increases the sensitivity of PFs to exogenously applied <g>transforming growth factor beta</g> <g>TGF-b</g>1; PFs on the most rigid gels E=900 kPa express <g>a-SMA</g> when treated with low concentrations of <g>TGF-b</g>1 1 ng ml-1, while those on less rigid gels E=20-60 kPa do not. These results demonstrate the importance of both mechanical and chemical cues in studying pulmonary fibroblast activation, and establish PEG hydrogels as a viable material for further study of <d>IPF</d> etiology.
22661007|a|Aberrant expression of miRNAs is closely associated with initiation and progression of pathological processes, including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in lung fibrosis is not well characterized. We sought to determine the role of <g>miR-31</g> in regulating the fibrogenic, contractile, and migratory activities of lung fibroblasts and modulating of <d>pulmonary fibrosis</d> in vivo. In vivo lung fibrosis models and ex vivo cell culture systems were employed. Real-time PCR and Western blot analysis were used to determine gene expression levels. <g>miR-31</g> mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic, contractile, and migratory activities of lung fibroblasts were determined. We found that <g>miR-31</g> expression is reduced in the lungs of mice with experimental <d>pulmonary fibrosis</d> and in IPF fibroblasts. <g>miR-31</g> inhibits the profibrotic activity of TGF-b1 in normal lung fibroblasts and diminishes the fibrogenic, contractile, and migratory activities of IPF fibroblasts. In these experiments, <g>miR-31</g> was shown to directly target integrin a5 and RhoA, two proteins that have been shown to regulate activation of fibroblasts. We found that levels of integrin a5 and RhoA are up-regulated in fibrotic mouse lungs. Knockdown of integrin a5 and RhoA attenuated fibrogenic, contractile, and migratory activities of IPF fibroblasts, in a manner similar to that observed with <g>miR-31</g>. We also found that introduction of <g>miR-31</g> ameliorated experimental lung fibrosis in mice. Our data suggest that <g>miR-31</g> is an important regulator of the pathological activities of lung fibroblasts and may be a potential target in the development of novel therapies to treat pathological fibrotic disorders, including <d>pulmonary fibrosis</d>.
22661007|a|Aberrant expression of miRNAs is closely associated with initiation and progression of pathological processes, including <d>diabetes</d>, cancer, and cardiovascular disease. However, the role of miRNAs in lung fibrosis is not well characterized. We sought to determine the role of <g>miR-31</g> in regulating the fibrogenic, contractile, and migratory activities of lung fibroblasts and modulating of <d>pulmonary fibrosis</d> in vivo. In vivo lung fibrosis models and ex vivo cell culture systems were employed. Real-time PCR and Western blot analysis were used to determine gene expression levels. <g>miR-31</g> mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic, contractile, and migratory activities of lung fibroblasts were determined. We found that <g>miR-31</g> expression is reduced in the lungs of mice with experimental <d>pulmonary fibrosis</d> and in IPF fibroblasts. <g>miR-31</g> inhibits the profibrotic activity of TGF-b1 in normal lung fibroblasts and diminishes the fibrogenic, contractile, and migratory activities of IPF fibroblasts. In these experiments, <g>miR-31</g> was shown to directly target integrin a5 and RhoA, two proteins that have been shown to regulate activation of fibroblasts. We found that levels of integrin a5 and RhoA are up-regulated in fibrotic mouse lungs. Knockdown of integrin a5 and RhoA attenuated fibrogenic, contractile, and migratory activities of IPF fibroblasts, in a manner similar to that observed with <g>miR-31</g>. We also found that introduction of <g>miR-31</g> ameliorated experimental lung fibrosis in mice. Our data suggest that <g>miR-31</g> is an important regulator of the pathological activities of lung fibroblasts and may be a potential target in the development of novel therapies to treat pathological fibrotic disorders, including <d>pulmonary fibrosis</d>.
22661007|a|Aberrant expression of miRNAs is closely associated with initiation and progression of pathological processes, including <d>diabetes</d>, <d>cancer</d>, and cardiovascular disease. However, the role of miRNAs in lung fibrosis is not well characterized. We sought to determine the role of <g>miR-31</g> in regulating the fibrogenic, contractile, and migratory activities of lung fibroblasts and modulating of <d>pulmonary fibrosis</d> in vivo. In vivo lung fibrosis models and ex vivo cell culture systems were employed. Real-time PCR and Western blot analysis were used to determine gene expression levels. <g>miR-31</g> mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic, contractile, and migratory activities of lung fibroblasts were determined. We found that <g>miR-31</g> expression is reduced in the lungs of mice with experimental <d>pulmonary fibrosis</d> and in IPF fibroblasts. <g>miR-31</g> inhibits the profibrotic activity of TGF-b1 in normal lung fibroblasts and diminishes the fibrogenic, contractile, and migratory activities of IPF fibroblasts. In these experiments, <g>miR-31</g> was shown to directly target integrin a5 and RhoA, two proteins that have been shown to regulate activation of fibroblasts. We found that levels of integrin a5 and RhoA are up-regulated in fibrotic mouse lungs. Knockdown of integrin a5 and RhoA attenuated fibrogenic, contractile, and migratory activities of IPF fibroblasts, in a manner similar to that observed with <g>miR-31</g>. We also found that introduction of <g>miR-31</g> ameliorated experimental lung fibrosis in mice. Our data suggest that <g>miR-31</g> is an important regulator of the pathological activities of lung fibroblasts and may be a potential target in the development of novel therapies to treat pathological fibrotic disorders, including <d>pulmonary fibrosis</d>.
22661007|a|Aberrant expression of miRNAs is closely associated with initiation and progression of pathological processes, including <d>diabetes</d>, <d>cancer</d>, and <d>cardiovascular disease</d>. However, the role of miRNAs in lung fibrosis is not well characterized. We sought to determine the role of <g>miR-31</g> in regulating the fibrogenic, contractile, and migratory activities of lung fibroblasts and modulating of <d>pulmonary fibrosis</d> in vivo. In vivo lung fibrosis models and ex vivo cell culture systems were employed. Real-time PCR and Western blot analysis were used to determine gene expression levels. <g>miR-31</g> mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic, contractile, and migratory activities of lung fibroblasts were determined. We found that <g>miR-31</g> expression is reduced in the lungs of mice with experimental <d>pulmonary fibrosis</d> and in IPF fibroblasts. <g>miR-31</g> inhibits the profibrotic activity of TGF-b1 in normal lung fibroblasts and diminishes the fibrogenic, contractile, and migratory activities of IPF fibroblasts. In these experiments, <g>miR-31</g> was shown to directly target integrin a5 and RhoA, two proteins that have been shown to regulate activation of fibroblasts. We found that levels of integrin a5 and RhoA are up-regulated in fibrotic mouse lungs. Knockdown of integrin a5 and RhoA attenuated fibrogenic, contractile, and migratory activities of IPF fibroblasts, in a manner similar to that observed with <g>miR-31</g>. We also found that introduction of <g>miR-31</g> ameliorated experimental lung fibrosis in mice. Our data suggest that <g>miR-31</g> is an important regulator of the pathological activities of lung fibroblasts and may be a potential target in the development of novel therapies to treat pathological fibrotic disorders, including <d>pulmonary fibrosis</d>.
22661007|a|Aberrant expression of miRNAs is closely associated with initiation and progression of pathological processes, including <d>diabetes</d>, <d>cancer</d>, and <d>cardiovascular disease</d>. However, the role of miRNAs in <d>lung fibrosis</d> is not well characterized. We sought to determine the role of <g>miR-31</g> in regulating the fibrogenic, contractile, and migratory activities of lung fibroblasts and modulating of <d>pulmonary fibrosis</d> in vivo. In vivo <d>lung fibrosis</d> models and ex vivo cell culture systems were employed. Real-time PCR and Western blot analysis were used to determine gene expression levels. <g>miR-31</g> mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic, contractile, and migratory activities of lung fibroblasts were determined. We found that <g>miR-31</g> expression is reduced in the lungs of mice with experimental <d>pulmonary fibrosis</d> and in IPF fibroblasts. <g>miR-31</g> inhibits the profibrotic activity of TGF-b1 in normal lung fibroblasts and diminishes the fibrogenic, contractile, and migratory activities of IPF fibroblasts. In these experiments, <g>miR-31</g> was shown to directly target integrin a5 and RhoA, two proteins that have been shown to regulate activation of fibroblasts. We found that levels of integrin a5 and RhoA are up-regulated in fibrotic mouse lungs. Knockdown of integrin a5 and RhoA attenuated fibrogenic, contractile, and migratory activities of IPF fibroblasts, in a manner similar to that observed with <g>miR-31</g>. We also found that introduction of <g>miR-31</g> ameliorated experimental <d>lung fibrosis</d> in mice. Our data suggest that <g>miR-31</g> is an important regulator of the pathological activities of lung fibroblasts and may be a potential target in the development of novel therapies to treat pathological fibrotic disorders, including <d>pulmonary fibrosis</d>.
22661007|a|Aberrant expression of miRNAs is closely associated with initiation and progression of pathological processes, including <d>diabetes</d>, <d>cancer</d>, and <d>cardiovascular disease</d>. However, the role of miRNAs in <d>lung fibrosis</d> is not well characterized. We sought to determine the role of <g>miR-31</g> in regulating the fibrogenic, contractile, and migratory activities of lung fibroblasts and modulating of <d>pulmonary fibrosis</d> in vivo. In vivo <d>lung fibrosis</d> models and ex vivo cell culture systems were employed. Real-time PCR and Western blot analysis were used to determine gene expression levels. <g>miR-31</g> mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic, contractile, and migratory activities of lung fibroblasts were determined. We found that <g>miR-31</g> expression is reduced in the lungs of mice with experimental <d>pulmonary fibrosis</d> and in <d>IPF</d> fibroblasts. <g>miR-31</g> inhibits the profibrotic activity of TGF-b1 in normal lung fibroblasts and diminishes the fibrogenic, contractile, and migratory activities of <d>IPF</d> fibroblasts. In these experiments, <g>miR-31</g> was shown to directly target integrin a5 and RhoA, two proteins that have been shown to regulate activation of fibroblasts. We found that levels of integrin a5 and RhoA are up-regulated in fibrotic mouse lungs. Knockdown of integrin a5 and RhoA attenuated fibrogenic, contractile, and migratory activities of <d>IPF</d> fibroblasts, in a manner similar to that observed with <g>miR-31</g>. We also found that introduction of <g>miR-31</g> ameliorated experimental <d>lung fibrosis</d> in mice. Our data suggest that <g>miR-31</g> is an important regulator of the pathological activities of lung fibroblasts and may be a potential target in the development of novel therapies to treat pathological fibrotic disorders, including <d>pulmonary fibrosis</d>.
22661007|a|Aberrant expression of miRNAs is closely associated with initiation and progression of pathological processes, including <d>diabetes</d>, <d>cancer</d>, and <d>cardiovascular disease</d>. However, the role of miRNAs in <d>lung fibrosis</d> is not well characterized. We sought to determine the role of <g>miR-31</g> in regulating the fibrogenic, contractile, and migratory activities of lung fibroblasts and modulating of <d>pulmonary fibrosis</d> in vivo. In vivo <d>lung fibrosis</d> models and ex vivo cell culture systems were employed. Real-time PCR and Western blot analysis were used to determine gene expression levels. <g>miR-31</g> mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic, contractile, and migratory activities of lung fibroblasts were determined. We found that <g>miR-31</g> expression is reduced in the lungs of mice with experimental <d>pulmonary fibrosis</d> and in <d>IPF</d> fibroblasts. <g>miR-31</g> inhibits the profibrotic activity of <g>TGF-b1</g> in normal lung fibroblasts and diminishes the fibrogenic, contractile, and migratory activities of <d>IPF</d> fibroblasts. In these experiments, <g>miR-31</g> was shown to directly target integrin a5 and <g>RhoA</g>, two proteins that have been shown to regulate activation of fibroblasts. We found that levels of integrin a5 and <g>RhoA</g> are up-regulated in fibrotic mouse lungs. Knockdown of integrin a5 and <g>RhoA</g> attenuated fibrogenic, contractile, and migratory activities of <d>IPF</d> fibroblasts, in a manner similar to that observed with <g>miR-31</g>. We also found that introduction of <g>miR-31</g> ameliorated experimental <d>lung fibrosis</d> in mice. Our data suggest that <g>miR-31</g> is an important regulator of the pathological activities of lung fibroblasts and may be a potential target in the development of novel therapies to treat pathological <d>fibrotic disorders</d>, including <d>pulmonary fibrosis</d>.
22684844|a|Idiopathic pulmonary fibrosis IPF is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin IL-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor TGF-b signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive <g>Stat3</g> activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;  MT-/- compound mutant mice, but fibrosis still occurred in their <g>Smad3</g>-/- counterparts consistent with the capacity of excessive <g>Stat3</g> activity to induce collagen 1a1 gene transcription independently of canonical TGF-b/<g>Smad3</g> signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of <g>Stat3</g> protected mice from bleomycin-induced <d>lung fibrosis</d>.
22684844|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin IL-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor TGF-b signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive <g>Stat3</g> activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;  MT-/- compound mutant mice, but fibrosis still occurred in their <g>Smad3</g>-/- counterparts consistent with the capacity of excessive <g>Stat3</g> activity to induce collagen 1a1 gene transcription independently of canonical TGF-b/<g>Smad3</g> signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of <g>Stat3</g> protected mice from bleomycin-induced <d>lung fibrosis</d>.
22684844|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin IL-6, are elevated in <d>IPF</d>, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor TGF-b signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive <g>Stat3</g> activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;  MT-/- compound mutant mice, but fibrosis still occurred in their <g>Smad3</g>-/- counterparts consistent with the capacity of excessive <g>Stat3</g> activity to induce collagen 1a1 gene transcription independently of canonical TGF-b/<g>Smad3</g> signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from <d>IPF</d> patients and showed that genetic reduction of <g>Stat3</g> protected mice from bleomycin-induced <d>lung fibrosis</d>.
22684844|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent <d>fibrosis</d>. While inflammatory cytokines, including interleukin IL-6, are elevated in <d>IPF</d>, the molecular mechanisms that underlie this disease are incompletely understood, although the development of <d>fibrosis</d> is believed to depend on canonical transforming growth factor TGF-b signalling. We examined bleomycin-induced inflammation and <d>fibrosis</d> in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive <g>Stat3</g> activity with inflammatory infiltrates in the lung and the severity of <d>fibrosis</d> in corresponding gp130757F mice. The extent of <d>fibrosis</d> was attenuated in B lymphocyte-deficient gp130757F;  MT-/- compound mutant mice, but <d>fibrosis</d> still occurred in their <g>Smad3</g>-/- counterparts consistent with the capacity of excessive <g>Stat3</g> activity to induce collagen 1a1 gene transcription independently of canonical TGF-b/<g>Smad3</g> signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from <d>IPF</d> patients and showed that genetic reduction of <g>Stat3</g> protected mice from bleomycin-induced <d>lung <d>fibrosis</d></d>.
22684844|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent <d>fibrosis</d>. While inflammatory cytokines, including <g>interleukin IL-6</g>, are elevated in <d>IPF</d>, the molecular mechanisms that underlie this disease are incompletely understood, although the development of <d>fibrosis</d> is believed to depend on canonical transforming growth factor TGF-b signalling. We examined bleomycin-induced <d>inflammation</d> and <d>fibrosis</d> in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive <g>Stat3</g> activity with inflammatory infiltrates in the lung and the severity of <d>fibrosis</d> in corresponding gp130757F mice. The extent of <d>fibrosis</d> was attenuated in B lymphocyte-deficient gp130757F;  MT-/- compound mutant mice, but <d>fibrosis</d> still occurred in their <g>Smad3</g>-/- counterparts consistent with the capacity of excessive <g>Stat3</g> activity to induce collagen 1a1 gene transcription independently of canonical TGF-b/<g>Smad3</g> signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from <d>IPF</d> patients and showed that genetic reduction of <g>Stat3</g> protected mice from bleomycin-induced <d>lung <d>fibrosis</d></d>.
22694981|a|BACKGROUND: Pirfenidone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis IPF. We previously showed that pirfenidone inhibits the over-expression of collagen type I and of <d>heat shock</d> protein HSP 47, a collagen-specific molecular chaperone, in human lung fibroblasts stimulated with transforming growth factor <g>TGF-b1</g> in vitro. The increased numbers of HSP47-positive type II pneumocytes as well as fibroblasts were also diminished by pirfenidone in an animal model of pulmonary fibrosis induced by bleomycin. The present study evaluates the effects of pirfenidone on collagen type I and HSP47 expression in the human alveolar epithelial cell line, A549 cells in vitro. METHODS: The expression of collagen type I, HSP47 and E-cadherin mRNAs in A549 cells stimulated with <g>TGF-b1</g> was evaluated by Northern blotting or real-time PCR. The expression of collagen type I, HSP47 and fibronectin proteins was assessed by immunocytochemical staining. RESULTS: <g>TGF-b1</g> stimulated collagen type I and HSP47 mRNA and protein expression in A549 cells, and pirfenidone significantly inhibited this process. Pirfenidone also inhibited over-expression of the fibroblast phenotypic marker fibronectin in A549 cells induced by <g>TGF-b1</g>. CONCLUSION: We concluded that the anti-fibrotic effects of pirfenidone might be mediated not only through the direct inhibition of collagen type I expression but also through the inhibition of HSP47 expression in alveolar epithelial cells, which results in reduced collagen synthesis in lung fibrosis. Furthermore, pirfenidone might partially inhibit the epithelial-mesenchymal transition.
22694981|a|BACKGROUND: Pirfenidone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of <d>fibrosis</d> in animal models and in patients with idiopathic pulmonary <d>fibrosis</d> IPF. We previously showed that pirfenidone inhibits the over-expression of collagen type I and of <d>heat shock</d> protein HSP 47, a collagen-specific molecular chaperone, in human lung fibroblasts stimulated with transforming growth factor <g>TGF-b1</g> in vitro. The increased numbers of HSP47-positive type II pneumocytes as well as fibroblasts were also diminished by pirfenidone in an animal model of pulmonary <d>fibrosis</d> induced by bleomycin. The present study evaluates the effects of pirfenidone on collagen type I and HSP47 expression in the human alveolar epithelial cell line, A549 cells in vitro. METHODS: The expression of collagen type I, HSP47 and E-cadherin mRNAs in A549 cells stimulated with <g>TGF-b1</g> was evaluated by Northern blotting or real-time PCR. The expression of collagen type I, HSP47 and fibronectin proteins was assessed by immunocytochemical staining. RESULTS: <g>TGF-b1</g> stimulated collagen type I and HSP47 mRNA and protein expression in A549 cells, and pirfenidone significantly inhibited this process. Pirfenidone also inhibited over-expression of the fibroblast phenotypic marker fibronectin in A549 cells induced by <g>TGF-b1</g>. CONCLUSION: We concluded that the anti-fibrotic effects of pirfenidone might be mediated not only through the direct inhibition of collagen type I expression but also through the inhibition of HSP47 expression in alveolar epithelial cells, which results in reduced collagen synthesis in lung <d>fibrosis</d>. Furthermore, pirfenidone might partially inhibit the epithelial-mesenchymal transition.
22694981|a|BACKGROUND: Pirfenidone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of <d>fibrosis</d> in animal models and in patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. We previously showed that pirfenidone inhibits the over-expression of collagen type I and of <d>heat shock</d> protein HSP 47, a collagen-specific molecular chaperone, in human lung fibroblasts stimulated with transforming growth factor <g>TGF-b1</g> in vitro. The increased numbers of HSP47-positive type II pneumocytes as well as fibroblasts were also diminished by pirfenidone in an animal model of pulmonary <d>fibrosis</d> induced by bleomycin. The present study evaluates the effects of pirfenidone on collagen type I and HSP47 expression in the human alveolar epithelial cell line, A549 cells in vitro. METHODS: The expression of collagen type I, HSP47 and E-cadherin mRNAs in A549 cells stimulated with <g>TGF-b1</g> was evaluated by Northern blotting or real-time PCR. The expression of collagen type I, HSP47 and fibronectin proteins was assessed by immunocytochemical staining. RESULTS: <g>TGF-b1</g> stimulated collagen type I and HSP47 mRNA and protein expression in A549 cells, and pirfenidone significantly inhibited this process. Pirfenidone also inhibited over-expression of the fibroblast phenotypic marker fibronectin in A549 cells induced by <g>TGF-b1</g>. CONCLUSION: We concluded that the anti-fibrotic effects of pirfenidone might be mediated not only through the direct inhibition of collagen type I expression but also through the inhibition of HSP47 expression in alveolar epithelial cells, which results in reduced collagen synthesis in lung <d>fibrosis</d>. Furthermore, pirfenidone might partially inhibit the epithelial-mesenchymal transition.
22703534|a|AIMS: Oxidants have been implicated in the pathophysiology of idiopathic pulmonary fibrosis IPF, especially in myofibroblastic differentiation. We aimed at testing the hypothesis that nuclear factor erythroid 2-related factor 2 Nrf2, the main regulator of endogenous antioxidant enzymes, is involved in fibrogenesis via myofibroblastic differentiation. Fibroblasts were cultured from the lungs of eight controls and eight IPF patients. Oxidants-antioxidants balance, nuclear Nrf2 expression, and fibroblast phenotype a-smooth muscle actin and collagen I expression, proliferation, migration, and contraction were studied under basal conditions and after Nrf2 knockdown or activation by Nrf2 or Keap1 siRNA transfection. The effects of sulforaphane SFN, an Nrf2 activator, on the fibroblast phenotype were tested under basal and pro-fibrosis conditions transforming growth factor b [TGF-b]. RESULTS: Decreased Nrf2 expression was associated with a myofibroblast phenotype in IPF compared with control fibroblasts. Nrf2 knockdown induced oxidative stress and myofibroblastic differentiation in control fibroblasts. Conversely, Nrf2 activation increased antioxidant defences and myofibroblastic dedifferentation in IPF fibroblasts. SFN treatment decreased oxidants, and induced Nrf2 expression, antioxidants, and <d>myofibroblastic dedifferentiation</d> in IPF fibroblasts. SFN inhibited TGF-b profibrotic deleterious effects in IPF and control fibroblasts and restored antioxidant defences. Nrf2 knockdown abolished SFN antifibrosis effects, suggesting that they were Nrf2 mediated. INNOVATION AND CONCLUSION: Our findings confirm that decreased nuclear Nrf2 plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via Nrf2 activation. Thus, Nrf2 could be a novel therapeutic target in IPF.
22703534|a|AIMS: Oxidants have been implicated in the pathophysiology of <d>idiopathic pulmonary fibrosis</d> IPF, especially in myofibroblastic differentiation. We aimed at testing the hypothesis that nuclear factor erythroid 2-related factor 2 Nrf2, the main regulator of endogenous antioxidant enzymes, is involved in fibrogenesis via myofibroblastic differentiation. Fibroblasts were cultured from the lungs of eight controls and eight IPF patients. Oxidants-antioxidants balance, nuclear Nrf2 expression, and fibroblast phenotype a-smooth muscle actin and collagen I expression, proliferation, migration, and contraction were studied under basal conditions and after Nrf2 knockdown or activation by Nrf2 or Keap1 siRNA transfection. The effects of sulforaphane SFN, an Nrf2 activator, on the fibroblast phenotype were tested under basal and pro-fibrosis conditions transforming growth factor b [TGF-b]. RESULTS: Decreased Nrf2 expression was associated with a myofibroblast phenotype in IPF compared with control fibroblasts. Nrf2 knockdown induced oxidative stress and myofibroblastic differentiation in control fibroblasts. Conversely, Nrf2 activation increased antioxidant defences and myofibroblastic dedifferentation in IPF fibroblasts. SFN treatment decreased oxidants, and induced Nrf2 expression, antioxidants, and <d>myofibroblastic dedifferentiation</d> in IPF fibroblasts. SFN inhibited TGF-b profibrotic deleterious effects in IPF and control fibroblasts and restored antioxidant defences. Nrf2 knockdown abolished SFN antifibrosis effects, suggesting that they were Nrf2 mediated. INNOVATION AND CONCLUSION: Our findings confirm that decreased nuclear Nrf2 plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via Nrf2 activation. Thus, Nrf2 could be a novel therapeutic target in IPF.
22703534|a|AIMS: Oxidants have been implicated in the pathophysiology of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, especially in myofibroblastic differentiation. We aimed at testing the hypothesis that nuclear factor erythroid 2-related factor 2 Nrf2, the main regulator of endogenous antioxidant enzymes, is involved in fibrogenesis via myofibroblastic differentiation. Fibroblasts were cultured from the lungs of eight controls and eight <d>IPF</d> patients. Oxidants-antioxidants balance, nuclear Nrf2 expression, and fibroblast phenotype a-smooth muscle actin and collagen I expression, proliferation, migration, and contraction were studied under basal conditions and after Nrf2 knockdown or activation by Nrf2 or Keap1 siRNA transfection. The effects of sulforaphane SFN, an Nrf2 activator, on the fibroblast phenotype were tested under basal and pro-fibrosis conditions transforming growth factor b [TGF-b]. RESULTS: Decreased Nrf2 expression was associated with a myofibroblast phenotype in <d>IPF</d> compared with control fibroblasts. Nrf2 knockdown induced oxidative stress and myofibroblastic differentiation in control fibroblasts. Conversely, Nrf2 activation increased antioxidant defences and myofibroblastic dedifferentation in <d>IPF</d> fibroblasts. SFN treatment decreased oxidants, and induced Nrf2 expression, antioxidants, and <d>myofibroblastic dedifferentiation</d> in <d>IPF</d> fibroblasts. SFN inhibited TGF-b profibrotic deleterious effects in <d>IPF</d> and control fibroblasts and restored antioxidant defences. Nrf2 knockdown abolished SFN antifibrosis effects, suggesting that they were Nrf2 mediated. INNOVATION AND CONCLUSION: Our findings confirm that decreased nuclear Nrf2 plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via Nrf2 activation. Thus, Nrf2 could be a novel therapeutic target in <d>IPF</d>.
22703534|a|AIMS: Oxidants have been implicated in the pathophysiology of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, especially in myofibroblastic differentiation. We aimed at testing the hypothesis that <g>nuclear factor erythroid 2-related factor 2</g> <g>Nrf2</g>, the main regulator of endogenous antioxidant enzymes, is involved in fibrogenesis via myofibroblastic differentiation. Fibroblasts were cultured from the lungs of eight controls and eight <d>IPF</d> patients. Oxidants-antioxidants balance, nuclear <g>Nrf2</g> expression, and fibroblast phenotype a-smooth muscle actin and collagen I expression, proliferation, migration, and contraction were studied under basal conditions and after <g>Nrf2</g> knockdown or activation by <g>Nrf2</g> or <g>Keap1</g> siRNA transfection. The effects of sulforaphane SFN, an <g>Nrf2</g> activator, on the fibroblast phenotype were tested under basal and pro-<d>fibrosis</d> conditions transforming growth factor b [TGF-b]. RESULTS: Decreased <g>Nrf2</g> expression was associated with a myofibroblast phenotype in <d>IPF</d> compared with control fibroblasts. <g>Nrf2</g> knockdown induced oxidative stress and myofibroblastic differentiation in control fibroblasts. Conversely, <g>Nrf2</g> activation increased antioxidant defences and myofibroblastic dedifferentation in <d>IPF</d> fibroblasts. SFN treatment decreased oxidants, and induced <g>Nrf2</g> expression, antioxidants, and <d>myofibroblastic dedifferentiation</d> in <d>IPF</d> fibroblasts. SFN inhibited TGF-b profibrotic deleterious effects in <d>IPF</d> and control fibroblasts and restored antioxidant defences. <g>Nrf2</g> knockdown abolished SFN anti<d>fibrosis</d> effects, suggesting that they were <g>Nrf2</g> mediated. INNOVATION AND CONCLUSION: Our findings confirm that decreased nuclear <g>Nrf2</g> plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via <g>Nrf2</g> activation. Thus, <g>Nrf2</g> could be a novel therapeutic target in <d>IPF</d>.
22771387|a|The disturbance of hemostatic balance, associated with increased <g>tissue factor</g> <g>TF</g> expression and activity, occurs in the lungs of patients with <d>idiopathic pulmonary fibrosis</d> IPF. However, the molecular mechanisms responsible for the regulation of <g>TF</g> expression under profibrotic conditions have not been assessed. We found that transforming growth factor-b1 <g>TGF-b1</g> markedly enhanced <g>TF</g> expression in primary human lung fibroblasts HLFs, whereas platelet-derived growth factor PDGF-BB and IGF insulin-like growth factor-1 showed only a moderate effect, and PDGB-CC exerted no effect. <g>TGF-b1</g>-induced <g>TF</g> expression correlated with its elevated cell-surface activity, it required de novo gene transcription and protein synthesis, and it was dependent on <g>JNK</g> and <g>Akt</g> activity, because pharmacological inhibition or the knockdown of the previously mentioned kinases prevented <g>TF</g> synthesis. Exposure of HLFs to <g>TGF-b1</g> activated <g>JNK</g> in a <g>PI3K</g>-dependent manner and induced <g>Akt</g> phosphorylation at threonine 308 and serine 473, but did not change the phosphorylation status of threonine 450. <g>Akt</g> phosphorylation at serine 473 correlated with <g>JNK</g> activity, and co-immunoprecipitation studies revealed a direct interaction between <g>JNK</g> and <g>Akt</g>. Furthermore, <g>TGF-b1</g>-induced <g>TF</g> expression required the recruitment of c-Fos and JunD into a heterodimeric activator protein <g>AP-1</g> complex. Moreover, strong immunoreactivity for phosphorylated <g>Akt</g> and <g>JNK</g> as well as c-Fos and JunD was observed in fibroblasts and myofibroblasts in IPF lungs. In conclusion, <g>PI3K</g>/<g>JNK</g>/<g>Akt</g> and <g>AP-1</g> synergize to induce <g>TF</g> expression in HLFs after <g>TGF-b1</g> challenge. Our findings provide new insights into the molecular mechanisms responsible for the regulation of <g>TF</g> expression, and open new perspectives on the treatment of pulmonary fibrosis and other diseases characterized by the inappropriate expression of this cell-surface receptor.
22771387|a|The disturbance of hemostatic balance, associated with increased <g>tissue factor</g> <g>TF</g> expression and activity, occurs in the lungs of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. However, the molecular mechanisms responsible for the regulation of <g>TF</g> expression under profibrotic conditions have not been assessed. We found that transforming growth factor-b1 <g>TGF-b1</g> markedly enhanced <g>TF</g> expression in primary human lung fibroblasts HLFs, whereas platelet-derived growth factor PDGF-BB and IGF insulin-like growth factor-1 showed only a moderate effect, and PDGB-CC exerted no effect. <g>TGF-b1</g>-induced <g>TF</g> expression correlated with its elevated cell-surface activity, it required de novo gene transcription and protein synthesis, and it was dependent on <g>JNK</g> and <g>Akt</g> activity, because pharmacological inhibition or the knockdown of the previously mentioned kinases prevented <g>TF</g> synthesis. Exposure of HLFs to <g>TGF-b1</g> activated <g>JNK</g> in a <g>PI3K</g>-dependent manner and induced <g>Akt</g> phosphorylation at threonine 308 and serine 473, but did not change the phosphorylation status of threonine 450. <g>Akt</g> phosphorylation at serine 473 correlated with <g>JNK</g> activity, and co-immunoprecipitation studies revealed a direct interaction between <g>JNK</g> and <g>Akt</g>. Furthermore, <g>TGF-b1</g>-induced <g>TF</g> expression required the recruitment of c-Fos and JunD into a heterodimeric activator protein <g>AP-1</g> complex. Moreover, strong immunoreactivity for phosphorylated <g>Akt</g> and <g>JNK</g> as well as c-Fos and JunD was observed in fibroblasts and myofibroblasts in <d>IPF</d> lungs. In conclusion, <g>PI3K</g>/<g>JNK</g>/<g>Akt</g> and <g>AP-1</g> synergize to induce <g>TF</g> expression in HLFs after <g>TGF-b1</g> challenge. Our findings provide new insights into the molecular mechanisms responsible for the regulation of <g>TF</g> expression, and open new perspectives on the treatment of pulmonary fibrosis and other diseases characterized by the inappropriate expression of this cell-surface receptor.
22771387|a|The disturbance of hemostatic balance, associated with increased <g>tissue factor</g> <g>TF</g> expression and activity, occurs in the lungs of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. However, the molecular mechanisms responsible for the regulation of <g>TF</g> expression under profibrotic conditions have not been assessed. We found that <g>transforming growth factor-b1</g> <g>TGF-b1</g> markedly enhanced <g>TF</g> expression in primary human lung fibroblasts HLFs, whereas platelet-derived growth factor PDGF-BB and IGF <g>insulin-like growth factor-1</g> showed only a moderate effect, and <g>PDGB</g>-CC exerted no effect. <g>TGF-b1</g>-induced <g>TF</g> expression correlated with its elevated cell-surface activity, it required de novo gene transcription and protein synthesis, and it was dependent on <g>JNK</g> and <g>Akt</g> activity, because pharmacological inhibition or the knockdown of the previously mentioned kinases prevented <g>TF</g> synthesis. Exposure of HLFs to <g>TGF-b1</g> activated <g>JNK</g> in a <g>PI3K</g>-dependent manner and induced <g>Akt</g> phosphorylation at threonine 308 and serine 473, but did not change the phosphorylation status of threonine 450. <g>Akt</g> phosphorylation at serine 473 correlated with <g>JNK</g> activity, and co-immunoprecipitation studies revealed a direct interaction between <g>JNK</g> and <g>Akt</g>. Furthermore, <g>TGF-b1</g>-induced <g>TF</g> expression required the recruitment of <g>c-Fos</g> and <g>JunD</g> into a heterodimeric activator protein <g>AP-1</g> complex. Moreover, strong immunoreactivity for phosphorylated <g>Akt</g> and <g>JNK</g> as well as <g>c-Fos</g> and <g>JunD</g> was observed in fibroblasts and myofibroblasts in <d>IPF</d> lungs. In conclusion, <g>PI3K</g>/<g>JNK</g>/<g>Akt</g> and <g>AP-1</g> synergize to induce <g>TF</g> expression in HLFs after <g>TGF-b1</g> challenge. Our findings provide new insights into the molecular mechanisms responsible for the regulation of <g>TF</g> expression, and open new perspectives on the treatment of <d>pulmonary fibrosis and other diseases</d> characterized by the inappropriate expression of this cell-surface receptor.
22802283|a|Transforming growth factor-b <g>TGF-b</g> is extensively involved in the development of <d>fibrosis</d> in different organs. Overproduction or potentiation of its profibrotic effects leads to an aberrant wound healing response during the initiation of fibrotic processes. Idiopathic pulmonary <d>fibrosis</d> IPF is a chronic, devastating disease, in which <g>TGF-b</g>\x{2013}induced disturbances of the homeostatic microenvironment are critical to promote cell activation, migration, invasion, or hyperplastic changes. In addition, excess extracellular matrix production contributes in a major way to disease pathogenesis. For this reason, this review will focus on discussing novel data and highlight growing interest in deepening the understanding of the profibrotic role of <g>TGF-b</g> and its direct or indirect targeting for disease modulation.
22802283|a|<g>Transforming growth factor-b</g> <g>TGF-b</g> is extensively involved in the development of <d>fibrosis</d> in different organs. Overproduction or potentiation of its profibrotic effects leads to an aberrant wound healing response during the initiation of fibrotic processes. Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic, devastating disease, in which <g>TGF-b</g>\x{2013}induced disturbances of the homeostatic microenvironment are critical to promote cell activation, migration, invasion, or hyperplastic changes. In addition, excess extracellular matrix production contributes in a major way to disease pathogenesis. For this reason, this review will focus on discussing novel data and highlight growing interest in deepening the understanding of the profibrotic role of <g>TGF-b</g> and its direct or indirect targeting for disease modulation.
22802287|a|Lung <d>fibrosis</d> can affect the parenchyma and the airways, classically giving rise to idiopathic pulmonary <d>fibrosis</d> IPF in the parenchyma or airway remodeling in asthma and chronic obstructive pulmonary disease. <g>TGF-b</g> activation has been implicated in the <d>fibrosis</d> of both IPF and airway remodeling. However, the mechanisms of <g>TGF-b</g> activation appear to differ depending on the cellular and anatomical compartments, with implications on disease pathogenesis. Although it appears that epithelial cell activation of <g>TGF-b</g> by the avb6 integrin is central in IPF, mesenchymal activation of <g>TGF-b</g> by the avb5 and avb8 integrins appears to predominate in airway remodeling. Interestingly, the mechanism of <g>TGF-b</g> by the integrins avb6 and avb5 is shared, relying on cytoskeletal changes, whereas activation of <g>TGF-b</g> by the avb8 integrin is distinct, relying on proteolytic cleavage of the latency-associated peptide of <g>TGF-b</g> by matrix metalloproteinase 14. This article describes the mechanisms through which epithelial cells activate <g>TGF-b</g> by the avb6 integrin and mesenchymal cells activate <g>TGF-b</g> by the avb5 integrin, and highlights their roles in lung <d>fibrosis</d>.
22802287|a|Lung <d>fibrosis</d> can affect the parenchyma and the airways, classically giving rise to idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> in the parenchyma or airway remodeling in asthma and chronic obstructive pulmonary disease. <g>TGF-b</g> activation has been implicated in the <d>fibrosis</d> of both <d>IPF</d> and airway remodeling. However, the mechanisms of <g>TGF-b</g> activation appear to differ depending on the cellular and anatomical compartments, with implications on disease pathogenesis. Although it appears that epithelial cell activation of <g>TGF-b</g> by the avb6 integrin is central in <d>IPF</d>, mesenchymal activation of <g>TGF-b</g> by the avb5 and avb8 integrins appears to predominate in airway remodeling. Interestingly, the mechanism of <g>TGF-b</g> by the integrins avb6 and avb5 is shared, relying on cytoskeletal changes, whereas activation of <g>TGF-b</g> by the avb8 integrin is distinct, relying on proteolytic cleavage of the latency-associated peptide of <g>TGF-b</g> by matrix metalloproteinase 14. This article describes the mechanisms through which epithelial cells activate <g>TGF-b</g> by the avb6 integrin and mesenchymal cells activate <g>TGF-b</g> by the avb5 integrin, and highlights their roles in lung <d>fibrosis</d>.
22802287|a|Lung <d>fibrosis</d> can affect the parenchyma and the airways, classically giving rise to idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> in the parenchyma or airway remodeling in <d>asthma</d> and chronic obstructive pulmonary disease. <g>TGF-b</g> activation has been implicated in the <d>fibrosis</d> of both <d>IPF</d> and airway remodeling. However, the mechanisms of <g>TGF-b</g> activation appear to differ depending on the cellular and anatomical compartments, with implications on disease pathogenesis. Although it appears that epithelial cell activation of <g>TGF-b</g> by the avb6 integrin is central in <d>IPF</d>, mesenchymal activation of <g>TGF-b</g> by the avb5 and avb8 integrins appears to predominate in airway remodeling. Interestingly, the mechanism of <g>TGF-b</g> by the integrins avb6 and avb5 is shared, relying on cytoskeletal changes, whereas activation of <g>TGF-b</g> by the avb8 integrin is distinct, relying on proteolytic cleavage of the latency-associated peptide of <g>TGF-b</g> by matrix metalloproteinase 14. This article describes the mechanisms through which epithelial cells activate <g>TGF-b</g> by the avb6 integrin and mesenchymal cells activate <g>TGF-b</g> by the avb5 integrin, and highlights their roles in lung <d>fibrosis</d>.
22802287|a|Lung <d>fibrosis</d> can affect the parenchyma and the airways, classically giving rise to idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> in the parenchyma or airway remodeling in <d>asthma</d> and <d>chronic obstructive pulmonary disease</d>. <g>TGF-b</g> activation has been implicated in the <d>fibrosis</d> of both <d>IPF</d> and airway remodeling. However, the mechanisms of <g>TGF-b</g> activation appear to differ depending on the cellular and anatomical compartments, with implications on disease pathogenesis. Although it appears that epithelial cell activation of <g>TGF-b</g> by the avb6 integrin is central in <d>IPF</d>, mesenchymal activation of <g>TGF-b</g> by the avb5 and avb8 integrins appears to predominate in airway remodeling. Interestingly, the mechanism of <g>TGF-b</g> by the integrins avb6 and avb5 is shared, relying on cytoskeletal changes, whereas activation of <g>TGF-b</g> by the avb8 integrin is distinct, relying on proteolytic cleavage of the latency-associated peptide of <g>TGF-b</g> by matrix metalloproteinase 14. This article describes the mechanisms through which epithelial cells activate <g>TGF-b</g> by the avb6 integrin and mesenchymal cells activate <g>TGF-b</g> by the avb5 integrin, and highlights their roles in lung <d>fibrosis</d>.
22802290|a|The fibrotic process that characterizes idiopathic pulmonary fibrosis IPF is commonly considered the result of a recurrent injury to the alveolar epithelium followed by an uncontrolled proliferation of fibroblasts. However, based on considerable scientific evidence, it has been recently hypothesized that IPF might be considered a neoproliferative disorder of the lung because this disease exhibits several pathogenic features similar to <d>cancer</d>. Indeed, epigenetic and genetic abnormalities, altered cell-to-cell communications, uncontrolled proliferation, and abnormal activation of specific signal transduction pathways are biological hallmarks that characterize the pathogenesis of IPF and <d>cancer</d>. IPF remains a disease marked by a survival of 3 years, and little therapeutic progress has been made in the last few years, underlining the urgent need to improve research and to change our approach to the comprehension of this disease. The concept of IPF as a <d>cancer</d>-like disease may be helpful in identifying new pathogenic mechanisms that can be borrowed from <d>cancer</d> biology, potentially leading to different and more effective therapeutic approaches. Such vision will hopefully increase the awareness of this disease among the public and the scientific community.
22802290|a|The fibrotic process that characterizes <d>idiopathic pulmonary fibrosis</d> IPF is commonly considered the result of a recurrent injury to the alveolar epithelium followed by an uncontrolled proliferation of fibroblasts. However, based on considerable scientific evidence, it has been recently hypothesized that IPF might be considered a neoproliferative disorder of the lung because this disease exhibits several pathogenic features similar to <d>cancer</d>. Indeed, epigenetic and genetic abnormalities, altered cell-to-cell communications, uncontrolled proliferation, and abnormal activation of specific signal transduction pathways are biological hallmarks that characterize the pathogenesis of IPF and <d>cancer</d>. IPF remains a disease marked by a survival of 3 years, and little therapeutic progress has been made in the last few years, underlining the urgent need to improve research and to change our approach to the comprehension of this disease. The concept of IPF as a <d>cancer</d>-like disease may be helpful in identifying new pathogenic mechanisms that can be borrowed from <d>cancer</d> biology, potentially leading to different and more effective therapeutic approaches. Such vision will hopefully increase the awareness of this disease among the public and the scientific community.
22802290|a|The fibrotic process that characterizes <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> is commonly considered the result of a recurrent injury to the alveolar epithelium followed by an uncontrolled proliferation of fibroblasts. However, based on considerable scientific evidence, it has been recently hypothesized that <d>IPF</d> might be considered a neoproliferative disorder of the lung because this disease exhibits several pathogenic features similar to <d>cancer</d>. Indeed, epigenetic and genetic abnormalities, altered cell-to-cell communications, uncontrolled proliferation, and abnormal activation of specific signal transduction pathways are biological hallmarks that characterize the pathogenesis of <d>IPF</d> and <d>cancer</d>. <d>IPF</d> remains a disease marked by a survival of 3 years, and little therapeutic progress has been made in the last few years, underlining the urgent need to improve research and to change our approach to the comprehension of this disease. The concept of <d>IPF</d> as a <d>cancer</d>-like disease may be helpful in identifying new pathogenic mechanisms that can be borrowed from <d>cancer</d> biology, potentially leading to different and more effective therapeutic approaches. Such vision will hopefully increase the awareness of this disease among the public and the scientific community.
22802290|a|The fibrotic process that characterizes <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> is commonly considered the result of a recurrent <d>injury to the alveolar epithelium</d> followed by an uncontrolled proliferation of fibroblasts. However, based on considerable scientific evidence, it has been recently hypothesized that <d>IPF</d> might be considered a neoproliferative disorder of the lung because this disease exhibits several pathogenic features similar to <d>cancer</d>. Indeed, epigenetic and genetic abnormalities, altered cell-to-cell communications, uncontrolled proliferation, and abnormal activation of specific signal transduction pathways are biological hallmarks that characterize the pathogenesis of <d>IPF</d> and <d>cancer</d>. <d>IPF</d> remains a disease marked by a survival of 3 years, and little therapeutic progress has been made in the last few years, underlining the urgent need to improve research and to change our approach to the comprehension of this disease. The concept of <d>IPF</d> as a <d>cancer</d>-like disease may be helpful in identifying new pathogenic mechanisms that can be borrowed from <d>cancer</d> biology, potentially leading to different and more effective therapeutic approaches. Such vision will hopefully increase the awareness of this disease among the public and the scientific community.
22802290|a|The fibrotic process that characterizes <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> is commonly considered the result of a recurrent <d>injury to the alveolar epithelium</d> followed by an uncontrolled proliferation of fibroblasts. However, based on considerable scientific evidence, it has been recently hypothesized that <d>IPF</d> might be considered a neoproliferative disorder of the lung because this disease exhibits several pathogenic features similar to <d>cancer</d>. Indeed, epigenetic and <d>genetic abnormalities</d>, altered cell-to-cell communications, uncontrolled proliferation, and abnormal activation of specific signal transduction pathways are biological hallmarks that characterize the pathogenesis of <d>IPF</d> and <d>cancer</d>. <d>IPF</d> remains a disease marked by a survival of 3 years, and little therapeutic progress has been made in the last few years, underlining the urgent need to improve research and to change our approach to the comprehension of this disease. The concept of <d>IPF</d> as a <d>cancer</d>-like disease may be helpful in identifying new pathogenic mechanisms that can be borrowed from <d>cancer</d> biology, potentially leading to different and more effective therapeutic approaches. Such vision will hopefully increase the awareness of this disease among the public and the scientific community.
22815997|a|BACKGROUND: Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in <d>idiopathic pulmonary fibrosis</d>. METHODS: Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-b1 on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. RESULTS: Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-b1 inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-b1. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of   -smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of   -smooth muscle actin and fibronectin. CONCLUSION: Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-b1 may represent a mechanism for the promotion of fibrogenesis in IPF.
22815997|a|BACKGROUND: Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including <d>cancer</d> and chronic obstructive lung disease. This study investigates the role of autophagy in <d>idiopathic pulmonary fibrosis</d>. METHODS: Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-b1 on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. RESULTS: Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-b1 inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-b1. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of   -smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of   -smooth muscle actin and fibronectin. CONCLUSION: Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-b1 may represent a mechanism for the promotion of fibrogenesis in IPF.
22815997|a|BACKGROUND: Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including <d>cancer</d> and <d>chronic obstructive lung disease</d>. This study investigates the role of autophagy in <d>idiopathic pulmonary fibrosis</d>. METHODS: Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-b1 on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. RESULTS: Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-b1 inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-b1. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of   -smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of   -smooth muscle actin and fibronectin. CONCLUSION: Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-b1 may represent a mechanism for the promotion of fibrogenesis in IPF.
22815997|a|BACKGROUND: Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including <d>cancer</d> and <d>chronic obstructive lung disease</d>. This study investigates the role of autophagy in <d>idiopathic pulmonary fibrosis</d>. METHODS: Human lung tissues from patients with <d>IPF</d> were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-b1 on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. RESULTS: Lung tissues from <d>IPF</d> patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-b1 inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-b1. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of   -smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of   -smooth muscle actin and fibronectin. CONCLUSION: Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-b1 may represent a mechanism for the promotion of fibrogenesis in <d>IPF</d>.
22815997|a|BACKGROUND: Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including <d>cancer</d> and <d>chronic obstructive lung disease</d>. This study investigates the role of autophagy in <d>idiopathic pulmonary <d>fibrosis</d></d>. METHODS: Human lung tissues from patients with <d>IPF</d> were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of <g>TGF-b1</g> on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced <d>fibrosis</d> mouse model. RESULTS: Lung tissues from <d>IPF</d> patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. <g>TGF-b1</g> inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to <g>TGF-b1</g>. In the bleomycin model of pulmonary <d>fibrosis</d>, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of   -smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of   -smooth muscle actin and fibronectin. CONCLUSION: Autophagy is not induced in pulmonary <d>fibrosis</d> despite activation of pathways known to promote autophagy. Impairment of autophagy by <g>TGF-b1</g> may represent a mechanism for the promotion of fibrogenesis in <d>IPF</d>.
22854509|a|PURPOSE OF REVIEW: Pathogenesis of <d>interstitial lung disease</d>s ILD has largely been investigated in the context of the most frequent ILD, idiopathic pulmonary fibrosis IPF. We review studies of epithelial-to-mesenchymal transition EMT and discuss its potential contribution to collagen-producing myofibroblasts in IPF. RECENT FINDINGS: Endoplasmic reticulum ER stress leading to epithelial apoptosis has been reported as a potential etiologic factor in fibrosis. Recent studies further suggest EMT as a link between ER stress and fibrosis. Combinatorial interactions among Smad3, b-catenin and other transcriptional co-activators at the a-smooth muscle actin a-SMA promoter provide direct evidence for crosstalk between transforming growth factor-b TGFb and b-catenin pathways during EMT. Lineage tracing yielded conflicting results, with two recent studies supporting and one opposing a role for EMT in lung fibrosis. SUMMARY: Advances have been made in elucidating causes and mechanisms of EMT, potentially leading to new treatment options, although contributions of EMT to lung fibrosis in vivo remain controversial. In addition to EMT providing a direct source of myofibroblasts, expression of mesenchymal markers may reflect epithelial injury, in which case inhibition of EMT might be deleterious. EMT-derived cells may also contribute to aberrant epithelial-mesenchymal crosstalk that promotes fibrogenesis.
22854509|a|PURPOSE OF REVIEW: Pathogenesis of <d>interstitial lung disease</d>s <d>ILD</d> has largely been investigated in the context of the most frequent <d>ILD</d>, idiopathic pulmonary fibrosis IPF. We review studies of epithelial-to-mesenchymal transition EMT and discuss its potential contribution to collagen-producing myofibroblasts in IPF. RECENT FINDINGS: Endoplasmic reticulum ER stress leading to epithelial apoptosis has been reported as a potential etiologic factor in fibrosis. Recent studies further suggest EMT as a link between ER stress and fibrosis. Combinatorial interactions among Smad3, b-catenin and other transcriptional co-activators at the a-smooth muscle actin a-SMA promoter provide direct evidence for crosstalk between transforming growth factor-b TGFb and b-catenin pathways during EMT. Lineage tracing yielded conflicting results, with two recent studies supporting and one opposing a role for EMT in lung fibrosis. SUMMARY: Advances have been made in elucidating causes and mechanisms of EMT, potentially leading to new treatment options, although contributions of EMT to lung fibrosis in vivo remain controversial. In addition to EMT providing a direct source of myofibroblasts, expression of mesenchymal markers may reflect epithelial injury, in which case inhibition of EMT might be deleterious. EMT-derived cells may also contribute to aberrant epithelial-mesenchymal crosstalk that promotes fibrogenesis.
22854509|a|PURPOSE OF REVIEW: Pathogenesis of <d>interstitial lung disease</d>s <d>ILD</d> has largely been investigated in the context of the most frequent <d>ILD</d>, <d>idiopathic pulmonary fibrosis</d> IPF. We review studies of epithelial-to-mesenchymal transition EMT and discuss its potential contribution to collagen-producing myofibroblasts in IPF. RECENT FINDINGS: Endoplasmic reticulum ER stress leading to epithelial apoptosis has been reported as a potential etiologic factor in fibrosis. Recent studies further suggest EMT as a link between ER stress and fibrosis. Combinatorial interactions among Smad3, b-catenin and other transcriptional co-activators at the a-smooth muscle actin a-SMA promoter provide direct evidence for crosstalk between transforming growth factor-b TGFb and b-catenin pathways during EMT. Lineage tracing yielded conflicting results, with two recent studies supporting and one opposing a role for EMT in lung fibrosis. SUMMARY: Advances have been made in elucidating causes and mechanisms of EMT, potentially leading to new treatment options, although contributions of EMT to lung fibrosis in vivo remain controversial. In addition to EMT providing a direct source of myofibroblasts, expression of mesenchymal markers may reflect epithelial injury, in which case inhibition of EMT might be deleterious. EMT-derived cells may also contribute to aberrant epithelial-mesenchymal crosstalk that promotes fibrogenesis.
22854509|a|PURPOSE OF REVIEW: Pathogenesis of <d>interstitial lung disease</d>s <d>ILD</d> has largely been investigated in the context of the most frequent <d>ILD</d>, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. We review studies of epithelial-to-mesenchymal transition EMT and discuss its potential contribution to collagen-producing myofibroblasts in <d>IPF</d>. RECENT FINDINGS: Endoplasmic reticulum ER stress leading to epithelial apoptosis has been reported as a potential etiologic factor in fibrosis. Recent studies further suggest EMT as a link between ER stress and fibrosis. Combinatorial interactions among Smad3, b-catenin and other transcriptional co-activators at the a-smooth muscle actin a-SMA promoter provide direct evidence for crosstalk between transforming growth factor-b TGFb and b-catenin pathways during EMT. Lineage tracing yielded conflicting results, with two recent studies supporting and one opposing a role for EMT in lung fibrosis. SUMMARY: Advances have been made in elucidating causes and mechanisms of EMT, potentially leading to new treatment options, although contributions of EMT to lung fibrosis in vivo remain controversial. In addition to EMT providing a direct source of myofibroblasts, expression of mesenchymal markers may reflect epithelial injury, in which case inhibition of EMT might be deleterious. EMT-derived cells may also contribute to aberrant epithelial-mesenchymal crosstalk that promotes fibrogenesis.
22854509|a|PURPOSE OF REVIEW: Pathogenesis of <d>interstitial lung disease</d>s <d>ILD</d> has largely been investigated in the context of the most frequent <d>ILD</d>, <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. We review studies of epithelial-to-mesenchymal transition EMT and discuss its potential contribution to collagen-producing myofibroblasts in <d>IPF</d>. RECENT FINDINGS: Endoplasmic reticulum ER stress leading to epithelial apoptosis has been reported as a potential etiologic factor in <d>fibrosis</d>. Recent studies further suggest EMT as a link between ER stress and <d>fibrosis</d>. Combinatorial interactions among Smad3, b-catenin and other transcriptional co-activators at the a-smooth muscle actin a-SMA promoter provide direct evidence for crosstalk between transforming growth factor-b TGFb and b-catenin pathways during EMT. Lineage tracing yielded conflicting results, with two recent studies supporting and one opposing a role for EMT in lung <d>fibrosis</d>. SUMMARY: Advances have been made in elucidating causes and mechanisms of EMT, potentially leading to new treatment options, although contributions of EMT to lung <d>fibrosis</d> in vivo remain controversial. In addition to EMT providing a direct source of myofibroblasts, expression of mesenchymal markers may reflect epithelial injury, in which case inhibition of EMT might be deleterious. EMT-derived cells may also contribute to aberrant epithelial-mesenchymal crosstalk that promotes fibrogenesis.
22892132|a|<d>Idiopathic pulmonary fibrosis</d> IPF involves pulmonary injury associated with inflammatory responses, fibrosis and dysfunction. Myofibroblasts and transforming growth factor TGF-b1 play major roles in the pathogenesis of this disease. Endoplasmic reticulum ER stress response is induced in the lungs of IPF patients. One of ER chaperones, the <g>150-kDa oxygen-regulated protein</g> <g>ORP150</g>, is essential for the maintenance of cellular viability under stress conditions. In this study, we used heterozygous <g>ORP150</g>-deficient mice <g>ORP150</g>+/- mice to examine the role of <g>ORP150</g> in bleomycin-induced pulmonary fibrosis. Treatment of mice with bleomycin induced the expression of <g>ORP150</g> in the lung. Bleomycin-induced inflammatory responses were slightly exacerbated in <g>ORP150</g>+/- mice compared to wild-type mice. On the other hand, bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction was clearly ameliorated in the <g>ORP150</g>+/- mice. Bleomycin-induced increases in pulmonary levels of both active TGF-b1 and myofibroblasts were suppressed in <g>ORP150</g>+/- mice. These results suggest that although <g>ORP150</g> is protective against bleomycin-induced lung injury, this protein could stimulate bleomycin-induced pulmonary fibrosis by increasing pulmonary levels of TGF-b1 and myofibroblasts.
22892132|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> involves pulmonary injury associated with inflammatory responses, fibrosis and dysfunction. Myofibroblasts and transforming growth factor TGF-b1 play major roles in the pathogenesis of this disease. Endoplasmic reticulum ER stress response is induced in the lungs of <d>IPF</d> patients. One of ER chaperones, the <g>150-kDa oxygen-regulated protein</g> <g>ORP150</g>, is essential for the maintenance of cellular viability under stress conditions. In this study, we used heterozygous <g>ORP150</g>-deficient mice <g>ORP150</g>+/- mice to examine the role of <g>ORP150</g> in bleomycin-induced pulmonary fibrosis. Treatment of mice with bleomycin induced the expression of <g>ORP150</g> in the lung. Bleomycin-induced inflammatory responses were slightly exacerbated in <g>ORP150</g>+/- mice compared to wild-type mice. On the other hand, bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction was clearly ameliorated in the <g>ORP150</g>+/- mice. Bleomycin-induced increases in pulmonary levels of both active TGF-b1 and myofibroblasts were suppressed in <g>ORP150</g>+/- mice. These results suggest that although <g>ORP150</g> is protective against bleomycin-induced lung injury, this protein could stimulate bleomycin-induced pulmonary fibrosis by increasing pulmonary levels of TGF-b1 and myofibroblasts.
22892132|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> involves <d>pulmonary injury</d> associated with inflammatory responses, fibrosis and dysfunction. Myofibroblasts and transforming growth factor TGF-b1 play major roles in the pathogenesis of this disease. Endoplasmic reticulum ER stress response is induced in the lungs of <d>IPF</d> patients. One of ER chaperones, the <g>150-kDa oxygen-regulated protein</g> <g>ORP150</g>, is essential for the maintenance of cellular viability under stress conditions. In this study, we used heterozygous <g>ORP150</g>-deficient mice <g>ORP150</g>+/- mice to examine the role of <g>ORP150</g> in bleomycin-induced pulmonary fibrosis. Treatment of mice with bleomycin induced the expression of <g>ORP150</g> in the lung. Bleomycin-induced inflammatory responses were slightly exacerbated in <g>ORP150</g>+/- mice compared to wild-type mice. On the other hand, bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction was clearly ameliorated in the <g>ORP150</g>+/- mice. Bleomycin-induced increases in pulmonary levels of both active TGF-b1 and myofibroblasts were suppressed in <g>ORP150</g>+/- mice. These results suggest that although <g>ORP150</g> is protective against bleomycin-induced lung injury, this protein could stimulate bleomycin-induced pulmonary fibrosis by increasing pulmonary levels of TGF-b1 and myofibroblasts.
22892132|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> involves <d>pulmonary injury</d> associated with <d>inflammatory responses</d>, fibrosis and dysfunction. Myofibroblasts and transforming growth factor TGF-b1 play major roles in the pathogenesis of this disease. Endoplasmic reticulum ER stress response is induced in the lungs of <d>IPF</d> patients. One of ER chaperones, the <g>150-kDa oxygen-regulated protein</g> <g>ORP150</g>, is essential for the maintenance of cellular viability under stress conditions. In this study, we used heterozygous <g>ORP150</g>-deficient mice <g>ORP150</g>+/- mice to examine the role of <g>ORP150</g> in bleomycin-induced pulmonary fibrosis. Treatment of mice with bleomycin induced the expression of <g>ORP150</g> in the lung. Bleomycin-induced <d>inflammatory responses</d> were slightly exacerbated in <g>ORP150</g>+/- mice compared to wild-type mice. On the other hand, bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction was clearly ameliorated in the <g>ORP150</g>+/- mice. Bleomycin-induced increases in pulmonary levels of both active TGF-b1 and myofibroblasts were suppressed in <g>ORP150</g>+/- mice. These results suggest that although <g>ORP150</g> is protective against bleomycin-induced lung injury, this protein could stimulate bleomycin-induced pulmonary fibrosis by increasing pulmonary levels of TGF-b1 and myofibroblasts.
22892132|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> involves <d>pulmonary injury</d> associated with <d>inflammatory responses</d>, <d>fibrosis</d> and dysfunction. Myofibroblasts and transforming growth factor TGF-b1 play major roles in the pathogenesis of this disease. Endoplasmic reticulum ER stress response is induced in the lungs of <d>IPF</d> patients. One of ER chaperones, the <g>150-kDa oxygen-regulated protein</g> <g>ORP150</g>, is essential for the maintenance of cellular viability under stress conditions. In this study, we used heterozygous <g>ORP150</g>-deficient mice <g>ORP150</g>+/- mice to examine the role of <g>ORP150</g> in bleomycin-induced pulmonary <d>fibrosis</d>. Treatment of mice with bleomycin induced the expression of <g>ORP150</g> in the lung. Bleomycin-induced <d>inflammatory responses</d> were slightly exacerbated in <g>ORP150</g>+/- mice compared to wild-type mice. On the other hand, bleomycin-induced pulmonary <d>fibrosis</d>, alteration of lung mechanics and respiratory dysfunction was clearly ameliorated in the <g>ORP150</g>+/- mice. Bleomycin-induced increases in pulmonary levels of both active TGF-b1 and myofibroblasts were suppressed in <g>ORP150</g>+/- mice. These results suggest that although <g>ORP150</g> is protective against bleomycin-induced lung injury, this protein could stimulate bleomycin-induced pulmonary <d>fibrosis</d> by increasing pulmonary levels of TGF-b1 and myofibroblasts.
22892132|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> involves <d>pulmonary injury</d> associated with <d>inflammatory responses</d>, <d>fibrosis</d> and dysfunction. Myofibroblasts and transforming growth factor TGF-b1 play major roles in the pathogenesis of this disease. Endoplasmic reticulum ER stress response is induced in the lungs of <d>IPF</d> patients. One of ER chaperones, the <g>150-kDa oxygen-regulated protein</g> <g>ORP150</g>, is essential for the maintenance of cellular viability under stress conditions. In this study, we used heterozygous <g>ORP150</g>-deficient mice <g>ORP150</g>+/- mice to examine the role of <g>ORP150</g> in bleomycin-induced pulmonary <d>fibrosis</d>. Treatment of mice with bleomycin induced the expression of <g>ORP150</g> in the lung. Bleomycin-induced <d>inflammatory responses</d> were slightly exacerbated in <g>ORP150</g>+/- mice compared to wild-type mice. On the other hand, bleomycin-induced pulmonary <d>fibrosis</d>, alteration of lung mechanics and <d>respiratory dysfunction</d> was clearly ameliorated in the <g>ORP150</g>+/- mice. Bleomycin-induced increases in pulmonary levels of both active TGF-b1 and myofibroblasts were suppressed in <g>ORP150</g>+/- mice. These results suggest that although <g>ORP150</g> is protective against bleomycin-induced lung injury, this protein could stimulate bleomycin-induced pulmonary <d>fibrosis</d> by increasing pulmonary levels of TGF-b1 and myofibroblasts.
22892132|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> involves <d>pulmonary injury</d> associated with <d>inflammatory responses</d>, <d>fibrosis</d> and dysfunction. Myofibroblasts and transforming growth factor <g>TGF-b1</g> play major roles in the pathogenesis of this disease. Endoplasmic reticulum ER stress response is induced in the lungs of <d>IPF</d> patients. One of ER chaperones, the <g>150-kDa oxygen-regulated protein</g> <g>ORP150</g>, is essential for the maintenance of cellular viability under stress conditions. In this study, we used heterozygous <g>ORP150</g>-deficient mice <g>ORP150</g>+/- mice to examine the role of <g>ORP150</g> in bleomycin-induced pulmonary <d>fibrosis</d>. Treatment of mice with bleomycin induced the expression of <g>ORP150</g> in the lung. Bleomycin-induced <d>inflammatory responses</d> were slightly exacerbated in <g>ORP150</g>+/- mice compared to wild-type mice. On the other hand, bleomycin-induced pulmonary <d>fibrosis</d>, alteration of lung mechanics and <d>respiratory dysfunction</d> was clearly ameliorated in the <g>ORP150</g>+/- mice. Bleomycin-induced increases in pulmonary levels of both active <g>TGF-b1</g> and myofibroblasts were suppressed in <g>ORP150</g>+/- mice. These results suggest that although <g>ORP150</g> is protective against bleomycin-induced <d>lung injury</d>, this protein could stimulate bleomycin-induced pulmonary <d>fibrosis</d> by increasing pulmonary levels of <g>TGF-b1</g> and myofibroblasts.
22900087|a|Extracellular matrix deposition and tissue scarring characterize the process of <d>fibrosis</d>. Transforming growth factor beta TGFb and Insulin-like growth factor binding protein-3 IGFBP-3 have been implicated in the pathogenesis of <d>fibrosis</d> in various tissues by inducing mesenchymal cell proliferation and extracellular matrix deposition. We identified <g>Syndecan-2</g> SDC2 as a gene induced by TGFb in an IGFBP-3-dependent manner. TGFb induction of SDC2 mRNA and protein required IGFBP-3. IGFBP-3 independently induced production of SDC2 in primary fibroblasts. Using an ex-vivo model of human skin in organ culture expressing IGFBP-3, we demonstrate that IGFBP-3 induces SDC2 ex vivo in human tissue. We also identified Mitogen-activated protein kinase-interacting kinase Mknk2 as a gene induced by IGFBP-3. IGFBP-3 triggered Mknk2 phosphorylation resulting in its activation. Mknk2 independently induced SDC2 in human skin. Since IGFBP-3 is over-expressed in fibrotic tissues, we examined SDC2 levels in skin and lung tissues of patients with systemic sclerosis SSc and lung tissues of patients with idiopathic pulmonary <d>fibrosis</d> IPF. SDC2 levels were increased in fibrotic dermal and lung tissues of patients with SSc and in lung tissues of patients with IPF. This is the first report describing elevated levels of SDC2 in <d>fibrosis</d>. Increased SDC2 expression is due, at least in part, to the activity of two pro-fibrotic factors, TGFb and IGFBP-3.
22900087|a|Extracellular matrix deposition and tissue scarring characterize the process of <d>fibrosis</d>. <g>Transforming growth factor beta</g> <g>TGFb</g> and <g>Insulin-like growth factor binding protein-3</g> <g>IGFBP-3</g> have been implicated in the pathogenesis of <d>fibrosis</d> in various tissues by inducing mesenchymal cell proliferation and extracellular matrix deposition. We identified <g>Syndecan-2</g> <g>SDC2</g> as a gene induced by <g>TGFb</g> in an <g>IGFBP-3</g>-dependent manner. <g>TGFb</g> induction of <g>SDC2</g> mRNA and protein required <g>IGFBP-3</g>. <g>IGFBP-3</g> independently induced production of <g>SDC2</g> in primary fibroblasts. Using an ex-vivo model of human skin in organ culture expressing <g>IGFBP-3</g>, we demonstrate that <g>IGFBP-3</g> induces <g>SDC2</g> ex vivo in human tissue. We also identified Mitogen-activated protein kinase-interacting kinase <g>Mknk2</g> as a gene induced by <g>IGFBP-3</g>. <g>IGFBP-3</g> triggered <g>Mknk2</g> phosphorylation resulting in its activation. <g>Mknk2</g> independently induced <g>SDC2</g> in human skin. Since <g>IGFBP-3</g> is over-expressed in fibrotic tissues, we examined <g>SDC2</g> levels in skin and lung tissues of patients with <d>systemic sclerosis</d> SSc and lung tissues of patients with idiopathic pulmonary <d>fibrosis</d> IPF. <g>SDC2</g> levels were increased in fibrotic dermal and lung tissues of patients with SSc and in lung tissues of patients with IPF. This is the first report describing elevated levels of <g>SDC2</g> in <d>fibrosis</d>. Increased <g>SDC2</g> expression is due, at least in part, to the activity of two pro-fibrotic factors, <g>TGFb</g> and <g>IGFBP-3</g>.
22900087|a|Extracellular matrix deposition and tissue scarring characterize the process of <d>fibrosis</d>. <g>Transforming growth factor beta</g> <g>TGFb</g> and <g>Insulin-like growth factor binding protein-3</g> <g>IGFBP-3</g> have been implicated in the pathogenesis of <d>fibrosis</d> in various tissues by inducing mesenchymal cell proliferation and extracellular matrix deposition. We identified <g>Syndecan-2</g> <g>SDC2</g> as a gene induced by <g>TGFb</g> in an <g>IGFBP-3</g>-dependent manner. <g>TGFb</g> induction of <g>SDC2</g> mRNA and protein required <g>IGFBP-3</g>. <g>IGFBP-3</g> independently induced production of <g>SDC2</g> in primary fibroblasts. Using an ex-vivo model of human skin in organ culture expressing <g>IGFBP-3</g>, we demonstrate that <g>IGFBP-3</g> induces <g>SDC2</g> ex vivo in human tissue. We also identified Mitogen-activated protein kinase-interacting kinase <g>Mknk2</g> as a gene induced by <g>IGFBP-3</g>. <g>IGFBP-3</g> triggered <g>Mknk2</g> phosphorylation resulting in its activation. <g>Mknk2</g> independently induced <g>SDC2</g> in human skin. Since <g>IGFBP-3</g> is over-expressed in fibrotic tissues, we examined <g>SDC2</g> levels in skin and lung tissues of patients with <d>systemic sclerosis</d> <d>SSc</d> and lung tissues of patients with idiopathic pulmonary <d>fibrosis</d> IPF. <g>SDC2</g> levels were increased in fibrotic dermal and lung tissues of patients with <d>SSc</d> and in lung tissues of patients with IPF. This is the first report describing elevated levels of <g>SDC2</g> in <d>fibrosis</d>. Increased <g>SDC2</g> expression is due, at least in part, to the activity of two pro-fibrotic factors, <g>TGFb</g> and <g>IGFBP-3</g>.
22900087|a|Extracellular matrix deposition and tissue scarring characterize the process of <d>fibrosis</d>. <g>Transforming growth factor beta</g> <g>TGFb</g> and <g>Insulin-like growth factor binding protein-3</g> <g>IGFBP-3</g> have been implicated in the pathogenesis of <d>fibrosis</d> in various tissues by inducing mesenchymal cell proliferation and extracellular matrix deposition. We identified <g>Syndecan-2</g> <g>SDC2</g> as a gene induced by <g>TGFb</g> in an <g>IGFBP-3</g>-dependent manner. <g>TGFb</g> induction of <g>SDC2</g> mRNA and protein required <g>IGFBP-3</g>. <g>IGFBP-3</g> independently induced production of <g>SDC2</g> in primary fibroblasts. Using an ex-vivo model of human skin in organ culture expressing <g>IGFBP-3</g>, we demonstrate that <g>IGFBP-3</g> induces <g>SDC2</g> ex vivo in human tissue. We also identified Mitogen-activated protein kinase-interacting kinase <g>Mknk2</g> as a gene induced by <g>IGFBP-3</g>. <g>IGFBP-3</g> triggered <g>Mknk2</g> phosphorylation resulting in its activation. <g>Mknk2</g> independently induced <g>SDC2</g> in human skin. Since <g>IGFBP-3</g> is over-expressed in fibrotic tissues, we examined <g>SDC2</g> levels in skin and lung tissues of patients with <d>systemic sclerosis</d> <d>SSc</d> and lung tissues of patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. <g>SDC2</g> levels were increased in fibrotic dermal and lung tissues of patients with <d>SSc</d> and in lung tissues of patients with <d>IPF</d>. This is the first report describing elevated levels of <g>SDC2</g> in <d>fibrosis</d>. Increased <g>SDC2</g> expression is due, at least in part, to the activity of two pro-fibrotic factors, <g>TGFb</g> and <g>IGFBP-3</g>.
22923663|a|RATIONALE: <d>Idiopathic pulmonary fibrosis</d> IPF is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. OBJECTIVES: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. METHODS: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 LDH5 overexpression on myofibroblast differentiation and transforming growth factor TGF-b activation in vitro. MEASUREMENTS AND MAIN RESULTS: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; a-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a HIF1a. Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b-induced myofibroblast differentiation. CONCLUSIONS: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-b. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.
22923663|a|RATIONALE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with <d>IPF</d>. OBJECTIVES: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. METHODS: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with <d>IPF</d> and determined the effects of lactic acid and lactate dehydrogenase-5 LDH5 overexpression on myofibroblast differentiation and transforming growth factor TGF-b activation in vitro. MEASUREMENTS AND MAIN RESULTS: Lactic acid concentrations from healthy and <d>IPF</d> lung tissue were determined by nuclear magnetic resonance spectroscopy; a-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in <d>IPF</d> lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a HIF1a. Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b-induced myofibroblast differentiation. CONCLUSIONS: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-b. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.
22923663|a|RATIONALE: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with <d>IPF</d>. OBJECTIVES: This study examines the effect of lactic acid on myofibroblast differentiation and <d>pulmonary fibrosis</d>. METHODS: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with <d>IPF</d> and determined the effects of lactic acid and lactate dehydrogenase-5 LDH5 overexpression on myofibroblast differentiation and transforming growth factor TGF-b activation in vitro. MEASUREMENTS AND MAIN RESULTS: Lactic acid concentrations from healthy and <d>IPF</d> lung tissue were determined by nuclear magnetic resonance spectroscopy; a-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in <d>IPF</d> lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a HIF1a. Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b-induced myofibroblast differentiation. CONCLUSIONS: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-b. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.
22923663|a|RATIONALE: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with <d>IPF</d>. OBJECTIVES: This study examines the effect of lactic acid on myofibroblast differentiation and <d>pulmonary fibrosis</d>. METHODS: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with <d>IPF</d> and determined the effects of lactic acid and lactate dehydrogenase-5 LDH5 overexpression on myofibroblast differentiation and transforming growth factor <g>TGF-b</g> activation in vitro. MEASUREMENTS AND MAIN RESULTS: Lactic acid concentrations from healthy and <d>IPF</d> lung tissue were determined by nuclear magnetic resonance spectroscopy; a-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in <d>IPF</d> lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of <g>TGF-b</g>. <g>TGF-b</g> induced expression of LDH5 via <g>hypoxia-inducible factor 1a</g> <g>HIF1a</g>. Importantly, overexpression of both <g>HIF1a</g> and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose <g>TGF-b</g> to induce differentiation. Furthermore, inhibition of both <g>HIF1a</g> and LDH5 inhibited <g>TGF-b</g>-induced myofibroblast differentiation. CONCLUSIONS: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of <g>TGF-b</g>. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of <d>fibrotic disorders</d>.
23006535|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive and fatal lung disease without beneficial therapy, except for lung transplantation. A high oral dose of N-acetylcysteine NAC added to prednisone and azathioprine has been found to improve lung function in IPF patients, though the mechanism of action remains poorly understood. OBJECTIVE: Based on our previous findings showing elevation of glutathione GSH content associated with downregulation of <g>lysyl oxidase</g> LOX activity, which is essential for collagen deposition, the aim of the present study was to test the hypothesis that NAC alleviates IPF by regulating LOX function. METHODS: We firstly analyzed the time course of collagen deposition in lung tissue, hydroxyproline content, LOX activity, GSH levels, and transforming growth factor-b1 TGF-b1 and a-smooth muscle actin a-SMA expression in bleomycin BLM-induced <d>pulmonary fibrosis</d> in a rat model. Then, we focused our studies on NAC modulation of LOX activity. RESULTS: LOX activity was increased on day 9 and peaked 14 days after BLM administration, while TGF-b1 protein peaked on day 9. Interestingly, NAC treatment for 14 days from day 0 reversed LOX activity to normal levels and increased GSH levels in the lung of BLM-dosed rats. Consistently, NAC partially attenuated <d>pulmonary fibrosis</d> and inhibited TGF-b1 and a-SMA expression in this model. CONCLUSIONS: Our study supports a novel mechanism of NAC alleviating IPF by inhibition of LOX activity via elevation of lung GSH in BLM-induced <d>pulmonary fibrosis</d>. The TGF-b1/a-SMA pathway may also play an important role in modulation of LOX activity.
23006535|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal lung disease without beneficial therapy, except for lung transplantation. A high oral dose of N-acetylcysteine NAC added to prednisone and azathioprine has been found to improve lung function in <d>IPF</d> patients, though the mechanism of action remains poorly understood. OBJECTIVE: Based on our previous findings showing elevation of glutathione GSH content associated with downregulation of <g>lysyl oxidase</g> LOX activity, which is essential for collagen deposition, the aim of the present study was to test the hypothesis that NAC alleviates <d>IPF</d> by regulating LOX function. METHODS: We firstly analyzed the time course of collagen deposition in lung tissue, hydroxyproline content, LOX activity, GSH levels, and transforming growth factor-b1 TGF-b1 and a-smooth muscle actin a-SMA expression in bleomycin BLM-induced <d>pulmonary fibrosis</d> in a rat model. Then, we focused our studies on NAC modulation of LOX activity. RESULTS: LOX activity was increased on day 9 and peaked 14 days after BLM administration, while TGF-b1 protein peaked on day 9. Interestingly, NAC treatment for 14 days from day 0 reversed LOX activity to normal levels and increased GSH levels in the lung of BLM-dosed rats. Consistently, NAC partially attenuated <d>pulmonary fibrosis</d> and inhibited TGF-b1 and a-SMA expression in this model. CONCLUSIONS: Our study supports a novel mechanism of NAC alleviating <d>IPF</d> by inhibition of LOX activity via elevation of lung GSH in BLM-induced <d>pulmonary fibrosis</d>. The TGF-b1/a-SMA pathway may also play an important role in modulation of LOX activity.
23006535|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal <d>lung disease</d> without beneficial therapy, except for lung transplantation. A high oral dose of N-acetylcysteine NAC added to prednisone and azathioprine has been found to improve lung function in <d>IPF</d> patients, though the mechanism of action remains poorly understood. OBJECTIVE: Based on our previous findings showing elevation of glutathione GSH content associated with downregulation of <g>lysyl oxidase</g> LOX activity, which is essential for collagen deposition, the aim of the present study was to test the hypothesis that NAC alleviates <d>IPF</d> by regulating LOX function. METHODS: We firstly analyzed the time course of collagen deposition in lung tissue, hydroxyproline content, LOX activity, GSH levels, and transforming growth factor-b1 TGF-b1 and a-smooth muscle actin a-SMA expression in bleomycin BLM-induced <d>pulmonary fibrosis</d> in a rat model. Then, we focused our studies on NAC modulation of LOX activity. RESULTS: LOX activity was increased on day 9 and peaked 14 days after BLM administration, while TGF-b1 protein peaked on day 9. Interestingly, NAC treatment for 14 days from day 0 reversed LOX activity to normal levels and increased GSH levels in the lung of BLM-dosed rats. Consistently, NAC partially attenuated <d>pulmonary fibrosis</d> and inhibited TGF-b1 and a-SMA expression in this model. CONCLUSIONS: Our study supports a novel mechanism of NAC alleviating <d>IPF</d> by inhibition of LOX activity via elevation of lung GSH in BLM-induced <d>pulmonary fibrosis</d>. The TGF-b1/a-SMA pathway may also play an important role in modulation of LOX activity.
23021430|a|Acute exacerbation of <d>idiopathic pulmonary fibrosis</d> AE-IPF is characterized by severe worsening dyspnea of unknown etiology and high mortality without effective treatment. Recently, direct hemoperfusion with polymyxin B PMX-immobilized fiber cartridge PMX-DHP has been reported to improve pulmonary oxygenation and survival in patients with AE-IPF although its mechanism of action remains unknown. To gain insights into the pathobiology of AE-IPF through the beneficial effects of PMX-DHP, we analyzed the profile of cytokines adsorbed onto PMX-fibers used in 9 AE-IPF patients. In addition, the sera of these AE-IPF patients collected immediately before and after PMX-DHP, 9 stable IPF patients and 8 healthy individuals were also analyzed. The serum levels of cytokines including IL-9, IL-12, IL-17, PDGF and VEGF were significantly decreased immediately after PMX-DHP P<0.02, and VEGF and IL-12 were most prominently reduced. In addition to PDGF and VEGF, IL-1b, IL-1ra, IL-8, IL-23, FGF basic, GM-CSF, IP-10, RANTES and TGF-b were eluted from used PMX-fibers. Interestingly, improved pulmonary oxygenation after PMX-DHP was correlated well with the quantities of eluted VEGF. These results suggest that adsorption of proinflammatory, profibrotic and proangiogenic cytokines onto PMX-fibers is one of the mechanisms of action of PMX-DHP in AE-IPF. Notably, removal of VEGF by PMX-DHP may contribute to the rapid improvement in oxygenation by suppressing vascular permeability in the lung.
23021430|a|Acute exacerbation of <d>idiopathic pulmonary fibrosis</d> AE-<d>IPF</d> is characterized by severe worsening dyspnea of unknown etiology and high mortality without effective treatment. Recently, direct hemoperfusion with polymyxin B PMX-immobilized fiber cartridge PMX-DHP has been reported to improve pulmonary oxygenation and survival in patients with AE-<d>IPF</d> although its mechanism of action remains unknown. To gain insights into the pathobiology of AE-<d>IPF</d> through the beneficial effects of PMX-DHP, we analyzed the profile of cytokines adsorbed onto PMX-fibers used in 9 AE-<d>IPF</d> patients. In addition, the sera of these AE-<d>IPF</d> patients collected immediately before and after PMX-DHP, 9 stable <d>IPF</d> patients and 8 healthy individuals were also analyzed. The serum levels of cytokines including IL-9, IL-12, IL-17, PDGF and VEGF were significantly decreased immediately after PMX-DHP P<0.02, and VEGF and IL-12 were most prominently reduced. In addition to PDGF and VEGF, IL-1b, IL-1ra, IL-8, IL-23, FGF basic, GM-CSF, IP-10, RANTES and TGF-b were eluted from used PMX-fibers. Interestingly, improved pulmonary oxygenation after PMX-DHP was correlated well with the quantities of eluted VEGF. These results suggest that adsorption of proinflammatory, profibrotic and proangiogenic cytokines onto PMX-fibers is one of the mechanisms of action of PMX-DHP in AE-<d>IPF</d>. Notably, removal of VEGF by PMX-DHP may contribute to the rapid improvement in oxygenation by suppressing vascular permeability in the lung.
23021430|a|Acute exacerbation of <d>idiopathic pulmonary fibrosis</d> AE-<d>IPF</d> is characterized by severe worsening <d>dyspnea</d> of unknown etiology and high mortality without effective treatment. Recently, direct hemoperfusion with polymyxin B PMX-immobilized fiber cartridge PMX-DHP has been reported to improve pulmonary oxygenation and survival in patients with AE-<d>IPF</d> although its mechanism of action remains unknown. To gain insights into the pathobiology of AE-<d>IPF</d> through the beneficial effects of PMX-DHP, we analyzed the profile of cytokines adsorbed onto PMX-fibers used in 9 AE-<d>IPF</d> patients. In addition, the sera of these AE-<d>IPF</d> patients collected immediately before and after PMX-DHP, 9 stable <d>IPF</d> patients and 8 healthy individuals were also analyzed. The serum levels of cytokines including IL-9, IL-12, IL-17, PDGF and VEGF were significantly decreased immediately after PMX-DHP P<0.02, and VEGF and IL-12 were most prominently reduced. In addition to PDGF and VEGF, IL-1b, IL-1ra, IL-8, IL-23, FGF basic, GM-CSF, IP-10, RANTES and TGF-b were eluted from used PMX-fibers. Interestingly, improved pulmonary oxygenation after PMX-DHP was correlated well with the quantities of eluted VEGF. These results suggest that adsorption of proinflammatory, profibrotic and proangiogenic cytokines onto PMX-fibers is one of the mechanisms of action of PMX-DHP in AE-<d>IPF</d>. Notably, removal of VEGF by PMX-DHP may contribute to the rapid improvement in oxygenation by suppressing vascular permeability in the lung.
23031257|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog SHH pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor TGF-b1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-b pathway in human lung fibroblasts. TGF-b1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-b1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-b1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis.
23031257|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in <d>IPF</d>. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog SHH pathway members in normal and <d>IPF</d> human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor TGF-b1. We showed that the hedgehog pathway was reactivated in the <d>IPF</d> lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-b pathway in human lung fibroblasts. TGF-b1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-b1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of <d>IPF</d> fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-b1 effects on normal and <d>IPF</d> fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis.
23031257|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in <d>IPF</d>. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog SHH pathway members in normal and <d>IPF</d> human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor <g>TGF-b</g>1. We showed that the hedgehog pathway was reactivated in the <d>IPF</d> lung. Importantly, we deciphered the cross talk between the hedgehog and <g>TGF-b</g> pathway in human lung fibroblasts. <g>TGF-b</g>1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for <g>TGF-b</g>1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of <d>IPF</d> fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the <g>TGF-b</g>1 effects on normal and <d>IPF</d> fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung <d>fibrosis</d>.
23043074|a|Idiopathic pulmonary <d>fibrosis</d> IPF is a progressive fibrotic lung disease without effective therapeutics. <g>Periostin</g> has been reported to be elevated in IPF patients relative to controls, but its sources and mechanisms of action remain unclear. We confirm excess periostin in lungs of IPF patients and show that IPF fibroblasts produce periostin. Blood was obtained from 54 IPF patients all but 1 with 48 wk of follow-up. We show that periostin levels predict clinical progression at 48 wk hazard ratio = 1.47, 95% confidence interval = 1.03-2.10, P < 0.05. Monocytes and fibrocytes are sources of periostin in circulation in IPF patients. Previous studies suggest that periostin may regulate the inflammatory phase of bleomycin-induced lung injury, but periostin effects during the fibroproliferative phase of the disease are unknown. Wild-type and periostin-deficient periostin-/- mice were anesthetized and challenged with bleomycin. Wild-type mice were injected with bleomycin and then treated with OC-20 Ab which blocks periostin and integrin interactions or control Ab during the fibroproliferative phase of disease, and <d>fibrosis</d> and survival were assessed. <g>Periostin</g> expression was upregulated quickly after treatment with bleomycin and remained elevated. <g>Periostin</g>-/- mice were protected from bleomycin-induced <d>fibrosis</d>. Instillation of OC-20 during the fibroproliferative phase improved survival and limited collagen deposition. Chimeric mouse studies suggest that hematopoietic and structural sources of periostin contribute to lung fibrogenesis. <g>Periostin</g> was upregulated by transforming growth factor-b in lung mesenchymal cells, and periostin promoted extracellular matrix deposition, mesenchymal cell proliferation, and wound closure. Thus periostin plays a vital role in late stages of pulmonary <d>fibrosis</d> and is a potential biomarker for disease progression and a target for therapeutic intervention.
23043074|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive fibrotic lung disease without effective therapeutics. <g>Periostin</g> has been reported to be elevated in <d>IPF</d> patients relative to controls, but its sources and mechanisms of action remain unclear. We confirm excess periostin in lungs of <d>IPF</d> patients and show that <d>IPF</d> fibroblasts produce periostin. Blood was obtained from 54 <d>IPF</d> patients all but 1 with 48 wk of follow-up. We show that periostin levels predict clinical progression at 48 wk hazard ratio = 1.47, 95% confidence interval = 1.03-2.10, P < 0.05. Monocytes and fibrocytes are sources of periostin in circulation in <d>IPF</d> patients. Previous studies suggest that periostin may regulate the inflammatory phase of bleomycin-induced lung injury, but periostin effects during the fibroproliferative phase of the disease are unknown. Wild-type and periostin-deficient periostin-/- mice were anesthetized and challenged with bleomycin. Wild-type mice were injected with bleomycin and then treated with OC-20 Ab which blocks periostin and integrin interactions or control Ab during the fibroproliferative phase of disease, and <d>fibrosis</d> and survival were assessed. <g>Periostin</g> expression was upregulated quickly after treatment with bleomycin and remained elevated. <g>Periostin</g>-/- mice were protected from bleomycin-induced <d>fibrosis</d>. Instillation of OC-20 during the fibroproliferative phase improved survival and limited collagen deposition. Chimeric mouse studies suggest that hematopoietic and structural sources of periostin contribute to lung fibrogenesis. <g>Periostin</g> was upregulated by transforming growth factor-b in lung mesenchymal cells, and periostin promoted extracellular matrix deposition, mesenchymal cell proliferation, and wound closure. Thus periostin plays a vital role in late stages of pulmonary <d>fibrosis</d> and is a potential biomarker for disease progression and a target for therapeutic intervention.
23043074|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> without effective therapeutics. <g>Periostin</g> has been reported to be elevated in <d>IPF</d> patients relative to controls, but its sources and mechanisms of action remain unclear. We confirm excess periostin in lungs of <d>IPF</d> patients and show that <d>IPF</d> fibroblasts produce periostin. Blood was obtained from 54 <d>IPF</d> patients all but 1 with 48 wk of follow-up. We show that periostin levels predict clinical progression at 48 wk hazard ratio = 1.47, 95% confidence interval = 1.03-2.10, P < 0.05. Monocytes and fibrocytes are sources of periostin in circulation in <d>IPF</d> patients. Previous studies suggest that periostin may regulate the inflammatory phase of bleomycin-induced lung injury, but periostin effects during the fibroproliferative phase of the disease are unknown. Wild-type and periostin-deficient periostin-/- mice were anesthetized and challenged with bleomycin. Wild-type mice were injected with bleomycin and then treated with OC-20 Ab which blocks periostin and integrin interactions or control Ab during the fibroproliferative phase of disease, and <d>fibrosis</d> and survival were assessed. <g>Periostin</g> expression was upregulated quickly after treatment with bleomycin and remained elevated. <g>Periostin</g>-/- mice were protected from bleomycin-induced <d>fibrosis</d>. Instillation of OC-20 during the fibroproliferative phase improved survival and limited collagen deposition. Chimeric mouse studies suggest that hematopoietic and structural sources of periostin contribute to lung fibrogenesis. <g>Periostin</g> was upregulated by transforming growth factor-b in lung mesenchymal cells, and periostin promoted extracellular matrix deposition, mesenchymal cell proliferation, and wound closure. Thus periostin plays a vital role in late stages of pulmonary <d>fibrosis</d> and is a potential biomarker for disease progression and a target for therapeutic intervention.
23043074|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> without effective therapeutics. <g>Periostin</g> has been reported to be elevated in <d>IPF</d> patients relative to controls, but its sources and mechanisms of action remain unclear. We confirm excess <g>periostin</g> in lungs of <d>IPF</d> patients and show that <d>IPF</d> fibroblasts produce <g>periostin</g>. Blood was obtained from 54 <d>IPF</d> patients all but 1 with 48 wk of follow-up. We show that <g>periostin</g> levels predict clinical progression at 48 wk hazard ratio = 1.47, 95% confidence interval = 1.03-2.10, P < 0.05. Monocytes and fibrocytes are sources of <g>periostin</g> in circulation in <d>IPF</d> patients. Previous studies suggest that <g>periostin</g> may regulate the inflammatory phase of bleomycin-induced <d>lung injury</d>, but <g>periostin</g> effects during the fibroproliferative phase of the disease are unknown. Wild-type and <g>periostin</g>-deficient <g>periostin</g>-/- mice were anesthetized and challenged with bleomycin. Wild-type mice were injected with bleomycin and then treated with OC-20 Ab which blocks <g>periostin</g> and integrin interactions or control Ab during the fibroproliferative phase of disease, and <d>fibrosis</d> and survival were assessed. <g>Periostin</g> expression was upregulated quickly after treatment with bleomycin and remained elevated. <g>Periostin</g>-/- mice were protected from bleomycin-induced <d>fibrosis</d>. Instillation of OC-20 during the fibroproliferative phase improved survival and limited collagen deposition. Chimeric mouse studies suggest that hematopoietic and structural sources of <g>periostin</g> contribute to lung fibrogenesis. <g>Periostin</g> was upregulated by transforming growth factor-b in lung mesenchymal cells, and <g>periostin</g> promoted extracellular matrix deposition, mesenchymal cell proliferation, and wound closure. Thus <g>periostin</g> plays a vital role in late stages of pulmonary <d>fibrosis</d> and is a potential biomarker for disease progression and a target for therapeutic intervention.
23043088|a|In this study, we explored the regulation and the role of up-regulated microRNAs in idiopathic <d>pulmonary fibrosis</d> IPF, a progressive interstitial lung disease of unknown origin. We analyzed the expression of microRNAs in IPF lungs and identified 43 significantly up-regulated microRNAs. Twenty-four of the 43 increased microRNAs were localized to the chromosome 14q32 microRNA cluster. We validated the increased expression of <g>miR-154</g>, miR-134, miR-299-5p, miR-410, miR-382, miR-409-3p, miR-487b, miR-31, and miR-127 by quantitative RT-PCR and determined that they were similarly expressed in embryonic lungs. We did not find evidence for differential methylation in this region, but analysis of transcription factor binding sites identified multiple SMAD3-binding elements in the 14q32 microRNA cluster. TGF-b1 stimulation of normal human lung fibroblasts NHLF caused up-regulation of microRNAs on chr14q32 that were also increased in IPF lungs. Chromatin immunoprecipitation confirmed binding of SMAD3 to the putative promoter of <g>miR-154</g>. Mir-154 was increased in IPF fibroblasts, and transfection of NHLF with <g>miR-154</g> caused significant increases in cell proliferation and migration. The increase in proliferation induced by TGF-b was not observed when NHLF or IPF fibroblasts were transfected with a mir-154 inhibitor. Transfection with <g>miR-154</g> caused activation of the WNT pathway in NHLF. ICG-001 and XAV939, inhibitors of the WNT/b-catenin pathway, reduced the proliferative effect of <g>miR-154</g>. The potential role of <g>miR-154</g>, one of multiple chr14q32 microRNA cluster members up-regulated in IPF and a regulator of fibroblast migration and proliferation, should be further explored in IPF.
23043088|a|In this study, we explored the regulation and the role of up-regulated microRNAs in idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, a progressive interstitial lung disease of unknown origin. We analyzed the expression of microRNAs in <d>IPF</d> lungs and identified 43 significantly up-regulated microRNAs. Twenty-four of the 43 increased microRNAs were localized to the chromosome 14q32 microRNA cluster. We validated the increased expression of <g>miR-154</g>, miR-134, miR-299-5p, miR-410, miR-382, miR-409-3p, miR-487b, miR-31, and miR-127 by quantitative RT-PCR and determined that they were similarly expressed in embryonic lungs. We did not find evidence for differential methylation in this region, but analysis of transcription factor binding sites identified multiple SMAD3-binding elements in the 14q32 microRNA cluster. TGF-b1 stimulation of normal human lung fibroblasts NHLF caused up-regulation of microRNAs on chr14q32 that were also increased in <d>IPF</d> lungs. Chromatin immunoprecipitation confirmed binding of SMAD3 to the putative promoter of <g>miR-154</g>. Mir-154 was increased in <d>IPF</d> fibroblasts, and transfection of NHLF with <g>miR-154</g> caused significant increases in cell proliferation and migration. The increase in proliferation induced by TGF-b was not observed when NHLF or <d>IPF</d> fibroblasts were transfected with a mir-154 inhibitor. Transfection with <g>miR-154</g> caused activation of the WNT pathway in NHLF. ICG-001 and XAV939, inhibitors of the WNT/b-catenin pathway, reduced the proliferative effect of <g>miR-154</g>. The potential role of <g>miR-154</g>, one of multiple chr14q32 microRNA cluster members up-regulated in <d>IPF</d> and a regulator of fibroblast migration and proliferation, should be further explored in <d>IPF</d>.
23043088|a|In this study, we explored the regulation and the role of up-regulated microRNAs in idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, a progressive <d>interstitial lung disease</d> of unknown origin. We analyzed the expression of microRNAs in <d>IPF</d> lungs and identified 43 significantly up-regulated microRNAs. Twenty-four of the 43 increased microRNAs were localized to the chromosome 14q32 microRNA cluster. We validated the increased expression of <g>miR-154</g>, miR-134, miR-299-5p, miR-410, miR-382, miR-409-3p, miR-487b, miR-31, and miR-127 by quantitative RT-PCR and determined that they were similarly expressed in embryonic lungs. We did not find evidence for differential methylation in this region, but analysis of transcription factor binding sites identified multiple SMAD3-binding elements in the 14q32 microRNA cluster. TGF-b1 stimulation of normal human lung fibroblasts NHLF caused up-regulation of microRNAs on chr14q32 that were also increased in <d>IPF</d> lungs. Chromatin immunoprecipitation confirmed binding of SMAD3 to the putative promoter of <g>miR-154</g>. Mir-154 was increased in <d>IPF</d> fibroblasts, and transfection of NHLF with <g>miR-154</g> caused significant increases in cell proliferation and migration. The increase in proliferation induced by TGF-b was not observed when NHLF or <d>IPF</d> fibroblasts were transfected with a mir-154 inhibitor. Transfection with <g>miR-154</g> caused activation of the WNT pathway in NHLF. ICG-001 and XAV939, inhibitors of the WNT/b-catenin pathway, reduced the proliferative effect of <g>miR-154</g>. The potential role of <g>miR-154</g>, one of multiple chr14q32 microRNA cluster members up-regulated in <d>IPF</d> and a regulator of fibroblast migration and proliferation, should be further explored in <d>IPF</d>.
23043088|a|In this study, we explored the regulation and the role of up-regulated microRNAs in idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, a progressive <d>interstitial lung disease</d> of unknown origin. We analyzed the expression of microRNAs in <d>IPF</d> lungs and identified 43 significantly up-regulated microRNAs. Twenty-four of the 43 increased microRNAs were localized to the chromosome 14q32 microRNA cluster. We validated the increased expression of <g>miR-154</g>, <g>miR-134</g>, miR-299-5p, <g>miR-410</g>, <g>miR-382</g>, miR-409-3p, <g>miR-487b</g>, <g>miR-31</g>, and <g>miR-127</g> by quantitative RT-PCR and determined that they were similarly expressed in embryonic lungs. We did not find evidence for differential methylation in this region, but analysis of transcription factor binding sites identified multiple <g>SMAD3</g>-binding elements in the 14q32 microRNA cluster. <g>TGF-b1</g> stimulation of <d>normal human lung fibroblasts</d> NHLF caused up-regulation of microRNAs on chr14q32 that were also increased in <d>IPF</d> lungs. Chromatin immunoprecipitation confirmed binding of <g>SMAD3</g> to the putative promoter of <g>miR-154</g>. Mir-154 was increased in <d>IPF</d> fibroblasts, and transfection of NHLF with <g>miR-154</g> caused significant increases in cell proliferation and migration. The increase in proliferation induced by TGF-b was not observed when NHLF or <d>IPF</d> fibroblasts were transfected with a mir-154 inhibitor. Transfection with <g>miR-154</g> caused activation of the WNT pathway in NHLF. ICG-001 and XAV939, inhibitors of the WNT/b-catenin pathway, reduced the proliferative effect of <g>miR-154</g>. The potential role of <g>miR-154</g>, one of multiple chr14q32 microRNA cluster members up-regulated in <d>IPF</d> and a regulator of fibroblast migration and proliferation, should be further explored in <d>IPF</d>.
23043088|a|In this study, we explored the regulation and the role of up-regulated microRNAs in idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, a progressive <d>interstitial lung disease</d> of unknown origin. We analyzed the expression of microRNAs in <d>IPF</d> lungs and identified 43 significantly up-regulated microRNAs. Twenty-four of the 43 increased microRNAs were localized to the chromosome 14q32 microRNA cluster. We validated the increased expression of <g>miR-154</g>, <g>miR-134</g>, miR-299-5p, <g>miR-410</g>, <g>miR-382</g>, miR-409-3p, <g>miR-487b</g>, <g>miR-31</g>, and <g>miR-127</g> by quantitative RT-PCR and determined that they were similarly expressed in embryonic lungs. We did not find evidence for differential methylation in this region, but analysis of transcription factor binding sites identified multiple <g>SMAD3</g>-binding elements in the 14q32 microRNA cluster. <g>TGF-b1</g> stimulation of <d>normal human lung fibroblasts</d> <d>NHLF</d> caused up-regulation of microRNAs on chr14q32 that were also increased in <d>IPF</d> lungs. Chromatin immunoprecipitation confirmed binding of <g>SMAD3</g> to the putative promoter of <g>miR-154</g>. Mir-154 was increased in <d>IPF</d> fibroblasts, and transfection of <d>NHLF</d> with <g>miR-154</g> caused significant increases in cell proliferation and migration. The increase in proliferation induced by TGF-b was not observed when <d>NHLF</d> or <d>IPF</d> fibroblasts were transfected with a mir-154 inhibitor. Transfection with <g>miR-154</g> caused activation of the WNT pathway in <d>NHLF</d>. ICG-001 and XAV939, inhibitors of the WNT/b-catenin pathway, reduced the proliferative effect of <g>miR-154</g>. The potential role of <g>miR-154</g>, one of multiple chr14q32 microRNA cluster members up-regulated in <d>IPF</d> and a regulator of fibroblast migration and proliferation, should be further explored in <d>IPF</d>.
23055696|a|Over the past decade, there has been a cohesive effort from patients, physicians, clinical and basic scientists, and the pharmaceutical industry to find definitive treatments for <d>idiopathic pulmonary fibrosis</d> IPF. As understanding of disease behavior and pathogenesis has improved, the aims of those treating IPF have shifted from reversing the disease to slowing or preventing progression of this chronic fibrotic illness. It is to be hoped that by slowing disease progression, survival will be improved from the current dismal median of 3.5 years following diagnosis. In Europe and Asia, a milestone has recently been reached with the licensing of the first IPF-specific drug, pirfenidone. This review assesses the current treatment modalities available for IPF, including pirfenidone. It also turns an eye to the future and discusses the growing number of promising compounds currently in development that it is hoped, in time, will make their way into the clinic as treatments for IPF.
23055696|a|Over the past decade, there has been a cohesive effort from patients, physicians, clinical and basic scientists, and the pharmaceutical industry to find definitive treatments for <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. As understanding of disease behavior and pathogenesis has improved, the aims of those treating <d>IPF</d> have shifted from reversing the disease to slowing or preventing progression of this chronic fibrotic illness. It is to be hoped that by slowing disease progression, survival will be improved from the current dismal median of 3.5 years following diagnosis. In Europe and Asia, a milestone has recently been reached with the licensing of the first <d>IPF</d>-specific drug, pirfenidone. This review assesses the current treatment modalities available for <d>IPF</d>, including pirfenidone. It also turns an eye to the future and discusses the growing number of promising compounds currently in development that it is hoped, in time, will make their way into the clinic as treatments for <d>IPF</d>.
23055696|a|Over the past decade, there has been a cohesive effort from patients, physicians, clinical and basic scientists, and the pharmaceutical industry to find definitive treatments for <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. As understanding of disease behavior and pathogenesis has improved, the aims of those treating <d>IPF</d> have shifted from reversing the disease to slowing or preventing progression of this chronic <d>fibrotic illness</d>. It is to be hoped that by slowing disease progression, survival will be improved from the current dismal median of 3.5 years following diagnosis. In Europe and Asia, a milestone has recently been reached with the licensing of the first <d>IPF</d>-specific drug, pirfenidone. This review assesses the current treatment modalities available for <d>IPF</d>, including pirfenidone. It also turns an eye to the future and discusses the growing number of promising compounds currently in development that it is hoped, in time, will make their way into the clinic as treatments for <d>IPF</d>.
23143540|a|<d>Idiopathic pulmonary fibrosis</d> IPF is an ageing-related lung disorder characterised by expansion of the myofibroblast population and aberrant lung remodelling. Dehydroepiandrosterone DHEA, a steroid pro-hormone, decreases with age but an exaggerated decline has been associated with chronic degenerative diseases. We quantified the plasma levels of DHEA and its sulfated form DHEA-S in 137 IPF patients and 58 controls and examined the effects of DHEA on human lung fibroblasts. Plasma DHEA/DHEA-S was significantly decreased in male IPF patients median range DHEA: 4.4 0.2-29.2 versus 6.7 2.1-15.2 ng    mL-1, p<0.01; DHEA-S: 47 15.0-211 versus 85.2 37.6-247.0  g    dL-1, p<0.001, while in females only DHEA-S was significantly decreased 32.6 15.0-303.0 versus 68.3 16.4-171  g    dL-1, p<0.001. DHEA caused a decrease in fibroblast proliferation and an approximately two-fold increase in fibroblast apoptosis, probably through the intrinsic pathway with activation of caspase-9. This effect was accompanied by upregulation of several pro-apoptotic proteins Bax and cyclin-dependent kinase-inhibitor CDNK1A and downregulation of anti-apoptotic proteins, such as cellular inhibitor of apoptosis c-IAP1 and c-IAP2. DHEA also caused a significant decrease of transforming growth factor-b1-induced collagen production and fibroblast to myofibroblast differentiation, and inhibited platelet-derived growth factor-induced fibroblast migration. These findings demonstrate a disproportionate decrease of DHEA/DHEA-S in IPF patients and indicate that this molecule has multiple antifibrotic properties.
23143540|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is an ageing-related lung disorder characterised by expansion of the myofibroblast population and aberrant lung remodelling. Dehydroepiandrosterone DHEA, a steroid pro-hormone, decreases with age but an exaggerated decline has been associated with chronic degenerative diseases. We quantified the plasma levels of DHEA and its sulfated form DHEA-S in 137 <d>IPF</d> patients and 58 controls and examined the effects of DHEA on human lung fibroblasts. Plasma DHEA/DHEA-S was significantly decreased in male <d>IPF</d> patients median range DHEA: 4.4 0.2-29.2 versus 6.7 2.1-15.2 ng    mL-1, p<0.01; DHEA-S: 47 15.0-211 versus 85.2 37.6-247.0  g    dL-1, p<0.001, while in females only DHEA-S was significantly decreased 32.6 15.0-303.0 versus 68.3 16.4-171  g    dL-1, p<0.001. DHEA caused a decrease in fibroblast proliferation and an approximately two-fold increase in fibroblast apoptosis, probably through the intrinsic pathway with activation of caspase-9. This effect was accompanied by upregulation of several pro-apoptotic proteins Bax and cyclin-dependent kinase-inhibitor CDNK1A and downregulation of anti-apoptotic proteins, such as cellular inhibitor of apoptosis c-IAP1 and c-IAP2. DHEA also caused a significant decrease of transforming growth factor-b1-induced collagen production and fibroblast to myofibroblast differentiation, and inhibited platelet-derived growth factor-induced fibroblast migration. These findings demonstrate a disproportionate decrease of DHEA/DHEA-S in <d>IPF</d> patients and indicate that this molecule has multiple antifibrotic properties.
23143540|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is an ageing-related <d>lung disorder</d> characterised by expansion of the myofibroblast population and aberrant lung remodelling. Dehydroepiandrosterone DHEA, a steroid pro-hormone, decreases with age but an exaggerated decline has been associated with chronic degenerative diseases. We quantified the plasma levels of DHEA and its sulfated form DHEA-S in 137 <d>IPF</d> patients and 58 controls and examined the effects of DHEA on human lung fibroblasts. Plasma DHEA/DHEA-S was significantly decreased in male <d>IPF</d> patients median range DHEA: 4.4 0.2-29.2 versus 6.7 2.1-15.2 ng    mL-1, p<0.01; DHEA-S: 47 15.0-211 versus 85.2 37.6-247.0  g    dL-1, p<0.001, while in females only DHEA-S was significantly decreased 32.6 15.0-303.0 versus 68.3 16.4-171  g    dL-1, p<0.001. DHEA caused a decrease in fibroblast proliferation and an approximately two-fold increase in fibroblast apoptosis, probably through the intrinsic pathway with activation of caspase-9. This effect was accompanied by upregulation of several pro-apoptotic proteins Bax and cyclin-dependent kinase-inhibitor CDNK1A and downregulation of anti-apoptotic proteins, such as cellular inhibitor of apoptosis c-IAP1 and c-IAP2. DHEA also caused a significant decrease of transforming growth factor-b1-induced collagen production and fibroblast to myofibroblast differentiation, and inhibited platelet-derived growth factor-induced fibroblast migration. These findings demonstrate a disproportionate decrease of DHEA/DHEA-S in <d>IPF</d> patients and indicate that this molecule has multiple antifibrotic properties.
23143540|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is an ageing-related <d>lung disorder</d> characterised by expansion of the myofibroblast population and aberrant lung remodelling. Dehydroepiandrosterone DHEA, a steroid pro-hormone, decreases with age but an exaggerated decline has been associated with chronic <d>degenerative diseases</d>. We quantified the plasma levels of DHEA and its sulfated form DHEA-S in 137 <d>IPF</d> patients and 58 controls and examined the effects of DHEA on human lung fibroblasts. Plasma DHEA/DHEA-S was significantly decreased in male <d>IPF</d> patients median range DHEA: 4.4 0.2-29.2 versus 6.7 2.1-15.2 ng    mL-1, p<0.01; DHEA-S: 47 15.0-211 versus 85.2 37.6-247.0  g    dL-1, p<0.001, while in females only DHEA-S was significantly decreased 32.6 15.0-303.0 versus 68.3 16.4-171  g    dL-1, p<0.001. DHEA caused a decrease in fibroblast proliferation and an approximately two-fold increase in fibroblast apoptosis, probably through the intrinsic pathway with activation of caspase-9. This effect was accompanied by upregulation of several pro-apoptotic proteins Bax and cyclin-dependent kinase-inhibitor CDNK1A and downregulation of anti-apoptotic proteins, such as cellular inhibitor of apoptosis c-IAP1 and c-IAP2. DHEA also caused a significant decrease of transforming growth factor-b1-induced collagen production and fibroblast to myofibroblast differentiation, and inhibited platelet-derived growth factor-induced fibroblast migration. These findings demonstrate a disproportionate decrease of DHEA/DHEA-S in <d>IPF</d> patients and indicate that this molecule has multiple antifibrotic properties.
23220917|a|RATIONALE: Lymphocytes are increasingly associated with <d>idiopathic pulmonary fibrosis</d> IPF. <g>Semaphorin 7a</g> Sema 7a participates in lymphocyte activation. OBJECTIVES: To define the relationship between Sema 7a and lymphocytes in IPF. METHODS: We characterized the significance of Sema 7a+ lymphocytes in humans with IPF and in a mouse model of lung fibrosis caused by lung-targeted, transgenic overexpression of TGF-b1. We determined the site of Sema 7a expression in human and murine lungs and circulation and used adoptive transfer approaches to define the relevance of lymphocytes coexpressing Sema7a and the markers CD19, CD4, or CD4+CD25+FoxP3+ in TGF-b1-induced murine lung fibrosis. MEASUREMENTS AND MAIN RESULTS: Subjects with IPF show expression of Sema 7a on lung CD4+ cells and circulating CD4+ or CD19+ cells. Sema 7a expression is increased on CD4+ cells and CD4+CD25+FoxP3+ regulatory T cells, but not CD19+ cells, in subjects with progressive IPF. Sema 7a is expressed on lymphocytes expressing CD4 but not CD19 in the lungs and spleen of TGF-b1-transgenic mice. Sema 7a expressing bone marrow-derived cells induce lung fibrosis and alter the production of T-cell mediators, including IFN-y, IL-4, IL-17A, and IL-10. These effects require CD4 but not CD19. In comparison to Sema 7a-CD4+CD25+FoxP3+ cells, Sema7a+CD4+CD25+FoxP3+ cells exhibit reduced expression of regulatory genes such as IL-10, and adoptive transfer of these cells induces fibrosis and remodeling in the TGF-b1-exposed murine lung. CONCLUSIONS: Sema 7a+CD4+CD25+FoxP3+ regulatory T cells are associated with disease progression in subjects with IPF and induce fibrosis in the TGF-b1-exposed murine lung.
23220917|a|RATIONALE: Lymphocytes are increasingly associated with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. <g>Semaphorin 7a</g> Sema 7a participates in lymphocyte activation. OBJECTIVES: To define the relationship between Sema 7a and lymphocytes in <d>IPF</d>. METHODS: We characterized the significance of Sema 7a+ lymphocytes in humans with <d>IPF</d> and in a mouse model of lung fibrosis caused by lung-targeted, transgenic overexpression of TGF-b1. We determined the site of Sema 7a expression in human and murine lungs and circulation and used adoptive transfer approaches to define the relevance of lymphocytes coexpressing Sema7a and the markers CD19, CD4, or CD4+CD25+FoxP3+ in TGF-b1-induced murine lung fibrosis. MEASUREMENTS AND MAIN RESULTS: Subjects with <d>IPF</d> show expression of Sema 7a on lung CD4+ cells and circulating CD4+ or CD19+ cells. Sema 7a expression is increased on CD4+ cells and CD4+CD25+FoxP3+ regulatory T cells, but not CD19+ cells, in subjects with progressive <d>IPF</d>. Sema 7a is expressed on lymphocytes expressing CD4 but not CD19 in the lungs and spleen of TGF-b1-transgenic mice. Sema 7a expressing bone marrow-derived cells induce lung fibrosis and alter the production of T-cell mediators, including IFN-y, IL-4, IL-17A, and IL-10. These effects require CD4 but not CD19. In comparison to Sema 7a-CD4+CD25+FoxP3+ cells, Sema7a+CD4+CD25+FoxP3+ cells exhibit reduced expression of regulatory genes such as IL-10, and adoptive transfer of these cells induces fibrosis and remodeling in the TGF-b1-exposed murine lung. CONCLUSIONS: Sema 7a+CD4+CD25+FoxP3+ regulatory T cells are associated with disease progression in subjects with <d>IPF</d> and induce fibrosis in the TGF-b1-exposed murine lung.
23220917|a|RATIONALE: Lymphocytes are increasingly associated with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. <g>Semaphorin 7a</g> <g>Sema 7a</g> participates in lymphocyte activation. OBJECTIVES: To define the relationship between <g>Sema 7a</g> and lymphocytes in <d>IPF</d>. METHODS: We characterized the significance of <g>Sema 7a</g>+ lymphocytes in humans with <d>IPF</d> and in a mouse model of <d>lung fibrosis</d> caused by lung-targeted, transgenic overexpression of TGF-b1. We determined the site of <g>Sema 7a</g> expression in human and murine lungs and circulation and used adoptive transfer approaches to define the relevance of lymphocytes coexpressing Sema7a and the markers CD19, CD4, or CD4+CD25+FoxP3+ in TGF-b1-induced murine <d>lung fibrosis</d>. MEASUREMENTS AND MAIN RESULTS: Subjects with <d>IPF</d> show expression of <g>Sema 7a</g> on lung CD4+ cells and circulating CD4+ or CD19+ cells. <g>Sema 7a</g> expression is increased on CD4+ cells and CD4+CD25+FoxP3+ regulatory T cells, but not CD19+ cells, in subjects with progressive <d>IPF</d>. <g>Sema 7a</g> is expressed on lymphocytes expressing CD4 but not CD19 in the lungs and spleen of TGF-b1-transgenic mice. <g>Sema 7a</g> expressing bone marrow-derived cells induce <d>lung fibrosis</d> and alter the production of T-cell mediators, including IFN-y, IL-4, IL-17A, and IL-10. These effects require CD4 but not CD19. In comparison to <g>Sema 7a</g>-CD4+CD25+FoxP3+ cells, Sema7a+CD4+CD25+FoxP3+ cells exhibit reduced expression of regulatory genes such as IL-10, and adoptive transfer of these cells induces fibrosis and remodeling in the TGF-b1-exposed murine lung. CONCLUSIONS: <g>Sema 7a</g>+CD4+CD25+FoxP3+ regulatory T cells are associated with disease progression in subjects with <d>IPF</d> and induce fibrosis in the TGF-b1-exposed murine lung.
23220917|a|RATIONALE: Lymphocytes are increasingly associated with <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. <g>Semaphorin 7a</g> <g>Sema 7a</g> participates in lymphocyte activation. OBJECTIVES: To define the relationship between <g>Sema 7a</g> and lymphocytes in <d>IPF</d>. METHODS: We characterized the significance of <g>Sema 7a</g>+ lymphocytes in humans with <d>IPF</d> and in a mouse model of <d>lung <d>fibrosis</d></d> caused by lung-targeted, transgenic overexpression of <g>TGF-b1</g>. We determined the site of <g>Sema 7a</g> expression in human and murine lungs and circulation and used adoptive transfer approaches to define the relevance of lymphocytes coexpressing <g>Sema7a</g> and the markers <g>CD19</g>, <g>CD4</g>, or <g>CD4</g>+<g>CD25</g>+<g>FoxP3</g>+ in <g>TGF-b1</g>-induced murine <d>lung <d>fibrosis</d></d>. MEASUREMENTS AND MAIN RESULTS: Subjects with <d>IPF</d> show expression of <g>Sema 7a</g> on lung <g>CD4</g>+ cells and circulating <g>CD4</g>+ or <g>CD19</g>+ cells. <g>Sema 7a</g> expression is increased on <g>CD4</g>+ cells and <g>CD4</g>+<g>CD25</g>+<g>FoxP3</g>+ regulatory T cells, but not <g>CD19</g>+ cells, in subjects with progressive <d>IPF</d>. <g>Sema 7a</g> is expressed on lymphocytes expressing <g>CD4</g> but not <g>CD19</g> in the lungs and spleen of <g>TGF-b1</g>-transgenic mice. <g>Sema 7a</g> expressing bone marrow-derived cells induce <d>lung <d>fibrosis</d></d> and alter the production of T-cell mediators, including IFN-y, <g>IL-4</g>, <g>IL-17A</g>, and <g>IL-10</g>. These effects require <g>CD4</g> but not <g>CD19</g>. In comparison to <g>Sema 7a</g>-<g>CD4</g>+<g>CD25</g>+<g>FoxP3</g>+ cells, <g>Sema7a</g>+<g>CD4</g>+<g>CD25</g>+<g>FoxP3</g>+ cells exhibit reduced expression of regulatory genes such as <g>IL-10</g>, and adoptive transfer of these cells induces <d>fibrosis</d> and remodeling in the <g>TGF-b1</g>-exposed murine lung. CONCLUSIONS: <g>Sema 7a</g>+<g>CD4</g>+<g>CD25</g>+<g>FoxP3</g>+ regulatory T cells are associated with disease progression in subjects with <d>IPF</d> and induce <d>fibrosis</d> in the <g>TGF-b1</g>-exposed murine lung.
23258233|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive lung disease with a poor prognosis and very few therapeutic options. On the molecular level, patients with IPF have increased amounts of the bone morphogenetic protein BMP inhibitor gremlin in their lungs, which results in decreased BMP signaling, and an increase in transforming growth factor-b signaling. Based on these findings, we hypothesized that restoration of the impaired BMP signaling would offer a novel strategy for the prevention of fibrosis progression or for the treatment of pulmonary fibrosis. We used reporter cell lines and high-throughput screening of a chemical compound library as an approach to finding molecules that increase BMP signaling in lung epithelial cells, without increasing transforming growth factor-b signaling. The most promising candidate drug was analyzed further by studying its effects on BMP target gene expression, Smad protein phosphorylation, and a mouse model of silica-induced pulmonary fibrosis. The most promising drug candidate, tilorone, induced BMP signaling in the reporter cells and increased the expression of BMP-7 and a BMP target gene, Id3, in lung epithelial A549 cells. In a mouse model of pulmonary fibrosis, tilorone decreased lung hydroxyproline content and the expression of collagen genes Col1A1 and Col3A1. Mice treated with tilorone showed markedly decreased histological changes, compared with untreated mice. These findings indicate that tilorone has biologically significant antifibrotic properties.
23258233|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive lung disease with a poor prognosis and very few therapeutic options. On the molecular level, patients with <d>IPF</d> have increased amounts of the bone morphogenetic protein BMP inhibitor gremlin in their lungs, which results in decreased BMP signaling, and an increase in transforming growth factor-b signaling. Based on these findings, we hypothesized that restoration of the impaired BMP signaling would offer a novel strategy for the prevention of fibrosis progression or for the treatment of pulmonary fibrosis. We used reporter cell lines and high-throughput screening of a chemical compound library as an approach to finding molecules that increase BMP signaling in lung epithelial cells, without increasing transforming growth factor-b signaling. The most promising candidate drug was analyzed further by studying its effects on BMP target gene expression, Smad protein phosphorylation, and a mouse model of silica-induced pulmonary fibrosis. The most promising drug candidate, tilorone, induced BMP signaling in the reporter cells and increased the expression of BMP-7 and a BMP target gene, Id3, in lung epithelial A549 cells. In a mouse model of pulmonary fibrosis, tilorone decreased lung hydroxyproline content and the expression of collagen genes Col1A1 and Col3A1. Mice treated with tilorone showed markedly decreased histological changes, compared with untreated mice. These findings indicate that tilorone has biologically significant antifibrotic properties.
23258233|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>lung disease</d> with a poor prognosis and very few therapeutic options. On the molecular level, patients with <d>IPF</d> have increased amounts of the bone morphogenetic protein BMP inhibitor gremlin in their lungs, which results in decreased BMP signaling, and an increase in transforming growth factor-b signaling. Based on these findings, we hypothesized that restoration of the impaired BMP signaling would offer a novel strategy for the prevention of fibrosis progression or for the treatment of pulmonary fibrosis. We used reporter cell lines and high-throughput screening of a chemical compound library as an approach to finding molecules that increase BMP signaling in lung epithelial cells, without increasing transforming growth factor-b signaling. The most promising candidate drug was analyzed further by studying its effects on BMP target gene expression, Smad protein phosphorylation, and a mouse model of silica-induced pulmonary fibrosis. The most promising drug candidate, tilorone, induced BMP signaling in the reporter cells and increased the expression of BMP-7 and a BMP target gene, Id3, in lung epithelial A549 cells. In a mouse model of pulmonary fibrosis, tilorone decreased lung hydroxyproline content and the expression of collagen genes Col1A1 and Col3A1. Mice treated with tilorone showed markedly decreased histological changes, compared with untreated mice. These findings indicate that tilorone has biologically significant antifibrotic properties.
23258233|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive <d>lung disease</d> with a poor prognosis and very few therapeutic options. On the molecular level, patients with <d>IPF</d> have increased amounts of the <g>bone morphogenetic protein</g> <g>BMP</g> inhibitor <g>gremlin</g> in their lungs, which results in decreased <g>BMP</g> signaling, and an increase in transforming growth factor-b signaling. Based on these findings, we hypothesized that restoration of the impaired <g>BMP</g> signaling would offer a novel strategy for the prevention of <d>fibrosis</d> progression or for the treatment of pulmonary <d>fibrosis</d>. We used reporter cell lines and high-throughput screening of a chemical compound library as an approach to finding molecules that increase <g>BMP</g> signaling in lung epithelial cells, without increasing transforming growth factor-b signaling. The most promising candidate drug was analyzed further by studying its effects on <g>BMP</g> target gene expression, Smad protein phosphorylation, and a mouse model of silica-induced pulmonary <d>fibrosis</d>. The most promising drug candidate, tilorone, induced <g>BMP</g> signaling in the reporter cells and increased the expression of <g>BMP</g>-7 and a <g>BMP</g> target gene, Id3, in lung epithelial A549 cells. In a mouse model of pulmonary <d>fibrosis</d>, tilorone decreased lung hydroxyproline content and the expression of collagen genes Col1A1 and Col3A1. Mice treated with tilorone showed markedly decreased histological changes, compared with untreated mice. These findings indicate that tilorone has biologically significant antifibrotic properties.
23288928|a|Idiopathic pulmonary <d>fibrosis</d> IPF is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial-to-mesenchymal transition EMT] occurs under the influence of transforming growth factor TGF-b1, with Snail being a major transcription factor. We study here the role of the heat-shock protein <g>HSP27</g> in fibrogenesis and EMT. In vitro, we have up- and down-modulated <g>HSP27</g> expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF-b1. In vivo, we inhibited <g>HSP27</g> with the antisense oligonucleotide OGX-427 in phase II clinical trials as anticancer agent in our rat subpleural/pulmonary <d>fibrosis</d> models. We demonstrate that <g>HSP27</g> is strongly expressed during the fibrotic process in patients with IPF and in different in vivo models. We showed that <g>HSP27</g> binds to and stabilizes Snail and consequently induces EMT. Conversely, <g>HSP27</g> knockdown leads to Snail proteasomal degradation, thus inhibiting TGF-b1-induced EMT. Inhibition of <g>HSP27</g> with OGX-427 efficiently blocks EMT and <d>fibrosis</d> development. Controls in vivo were an empty adenovirus that did not induce <d>fibrosis</d> and a control antisense oligonucleotide. The present work opens the possibility of a new therapeutic use for <g>HSP27</g> inhibitors against IPF, for which there is no conclusively effective treatment.
23288928|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial-to-mesenchymal transition EMT] occurs under the influence of transforming growth factor TGF-b1, with <g>Snail</g> being a major transcription factor. We study here the role of the heat-shock protein <g>HSP27</g> in fibrogenesis and EMT. In vitro, we have up- and down-modulated <g>HSP27</g> expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF-b1. In vivo, we inhibited <g>HSP27</g> with the antisense oligonucleotide OGX-427 in phase II clinical trials as anticancer agent in our rat subpleural/pulmonary <d>fibrosis</d> models. We demonstrate that <g>HSP27</g> is strongly expressed during the fibrotic process in patients with <d>IPF</d> and in different in vivo models. We showed that <g>HSP27</g> binds to and stabilizes <g>Snail</g> and consequently induces EMT. Conversely, <g>HSP27</g> knockdown leads to <g>Snail</g> proteasomal degradation, thus inhibiting TGF-b1-induced EMT. Inhibition of <g>HSP27</g> with OGX-427 efficiently blocks EMT and <d>fibrosis</d> development. Controls in vivo were an empty adenovirus that did not induce <d>fibrosis</d> and a control antisense oligonucleotide. The present work opens the possibility of a new therapeutic use for <g>HSP27</g> inhibitors against <d>IPF</d>, for which there is no conclusively effective treatment.
23315259|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a chronic and progressive interstitial lung disease, wherein transforming growth factor b TGF-b and sphingosine-1-phosphate S1P contribute to the pathogenesis of fibrosis. However, the in vivo contribution of sphingosine kinase SphK in fibrotic processes has not been documented. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1- or SphK2-knockdown mice and SphK inhibitor were used to assess the role of SphKs in fibrogenesis. The expression of SphK1/2 negatively correlated with lung function and survival in patients with IPF. Also, the expression of SphK1 was increased in lung tissues from patients with IPF and bleomycin-challenged mice. Knockdown of SphK1, but not SphK2, increased survival and resistance to <d>pulmonary fibrosis</d> in bleomycin-challenged mice. Administration of SphK inhibitor reduced bleomycin-induced mortality and <d>pulmonary fibrosis</d> in mice. Knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-b secretion in a bleomycin-induced lung fibrosis mouse model that was accompanied by reduced phosphorylation of Smad2 and MAPKs in lung tissue. In vitro, bleomycin-induced expression of SphK1 in lung fibroblast was found to be TGF-b dependent. Taken together, these data indicate that SphK1 plays a critical role in the pathology of lung fibrosis and is a novel therapeutic target.
23315259|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic and progressive interstitial lung disease, wherein transforming growth factor b TGF-b and sphingosine-1-phosphate S1P contribute to the pathogenesis of fibrosis. However, the in vivo contribution of sphingosine kinase SphK in fibrotic processes has not been documented. Microarray analysis of blood mononuclear cells from patients with <d>IPF</d> and SphK1- or SphK2-knockdown mice and SphK inhibitor were used to assess the role of SphKs in fibrogenesis. The expression of SphK1/2 negatively correlated with lung function and survival in patients with <d>IPF</d>. Also, the expression of SphK1 was increased in lung tissues from patients with <d>IPF</d> and bleomycin-challenged mice. Knockdown of SphK1, but not SphK2, increased survival and resistance to <d>pulmonary fibrosis</d> in bleomycin-challenged mice. Administration of SphK inhibitor reduced bleomycin-induced mortality and <d>pulmonary fibrosis</d> in mice. Knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-b secretion in a bleomycin-induced lung fibrosis mouse model that was accompanied by reduced phosphorylation of Smad2 and MAPKs in lung tissue. In vitro, bleomycin-induced expression of SphK1 in lung fibroblast was found to be TGF-b dependent. Taken together, these data indicate that SphK1 plays a critical role in the pathology of lung fibrosis and is a novel therapeutic target.
23315259|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic and progressive <d>interstitial lung disease</d>, wherein transforming growth factor b TGF-b and sphingosine-1-phosphate S1P contribute to the pathogenesis of fibrosis. However, the in vivo contribution of sphingosine kinase SphK in fibrotic processes has not been documented. Microarray analysis of blood mononuclear cells from patients with <d>IPF</d> and SphK1- or SphK2-knockdown mice and SphK inhibitor were used to assess the role of SphKs in fibrogenesis. The expression of SphK1/2 negatively correlated with lung function and survival in patients with <d>IPF</d>. Also, the expression of SphK1 was increased in lung tissues from patients with <d>IPF</d> and bleomycin-challenged mice. Knockdown of SphK1, but not SphK2, increased survival and resistance to <d>pulmonary fibrosis</d> in bleomycin-challenged mice. Administration of SphK inhibitor reduced bleomycin-induced mortality and <d>pulmonary fibrosis</d> in mice. Knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-b secretion in a bleomycin-induced lung fibrosis mouse model that was accompanied by reduced phosphorylation of Smad2 and MAPKs in lung tissue. In vitro, bleomycin-induced expression of SphK1 in lung fibroblast was found to be TGF-b dependent. Taken together, these data indicate that SphK1 plays a critical role in the pathology of lung fibrosis and is a novel therapeutic target.
23315259|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic and progressive <d>interstitial lung disease</d>, wherein <g>transforming growth factor b</g> <g>TGF-b</g> and sphingosine-1-phosphate S1P contribute to the pathogenesis of <d>fibrosis</d>. However, the in vivo contribution of sphingosine kinase SphK in fibrotic processes has not been documented. Microarray analysis of blood mononuclear cells from patients with <d>IPF</d> and SphK1- or SphK2-knockdown mice and SphK inhibitor were used to assess the role of SphKs in fibrogenesis. The expression of SphK1/2 negatively correlated with lung function and survival in patients with <d>IPF</d>. Also, the expression of SphK1 was increased in lung tissues from patients with <d>IPF</d> and bleomycin-challenged mice. Knockdown of SphK1, but not SphK2, increased survival and resistance to <d>pulmonary <d>fibrosis</d></d> in bleomycin-challenged mice. Administration of SphK inhibitor reduced bleomycin-induced mortality and <d>pulmonary <d>fibrosis</d></d> in mice. Knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and <g>TGF-b</g> secretion in a bleomycin-induced lung <d>fibrosis</d> mouse model that was accompanied by reduced phosphorylation of Smad2 and MAPKs in lung tissue. In vitro, bleomycin-induced expression of SphK1 in lung fibroblast was found to be <g>TGF-b</g> dependent. Taken together, these data indicate that SphK1 plays a critical role in the pathology of lung <d>fibrosis</d> and is a novel therapeutic target.
23344525|a|BACKGROUND: Transforming growth factor-b1 TGF-b1 is a key cytokine that plays a critical role in <d>idiopathic pulmonary fibrosis</d> IPF. The genotypes of T869C polymorphism may be associated with the susceptibility to fibrotic lung disease. METHODS: We investigated a single-nucleotide polymorphism at exon 1 nucleotide position 29 T   >   C of the TGF-b1 gene. Eighty-five healthy controls and 85 subjects with surgically confirmed IPF were investigated using polymerase chain reaction and restriction enzyme fragment length polymorphism techniques. RESULTS: The IPF patients consisted of 55 men and 30 women. The mean age was 61      8  years. Fifty-one 60  % of the 85 IPF patients were smokers and 34 were nonsmokers. The distribution of genotypes between IPF patients and controls was significantly different IPF: TT 43.5  % and TC or CC 56.5  %; controls: TT 27.1  % and TC or CC 72.9  %, p  =  0.037. TT genotype was significantly associated with decreased PaO2 and increased DA-aO2 upon initial diagnosis p  =  0.006 and 0.009, respectively. There was a positive association between TT genotype and IPF development odds ratio [OR]  =  2.1, 95  % confidence interval [CI]  =  1.1-4.0, p  =  0.028. CONCLUSIONS: This study suggests that the TGF-b1 gene T869C polymorphism may affect susceptibility to IPF in Koreans. Larger studies are required to confirm the genetic association of TGF-b1 gene polymorphism and IPF.
23344525|a|BACKGROUND: Transforming growth factor-b1 TGF-b1 is a key cytokine that plays a critical role in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The genotypes of T869C polymorphism may be associated with the susceptibility to fibrotic lung disease. METHODS: We investigated a single-nucleotide polymorphism at exon 1 nucleotide position 29 T   >   C of the TGF-b1 gene. Eighty-five healthy controls and 85 subjects with surgically confirmed <d>IPF</d> were investigated using polymerase chain reaction and restriction enzyme fragment length polymorphism techniques. RESULTS: The <d>IPF</d> patients consisted of 55 men and 30 women. The mean age was 61      8  years. Fifty-one 60  % of the 85 <d>IPF</d> patients were smokers and 34 were nonsmokers. The distribution of genotypes between <d>IPF</d> patients and controls was significantly different <d>IPF</d>: TT 43.5  % and TC or CC 56.5  %; controls: TT 27.1  % and TC or CC 72.9  %, p  =  0.037. TT genotype was significantly associated with decreased PaO2 and increased DA-aO2 upon initial diagnosis p  =  0.006 and 0.009, respectively. There was a positive association between TT genotype and <d>IPF</d> development odds ratio [OR]  =  2.1, 95  % confidence interval [CI]  =  1.1-4.0, p  =  0.028. CONCLUSIONS: This study suggests that the TGF-b1 gene T869C polymorphism may affect susceptibility to <d>IPF</d> in Koreans. Larger studies are required to confirm the genetic association of TGF-b1 gene polymorphism and <d>IPF</d>.
23344525|a|BACKGROUND: Transforming growth factor-b1 TGF-b1 is a key cytokine that plays a critical role in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The genotypes of T869C polymorphism may be associated with the susceptibility to <d>fibrotic lung disease</d>. METHODS: We investigated a single-nucleotide polymorphism at exon 1 nucleotide position 29 T   >   C of the TGF-b1 gene. Eighty-five healthy controls and 85 subjects with surgically confirmed <d>IPF</d> were investigated using polymerase chain reaction and restriction enzyme fragment length polymorphism techniques. RESULTS: The <d>IPF</d> patients consisted of 55 men and 30 women. The mean age was 61      8  years. Fifty-one 60  % of the 85 <d>IPF</d> patients were smokers and 34 were nonsmokers. The distribution of genotypes between <d>IPF</d> patients and controls was significantly different <d>IPF</d>: TT 43.5  % and TC or CC 56.5  %; controls: TT 27.1  % and TC or CC 72.9  %, p  =  0.037. TT genotype was significantly associated with decreased PaO2 and increased DA-aO2 upon initial diagnosis p  =  0.006 and 0.009, respectively. There was a positive association between TT genotype and <d>IPF</d> development odds ratio [OR]  =  2.1, 95  % confidence interval [CI]  =  1.1-4.0, p  =  0.028. CONCLUSIONS: This study suggests that the TGF-b1 gene T869C polymorphism may affect susceptibility to <d>IPF</d> in Koreans. Larger studies are required to confirm the genetic association of TGF-b1 gene polymorphism and <d>IPF</d>.
23376055|a|BACKGROUND AND AIMS: <d>Idiopathic pulmonary fibrosis</d> IPF is associated with significant morbidity and mortality despite aggressive therapy. The aim of the present study is to investigate the roles of p38 MAPK and <g>JNK</g> in <g>TGF-b1</g>-induced human alveolar epithelial to mesenchymal transition EMT, which could be a possible mechanism of IPF. METHODS: A549 cells were treated with <g>TGF-b1</g> 3 ng/mL for 48 h to induce EMT. The expression of mesenchymal phenotypic markers including desmin, a-smooth muscle actin a-SMA and vimentin, and expression of epithelial phenotypic markers including E-cadherin, zonula occludens-1 ZO-1 and aquaporin-5 AQP5 were detected by Western blot. The roles of p38 MAPK and <g>JNK</g> in <g>TGF-b1</g>-mediated EMT were investigated using gene silencing and inhibitor SB-203580 and SP-600125. RESULTS: The data showed that <g>TGF-b1</g> induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT. The process of EMT was accompanied by morphological alteration and expression of the myofibroblast marker desmin, a-SMA and vimentin, concomitant with a downregulation of the epithelial cell marker E-cadherin, ZO-1 and AQP5. <g>TGF-b1</g>-induced EMT occurred through phosphorylation of p38 MAPK and <g>JNK</g> and was inhibited by inhibitor SB-203580 and SP-600125 and gene silencing. CONCLUSIONS: <g>TGF-b1</g> induces A549 alveolar epithelial cells AECs to undergo EMT partially via p38 MAPK and <g>JNK</g> activation and supports the concept of EMT in lung epithelial cells.
23376055|a|BACKGROUND AND AIMS: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is associated with significant morbidity and mortality despite aggressive therapy. The aim of the present study is to investigate the roles of p38 MAPK and <g>JNK</g> in <g>TGF-b1</g>-induced human alveolar epithelial to mesenchymal transition EMT, which could be a possible mechanism of <d>IPF</d>. METHODS: A549 cells were treated with <g>TGF-b1</g> 3 ng/mL for 48 h to induce EMT. The expression of mesenchymal phenotypic markers including desmin, a-smooth muscle actin a-SMA and vimentin, and expression of epithelial phenotypic markers including E-cadherin, zonula occludens-1 ZO-1 and aquaporin-5 AQP5 were detected by Western blot. The roles of p38 MAPK and <g>JNK</g> in <g>TGF-b1</g>-mediated EMT were investigated using gene silencing and inhibitor SB-203580 and SP-600125. RESULTS: The data showed that <g>TGF-b1</g> induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT. The process of EMT was accompanied by morphological alteration and expression of the myofibroblast marker desmin, a-SMA and vimentin, concomitant with a downregulation of the epithelial cell marker E-cadherin, ZO-1 and AQP5. <g>TGF-b1</g>-induced EMT occurred through phosphorylation of p38 MAPK and <g>JNK</g> and was inhibited by inhibitor SB-203580 and SP-600125 and gene silencing. CONCLUSIONS: <g>TGF-b1</g> induces A549 alveolar epithelial cells AECs to undergo EMT partially via p38 MAPK and <g>JNK</g> activation and supports the concept of EMT in lung epithelial cells.
23380438|a|PRM-151, recombinant human Pentraxin-2 PTX-2 also referred to as <g>serum amyloid P</g> SAP, is under development for treatment of fibrosis. A First-in-Human FIH trial was performed to assess the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects PRM-151:placebo; 2:1. SAP levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous SAP. At a dose level of 10 mg/kg, at which a physiologic plasma level of SAP was reached, two additional healthy volunteers and three <d>pulmonary fibrosis</d> PF patients were enrolled enabling comparison of the pharmacokinetic SAP profile between healthy volunteers and PF patients. In addition, the percentage of fibrocytes CD45+/Procollagen-1+ cells in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population. PRM-151 administration was generally well tolerated. In two <d>pulmonary fibrosis</d> patients non-specific, transient skin reactions urticaria and erythema were observed. PRM-151 administration resulted in a 6-to 13-fold increase in mean baseline plasma SAP levels at dose levels of 5, 10, and 20 mg/kg. The estimated t1/2 of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and PF patients. PRM-151 administration resulted in a 30-50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in PF patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research.
23380438|a|PRM-151, recombinant human <g>Pentraxin-2</g> <g>PTX-2</g> also referred to as <g>serum amyloid P</g> <g>SAP</g>, is under development for treatment of <d>fibrosis</d>. A First-in-Human FIH trial was performed to assess the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects PRM-151:placebo; 2:1. <g>SAP</g> levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous <g>SAP</g>. At a dose level of 10 mg/kg, at which a physiologic plasma level of <g>SAP</g> was reached, two additional healthy volunteers and three <d>pulmonary <d>fibrosis</d></d> PF patients were enrolled enabling comparison of the pharmacokinetic <g>SAP</g> profile between healthy volunteers and PF patients. In addition, the percentage of fibrocytes CD45+/Procollagen-1+ cells in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population. PRM-151 administration was generally well tolerated. In two <d>pulmonary <d>fibrosis</d></d> patients non-specific, transient skin reactions urticaria and erythema were observed. PRM-151 administration resulted in a 6-to 13-fold increase in mean baseline plasma <g>SAP</g> levels at dose levels of 5, 10, and 20 mg/kg. The estimated t1/2 of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and PF patients. PRM-151 administration resulted in a 30-50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in PF patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research.
23380438|a|PRM-151, recombinant human <g>Pentraxin-2</g> <g>PTX-2</g> also referred to as <g>serum amyloid P</g> <g>SAP</g>, is under development for treatment of <d>fibrosis</d>. A First-in-Human FIH trial was performed to assess the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects PRM-151:placebo; 2:1. <g>SAP</g> levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous <g>SAP</g>. At a dose level of 10 mg/kg, at which a physiologic plasma level of <g>SAP</g> was reached, two additional healthy volunteers and three <d>pulmonary <d>fibrosis</d></d> <d>PF</d> patients were enrolled enabling comparison of the pharmacokinetic <g>SAP</g> profile between healthy volunteers and <d>PF</d> patients. In addition, the percentage of fibrocytes CD45+/Procollagen-1+ cells in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population. PRM-151 administration was generally well tolerated. In two <d>pulmonary <d>fibrosis</d></d> patients non-specific, transient skin reactions urticaria and erythema were observed. PRM-151 administration resulted in a 6-to 13-fold increase in mean baseline plasma <g>SAP</g> levels at dose levels of 5, 10, and 20 mg/kg. The estimated t1/2 of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and <d>PF</d> patients. PRM-151 administration resulted in a 30-50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in <d>PF</d> patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research.
23380438|a|PRM-151, recombinant human <g>Pentraxin-2</g> <g>PTX-2</g> also referred to as <g>serum amyloid P</g> <g>SAP</g>, is under development for treatment of <d>fibrosis</d>. A First-in-Human FIH trial was performed to assess the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects PRM-151:placebo; 2:1. <g>SAP</g> levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous <g>SAP</g>. At a dose level of 10 mg/kg, at which a physiologic plasma level of <g>SAP</g> was reached, two additional healthy volunteers and three <d>pulmonary <d>fibrosis</d></d> <d>PF</d> patients were enrolled enabling comparison of the pharmacokinetic <g>SAP</g> profile between healthy volunteers and <d>PF</d> patients. In addition, the percentage of fibrocytes CD45+/Procollagen-1+ cells in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population. PRM-151 administration was generally well tolerated. In two <d>pulmonary <d>fibrosis</d></d> patients non-specific, transient skin reactions <d>urticaria</d> and erythema were observed. PRM-151 administration resulted in a 6-to 13-fold increase in mean baseline plasma <g>SAP</g> levels at dose levels of 5, 10, and 20 mg/kg. The estimated t1/2 of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and <d>PF</d> patients. PRM-151 administration resulted in a 30-50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in <d>PF</d> patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research.
23399488|a|The origin of the myofibroblast in fibrotic <d>lung disease</d> is uncertain, and no effective medical therapy for fibrosis exists. We have previously demonstrated that transforming growth factor-b1 TGF-b1 induces pleural mesothelial cell PMC transformation into myofibroblasts and haptotactic migration in  vitro. Whether PMC differentiation and migration occurs in  vivo, and whether this response can be modulated for therapeutic benefit, is unknown. Here, using mice recombinant for green fluorescent protein GFP driven by the Wilms tumor-1 WT-1 promoter, we demonstrate PMC trafficking into the lung and differentiation into myofibroblasts. Carbon monoxide or the induction of heme oxygenase-1 HO-1 inhibited the expression of myofibroblast markers, contractility, and haptotaxis in PMCs treated with TGF-b1. Intrapleural HO-1 induction inhibited PMC migration after intratracheal fibrogenic injury. PMCs from patients with idiopathic pulmonary fibrosis IPF exhibited increased expression of myofibroblast markers and enhanced contractility and haptotaxis, compared with normal PMCs. Carbon monoxide reversed this IPF PMC profibrotic phenotype. WT-1-expressing cells were present within fibrotic regions of the lungs in IPF subjects, supporting a role for PMC differentiation and trafficking as contributors to the myofibroblast population in lung fibrosis. Our findings also support a potential role for pleural-based therapies to modulate pleural mesothelial activation and parenchymal fibrosis progression.
23399488|a|The origin of the myofibroblast in fibrotic <d>lung disease</d> is uncertain, and no effective medical therapy for <d>fibrosis</d> exists. We have previously demonstrated that transforming growth factor-b1 TGF-b1 induces pleural mesothelial cell PMC transformation into myofibroblasts and haptotactic migration in  vitro. Whether PMC differentiation and migration occurs in  vivo, and whether this response can be modulated for therapeutic benefit, is unknown. Here, using mice recombinant for green fluorescent protein GFP driven by the Wilms tumor-1 WT-1 promoter, we demonstrate PMC trafficking into the lung and differentiation into myofibroblasts. Carbon monoxide or the induction of heme oxygenase-1 HO-1 inhibited the expression of myofibroblast markers, contractility, and haptotaxis in PMCs treated with TGF-b1. Intrapleural HO-1 induction inhibited PMC migration after intratracheal fibrogenic injury. PMCs from patients with idiopathic pulmonary <d>fibrosis</d> IPF exhibited increased expression of myofibroblast markers and enhanced contractility and haptotaxis, compared with normal PMCs. Carbon monoxide reversed this IPF PMC profibrotic phenotype. WT-1-expressing cells were present within fibrotic regions of the lungs in IPF subjects, supporting a role for PMC differentiation and trafficking as contributors to the myofibroblast population in lung <d>fibrosis</d>. Our findings also support a potential role for pleural-based therapies to modulate pleural mesothelial activation and parenchymal <d>fibrosis</d> progression.
23399488|a|The origin of the myofibroblast in fibrotic <d>lung disease</d> is uncertain, and no effective medical therapy for <d>fibrosis</d> exists. We have previously demonstrated that <g>transforming growth factor-b1</g> <g>TGF-b1</g> induces pleural mesothelial cell PMC transformation into myofibroblasts and haptotactic migration in  vitro. Whether PMC differentiation and migration occurs in  vivo, and whether this response can be modulated for therapeutic benefit, is unknown. Here, using mice recombinant for green fluorescent protein GFP driven by the <d>Wilms tumor</d>-1 WT-1 promoter, we demonstrate PMC trafficking into the lung and differentiation into myofibroblasts. Carbon monoxide or the induction of heme oxygenase-1 HO-1 inhibited the expression of myofibroblast markers, contractility, and haptotaxis in PMCs treated with <g>TGF-b1</g>. Intrapleural HO-1 induction inhibited PMC migration after intratracheal fibrogenic injury. PMCs from patients with idiopathic pulmonary <d>fibrosis</d> IPF exhibited increased expression of myofibroblast markers and enhanced contractility and haptotaxis, compared with normal PMCs. Carbon monoxide reversed this IPF PMC profibrotic phenotype. WT-1-expressing cells were present within fibrotic regions of the lungs in IPF subjects, supporting a role for PMC differentiation and trafficking as contributors to the myofibroblast population in lung <d>fibrosis</d>. Our findings also support a potential role for pleural-based therapies to modulate pleural mesothelial activation and parenchymal <d>fibrosis</d> progression.
23399488|a|The origin of the myofibroblast in fibrotic <d>lung disease</d> is uncertain, and no effective medical therapy for <d>fibrosis</d> exists. We have previously demonstrated that <g>transforming growth factor-b1</g> <g>TGF-b1</g> induces pleural mesothelial cell PMC transformation into myofibroblasts and haptotactic migration in  vitro. Whether PMC differentiation and migration occurs in  vivo, and whether this response can be modulated for therapeutic benefit, is unknown. Here, using mice recombinant for green fluorescent protein GFP driven by the <d>Wilms tumor</d>-1 <d>WT</d>-1 promoter, we demonstrate PMC trafficking into the lung and differentiation into myofibroblasts. Carbon monoxide or the induction of heme oxygenase-1 HO-1 inhibited the expression of myofibroblast markers, contractility, and haptotaxis in PMCs treated with <g>TGF-b1</g>. Intrapleural HO-1 induction inhibited PMC migration after intratracheal fibrogenic injury. PMCs from patients with idiopathic pulmonary <d>fibrosis</d> IPF exhibited increased expression of myofibroblast markers and enhanced contractility and haptotaxis, compared with normal PMCs. Carbon monoxide reversed this IPF PMC profibrotic phenotype. <d>WT</d>-1-expressing cells were present within fibrotic regions of the lungs in IPF subjects, supporting a role for PMC differentiation and trafficking as contributors to the myofibroblast population in lung <d>fibrosis</d>. Our findings also support a potential role for pleural-based therapies to modulate pleural mesothelial activation and parenchymal <d>fibrosis</d> progression.
23399488|a|The origin of the myofibroblast in fibrotic <d>lung disease</d> is uncertain, and no effective medical therapy for <d>fibrosis</d> exists. We have previously demonstrated that <g>transforming growth factor-b1</g> <g>TGF-b1</g> induces pleural mesothelial cell PMC transformation into myofibroblasts and haptotactic migration in  vitro. Whether PMC differentiation and migration occurs in  vivo, and whether this response can be modulated for therapeutic benefit, is unknown. Here, using mice recombinant for green fluorescent protein GFP driven by the <d>Wilms tumor</d>-1 <d>WT</d>-1 promoter, we demonstrate PMC trafficking into the lung and differentiation into myofibroblasts. Carbon monoxide or the induction of <g>heme oxygenase-1</g> HO-1 inhibited the expression of myofibroblast markers, contractility, and haptotaxis in PMCs treated with <g>TGF-b1</g>. Intrapleural HO-1 induction inhibited PMC migration after intratracheal fibrogenic injury. PMCs from patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> exhibited increased expression of myofibroblast markers and enhanced contractility and haptotaxis, compared with normal PMCs. Carbon monoxide reversed this <d>IPF</d> PMC profibrotic phenotype. <d>WT</d>-1-expressing cells were present within fibrotic regions of the lungs in <d>IPF</d> subjects, supporting a role for PMC differentiation and trafficking as contributors to the myofibroblast population in lung <d>fibrosis</d>. Our findings also support a potential role for pleural-based therapies to modulate pleural mesothelial activation and parenchymal <d>fibrosis</d> progression.
23418199|a|Previously, we have shown that heparan sulfate HS 6-O-endosulfatase 1 Sulf1 is a transforming growth factor-b1 TGF-b1-responsive gene in normal human lung fibroblasts and functions as a negative feedback regulator of TGF-b1 and that TGF-b1 induces the expression of Sulf1 as well as that of the closely related <g>Sulf2</g> in a murine model of pulmonary fibrosis. In this study, we focused on the role of <g>Sulf2</g> in modulating TGF-b1 function and the development of pulmonary fibrosis. We found that <g>Sulf2</g> mRNA was overexpressed in lung samples from human patients with <d>idiopathic pulmonary fibrosis</d> IPF, and <g>Sulf2</g> protein was specifically localized to the hyperplastic type II alveolar epithelial cells AECs. In vitro, TGF-b1 induced the expression of <g>Sulf2</g> with accompanied HS 6-O-desulfation in A549 cells, adenocarcinoma cells derived from the type II alveolar epithelium. Using small interference RNA to block <g>Sulf2</g> expression, we observed a biphasic TGF-b1 response with early enhanced Smad activation, but eventually reduced TGF-b1 target gene expression in <g>Sulf2</g> knockdown A549 cells compared with the control cells. To study the role of <g>Sulf2</g> in normal type II AECs, we isolated primary type II cells from wild-type and <g>Sulf2</g> knockout mice. We observed enhanced Smad activation as well as enhanced TGF-b1 target gene expression in <g>Sulf2</g> knockout type II AECs compared with wild-type type II AECs. In conclusion, <g>Sulf2</g> is overexpressed in IPF and may play a role in regulating TGF-b1 signaling in type II AECs.
23418199|a|Previously, we have shown that heparan sulfate HS 6-O-endosulfatase 1 <g>Sulf1</g> is a <g>transforming growth factor-b1</g> <g>TGF-b1</g>-responsive gene in normal human lung fibroblasts and functions as a negative feedback regulator of <g>TGF-b1</g> and that <g>TGF-b1</g> induces the expression of <g>Sulf1</g> as well as that of the closely related <g>Sulf2</g> in a murine model of <d>pulmonary fibrosis</d>. In this study, we focused on the role of <g>Sulf2</g> in modulating <g>TGF-b1</g> function and the development of <d>pulmonary fibrosis</d>. We found that <g>Sulf2</g> mRNA was overexpressed in lung samples from human patients with <d>idiopathic <d>pulmonary fibrosis</d></d> IPF, and <g>Sulf2</g> protein was specifically localized to the hyperplastic type II alveolar epithelial cells AECs. In vitro, <g>TGF-b1</g> induced the expression of <g>Sulf2</g> with accompanied HS 6-O-desulfation in A549 cells, adenocarcinoma cells derived from the type II alveolar epithelium. Using small interference RNA to block <g>Sulf2</g> expression, we observed a biphasic <g>TGF-b1</g> response with early enhanced Smad activation, but eventually reduced <g>TGF-b1</g> target gene expression in <g>Sulf2</g> knockdown A549 cells compared with the control cells. To study the role of <g>Sulf2</g> in normal type II AECs, we isolated primary type II cells from wild-type and <g>Sulf2</g> knockout mice. We observed enhanced Smad activation as well as enhanced <g>TGF-b1</g> target gene expression in <g>Sulf2</g> knockout type II AECs compared with wild-type type II AECs. In conclusion, <g>Sulf2</g> is overexpressed in IPF and may play a role in regulating <g>TGF-b1</g> signaling in type II AECs.
23418199|a|Previously, we have shown that heparan sulfate HS 6-O-endosulfatase 1 <g>Sulf1</g> is a <g>transforming growth factor-b1</g> <g>TGF-b1</g>-responsive gene in normal human lung fibroblasts and functions as a negative feedback regulator of <g>TGF-b1</g> and that <g>TGF-b1</g> induces the expression of <g>Sulf1</g> as well as that of the closely related <g>Sulf2</g> in a murine model of <d>pulmonary fibrosis</d>. In this study, we focused on the role of <g>Sulf2</g> in modulating <g>TGF-b1</g> function and the development of <d>pulmonary fibrosis</d>. We found that <g>Sulf2</g> mRNA was overexpressed in lung samples from human patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, and <g>Sulf2</g> protein was specifically localized to the hyperplastic type II alveolar epithelial cells AECs. In vitro, <g>TGF-b1</g> induced the expression of <g>Sulf2</g> with accompanied HS 6-O-desulfation in A549 cells, adenocarcinoma cells derived from the type II alveolar epithelium. Using small interference RNA to block <g>Sulf2</g> expression, we observed a biphasic <g>TGF-b1</g> response with early enhanced Smad activation, but eventually reduced <g>TGF-b1</g> target gene expression in <g>Sulf2</g> knockdown A549 cells compared with the control cells. To study the role of <g>Sulf2</g> in normal type II AECs, we isolated primary type II cells from wild-type and <g>Sulf2</g> knockout mice. We observed enhanced Smad activation as well as enhanced <g>TGF-b1</g> target gene expression in <g>Sulf2</g> knockout type II AECs compared with wild-type type II AECs. In conclusion, <g>Sulf2</g> is overexpressed in <d>IPF</d> and may play a role in regulating <g>TGF-b1</g> signaling in type II AECs.
23418199|a|Previously, we have shown that heparan sulfate HS 6-O-endosulfatase 1 <g>Sulf1</g> is a <g>transforming growth factor-b1</g> <g>TGF-b1</g>-responsive gene in normal human lung fibroblasts and functions as a negative feedback regulator of <g>TGF-b1</g> and that <g>TGF-b1</g> induces the expression of <g>Sulf1</g> as well as that of the closely related <g>Sulf2</g> in a murine model of <d>pulmonary fibrosis</d>. In this study, we focused on the role of <g>Sulf2</g> in modulating <g>TGF-b1</g> function and the development of <d>pulmonary fibrosis</d>. We found that <g>Sulf2</g> mRNA was overexpressed in lung samples from human patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, and <g>Sulf2</g> protein was specifically localized to the hyperplastic type II alveolar epithelial cells AECs. In vitro, <g>TGF-b1</g> induced the expression of <g>Sulf2</g> with accompanied HS 6-O-desulfation in A549 cells, <d>adenocarcinoma</d> cells derived from the type II alveolar epithelium. Using small interference RNA to block <g>Sulf2</g> expression, we observed a biphasic <g>TGF-b1</g> response with early enhanced Smad activation, but eventually reduced <g>TGF-b1</g> target gene expression in <g>Sulf2</g> knockdown A549 cells compared with the control cells. To study the role of <g>Sulf2</g> in normal type II AECs, we isolated primary type II cells from wild-type and <g>Sulf2</g> knockout mice. We observed enhanced Smad activation as well as enhanced <g>TGF-b1</g> target gene expression in <g>Sulf2</g> knockout type II AECs compared with wild-type type II AECs. In conclusion, <g>Sulf2</g> is overexpressed in <d>IPF</d> and may play a role in regulating <g>TGF-b1</g> signaling in type II AECs.
23418199|a|Previously, we have shown that heparan sulfate HS 6-O-endosulfatase 1 <g>Sulf1</g> is a <g>transforming growth factor-b1</g> <g>TGF-b1</g>-responsive gene in normal human lung fibroblasts and functions as a negative feedback regulator of <g>TGF-b1</g> and that <g>TGF-b1</g> induces the expression of <g>Sulf1</g> as well as that of the closely related <g>Sulf2</g> in a murine model of <d>pulmonary fibrosis</d>. In this study, we focused on the role of <g>Sulf2</g> in modulating <g>TGF-b1</g> function and the development of <d>pulmonary fibrosis</d>. We found that <g>Sulf2</g> mRNA was overexpressed in lung samples from human patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, and <g>Sulf2</g> protein was specifically localized to the hyperplastic type II alveolar epithelial cells AECs. In vitro, <g>TGF-b1</g> induced the expression of <g>Sulf2</g> with accompanied HS 6-O-desulfation in A549 cells, <d>adenocarcinoma</d> cells derived from the <d>type II alveolar epithelium</d>. Using small interference RNA to block <g>Sulf2</g> expression, we observed a biphasic <g>TGF-b1</g> response with early enhanced Smad activation, but eventually reduced <g>TGF-b1</g> target gene expression in <g>Sulf2</g> knockdown A549 cells compared with the control cells. To study the role of <g>Sulf2</g> in normal type II AECs, we isolated primary type II cells from wild-type and <g>Sulf2</g> knockout mice. We observed enhanced Smad activation as well as enhanced <g>TGF-b1</g> target gene expression in <g>Sulf2</g> knockout type II AECs compared with wild-type type II AECs. In conclusion, <g>Sulf2</g> is overexpressed in <d>IPF</d> and may play a role in regulating <g>TGF-b1</g> signaling in type II AECs.
23434591|a|Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic fibrotic diseases involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase Rho/ROCK, actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 MKL1, that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic <d>pulmonary fibrosis</d> IPF, we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung fibrosis. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.
23434591|a|Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic <d>fibrotic diseases</d> involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase Rho/ROCK, actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 MKL1, that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic <d>pulmonary fibrosis</d> IPF, we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung fibrosis. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.
23434591|a|Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic <d>fibrotic diseases</d> involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive <d>fibrosis</d> are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase Rho/ROCK, actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 MKL1, that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung <d>fibrosis</d> and in human subjects with idiopathic <d>pulmonary <d>fibrosis</d></d> IPF, we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung <d>fibrosis</d>. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.
23434591|a|Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic <d>fibrotic diseases</d> involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive <d>fibrosis</d> are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase Rho/ROCK, actin cytoskeletal remodeling, and a mechanosensitive transcription factor, <g>megakaryoblastic leukemia 1</g> <g>MKL1</g>, that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung <d>fibrosis</d> and in human subjects with idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>, we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and <g>MKL1</g> cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung <d>fibrosis</d>. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.
23434591|a|Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic <d>fibrotic diseases</d> involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive <d>fibrosis</d> are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase Rho/ROCK, actin cytoskeletal remodeling, and a mechanosensitive transcription factor, <g>megakaryoblastic leukemia 1</g> <g>MKL1</g>, that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung <d>fibrosis</d> and in human subjects with idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>, we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and <g>MKL1</g> cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of <g>BCL-2</g> and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of <d>lung injury</d> or genetic ablation of Mkl1 protected mice from experimental lung <d>fibrosis</d>. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.
23434591|a|Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic <d>fibrotic diseases</d> involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive <d>fibrosis</d> are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase Rho/ROCK, actin cytoskeletal remodeling, and a mechanosensitive transcription factor, <g>megakaryoblastic leukemia 1</g> <g>MKL1</g>, that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung <d>fibrosis</d> and in human subjects with idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>, we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and <g>MKL1</g> cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of <g>BCL-2</g> and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of <d>lung injury</d> or genetic ablation of <g>Mkl1</g> protected mice from experimental lung <d>fibrosis</d>. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of <d>fibrotic disorders</d>.
23436625|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic, progressive and fatal lung disease with no known etiology and treatment options. The hallmarks of the histopathology, which is characteristic of usual interstitial pneumonia UIP pattern, include interstitial fibrosis, honeycomb changes and fibroblast foci that develop owing to fibroblast proliferation and excessive matrix deposition. Although the complete pathomechanism is not yet understood, several molecular culprits, including transforming growth factor TGF-b, Angiotensin Ang II, endothelin ET-1, matrix metalloproteinases MMPs and cytokines have been identified. IPF is increasingly believed to be an epithelial-driven disease; however, the literature does support an implication of altered immune response and inflammatory processes in the onset or progression of the disease. Mast cells MCs are multifunctional tissue resident cells involved in the inflammatory and immune response. An increasing body of evidence suggests a role of MCs and their mediator chymase in the pathology of IPF. With regard to the underlying mechanisms, it is conceivable that MC chymase may function via activation or processing of factors such as proteases, cytokines and growth factors. In this review, we will discuss how MC chymase is linked to and can potentially contribute to the development of IPF. Moreover, the findings from animal model studies will be discussed to highlight the chymase inhibitors as a promising strategy for the treatment of pulmonary fibrosis.
23436625|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and fatal lung disease with no known etiology and treatment options. The hallmarks of the histopathology, which is characteristic of usual interstitial pneumonia UIP pattern, include interstitial fibrosis, honeycomb changes and fibroblast foci that develop owing to fibroblast proliferation and excessive matrix deposition. Although the complete pathomechanism is not yet understood, several molecular culprits, including transforming growth factor TGF-b, Angiotensin Ang II, endothelin ET-1, matrix metalloproteinases MMPs and cytokines have been identified. <d>IPF</d> is increasingly believed to be an epithelial-driven disease; however, the literature does support an implication of altered immune response and inflammatory processes in the onset or progression of the disease. Mast cells MCs are multifunctional tissue resident cells involved in the inflammatory and immune response. An increasing body of evidence suggests a role of MCs and their mediator chymase in the pathology of <d>IPF</d>. With regard to the underlying mechanisms, it is conceivable that MC chymase may function via activation or processing of factors such as proteases, cytokines and growth factors. In this review, we will discuss how MC chymase is linked to and can potentially contribute to the development of <d>IPF</d>. Moreover, the findings from animal model studies will be discussed to highlight the chymase inhibitors as a promising strategy for the treatment of pulmonary fibrosis.
23436625|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and fatal <d>lung disease</d> with no known etiology and treatment options. The hallmarks of the histopathology, which is characteristic of usual interstitial pneumonia UIP pattern, include interstitial fibrosis, honeycomb changes and fibroblast foci that develop owing to fibroblast proliferation and excessive matrix deposition. Although the complete pathomechanism is not yet understood, several molecular culprits, including transforming growth factor TGF-b, Angiotensin Ang II, endothelin ET-1, matrix metalloproteinases MMPs and cytokines have been identified. <d>IPF</d> is increasingly believed to be an epithelial-driven disease; however, the literature does support an implication of altered immune response and inflammatory processes in the onset or progression of the disease. Mast cells MCs are multifunctional tissue resident cells involved in the inflammatory and immune response. An increasing body of evidence suggests a role of MCs and their mediator chymase in the pathology of <d>IPF</d>. With regard to the underlying mechanisms, it is conceivable that MC chymase may function via activation or processing of factors such as proteases, cytokines and growth factors. In this review, we will discuss how MC chymase is linked to and can potentially contribute to the development of <d>IPF</d>. Moreover, the findings from animal model studies will be discussed to highlight the chymase inhibitors as a promising strategy for the treatment of pulmonary fibrosis.
23436625|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and fatal <d>lung disease</d> with no known etiology and treatment options. The hallmarks of the histopathology, which is characteristic of <d>usual interstitial pneumonia</d> UIP pattern, include interstitial fibrosis, honeycomb changes and fibroblast foci that develop owing to fibroblast proliferation and excessive matrix deposition. Although the complete pathomechanism is not yet understood, several molecular culprits, including transforming growth factor TGF-b, Angiotensin Ang II, endothelin ET-1, matrix metalloproteinases MMPs and cytokines have been identified. <d>IPF</d> is increasingly believed to be an epithelial-driven disease; however, the literature does support an implication of altered immune response and inflammatory processes in the onset or progression of the disease. Mast cells MCs are multifunctional tissue resident cells involved in the inflammatory and immune response. An increasing body of evidence suggests a role of MCs and their mediator chymase in the pathology of <d>IPF</d>. With regard to the underlying mechanisms, it is conceivable that MC chymase may function via activation or processing of factors such as proteases, cytokines and growth factors. In this review, we will discuss how MC chymase is linked to and can potentially contribute to the development of <d>IPF</d>. Moreover, the findings from animal model studies will be discussed to highlight the chymase inhibitors as a promising strategy for the treatment of pulmonary fibrosis.
23436625|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and fatal <d>lung disease</d> with no known etiology and treatment options. The hallmarks of the histopathology, which is characteristic of <d>usual interstitial pneumonia</d> <d>UIP</d> pattern, include interstitial fibrosis, honeycomb changes and fibroblast foci that develop owing to fibroblast proliferation and excessive matrix deposition. Although the complete pathomechanism is not yet understood, several molecular culprits, including transforming growth factor TGF-b, Angiotensin Ang II, endothelin ET-1, matrix metalloproteinases MMPs and cytokines have been identified. <d>IPF</d> is increasingly believed to be an epithelial-driven disease; however, the literature does support an implication of altered immune response and inflammatory processes in the onset or progression of the disease. Mast cells MCs are multifunctional tissue resident cells involved in the inflammatory and immune response. An increasing body of evidence suggests a role of MCs and their mediator chymase in the pathology of <d>IPF</d>. With regard to the underlying mechanisms, it is conceivable that MC chymase may function via activation or processing of factors such as proteases, cytokines and growth factors. In this review, we will discuss how MC chymase is linked to and can potentially contribute to the development of <d>IPF</d>. Moreover, the findings from animal model studies will be discussed to highlight the chymase inhibitors as a promising strategy for the treatment of pulmonary fibrosis.
23436625|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and fatal <d>lung disease</d> with no known etiology and treatment options. The hallmarks of the histopathology, which is characteristic of <d>usual interstitial pneumonia</d> <d>UIP</d> pattern, include <d>interstitial fibrosis</d>, honeycomb changes and fibroblast foci that develop owing to fibroblast proliferation and excessive matrix deposition. Although the complete pathomechanism is not yet understood, several molecular culprits, including transforming growth factor TGF-b, Angiotensin Ang II, endothelin ET-1, matrix metalloproteinases MMPs and cytokines have been identified. <d>IPF</d> is increasingly believed to be an epithelial-driven disease; however, the literature does support an implication of altered immune response and inflammatory processes in the onset or progression of the disease. Mast cells MCs are multifunctional tissue resident cells involved in the inflammatory and immune response. An increasing body of evidence suggests a role of MCs and their mediator chymase in the pathology of <d>IPF</d>. With regard to the underlying mechanisms, it is conceivable that MC chymase may function via activation or processing of factors such as proteases, cytokines and growth factors. In this review, we will discuss how MC chymase is linked to and can potentially contribute to the development of <d>IPF</d>. Moreover, the findings from animal model studies will be discussed to highlight the chymase inhibitors as a promising strategy for the treatment of pulmonary fibrosis.
23436625|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a chronic, progressive and fatal <d>lung disease</d> with no known etiology and treatment options. The hallmarks of the histopathology, which is characteristic of <d>usual interstitial pneumonia</d> <d>UIP</d> pattern, include <d>interstitial fibrosis</d>, honeycomb changes and fibroblast foci that develop owing to fibroblast proliferation and excessive matrix deposition. Although the complete pathomechanism is not yet understood, several molecular culprits, including transforming growth factor TGF-b, Angiotensin Ang II, endothelin ET-1, matrix metalloproteinases MMPs and cytokines have been identified. <d>IPF</d> is increasingly believed to be an epithelial-driven disease; however, the literature does support an implication of altered immune response and inflammatory processes in the onset or progression of the disease. Mast cells MCs are multifunctional tissue resident cells involved in the inflammatory and immune response. An increasing body of evidence suggests a role of MCs and their mediator chymase in the pathology of <d>IPF</d>. With regard to the underlying mechanisms, it is conceivable that MC chymase may function via activation or processing of factors such as proteases, cytokines and growth factors. In this review, we will discuss how MC chymase is linked to and can potentially contribute to the development of <d>IPF</d>. Moreover, the findings from animal model studies will be discussed to highlight the chymase inhibitors as a promising strategy for the treatment of <d>pulmonary fibrosis</d>.
23439433|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive fibroproliferative disease whose molecular pathogenesis remains unclear. In a recent paper, we demonstrated a key role for the <g>PI3K</g> pathway in both proliferation and differentiation into myofibroblasts of normal human lung fibroblasts treated with TGF-b. In this research, we assessed the expression of class I <g>PI3K</g> p110 isoforms in IPF lung tissue as well as in tissue-derived fibroblast cell lines. Moreover, we investigated the in vitro effects of the selective inhibition of p110 isoforms on IPF fibroblast proliferation and fibrogenic activity. IHC was performed on normal and IPF lung tissue. Expression levels of <g>PI3K</g> p110 isoforms were evaluated by western blot and flow cytometry analysis. Fibroblast cell lines were established from both normal and IPF tissue and the effects of selective pharmacological inhibition as well as specific gene silencing by small interfering RNAs were studied in vitro. No significant differences between normal and IPF tissue/tissue-derived fibroblasts were observed for the expression of <g>PI3K</g> p110 a, b and    isoforms whereas p110y was more greatly expressed in both IPF lung homogenates and ex vivo fibroblast cell lines. Myofibroblasts and bronchiolar basal cells in IPF lungs exhibited strong immunoreactivity for p110y. Positive staining for the markers of proliferation proliferating cell nuclear antigen and cyclin D1 was also shown in cells of fibrolastic foci. Furthermore, both p110y pharmacological inhibition and gene silencing were able to significantly inhibit proliferation rate as well as a-SMA expression in IPF fibroblasts. Our data suggest that <g>PI3K</g> p110y isoform may have an important role in the etio-pathology of IPF and can be a specific pharmacological target.
23439433|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive fibroproliferative disease whose molecular pathogenesis remains unclear. In a recent paper, we demonstrated a key role for the <g>PI3K</g> pathway in both proliferation and differentiation into myofibroblasts of normal human lung fibroblasts treated with TGF-b. In this research, we assessed the expression of class I <g>PI3K</g> p110 isoforms in <d>IPF</d> lung tissue as well as in tissue-derived fibroblast cell lines. Moreover, we investigated the in vitro effects of the selective inhibition of p110 isoforms on <d>IPF</d> fibroblast proliferation and fibrogenic activity. IHC was performed on normal and <d>IPF</d> lung tissue. Expression levels of <g>PI3K</g> p110 isoforms were evaluated by western blot and flow cytometry analysis. Fibroblast cell lines were established from both normal and <d>IPF</d> tissue and the effects of selective pharmacological inhibition as well as specific gene silencing by small interfering RNAs were studied in vitro. No significant differences between normal and <d>IPF</d> tissue/tissue-derived fibroblasts were observed for the expression of <g>PI3K</g> p110 a, b and    isoforms whereas p110y was more greatly expressed in both <d>IPF</d> lung homogenates and ex vivo fibroblast cell lines. Myofibroblasts and bronchiolar basal cells in <d>IPF</d> lungs exhibited strong immunoreactivity for p110y. Positive staining for the markers of proliferation proliferating cell nuclear antigen and cyclin D1 was also shown in cells of fibrolastic foci. Furthermore, both p110y pharmacological inhibition and gene silencing were able to significantly inhibit proliferation rate as well as a-SMA expression in <d>IPF</d> fibroblasts. Our data suggest that <g>PI3K</g> p110y isoform may have an important role in the etio-pathology of <d>IPF</d> and can be a specific pharmacological target.
23442250|a|<d>Idiopathic pulmonary fibrosis</d> IPF is thought to involve inflammatory cells and reactive oxygen species ROS, such as superoxide anion radical O2  -. There is currently no effective treatment of IPF. We previously developed a human serum albumin HSA-thioredoxin 1 Trx fusion protein HSA-Trx designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an antioxidative and anti-inflammatory protein. In this study, we examined the therapeutic effect of HSA-Trx on an IPF animal model of bleomycin BLM-induced pulmonary fibrosis. A pharmacokinetic study of HSA-Trx or Trx in BLM mice showed that the plasma retention and lung distribution of Trxc was markedly improved by fusion with HSA. A weekly intravenous administration of HSA-Trx, but not Trx, ameliorated BLM-induced fibrosis, as evidenced by a histopathological analysis and pulmonary hydroxyproline levels. HSA-Trx suppressed active-transforming growth factor TGF-b levels in the lung and inhibited the increase of inflammatory cells in bronchoalveolar lavage fluid, pulmonary inflammatory cytokines, and oxidative stress markers. An in vitro EPR experiment using phosphate-buffered saline-stimulated neutrophils confirmed the O2  - scavenging ability of HSA-Trx. Furthermore, post-treatment of HSA-Trx had a suppressive effect against BLM-induced fibrosis. These results suggest that HSA-Trx has potential as a novel therapeutic agent for IPF, because of its long-acting antioxidative and anti-inflammatory modulation effects.
23442250|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is thought to involve inflammatory cells and reactive oxygen species ROS, such as superoxide anion radical O2  -. There is currently no effective treatment of <d>IPF</d>. We previously developed a human serum albumin HSA-thioredoxin 1 Trx fusion protein HSA-Trx designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an antioxidative and anti-inflammatory protein. In this study, we examined the therapeutic effect of HSA-Trx on an <d>IPF</d> animal model of bleomycin BLM-induced pulmonary fibrosis. A pharmacokinetic study of HSA-Trx or Trx in BLM mice showed that the plasma retention and lung distribution of Trxc was markedly improved by fusion with HSA. A weekly intravenous administration of HSA-Trx, but not Trx, ameliorated BLM-induced fibrosis, as evidenced by a histopathological analysis and pulmonary hydroxyproline levels. HSA-Trx suppressed active-transforming growth factor TGF-b levels in the lung and inhibited the increase of inflammatory cells in bronchoalveolar lavage fluid, pulmonary inflammatory cytokines, and oxidative stress markers. An in vitro EPR experiment using phosphate-buffered saline-stimulated neutrophils confirmed the O2  - scavenging ability of HSA-Trx. Furthermore, post-treatment of HSA-Trx had a suppressive effect against BLM-induced fibrosis. These results suggest that HSA-Trx has potential as a novel therapeutic agent for <d>IPF</d>, because of its long-acting antioxidative and anti-inflammatory modulation effects.
23442250|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is thought to involve inflammatory cells and reactive oxygen species ROS, such as superoxide anion radical O2  -. There is currently no effective treatment of <d>IPF</d>. We previously developed a human <g>serum albumin HSA-thioredoxin 1</g> <g>Trx</g> fusion protein HSA-<g>Trx</g> designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of <g>Trx</g>, an antioxidative and anti-inflammatory protein. In this study, we examined the therapeutic effect of HSA-<g>Trx</g> on an <d>IPF</d> animal model of bleomycin BLM-induced <d>pulmonary fibrosis</d>. A pharmacokinetic study of HSA-<g>Trx</g> or <g>Trx</g> in BLM mice showed that the plasma retention and lung distribution of <g>Trx</g>c was markedly improved by fusion with HSA. A weekly intravenous administration of HSA-<g>Trx</g>, but not <g>Trx</g>, ameliorated BLM-induced fibrosis, as evidenced by a histopathological analysis and pulmonary hydroxyproline levels. HSA-<g>Trx</g> suppressed active-transforming growth factor TGF-b levels in the lung and inhibited the increase of inflammatory cells in bronchoalveolar lavage fluid, pulmonary inflammatory cytokines, and oxidative stress markers. An in vitro EPR experiment using phosphate-buffered saline-stimulated neutrophils confirmed the O2  - scavenging ability of HSA-<g>Trx</g>. Furthermore, post-treatment of HSA-<g>Trx</g> had a suppressive effect against BLM-induced fibrosis. These results suggest that HSA-<g>Trx</g> has potential as a novel therapeutic agent for <d>IPF</d>, because of its long-acting antioxidative and anti-inflammatory modulation effects.
23442250|a|<d>Idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d> is thought to involve inflammatory cells and reactive oxygen species ROS, such as superoxide anion radical O2  -. There is currently no effective treatment of <d>IPF</d>. We previously developed a human <g>serum albumin HSA-thioredoxin 1</g> <g>Trx</g> fusion protein HSA-<g>Trx</g> designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of <g>Trx</g>, an antioxidative and anti-inflammatory protein. In this study, we examined the therapeutic effect of HSA-<g>Trx</g> on an <d>IPF</d> animal model of bleomycin BLM-induced <d>pulmonary <d>fibrosis</d></d>. A pharmacokinetic study of HSA-<g>Trx</g> or <g>Trx</g> in BLM mice showed that the plasma retention and lung distribution of <g>Trx</g>c was markedly improved by fusion with HSA. A weekly intravenous administration of HSA-<g>Trx</g>, but not <g>Trx</g>, ameliorated BLM-induced <d>fibrosis</d>, as evidenced by a histopathological analysis and pulmonary hydroxyproline levels. HSA-<g>Trx</g> suppressed active-transforming growth factor TGF-b levels in the lung and inhibited the increase of inflammatory cells in bronchoalveolar lavage fluid, pulmonary inflammatory cytokines, and oxidative stress markers. An in vitro EPR experiment using phosphate-buffered saline-stimulated neutrophils confirmed the O2  - scavenging ability of HSA-<g>Trx</g>. Furthermore, post-treatment of HSA-<g>Trx</g> had a suppressive effect against BLM-induced <d>fibrosis</d>. These results suggest that HSA-<g>Trx</g> has potential as a novel therapeutic agent for <d>IPF</d>, because of its long-acting antioxidative and anti-inflammatory modulation effects.
23459460|a|As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic <d>lung diseases</d>, especially the idiopathic form IPF, remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients 94 IPF versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFb exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFb signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
23459460|a|As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic <d>lung diseases</d>, especially the <d>idiopathic form</d> IPF, remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients 94 IPF versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFb exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFb signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
23459460|a|As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic <d>lung diseases</d>, especially the <d>idiopathic form</d> <d>IPF</d>, remains poorly understood. Given the poor response rate of <d>IPF</d> patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in <d>IPF</d> patients 94 <d>IPF</d> versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with <d>IPF</d>. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFb exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFb signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
23459460|a|As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic <d>lung diseases</d>, especially the <d>idiopathic form</d> <d>IPF</d>, remains poorly understood. Given the poor response rate of <d>IPF</d> patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop <d>lung fibrosis</d> after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in <d>IPF</d> patients 94 <d>IPF</d> versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with <d>IPF</d>. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFb exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFb signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
23459460|a|As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic <d>lung diseases</d>, especially the <d>idiopathic form</d> <d>IPF</d>, remains poorly understood. Given the poor response rate of <d>IPF</d> patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop <d>lung fibrosis</d> after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in <d>IPF</d> patients 94 <d>IPF</d> versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with <d>IPF</d>. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon <g>TGFb</g> exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of <g>TGFb</g> signaling in lung fibroblasts by regulating <g>CAV1</g>, a critical mediator of <d>pulmonary fibrosis</d>. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
23459460|a|As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic <d>lung diseases</d>, especially the <d>idiopathic form</d> <d>IPF</d>, remains poorly understood. Given the poor response rate of <d>IPF</d> patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop <d>lung fibrosis</d> after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in <d>IPF</d> patients 94 <d>IPF</d> versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with <d>IPF</d>. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon <g>TGFb</g> exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of <g>TGFb</g> signaling in lung fibroblasts by regulating <g>CAV1</g>, a critical mediator of <d>pulmonary fibrosis</d>. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of <d>kidney fibrosis</d>, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
23459460|a|As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic <d>lung diseases</d>, especially the <d>idiopathic form</d> <d>IPF</d>, remains poorly understood. Given the poor response rate of <d>IPF</d> patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop <d>lung fibrosis</d> after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in <d>IPF</d> patients 94 <d>IPF</d> versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with <d>IPF</d>. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon <g>TGFb</g> exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of <g>TGFb</g> signaling in lung fibroblasts by regulating <g>CAV1</g>, a critical mediator of <d>pulmonary fibrosis</d>. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of <d>kidney fibrosis</d>, as well as in both bile duct ligation and <g>CCl4</g>-induced mouse models of <d>liver fibrosis</d>, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
23459460|a|As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic <d>lung diseases</d>, especially the <d>idiopathic form</d> <d>IPF</d>, remains poorly understood. Given the poor response rate of <d>IPF</d> patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop <d>lung <d>fibrosis</d></d> after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in <d>IPF</d> patients 94 <d>IPF</d> versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with <d>IPF</d>. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon <g>TGFb</g> exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of <g>TGFb</g> signaling in lung fibroblasts by regulating <g>CAV1</g>, a critical mediator of <d>pulmonary <d>fibrosis</d></d>. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of <d>kidney <d>fibrosis</d></d>, as well as in both bile duct ligation and <g>CCl4</g>-induced mouse models of <d>liver <d>fibrosis</d></d>, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue <d>fibrosis</d> with therapeutic potency to treat fibroproliferative diseases.
23459460|a|As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic <d>lung diseases</d>, especially the <d>idiopathic form</d> <d>IPF</d>, remains poorly understood. Given the poor response rate of <d>IPF</d> patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop <d>lung <d>fibrosis</d></d> after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in <d>IPF</d> patients 94 <d>IPF</d> versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with <d>IPF</d>. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon <g>TGFb</g> exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of <g>TGFb</g> signaling in lung fibroblasts by regulating <g>CAV1</g>, a critical mediator of <d>pulmonary <d>fibrosis</d></d>. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of <d>kidney <d>fibrosis</d></d>, as well as in both bile duct ligation and <g>CCl4</g>-induced mouse models of <d>liver <d>fibrosis</d></d>, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue <d>fibrosis</d> with therapeutic potency to treat <d>fibroproliferative diseases</d>.
23468849|a|BACKGROUND: Pulmonary hypertension PH represents an important complication of <d>idiopathic pulmonary fibrosis</d> IPF with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus MHV-68 induced pulmonary fibrosis was also assessed. METHODS: Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure mPAP and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. RESULTS: A higher frequency of virus positive cases was found in IPF patients than in controls p=0.0003 and only herpes virus genomes were detected. Viral cases showed higher mPAP p=0.01, poorer performance in the six minute walking test 6MWT; p=0.002 and higher frequency of primary graft PGD dysfunction after lung transplant p=0.02. Increased arterial thickening, particularly of the intimal layer p=0.002 and p=0.004 and higher TGF-b expression p=0.002 were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation Ki-67 positive cells in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP p=0.03, poorer performance in the 6MWT p=0.008 and PGD p=0.02 after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. CONCLUSION: Herpesviral infections may contribute to the development of PH in IPF patients.
23468849|a|BACKGROUND: <d>Pulmonary hypertension</d> PH represents an important complication of <d>idiopathic pulmonary fibrosis</d> IPF with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus MHV-68 induced pulmonary fibrosis was also assessed. METHODS: Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure mPAP and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. RESULTS: A higher frequency of virus positive cases was found in IPF patients than in controls p=0.0003 and only herpes virus genomes were detected. Viral cases showed higher mPAP p=0.01, poorer performance in the six minute walking test 6MWT; p=0.002 and higher frequency of primary graft PGD dysfunction after lung transplant p=0.02. Increased arterial thickening, particularly of the intimal layer p=0.002 and p=0.004 and higher TGF-b expression p=0.002 were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation Ki-67 positive cells in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP p=0.03, poorer performance in the 6MWT p=0.008 and PGD p=0.02 after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. CONCLUSION: Herpesviral infections may contribute to the development of PH in IPF patients.
23468849|a|BACKGROUND: <d>Pulmonary hypertension</d> <d>PH</d> represents an important complication of <d>idiopathic pulmonary fibrosis</d> IPF with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on <d>PH</d> associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to <d>PH</d>. A laboratory mouse model of gamma-herpesvirus MHV-68 induced pulmonary fibrosis was also assessed. METHODS: Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure mPAP and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. RESULTS: A higher frequency of virus positive cases was found in IPF patients than in controls p=0.0003 and only herpes virus genomes were detected. Viral cases showed higher mPAP p=0.01, poorer performance in the six minute walking test 6MWT; p=0.002 and higher frequency of primary graft PGD dysfunction after lung transplant p=0.02. Increased arterial thickening, particularly of the intimal layer p=0.002 and p=0.004 and higher TGF-b expression p=0.002 were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation Ki-67 positive cells in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP p=0.03, poorer performance in the 6MWT p=0.008 and PGD p=0.02 after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. CONCLUSION: Herpesviral infections may contribute to the development of <d>PH</d> in IPF patients.
23468849|a|BACKGROUND: <d>Pulmonary hypertension</d> <d>PH</d> represents an important complication of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of <d>IPF</d>. The influence of viruses on <d>PH</d> associated with <d>IPF</d> is unknown. We aimed to investigate the influence of viruses in <d>IPF</d> patients focusing on aspects related to <d>PH</d>. A laboratory mouse model of gamma-herpesvirus MHV-68 induced pulmonary fibrosis was also assessed. METHODS: Lung tissue samples from 55 <d>IPF</d> patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure mPAP and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. RESULTS: A higher frequency of virus positive cases was found in <d>IPF</d> patients than in controls p=0.0003 and only herpes virus genomes were detected. Viral cases showed higher mPAP p=0.01, poorer performance in the six minute walking test 6MWT; p=0.002 and higher frequency of primary graft PGD dysfunction after lung transplant p=0.02. Increased arterial thickening, particularly of the intimal layer p=0.002 and p=0.004 and higher TGF-b expression p=0.002 were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation Ki-67 positive cells in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP p=0.03, poorer performance in the 6MWT p=0.008 and PGD p=0.02 after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. CONCLUSION: Herpesviral infections may contribute to the development of <d>PH</d> in <d>IPF</d> patients.
23468849|a|BACKGROUND: <d>Pulmonary hypertension</d> <d>PH</d> represents an important complication of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of <d>IPF</d>. The influence of viruses on <d>PH</d> associated with <d>IPF</d> is unknown. We aimed to investigate the influence of viruses in <d>IPF</d> patients focusing on aspects related to <d>PH</d>. A laboratory mouse model of gamma-herpesvirus MHV-68 induced <d>pulmonary fibrosis</d> was also assessed. METHODS: Lung tissue samples from 55 <d>IPF</d> patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure mPAP and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. RESULTS: A higher frequency of virus positive cases was found in <d>IPF</d> patients than in controls p=0.0003 and only herpes virus genomes were detected. Viral cases showed higher mPAP p=0.01, poorer performance in the six minute walking test 6MWT; p=0.002 and higher frequency of primary graft PGD dysfunction after lung transplant p=0.02. Increased arterial thickening, particularly of the intimal layer p=0.002 and p=0.004 and higher TGF-b expression p=0.002 were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation Ki-67 positive cells in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP p=0.03, poorer performance in the 6MWT p=0.008 and PGD p=0.02 after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. CONCLUSION: Herpesviral infections may contribute to the development of <d>PH</d> in <d>IPF</d> patients.
23468849|a|BACKGROUND: <d>Pulmonary hypertension</d> <d>PH</d> represents an important complication of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of <d>IPF</d>. The influence of viruses on <d>PH</d> associated with <d>IPF</d> is unknown. We aimed to investigate the influence of viruses in <d>IPF</d> patients focusing on aspects related to <d>PH</d>. A laboratory mouse model of gamma-herpesvirus MHV-68 induced <d>pulmonary fibrosis</d> was also assessed. METHODS: Lung tissue samples from 55 <d>IPF</d> patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure mPAP and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. RESULTS: A higher frequency of virus positive cases was found in <d>IPF</d> patients than in controls p=0.0003 and only herpes virus genomes were detected. Viral cases showed higher mPAP p=0.01, poorer performance in the six minute walking test 6MWT; p=0.002 and higher frequency of primary graft PGD dysfunction after lung transplant p=0.02. Increased arterial thickening, particularly of the intimal layer p=0.002 and p=0.004 and higher <g>TGF-b</g> expression p=0.002 were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation Ki-67 positive cells in the proximity to metaplastic epithelial cells and macrophages. <d>Viral infection</d> was associated with higher mPAP p=0.03, poorer performance in the 6MWT p=0.008 and PGD p=0.02 after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. CONCLUSION: Herpesviral infections may contribute to the development of <d>PH</d> in <d>IPF</d> patients.
23470623|a|Mitogen-activated protein kinase-activated protein kinase-2 MAPKAPK2, or MK2, a serine/threonine kinase downstream of p38 mitogen-activated protein kinase, has been implicated in inflammation and fibrosis. Compared with pathologically normal lung tissue, significantly higher concentrations of activated MK2 are evident in lung biopsies of patients with idiopathic <d>pulmonary fibrosis</d> IPF. Expression is localized to fibroblasts and epithelial cells. In the murine bleomycin model of <d>pulmonary fibrosis</d>, we observed robust, activated MK2 expression on Day 7 prefibrotic stage and Day 14 postfibrotic stage. To determine the effects of MK2 inhibition during the postinflammatory/prefibrotic and postfibrotic stages, C57BL/6 mice received intratracheal bleomycin instillation 0.025 U; Day 0, followed by PBS or the MK2 inhibitor MK2i; 37.5  g/kg, administered via either local nebulized or systemic intraperitoneal routes. MK2i or PBS was dosed daily for 14 days subsequent to bleomycin injury, beginning on either Day 7 or Day 14. Regardless of mode of administration or stage of intervention, MK2i significantly abrogated collagen deposition, myofibroblast differentiation and activated MK2 expression. MK2i also decreased circulating TNF-a and IL-6 concentrations, and modulated the local mRNA expression of profibrotic cytokine il-1b, matrix-related genes col1a2, col3a1, and lox, and transforming growth factor-b family members, including smad3, serpine1 pai1, and smad6/7. In vitro, MK2i dose-dependently attenuated total MK2, myofibroblast differentiation, the secretion of collagen Type I, fibronectin, and the activation of focal adhesion kinase, whereas activated MK2 was attenuated at optimal doses. The peptide-mediated inhibition of MK2 affects both inflammatory and fibrotic responses, and thus may offer a promising therapeutic target for IPF.
23470623|a|<g>Mitogen-activated protein kinase-activated protein kinase-2</g> <g>MAPKAPK2</g>, or <g>MK2</g>, a serine/threonine kinase downstream of p38 mitogen-activated protein kinase, has been implicated in <d>inflammation</d> and fibrosis. Compared with pathologically normal lung tissue, significantly higher concentrations of activated <g>MK2</g> are evident in lung biopsies of patients with idiopathic <d>pulmonary fibrosis</d> IPF. Expression is localized to fibroblasts and epithelial cells. In the murine bleomycin model of <d>pulmonary fibrosis</d>, we observed robust, activated <g>MK2</g> expression on Day 7 prefibrotic stage and Day 14 postfibrotic stage. To determine the effects of <g>MK2</g> inhibition during the postinflammatory/prefibrotic and postfibrotic stages, C57BL/6 mice received intratracheal bleomycin instillation 0.025 U; Day 0, followed by PBS or the <g>MK2</g> inhibitor <g>MK2</g>i; 37.5  g/kg, administered via either local nebulized or systemic intraperitoneal routes. <g>MK2</g>i or PBS was dosed daily for 14 days subsequent to bleomycin injury, beginning on either Day 7 or Day 14. Regardless of mode of administration or stage of intervention, <g>MK2</g>i significantly abrogated collagen deposition, myofibroblast differentiation and activated <g>MK2</g> expression. <g>MK2</g>i also decreased circulating TNF-a and IL-6 concentrations, and modulated the local mRNA expression of profibrotic cytokine il-1b, matrix-related genes col1a2, col3a1, and lox, and transforming growth factor-b family members, including smad3, serpine1 pai1, and smad6/7. In vitro, <g>MK2</g>i dose-dependently attenuated total <g>MK2</g>, myofibroblast differentiation, the secretion of collagen Type I, fibronectin, and the activation of focal adhesion kinase, whereas activated <g>MK2</g> was attenuated at optimal doses. The peptide-mediated inhibition of <g>MK2</g> affects both inflammatory and fibrotic responses, and thus may offer a promising therapeutic target for IPF.
23470623|a|<g>Mitogen-activated protein kinase-activated protein kinase-2</g> <g>MAPKAPK2</g>, or <g>MK2</g>, a serine/threonine kinase downstream of p38 mitogen-activated protein kinase, has been implicated in <d>inflammation</d> and <d>fibrosis</d>. Compared with pathologically normal lung tissue, significantly higher concentrations of activated <g>MK2</g> are evident in lung biopsies of patients with idiopathic <d>pulmonary <d>fibrosis</d></d> IPF. Expression is localized to fibroblasts and epithelial cells. In the murine bleomycin model of <d>pulmonary <d>fibrosis</d></d>, we observed robust, activated <g>MK2</g> expression on Day 7 prefibrotic stage and Day 14 postfibrotic stage. To determine the effects of <g>MK2</g> inhibition during the postinflammatory/prefibrotic and postfibrotic stages, C57BL/6 mice received intratracheal bleomycin instillation 0.025 U; Day 0, followed by PBS or the <g>MK2</g> inhibitor <g>MK2</g>i; 37.5  g/kg, administered via either local nebulized or systemic intraperitoneal routes. <g>MK2</g>i or PBS was dosed daily for 14 days subsequent to bleomycin injury, beginning on either Day 7 or Day 14. Regardless of mode of administration or stage of intervention, <g>MK2</g>i significantly abrogated collagen deposition, myofibroblast differentiation and activated <g>MK2</g> expression. <g>MK2</g>i also decreased circulating TNF-a and IL-6 concentrations, and modulated the local mRNA expression of profibrotic cytokine il-1b, matrix-related genes col1a2, col3a1, and lox, and transforming growth factor-b family members, including smad3, serpine1 pai1, and smad6/7. In vitro, <g>MK2</g>i dose-dependently attenuated total <g>MK2</g>, myofibroblast differentiation, the secretion of collagen Type I, fibronectin, and the activation of focal adhesion kinase, whereas activated <g>MK2</g> was attenuated at optimal doses. The peptide-mediated inhibition of <g>MK2</g> affects both inflammatory and fibrotic responses, and thus may offer a promising therapeutic target for IPF.
23470623|a|<g>Mitogen-activated protein kinase-activated protein kinase-2</g> <g>MAPKAPK2</g>, or <g>MK2</g>, a serine/threonine kinase downstream of p38 mitogen-activated protein kinase, has been implicated in <d>inflammation</d> and <d>fibrosis</d>. Compared with pathologically normal lung tissue, significantly higher concentrations of activated <g>MK2</g> are evident in lung biopsies of patients with idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Expression is localized to fibroblasts and epithelial cells. In the murine bleomycin model of <d>pulmonary <d>fibrosis</d></d>, we observed robust, activated <g>MK2</g> expression on Day 7 prefibrotic stage and Day 14 postfibrotic stage. To determine the effects of <g>MK2</g> inhibition during the postinflammatory/prefibrotic and postfibrotic stages, C57BL/6 mice received intratracheal bleomycin instillation 0.025 U; Day 0, followed by PBS or the <g>MK2</g> inhibitor <g>MK2</g>i; 37.5  g/kg, administered via either local nebulized or systemic intraperitoneal routes. <g>MK2</g>i or PBS was dosed daily for 14 days subsequent to bleomycin injury, beginning on either Day 7 or Day 14. Regardless of mode of administration or stage of intervention, <g>MK2</g>i significantly abrogated collagen deposition, myofibroblast differentiation and activated <g>MK2</g> expression. <g>MK2</g>i also decreased circulating TNF-a and IL-6 concentrations, and modulated the local mRNA expression of profibrotic cytokine il-1b, matrix-related genes col1a2, col3a1, and lox, and transforming growth factor-b family members, including smad3, serpine1 pai1, and smad6/7. In vitro, <g>MK2</g>i dose-dependently attenuated total <g>MK2</g>, myofibroblast differentiation, the secretion of collagen Type I, fibronectin, and the activation of focal adhesion kinase, whereas activated <g>MK2</g> was attenuated at optimal doses. The peptide-mediated inhibition of <g>MK2</g> affects both inflammatory and fibrotic responses, and thus may offer a promising therapeutic target for <d>IPF</d>.
23492187|a|The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of <d>idiopathic pulmonary fibrosis</d> IPF, but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis IAP protein family member <g>X-linked inhibitor of apoptosis</g> XIAP has been suggested by prior studies showing that 1 XIAP is localized to fibroblastic foci in IPF tissue and 2 prostaglandin E    suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor TGFb-1 and endothelin ET-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-b1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fas-mediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.
23492187|a|The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis IAP protein family member <g>X-linked inhibitor of apoptosis</g> XIAP has been suggested by prior studies showing that 1 XIAP is localized to fibroblastic foci in <d>IPF</d> tissue and 2 prostaglandin E    suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor TGFb-1 and endothelin ET-1 and that increased XIAP would contribute to apoptosis resistance in <d>IPF</d> fibroblasts. To address these hypotheses, we examined XIAP expression in normal and <d>IPF</d> fibroblasts at baseline and in normal fibroblasts after treatment with TGF-b1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from <d>IPF</d> lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, <d>IPF</d> fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fas-mediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of <d>IPF</d> fibroblasts.
23499373|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive fibrotic lung disease whose underlying molecular mechanisms are largely unknown. Herein, we show that focal adhesion kinase-related nonkinase FRNK plays a key role in limiting the development of lung fibrosis. Loss of FRNK function in vivo leads to increased lung fibrosis in an experimental mouse model. The increase in lung fibrosis is confirmed at the histological, biochemical, and physiological levels. Concordantly, loss of FRNK function results in increased fibroblast migration and myofibroblast differentiation and activation of signaling proteins that drive these phenotypes. FRNK-deficient murine lung fibroblasts also have an increased capacity to produce and contract matrix proteins. Restoration of FRNK expression in vivo and in vitro reverses these profibrotic phenotypes. These data demonstrate the multiple antifibrotic actions of FRNK. More important, FRNK expression is down-regulated in human IPF, and down-regulation of FRNK in normal human lung fibroblasts recapitulates the profibrotic phenotype seen in FRNK-deficient cells. The effect of loss and gain of FRNK in the experimental model, when taken together with its down-regulation in human IPF, suggests that FRNK acts as an endogenous negative regulator of lung fibrosis by repressing multiple profibrotic responses.
23499373|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive fibrotic lung disease whose underlying molecular mechanisms are largely unknown. Herein, we show that focal adhesion kinase-related nonkinase FRNK plays a key role in limiting the development of lung fibrosis. Loss of FRNK function in vivo leads to increased lung fibrosis in an experimental mouse model. The increase in lung fibrosis is confirmed at the histological, biochemical, and physiological levels. Concordantly, loss of FRNK function results in increased fibroblast migration and myofibroblast differentiation and activation of signaling proteins that drive these phenotypes. FRNK-deficient murine lung fibroblasts also have an increased capacity to produce and contract matrix proteins. Restoration of FRNK expression in vivo and in vitro reverses these profibrotic phenotypes. These data demonstrate the multiple antifibrotic actions of FRNK. More important, FRNK expression is down-regulated in human <d>IPF</d>, and down-regulation of FRNK in normal human lung fibroblasts recapitulates the profibrotic phenotype seen in FRNK-deficient cells. The effect of loss and gain of FRNK in the experimental model, when taken together with its down-regulation in human <d>IPF</d>, suggests that FRNK acts as an endogenous negative regulator of lung fibrosis by repressing multiple profibrotic responses.
23499373|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> whose underlying molecular mechanisms are largely unknown. Herein, we show that focal adhesion kinase-related nonkinase FRNK plays a key role in limiting the development of lung fibrosis. Loss of FRNK function in vivo leads to increased lung fibrosis in an experimental mouse model. The increase in lung fibrosis is confirmed at the histological, biochemical, and physiological levels. Concordantly, loss of FRNK function results in increased fibroblast migration and myofibroblast differentiation and activation of signaling proteins that drive these phenotypes. FRNK-deficient murine lung fibroblasts also have an increased capacity to produce and contract matrix proteins. Restoration of FRNK expression in vivo and in vitro reverses these profibrotic phenotypes. These data demonstrate the multiple antifibrotic actions of FRNK. More important, FRNK expression is down-regulated in human <d>IPF</d>, and down-regulation of FRNK in normal human lung fibroblasts recapitulates the profibrotic phenotype seen in FRNK-deficient cells. The effect of loss and gain of FRNK in the experimental model, when taken together with its down-regulation in human <d>IPF</d>, suggests that FRNK acts as an endogenous negative regulator of lung fibrosis by repressing multiple profibrotic responses.
23499373|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> whose underlying molecular mechanisms are largely unknown. Herein, we show that <g>focal adhesion kinase-related nonkinase</g> <g>FRNK</g> plays a key role in limiting the development of <d>lung fibrosis</d>. Loss of <g>FRNK</g> function in vivo leads to increased <d>lung fibrosis</d> in an experimental mouse model. The increase in <d>lung fibrosis</d> is confirmed at the histological, biochemical, and physiological levels. Concordantly, loss of <g>FRNK</g> function results in increased fibroblast migration and myofibroblast differentiation and activation of signaling proteins that drive these phenotypes. <g>FRNK</g>-deficient murine lung fibroblasts also have an increased capacity to produce and contract matrix proteins. Restoration of <g>FRNK</g> expression in vivo and in vitro reverses these profibrotic phenotypes. These data demonstrate the multiple antifibrotic actions of <g>FRNK</g>. More important, <g>FRNK</g> expression is down-regulated in human <d>IPF</d>, and down-regulation of <g>FRNK</g> in normal human lung fibroblasts recapitulates the profibrotic phenotype seen in <g>FRNK</g>-deficient cells. The effect of loss and gain of <g>FRNK</g> in the experimental model, when taken together with its down-regulation in human <d>IPF</d>, suggests that <g>FRNK</g> acts as an endogenous negative regulator of <d>lung fibrosis</d> by repressing multiple profibrotic responses.
23499992|a|Idiopathic pulmonary fibrosis IPF is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. IPF is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological fibrosis due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger IPF remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the "pas de deux" steps of two, or perhaps more appropriate to IPF pathogenesis, the "folie    deux" madness of two of epithelial cells and fibroblasts that drives the progression of pulmonary fibrosis. We describe the signaling molecules that mediate the interactions of these cell types in their "fibrosis of two", including transforming growth factor-b, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. This article is part of a Special Issue entitled: <d>Fibrosis</d>: Translation of basic research to human disease.
23499992|a|Idiopathic <d>pulmonary fibrosis</d> IPF is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. IPF is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological fibrosis due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger IPF remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the "pas de deux" steps of two, or perhaps more appropriate to IPF pathogenesis, the "folie    deux" madness of two of epithelial cells and fibroblasts that drives the progression of <d>pulmonary fibrosis</d>. We describe the signaling molecules that mediate the interactions of these cell types in their "fibrosis of two", including transforming growth factor-b, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. This article is part of a Special Issue entitled: <d>Fibrosis</d>: Translation of basic research to human disease.
23499992|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. <d>IPF</d> is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological fibrosis due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger <d>IPF</d> remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the "pas de deux" steps of two, or perhaps more appropriate to <d>IPF</d> pathogenesis, the "folie    deux" madness of two of epithelial cells and fibroblasts that drives the progression of <d>pulmonary fibrosis</d>. We describe the signaling molecules that mediate the interactions of these cell types in their "fibrosis of two", including transforming growth factor-b, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. This article is part of a Special Issue entitled: <d>Fibrosis</d>: Translation of basic research to human disease.
23499992|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. <d>IPF</d> is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological <d>fibrosis</d> due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger <d>IPF</d> remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the "pas de deux" steps of two, or perhaps more appropriate to <d>IPF</d> pathogenesis, the "folie    deux" madness of two of epithelial cells and fibroblasts that drives the progression of <d>pulmonary <d>fibrosis</d></d>. We describe the signaling molecules that mediate the interactions of these cell types in their "<d>fibrosis</d> of two", including transforming growth factor-b, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. This article is part of a Special Issue entitled: <d>Fibrosis</d>: Translation of basic research to human disease.
23499992|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. <d>IPF</d> is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological <d>fibrosis</d> due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger <d>IPF</d> remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell <d>death</d> provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and <d>death</d>, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the "pas de deux" steps of two, or perhaps more appropriate to <d>IPF</d> pathogenesis, the "folie    deux" madness of two of epithelial cells and fibroblasts that drives the progression of <d>pulmonary <d>fibrosis</d></d>. We describe the signaling molecules that mediate the interactions of these cell types in their "<d>fibrosis</d> of two", including transforming growth factor-b, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. This article is part of a Special Issue entitled: <d>Fibrosis</d>: Translation of basic research to human disease.
23499992|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. <d>IPF</d> is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological <d>fibrosis</d> due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger <d>IPF</d> remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell <d>death</d> provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further <d>alveolar epithelial cell injury</d> and <d>death</d>, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the "pas de deux" steps of two, or perhaps more appropriate to <d>IPF</d> pathogenesis, the "folie    deux" madness of two of epithelial cells and fibroblasts that drives the progression of <d>pulmonary <d>fibrosis</d></d>. We describe the signaling molecules that mediate the interactions of these cell types in their "<d>fibrosis</d> of two", including transforming growth factor-b, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. This article is part of a Special Issue entitled: <d>Fibrosis</d>: Translation of basic research to human disease.
23517551|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a poorly understood progressive disease characterized by the recurrent damage of alveolar epithelial cells as well as inappropriate expansion and activation of fibroblasts resulting in pronounced extracellular matrix ECM deposition. Although recent studies have indicated the involvement of secreted protein acidic and rich in cysteine <g>SPARC</g>, a matricellular protein regulating ECM deposition, in the pathogenesis of fibrosis, factors regulating <g>SPARC</g> expression or roles of <g>SPARC</g> in fibrosis have not been fully elucidated. RESULTS: Among the profibrotic factors examined in cultured fibroblasts, we showed that <g>SPARC</g> expression was upregulated mainly by transforming growth factor <g>TGF-b</g>. We also showed that expression of <g>SPARC</g> in the lung was upregulated in the murine bleomycin-induced pulmonary fibrosis model, which was inhibited by <g>TGF-b</g> receptor I inhibitor. Knockdown of <g>SPARC</g> in fibroblasts using siRNA or treatment with the antioxidant N-acetylcysteine attenuated epithelial cell injury induced by <g>TGF-b</g>-activated fibroblasts in a coculture system. We also demonstrated that <g>SPARC</g> was required for hydrogen peroxide H2O2 production in fibroblasts treated with <g>TGF-b</g>. Furthermore, <g>TGF-b</g> activated integrin-linked kinase ILK, which was inhibited by <g>SPARC</g> siRNA. Knockdown of ILK attenuated extracellular H2O2 generation in <g>TGF-b</g>-stimulated fibroblasts. Our results indicated that <g>SPARC</g> is upregulated by <g>TGF-b</g> and is required for <g>TGF-b</g>-induced H2O2 production via activation of ILK, and this H2O2 production from fibroblasts is capable of causing epithelial cell injury. CONCLUSIONS: The results presented in this study suggest that <g>SPARC</g> plays a role in epithelial damage in the IPF lung via enhanced H2O2 production from fibroblasts activated by <g>TGF-b</g>. Therefore, <g>SPARC</g> inhibition may prevent epithelial injury in IPF lung and represent a potential therapeutic approach for IPF.
23517551|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a poorly understood progressive disease characterized by the recurrent damage of alveolar epithelial cells as well as inappropriate expansion and activation of fibroblasts resulting in pronounced extracellular matrix ECM deposition. Although recent studies have indicated the involvement of secreted protein acidic and rich in cysteine <g>SPARC</g>, a matricellular protein regulating ECM deposition, in the pathogenesis of fibrosis, factors regulating <g>SPARC</g> expression or roles of <g>SPARC</g> in fibrosis have not been fully elucidated. RESULTS: Among the profibrotic factors examined in cultured fibroblasts, we showed that <g>SPARC</g> expression was upregulated mainly by transforming growth factor <g>TGF-b</g>. We also showed that expression of <g>SPARC</g> in the lung was upregulated in the murine bleomycin-induced pulmonary fibrosis model, which was inhibited by <g>TGF-b</g> receptor I inhibitor. Knockdown of <g>SPARC</g> in fibroblasts using siRNA or treatment with the antioxidant N-acetylcysteine attenuated epithelial cell injury induced by <g>TGF-b</g>-activated fibroblasts in a coculture system. We also demonstrated that <g>SPARC</g> was required for hydrogen peroxide H2O2 production in fibroblasts treated with <g>TGF-b</g>. Furthermore, <g>TGF-b</g> activated integrin-linked kinase ILK, which was inhibited by <g>SPARC</g> siRNA. Knockdown of ILK attenuated extracellular H2O2 generation in <g>TGF-b</g>-stimulated fibroblasts. Our results indicated that <g>SPARC</g> is upregulated by <g>TGF-b</g> and is required for <g>TGF-b</g>-induced H2O2 production via activation of ILK, and this H2O2 production from fibroblasts is capable of causing epithelial cell injury. CONCLUSIONS: The results presented in this study suggest that <g>SPARC</g> plays a role in epithelial damage in the <d>IPF</d> lung via enhanced H2O2 production from fibroblasts activated by <g>TGF-b</g>. Therefore, <g>SPARC</g> inhibition may prevent epithelial injury in <d>IPF</d> lung and represent a potential therapeutic approach for <d>IPF</d>.
23517551|a|BACKGROUND: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a poorly understood progressive disease characterized by the recurrent damage of alveolar epithelial cells as well as inappropriate expansion and activation of fibroblasts resulting in pronounced extracellular matrix ECM deposition. Although recent studies have indicated the involvement of <g>secreted protein acidic and rich in cysteine</g> <g>SPARC</g>, a matricellular protein regulating ECM deposition, in the pathogenesis of <d>fibrosis</d>, factors regulating <g>SPARC</g> expression or roles of <g>SPARC</g> in <d>fibrosis</d> have not been fully elucidated. RESULTS: Among the profibrotic factors examined in cultured fibroblasts, we showed that <g>SPARC</g> expression was upregulated mainly by transforming growth factor <g>TGF-b</g>. We also showed that expression of <g>SPARC</g> in the lung was upregulated in the murine bleomycin-induced pulmonary <d>fibrosis</d> model, which was inhibited by <g>TGF-b</g> receptor I inhibitor. Knockdown of <g>SPARC</g> in fibroblasts using siRNA or treatment with the antioxidant N-acetylcysteine attenuated epithelial cell injury induced by <g>TGF-b</g>-activated fibroblasts in a coculture system. We also demonstrated that <g>SPARC</g> was required for hydrogen peroxide H2O2 production in fibroblasts treated with <g>TGF-b</g>. Furthermore, <g>TGF-b</g> activated integrin-linked kinase ILK, which was inhibited by <g>SPARC</g> siRNA. Knockdown of ILK attenuated extracellular H2O2 generation in <g>TGF-b</g>-stimulated fibroblasts. Our results indicated that <g>SPARC</g> is upregulated by <g>TGF-b</g> and is required for <g>TGF-b</g>-induced H2O2 production via activation of ILK, and this H2O2 production from fibroblasts is capable of causing epithelial cell injury. CONCLUSIONS: The results presented in this study suggest that <g>SPARC</g> plays a role in epithelial damage in the <d>IPF</d> lung via enhanced H2O2 production from fibroblasts activated by <g>TGF-b</g>. Therefore, <g>SPARC</g> inhibition may prevent epithelial injury in <d>IPF</d> lung and represent a potential therapeutic approach for <d>IPF</d>.
23517551|a|BACKGROUND: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a poorly understood progressive disease characterized by the recurrent damage of alveolar epithelial cells as well as inappropriate expansion and activation of fibroblasts resulting in pronounced extracellular matrix ECM deposition. Although recent studies have indicated the involvement of <g>secreted protein acidic and rich in cysteine</g> <g>SPARC</g>, a matricellular protein regulating ECM deposition, in the pathogenesis of <d>fibrosis</d>, factors regulating <g>SPARC</g> expression or roles of <g>SPARC</g> in <d>fibrosis</d> have not been fully elucidated. RESULTS: Among the profibrotic factors examined in cultured fibroblasts, we showed that <g>SPARC</g> expression was upregulated mainly by transforming growth factor <g>TGF-b</g>. We also showed that expression of <g>SPARC</g> in the lung was upregulated in the murine bleomycin-induced pulmonary <d>fibrosis</d> model, which was inhibited by <g>TGF-b</g> receptor I inhibitor. Knockdown of <g>SPARC</g> in fibroblasts using siRNA or treatment with the antioxidant N-acetylcysteine attenuated <d>epithelial cell injury</d> induced by <g>TGF-b</g>-activated fibroblasts in a coculture system. We also demonstrated that <g>SPARC</g> was required for hydrogen peroxide H2O2 production in fibroblasts treated with <g>TGF-b</g>. Furthermore, <g>TGF-b</g> activated integrin-linked kinase ILK, which was inhibited by <g>SPARC</g> siRNA. Knockdown of ILK attenuated extracellular H2O2 generation in <g>TGF-b</g>-stimulated fibroblasts. Our results indicated that <g>SPARC</g> is upregulated by <g>TGF-b</g> and is required for <g>TGF-b</g>-induced H2O2 production via activation of ILK, and this H2O2 production from fibroblasts is capable of causing <d>epithelial cell injury</d>. CONCLUSIONS: The results presented in this study suggest that <g>SPARC</g> plays a role in epithelial damage in the <d>IPF</d> lung via enhanced H2O2 production from fibroblasts activated by <g>TGF-b</g>. Therefore, <g>SPARC</g> inhibition may prevent epithelial injury in <d>IPF</d> lung and represent a potential therapeutic approach for <d>IPF</d>.
23517551|a|BACKGROUND: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a poorly understood progressive disease characterized by the recurrent damage of alveolar epithelial cells as well as inappropriate expansion and activation of fibroblasts resulting in pronounced extracellular matrix ECM deposition. Although recent studies have indicated the involvement of <g>secreted protein acidic and rich in cysteine</g> <g>SPARC</g>, a matricellular protein regulating ECM deposition, in the pathogenesis of <d>fibrosis</d>, factors regulating <g>SPARC</g> expression or roles of <g>SPARC</g> in <d>fibrosis</d> have not been fully elucidated. RESULTS: Among the profibrotic factors examined in cultured fibroblasts, we showed that <g>SPARC</g> expression was upregulated mainly by transforming growth factor <g>TGF-b</g>. We also showed that expression of <g>SPARC</g> in the lung was upregulated in the murine bleomycin-induced pulmonary <d>fibrosis</d> model, which was inhibited by <g>TGF-b</g> receptor I inhibitor. Knockdown of <g>SPARC</g> in fibroblasts using siRNA or treatment with the antioxidant N-acetylcysteine attenuated <d>epithelial cell injury</d> induced by <g>TGF-b</g>-activated fibroblasts in a coculture system. We also demonstrated that <g>SPARC</g> was required for hydrogen peroxide H2O2 production in fibroblasts treated with <g>TGF-b</g>. Furthermore, <g>TGF-b</g> activated <g>integrin-linked kinase</g> <g>ILK</g>, which was inhibited by <g>SPARC</g> siRNA. Knockdown of <g>ILK</g> attenuated extracellular H2O2 generation in <g>TGF-b</g>-stimulated fibroblasts. Our results indicated that <g>SPARC</g> is upregulated by <g>TGF-b</g> and is required for <g>TGF-b</g>-induced H2O2 production via activation of <g>ILK</g>, and this H2O2 production from fibroblasts is capable of causing <d>epithelial cell injury</d>. CONCLUSIONS: The results presented in this study suggest that <g>SPARC</g> plays a role in epithelial damage in the <d>IPF</d> lung via enhanced H2O2 production from fibroblasts activated by <g>TGF-b</g>. Therefore, <g>SPARC</g> inhibition may prevent <d>epithelial injury</d> in <d>IPF</d> lung and represent a potential therapeutic approach for <d>IPF</d>.
23523906|a|Idiopathic pulmonary <d>fibrosis</d> IPF is a progressive, debilitating and fatal lung disorder with high mortality rate. Unfortunately, to date the treatment for IPF remains unsatisfying and in severe cases lung transplantations are performed as a therapeutic measure. Thus, it becomes great interest to find novel agents to treat IPF. Berberine, a plant alkaloid known for its broad pharmacological activities remains a remedy against multiple diseases. This study was hypothesized to investigate the antifibrotic potential of berberine against bleomycin-induced lung injury and <d>fibrosis</d>, a tentative animal model. Male wistar rats were subjected to single intratracheal instillation of 2.5 U/kg of bleomycin on day 0. Berberine treatments were either provided in preventive or therapeutic mode respectively. Berberine administration significantly ameliorated the bleomycin mediated histological alterations and reduced the inflammatory cell infiltrate in BALF. Berberine significantly blocked collagen accumulations with parallel reduction in the hydroxyproline level. The immunological sign of bleomycin stimulated mast cell deposition and histamine release were considerably reduced by berberine. Berberine enhanced the antioxidant status, through upregulating the redox sensing transcription factor nuclear factor E2-related factor 2 Nrf2. Berberine inhibited the bleomycin mediated activation of inflammatory mediator nuclear factor kappa B NF-kB and suppressed its downstream target inducible nitric oxide synthase iNOS. Strikingly, berberine exhibited target attenuation of tumor necrosis factor alpha TNF-a and key pro-fibrotic mediator, transforming growth factor beta 1 TGF-b1. Taken together, this study reveals the beneficial effects of berberine against bleomycin mediated fibrotic challenge through activating Nrf2 and suppressing NF-kB dependent inflammatory and TGF-b1 mediated fibrotic events.
23523906|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive, debilitating and fatal lung disorder with high mortality rate. Unfortunately, to date the treatment for <d>IPF</d> remains unsatisfying and in severe cases lung transplantations are performed as a therapeutic measure. Thus, it becomes great interest to find novel agents to treat <d>IPF</d>. Berberine, a plant alkaloid known for its broad pharmacological activities remains a remedy against multiple diseases. This study was hypothesized to investigate the antifibrotic potential of berberine against bleomycin-induced lung injury and <d>fibrosis</d>, a tentative animal model. Male wistar rats were subjected to single intratracheal instillation of 2.5 U/kg of bleomycin on day 0. Berberine treatments were either provided in preventive or therapeutic mode respectively. Berberine administration significantly ameliorated the bleomycin mediated histological alterations and reduced the inflammatory cell infiltrate in BALF. Berberine significantly blocked collagen accumulations with parallel reduction in the hydroxyproline level. The immunological sign of bleomycin stimulated mast cell deposition and histamine release were considerably reduced by berberine. Berberine enhanced the antioxidant status, through upregulating the redox sensing transcription factor nuclear factor E2-related factor 2 Nrf2. Berberine inhibited the bleomycin mediated activation of inflammatory mediator nuclear factor kappa B <g>NF-kB</g> and suppressed its downstream target inducible nitric oxide synthase iNOS. Strikingly, berberine exhibited target attenuation of tumor necrosis factor alpha TNF-a and key pro-fibrotic mediator, transforming growth factor beta 1 <g>TGF-b</g>1. Taken together, this study reveals the beneficial effects of berberine against bleomycin mediated fibrotic challenge through activating Nrf2 and suppressing <g>NF-kB</g> dependent inflammatory and <g>TGF-b</g>1 mediated fibrotic events.
23523906|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive, debilitating and fatal <d>lung disorder</d> with high mortality rate. Unfortunately, to date the treatment for <d>IPF</d> remains unsatisfying and in severe cases lung transplantations are performed as a therapeutic measure. Thus, it becomes great interest to find novel agents to treat <d>IPF</d>. Berberine, a plant alkaloid known for its broad pharmacological activities remains a remedy against multiple diseases. This study was hypothesized to investigate the antifibrotic potential of berberine against bleomycin-induced lung injury and <d>fibrosis</d>, a tentative animal model. Male wistar rats were subjected to single intratracheal instillation of 2.5 U/kg of bleomycin on day 0. Berberine treatments were either provided in preventive or therapeutic mode respectively. Berberine administration significantly ameliorated the bleomycin mediated histological alterations and reduced the inflammatory cell infiltrate in BALF. Berberine significantly blocked collagen accumulations with parallel reduction in the hydroxyproline level. The immunological sign of bleomycin stimulated mast cell deposition and histamine release were considerably reduced by berberine. Berberine enhanced the antioxidant status, through upregulating the redox sensing transcription factor nuclear factor E2-related factor 2 Nrf2. Berberine inhibited the bleomycin mediated activation of inflammatory mediator nuclear factor kappa B <g>NF-kB</g> and suppressed its downstream target inducible nitric oxide synthase iNOS. Strikingly, berberine exhibited target attenuation of tumor necrosis factor alpha TNF-a and key pro-fibrotic mediator, transforming growth factor beta 1 <g>TGF-b</g>1. Taken together, this study reveals the beneficial effects of berberine against bleomycin mediated fibrotic challenge through activating Nrf2 and suppressing <g>NF-kB</g> dependent inflammatory and <g>TGF-b</g>1 mediated fibrotic events.
23523906|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive, debilitating and fatal <d>lung disorder</d> with high mortality rate. Unfortunately, to date the treatment for <d>IPF</d> remains unsatisfying and in severe cases lung transplantations are performed as a therapeutic measure. Thus, it becomes great interest to find novel agents to treat <d>IPF</d>. Berberine, a plant alkaloid known for its broad pharmacological activities remains a remedy against <d>multiple diseases</d>. This study was hypothesized to investigate the antifibrotic potential of berberine against bleomycin-induced lung injury and <d>fibrosis</d>, a tentative animal model. Male wistar rats were subjected to single intratracheal instillation of 2.5 U/kg of bleomycin on day 0. Berberine treatments were either provided in preventive or therapeutic mode respectively. Berberine administration significantly ameliorated the bleomycin mediated histological alterations and reduced the inflammatory cell infiltrate in BALF. Berberine significantly blocked collagen accumulations with parallel reduction in the hydroxyproline level. The immunological sign of bleomycin stimulated mast cell deposition and histamine release were considerably reduced by berberine. Berberine enhanced the antioxidant status, through upregulating the redox sensing transcription factor nuclear factor E2-related factor 2 Nrf2. Berberine inhibited the bleomycin mediated activation of inflammatory mediator nuclear factor kappa B <g>NF-kB</g> and suppressed its downstream target inducible nitric oxide synthase iNOS. Strikingly, berberine exhibited target attenuation of tumor necrosis factor alpha TNF-a and key pro-fibrotic mediator, transforming growth factor beta 1 <g>TGF-b</g>1. Taken together, this study reveals the beneficial effects of berberine against bleomycin mediated fibrotic challenge through activating Nrf2 and suppressing <g>NF-kB</g> dependent inflammatory and <g>TGF-b</g>1 mediated fibrotic events.
23523906|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive, debilitating and fatal <d>lung disorder</d> with high mortality rate. Unfortunately, to date the treatment for <d>IPF</d> remains unsatisfying and in severe cases lung transplantations are performed as a therapeutic measure. Thus, it becomes great interest to find novel agents to treat <d>IPF</d>. Berberine, a plant alkaloid known for its broad pharmacological activities remains a remedy against <d>multiple diseases</d>. This study was hypothesized to investigate the antifibrotic potential of berberine against bleomycin-induced <d>lung injury</d> and <d>fibrosis</d>, a tentative animal model. Male wistar rats were subjected to single intratracheal instillation of 2.5 U/kg of bleomycin on day 0. Berberine treatments were either provided in preventive or therapeutic mode respectively. Berberine administration significantly ameliorated the bleomycin mediated histological alterations and reduced the inflammatory cell infiltrate in BALF. Berberine significantly blocked collagen accumulations with parallel reduction in the hydroxyproline level. The immunological sign of bleomycin stimulated mast cell deposition and histamine release were considerably reduced by berberine. Berberine enhanced the antioxidant status, through upregulating the redox sensing transcription factor nuclear factor E2-related factor 2 Nrf2. Berberine inhibited the bleomycin mediated activation of inflammatory mediator nuclear factor kappa B <g>NF-kB</g> and suppressed its downstream target inducible nitric oxide synthase iNOS. Strikingly, berberine exhibited target attenuation of tumor necrosis factor alpha TNF-a and key pro-fibrotic mediator, transforming growth factor beta 1 <g>TGF-b</g>1. Taken together, this study reveals the beneficial effects of berberine against bleomycin mediated fibrotic challenge through activating Nrf2 and suppressing <g>NF-kB</g> dependent inflammatory and <g>TGF-b</g>1 mediated fibrotic events.
23565148|a|The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to <d>idiopathic pulmonary fibrosis</d> IPF, has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFb was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.
23565148|a|The preclinical model of bleomycin-induced <d>lung fibrosis</d>, used to investigate mechanisms related to <d>idiopathic pulmonary fibrosis</d> IPF, has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFb was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.
23565148|a|The preclinical model of bleomycin-induced <d>lung fibrosis</d>, used to investigate mechanisms related to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with <d>IPF</d>. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of <d>IPF</d> patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, <d>IPF</d> patients relative to control subjects. The data also indicated that TGFb was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model <d>IPF</d>-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with <d>IPF</d>, and may be best used as a model for patients with active disease.
23565148|a|The preclinical model of bleomycin-induced <d>lung <d>fibrosis</d></d>, used to investigate mechanisms related to <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with <d>IPF</d>. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of <d>IPF</d> patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, <d>IPF</d> patients relative to control subjects. The data also indicated that <g>TGFb</g> was not the sole mediator responsible for the changes observed in this model since the <g>ALK-5</g> inhibitor SB525334 effectively attenuated some but not all of the <d>fibrosis</d> associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model <d>IPF</d>-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with <d>IPF</d>, and may be best used as a model for patients with active disease.
23583521|a|<d>Fibrosis</d> underlies the pathogenesis of numerous diseases and leads to severe damage of vital body organs and, frequently, to death. Better understanding of the mechanisms resulting in fibrosis is essential for developing appropriate treatment solutions and is therefore of upmost importance. Recent evidence suggests a significant antifibrotic potential of an integral membrane protein, <g>caveolin-1</g>. While <g>caveolin-1</g> has been widely studied for its role in the regulation of cell signaling and endocytosis, its possible implication in fibrosis remains largely unclear. In this review we survey involvement of <g>caveolin-1</g> in various cellular processes and highlight different aspects of its antifibrotic activity. We hypothesize that <g>caveolin-1</g> conveys a homeostatic function in the process of fibrosis by a regulating TGF-b1 and its downstream signaling; b regulating critical cellular processes involved in tissue repair, such as migration, adhesion and cellular response to mechanical stress; and c antagonizing profibrotic processes, such as proliferation. Finally, we consider this homeostatic function of <g>caveolin-1</g> as a possible novel approach in treatment of fibroproliferative diseases.
23583521|a|<d>Fibrosis</d> underlies the pathogenesis of <d>numerous diseases</d> and leads to severe damage of vital body organs and, frequently, to death. Better understanding of the mechanisms resulting in fibrosis is essential for developing appropriate treatment solutions and is therefore of upmost importance. Recent evidence suggests a significant antifibrotic potential of an integral membrane protein, <g>caveolin-1</g>. While <g>caveolin-1</g> has been widely studied for its role in the regulation of cell signaling and endocytosis, its possible implication in fibrosis remains largely unclear. In this review we survey involvement of <g>caveolin-1</g> in various cellular processes and highlight different aspects of its antifibrotic activity. We hypothesize that <g>caveolin-1</g> conveys a homeostatic function in the process of fibrosis by a regulating TGF-b1 and its downstream signaling; b regulating critical cellular processes involved in tissue repair, such as migration, adhesion and cellular response to mechanical stress; and c antagonizing profibrotic processes, such as proliferation. Finally, we consider this homeostatic function of <g>caveolin-1</g> as a possible novel approach in treatment of fibroproliferative diseases.
23583521|a|<d>Fibrosis</d> underlies the pathogenesis of <d>numerous diseases</d> and leads to severe <d>damage of vital body organs</d> and, frequently, to death. Better understanding of the mechanisms resulting in fibrosis is essential for developing appropriate treatment solutions and is therefore of upmost importance. Recent evidence suggests a significant antifibrotic potential of an integral membrane protein, <g>caveolin-1</g>. While <g>caveolin-1</g> has been widely studied for its role in the regulation of cell signaling and endocytosis, its possible implication in fibrosis remains largely unclear. In this review we survey involvement of <g>caveolin-1</g> in various cellular processes and highlight different aspects of its antifibrotic activity. We hypothesize that <g>caveolin-1</g> conveys a homeostatic function in the process of fibrosis by a regulating TGF-b1 and its downstream signaling; b regulating critical cellular processes involved in tissue repair, such as migration, adhesion and cellular response to mechanical stress; and c antagonizing profibrotic processes, such as proliferation. Finally, we consider this homeostatic function of <g>caveolin-1</g> as a possible novel approach in treatment of fibroproliferative diseases.
23583521|a|<d>Fibrosis</d> underlies the pathogenesis of <d>numerous diseases</d> and leads to severe <d>damage of vital body organs</d> and, frequently, to <d>death</d>. Better understanding of the mechanisms resulting in fibrosis is essential for developing appropriate treatment solutions and is therefore of upmost importance. Recent evidence suggests a significant antifibrotic potential of an integral membrane protein, <g>caveolin-1</g>. While <g>caveolin-1</g> has been widely studied for its role in the regulation of cell signaling and endocytosis, its possible implication in fibrosis remains largely unclear. In this review we survey involvement of <g>caveolin-1</g> in various cellular processes and highlight different aspects of its antifibrotic activity. We hypothesize that <g>caveolin-1</g> conveys a homeostatic function in the process of fibrosis by a regulating TGF-b1 and its downstream signaling; b regulating critical cellular processes involved in tissue repair, such as migration, adhesion and cellular response to mechanical stress; and c antagonizing profibrotic processes, such as proliferation. Finally, we consider this homeostatic function of <g>caveolin-1</g> as a possible novel approach in treatment of fibroproliferative diseases.
23583521|a|<d>Fibrosis</d> underlies the pathogenesis of <d>numerous diseases</d> and leads to severe <d>damage of vital body organs</d> and, frequently, to <d>death</d>. Better understanding of the mechanisms resulting in <d>fibrosis</d> is essential for developing appropriate treatment solutions and is therefore of upmost importance. Recent evidence suggests a significant antifibrotic potential of an integral membrane protein, <g>caveolin-1</g>. While <g>caveolin-1</g> has been widely studied for its role in the regulation of cell signaling and endocytosis, its possible implication in <d>fibrosis</d> remains largely unclear. In this review we survey involvement of <g>caveolin-1</g> in various cellular processes and highlight different aspects of its antifibrotic activity. We hypothesize that <g>caveolin-1</g> conveys a homeostatic function in the process of <d>fibrosis</d> by a regulating TGF-b1 and its downstream signaling; b regulating critical cellular processes involved in tissue repair, such as migration, adhesion and cellular response to mechanical stress; and c antagonizing profibrotic processes, such as proliferation. Finally, we consider this homeostatic function of <g>caveolin-1</g> as a possible novel approach in treatment of fibroproliferative diseases.
23583521|a|<d>Fibrosis</d> underlies the pathogenesis of <d>numerous diseases</d> and leads to severe <d>damage of vital body organs</d> and, frequently, to <d>death</d>. Better understanding of the mechanisms resulting in <d>fibrosis</d> is essential for developing appropriate treatment solutions and is therefore of upmost importance. Recent evidence suggests a significant antifibrotic potential of an integral membrane protein, <g>caveolin-1</g>. While <g>caveolin-1</g> has been widely studied for its role in the regulation of cell signaling and endocytosis, its possible implication in <d>fibrosis</d> remains largely unclear. In this review we survey involvement of <g>caveolin-1</g> in various cellular processes and highlight different aspects of its antifibrotic activity. We hypothesize that <g>caveolin-1</g> conveys a homeostatic function in the process of <d>fibrosis</d> by a regulating <g>TGF-b1</g> and its downstream signaling; b regulating critical cellular processes involved in tissue repair, such as migration, adhesion and cellular response to mechanical stress; and c antagonizing profibrotic processes, such as proliferation. Finally, we consider this homeostatic function of <g>caveolin-1</g> as a possible novel approach in treatment of <d>fibroproliferative diseases</d>.
23755232|a|BACKGROUND: Prostaglandin E2 PGE2, the main metabolite of cyclooxygenase COX, is a well-known anti-fibrotic agent. Moreover, myofibroblasts expressing a-smooth muscle actin <g>a-SMA</g>, fibroblast expansion and epithelial-mesenchymal transition EMT are critical to the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF. Our aim was to investigate the expression of COX-2 and PGE2 in human lung myofibroblasts and establish whether fibroblast-myofibroblast transition FMT and EMT are associated with COX-2 and PGE2 down-regulation. METHODS: Fibroblasts obtained from IPF patients n = 6 and patients undergoing spontaneous pneumothorax control, n = 6 and alveolar epithelial cell line A549 were incubated with TGF-b1 and FMT and EMT markers were evaluated. COX-2 and <g>a-SMA</g> expression, PGE2 secretion and cell proliferation were measured after IL-1b and PGE2 incubation. RESULTS: Myofibroblasts from both control and IPF fibroblast cultures stimulated with IL-1b showed no COX-2 expression. IPF fibroblasts showed increased myofibroblast population and reduced COX-2 expression in response to IL-1b. TGF-b1 increased the number of myofibroblasts in a time-dependent manner. In contrast, TGF-b1 induced slight COX-2 expression at 4 h without increase in myofibroblasts and 24 h, but not at 72 h. Both IPF and control cultures incubated with TGF-b1 for 72 h showed diminished COX-2 induction, PGE2 secretion and <g>a-SMA</g> expression after IL-1b addition. The latter decreased proliferation in fibroblasts but not in myofibroblasts. A549 cells incubated with TGF-b1 for 72 h showed down-regulated COX-2 expression and low basal PGE2 secretion in response to IL-1b. Immuno-histochemical analysis of IPF lung tissue showed no COX-2 immuno-reactivity in myofibroblast foci. CONCLUSIONS: Myofibroblasts are associated with COX-2 down-regulation and reduced PGE2 production, which could be crucial in IPF development and progression.
23755232|a|BACKGROUND: Prostaglandin E2 PGE2, the main metabolite of cyclooxygenase COX, is a well-known anti-fibrotic agent. Moreover, myofibroblasts expressing a-smooth muscle actin <g>a-SMA</g>, fibroblast expansion and epithelial-mesenchymal transition EMT are critical to the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Our aim was to investigate the expression of COX-2 and PGE2 in human lung myofibroblasts and establish whether fibroblast-myofibroblast transition FMT and EMT are associated with COX-2 and PGE2 down-regulation. METHODS: Fibroblasts obtained from <d>IPF</d> patients n = 6 and patients undergoing spontaneous pneumothorax control, n = 6 and alveolar epithelial cell line A549 were incubated with TGF-b1 and FMT and EMT markers were evaluated. COX-2 and <g>a-SMA</g> expression, PGE2 secretion and cell proliferation were measured after IL-1b and PGE2 incubation. RESULTS: Myofibroblasts from both control and <d>IPF</d> fibroblast cultures stimulated with IL-1b showed no COX-2 expression. <d>IPF</d> fibroblasts showed increased myofibroblast population and reduced COX-2 expression in response to IL-1b. TGF-b1 increased the number of myofibroblasts in a time-dependent manner. In contrast, TGF-b1 induced slight COX-2 expression at 4 h without increase in myofibroblasts and 24 h, but not at 72 h. Both <d>IPF</d> and control cultures incubated with TGF-b1 for 72 h showed diminished COX-2 induction, PGE2 secretion and <g>a-SMA</g> expression after IL-1b addition. The latter decreased proliferation in fibroblasts but not in myofibroblasts. A549 cells incubated with TGF-b1 for 72 h showed down-regulated COX-2 expression and low basal PGE2 secretion in response to IL-1b. Immuno-histochemical analysis of <d>IPF</d> lung tissue showed no COX-2 immuno-reactivity in myofibroblast foci. CONCLUSIONS: Myofibroblasts are associated with COX-2 down-regulation and reduced PGE2 production, which could be crucial in <d>IPF</d> development and progression.
23760654|a|Epithelial-mesenchymal transition EMT has been considered to be involved in <d>idiopathic pulmonary fibrosis</d> IPF. However, the EMT process in vivo is much more complex and controversial. Studies regarding the opposite process, mesenchymal-epithelial transition MET in fibroblasts, are limited. Therefore, the aim of this study was to verify the involvement of the transforming growth factor TGF-b1-dependent EMT network in the process of pulmonary fibrosis and to explore the possibility of MET. Fibrotic lung tissues were obtained from patients with IPF with histological evidence of usual interstitial pneumonia at the time of surgical lung biopsy. For the controls, histologically normal lung tissues were obtained from patients with primary spontaneous pneumothorax at the time of thoracoscopy with stapling of any air leaks. Real-time RT-PCR and western blot analysis revealed that the mRNA and protein levels of TGF-b1, TGF-b1 receptor type I/II/III TbRI/II/III, Smad2/3/4 and Snail1/2 were significantly upregulated in the fibrotic lung tissue. Inhibitors of various kinases implicated in EMT, including TGF-b1/Smad, Rho kinase ROCK, p38 mitogen-activated protein kinase p38 MAPK and c-Jun NH-terminal kinase JNK were used to determine the MET potential in fibroblasts from fibrotic lung tissue. Western blot analysis or indirect immunofluorescence staining revealed that Smad inhibitor, as well as other kinase inhibitors failed to induce the MET process, determined by cellular morphology and protein markers. Our data suggest that the MET process may not be the exact reversal of EMT. In addition to using kinase inhibitors, other intervention measures should be used to explore the possibility of the MET process in fibroblasts from fibrotic lung tissue.
23760654|a|Epithelial-mesenchymal transition EMT has been considered to be involved in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. However, the EMT process in vivo is much more complex and controversial. Studies regarding the opposite process, mesenchymal-epithelial transition MET in fibroblasts, are limited. Therefore, the aim of this study was to verify the involvement of the transforming growth factor TGF-b1-dependent EMT network in the process of pulmonary fibrosis and to explore the possibility of MET. Fibrotic lung tissues were obtained from patients with <d>IPF</d> with histological evidence of usual interstitial pneumonia at the time of surgical lung biopsy. For the controls, histologically normal lung tissues were obtained from patients with primary spontaneous pneumothorax at the time of thoracoscopy with stapling of any air leaks. Real-time RT-PCR and western blot analysis revealed that the mRNA and protein levels of TGF-b1, TGF-b1 receptor type I/II/III TbRI/II/III, Smad2/3/4 and Snail1/2 were significantly upregulated in the fibrotic lung tissue. Inhibitors of various kinases implicated in EMT, including TGF-b1/Smad, Rho kinase ROCK, p38 mitogen-activated protein kinase p38 MAPK and c-Jun NH-terminal kinase JNK were used to determine the MET potential in fibroblasts from fibrotic lung tissue. Western blot analysis or indirect immunofluorescence staining revealed that Smad inhibitor, as well as other kinase inhibitors failed to induce the MET process, determined by cellular morphology and protein markers. Our data suggest that the MET process may not be the exact reversal of EMT. In addition to using kinase inhibitors, other intervention measures should be used to explore the possibility of the MET process in fibroblasts from fibrotic lung tissue.
23760654|a|Epithelial-mesenchymal transition EMT has been considered to be involved in <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. However, the EMT process in vivo is much more complex and controversial. Studies regarding the opposite process, mesenchymal-epithelial transition MET in fibroblasts, are limited. Therefore, the aim of this study was to verify the involvement of the transforming growth factor TGF-b1-dependent EMT network in the process of <d>pulmonary fibrosis</d> and to explore the possibility of MET. Fibrotic lung tissues were obtained from patients with <d>IPF</d> with histological evidence of usual interstitial pneumonia at the time of surgical lung biopsy. For the controls, histologically normal lung tissues were obtained from patients with primary spontaneous pneumothorax at the time of thoracoscopy with stapling of any air leaks. Real-time RT-PCR and western blot analysis revealed that the mRNA and protein levels of TGF-b1, TGF-b1 receptor type I/II/III TbRI/II/III, Smad2/3/4 and Snail1/2 were significantly upregulated in the fibrotic lung tissue. Inhibitors of various kinases implicated in EMT, including TGF-b1/Smad, Rho kinase ROCK, p38 mitogen-activated protein kinase p38 MAPK and c-Jun NH-terminal kinase JNK were used to determine the MET potential in fibroblasts from fibrotic lung tissue. Western blot analysis or indirect immunofluorescence staining revealed that Smad inhibitor, as well as other kinase inhibitors failed to induce the MET process, determined by cellular morphology and protein markers. Our data suggest that the MET process may not be the exact reversal of EMT. In addition to using kinase inhibitors, other intervention measures should be used to explore the possibility of the MET process in fibroblasts from fibrotic lung tissue.
23760654|a|Epithelial-mesenchymal transition EMT has been considered to be involved in <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. However, the EMT process in vivo is much more complex and controversial. Studies regarding the opposite process, mesenchymal-epithelial transition MET in fibroblasts, are limited. Therefore, the aim of this study was to verify the involvement of the transforming growth factor TGF-b1-dependent EMT network in the process of <d>pulmonary fibrosis</d> and to explore the possibility of MET. Fibrotic lung tissues were obtained from patients with <d>IPF</d> with histological evidence of <d>usual interstitial pneumonia</d> at the time of surgical lung biopsy. For the controls, histologically normal lung tissues were obtained from patients with primary spontaneous pneumothorax at the time of thoracoscopy with stapling of any air leaks. Real-time RT-PCR and western blot analysis revealed that the mRNA and protein levels of TGF-b1, TGF-b1 receptor type I/II/III TbRI/II/III, Smad2/3/4 and Snail1/2 were significantly upregulated in the fibrotic lung tissue. Inhibitors of various kinases implicated in EMT, including TGF-b1/Smad, Rho kinase ROCK, p38 mitogen-activated protein kinase p38 MAPK and c-Jun NH-terminal kinase JNK were used to determine the MET potential in fibroblasts from fibrotic lung tissue. Western blot analysis or indirect immunofluorescence staining revealed that Smad inhibitor, as well as other kinase inhibitors failed to induce the MET process, determined by cellular morphology and protein markers. Our data suggest that the MET process may not be the exact reversal of EMT. In addition to using kinase inhibitors, other intervention measures should be used to explore the possibility of the MET process in fibroblasts from fibrotic lung tissue.
23760654|a|Epithelial-mesenchymal transition EMT has been considered to be involved in <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. However, the EMT process in vivo is much more complex and controversial. Studies regarding the opposite process, mesenchymal-epithelial transition MET in fibroblasts, are limited. Therefore, the aim of this study was to verify the involvement of the transforming growth factor TGF-b1-dependent EMT network in the process of <d>pulmonary fibrosis</d> and to explore the possibility of MET. Fibrotic lung tissues were obtained from patients with <d>IPF</d> with histological evidence of <d>usual interstitial pneumonia</d> at the time of surgical lung biopsy. For the controls, histologically normal lung tissues were obtained from patients with <d>primary spontaneous pneumothorax</d> at the time of thoracoscopy with stapling of any air leaks. Real-time RT-PCR and western blot analysis revealed that the mRNA and protein levels of TGF-b1, TGF-b1 receptor type I/II/III TbRI/II/III, Smad2/3/4 and Snail1/2 were significantly upregulated in the fibrotic lung tissue. Inhibitors of various kinases implicated in EMT, including TGF-b1/Smad, Rho kinase ROCK, p38 mitogen-activated protein kinase p38 MAPK and c-Jun NH-terminal kinase JNK were used to determine the MET potential in fibroblasts from fibrotic lung tissue. Western blot analysis or indirect immunofluorescence staining revealed that Smad inhibitor, as well as other kinase inhibitors failed to induce the MET process, determined by cellular morphology and protein markers. Our data suggest that the MET process may not be the exact reversal of EMT. In addition to using kinase inhibitors, other intervention measures should be used to explore the possibility of the MET process in fibroblasts from fibrotic lung tissue.
23764846|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a serious progressive and irreversible lung disease with unknown etiology and few treatment options. This disease was once thought to be a chronic inflammatory-driven process, but it is increasingly recognized that the epithelial-mesenchymal transition EMT contributes to the cellular origin of fibroblast accumulation in response to injury. During the pathogenesis of pulmonary fibrotic diseases, transforming growth factor-b TGF-b signaling is considered a pivotal inducer of EMT and fibroblast activation, and a number of therapeutic interventions that interfere with TGF-b signaling have been developed to reverse established fibrosis. However, efficient and well-tolerated antifibrotic agents are not currently available. Previously, we reported the identification of sorafenib to antagonize TGF-b signaling in mouse hepatocytes in vitro. In this manuscript, we continued to evaluate the antifibrotic effects of sorafenib on bleomycin BLM-induced <d>pulmonary fibrosis</d> in mice. We further demonstrated that sorafenib not only profoundly inhibited TGF-b1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and collagen synthesis in fibroblasts. Additionally, we presented in vivo evidence that sorafenib inhibited the symptoms of BLM-mediated EMT and fibroblast activation in mice, warranting the therapeutic potential of this drug for patients with IPF.
23764846|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a serious progressive and irreversible lung disease with unknown etiology and few treatment options. This disease was once thought to be a chronic inflammatory-driven process, but it is increasingly recognized that the epithelial-mesenchymal transition EMT contributes to the cellular origin of fibroblast accumulation in response to injury. During the pathogenesis of pulmonary fibrotic diseases, transforming growth factor-b TGF-b signaling is considered a pivotal inducer of EMT and fibroblast activation, and a number of therapeutic interventions that interfere with TGF-b signaling have been developed to reverse established fibrosis. However, efficient and well-tolerated antifibrotic agents are not currently available. Previously, we reported the identification of sorafenib to antagonize TGF-b signaling in mouse hepatocytes in vitro. In this manuscript, we continued to evaluate the antifibrotic effects of sorafenib on bleomycin BLM-induced <d>pulmonary fibrosis</d> in mice. We further demonstrated that sorafenib not only profoundly inhibited TGF-b1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and collagen synthesis in fibroblasts. Additionally, we presented in vivo evidence that sorafenib inhibited the symptoms of BLM-mediated EMT and fibroblast activation in mice, warranting the therapeutic potential of this drug for patients with <d>IPF</d>.
23764846|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a serious progressive and irreversible <d>lung disease</d> with unknown etiology and few treatment options. This disease was once thought to be a chronic inflammatory-driven process, but it is increasingly recognized that the epithelial-mesenchymal transition EMT contributes to the cellular origin of fibroblast accumulation in response to injury. During the pathogenesis of pulmonary fibrotic diseases, transforming growth factor-b TGF-b signaling is considered a pivotal inducer of EMT and fibroblast activation, and a number of therapeutic interventions that interfere with TGF-b signaling have been developed to reverse established fibrosis. However, efficient and well-tolerated antifibrotic agents are not currently available. Previously, we reported the identification of sorafenib to antagonize TGF-b signaling in mouse hepatocytes in vitro. In this manuscript, we continued to evaluate the antifibrotic effects of sorafenib on bleomycin BLM-induced <d>pulmonary fibrosis</d> in mice. We further demonstrated that sorafenib not only profoundly inhibited TGF-b1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and collagen synthesis in fibroblasts. Additionally, we presented in vivo evidence that sorafenib inhibited the symptoms of BLM-mediated EMT and fibroblast activation in mice, warranting the therapeutic potential of this drug for patients with <d>IPF</d>.
23764846|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a serious progressive and irreversible <d>lung disease</d> with unknown etiology and few treatment options. This disease was once thought to be a chronic inflammatory-driven process, but it is increasingly recognized that the epithelial-mesenchymal transition EMT contributes to the cellular origin of fibroblast accumulation in response to injury. During the pathogenesis of pulmonary <d>fibrotic diseases</d>, transforming growth factor-b TGF-b signaling is considered a pivotal inducer of EMT and fibroblast activation, and a number of therapeutic interventions that interfere with TGF-b signaling have been developed to reverse established fibrosis. However, efficient and well-tolerated antifibrotic agents are not currently available. Previously, we reported the identification of sorafenib to antagonize TGF-b signaling in mouse hepatocytes in vitro. In this manuscript, we continued to evaluate the antifibrotic effects of sorafenib on bleomycin BLM-induced <d>pulmonary fibrosis</d> in mice. We further demonstrated that sorafenib not only profoundly inhibited TGF-b1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and collagen synthesis in fibroblasts. Additionally, we presented in vivo evidence that sorafenib inhibited the symptoms of BLM-mediated EMT and fibroblast activation in mice, warranting the therapeutic potential of this drug for patients with <d>IPF</d>.
23764846|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a serious progressive and irreversible <d>lung disease</d> with unknown etiology and few treatment options. This disease was once thought to be a chronic inflammatory-driven process, but it is increasingly recognized that the epithelial-mesenchymal transition EMT contributes to the cellular origin of fibroblast accumulation in response to injury. During the pathogenesis of pulmonary <d>fibrotic diseases</d>, <g>transforming growth factor-b</g> <g>TGF-b</g> signaling is considered a pivotal inducer of EMT and fibroblast activation, and a number of therapeutic interventions that interfere with <g>TGF-b</g> signaling have been developed to reverse established <d>fibrosis</d>. However, efficient and well-tolerated antifibrotic agents are not currently available. Previously, we reported the identification of sorafenib to antagonize <g>TGF-b</g> signaling in mouse hepatocytes in vitro. In this manuscript, we continued to evaluate the antifibrotic effects of sorafenib on bleomycin BLM-induced <d>pulmonary <d>fibrosis</d></d> in mice. We further demonstrated that sorafenib not only profoundly inhibited <g>TGF-b</g>1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and collagen synthesis in fibroblasts. Additionally, we presented in vivo evidence that sorafenib inhibited the symptoms of BLM-mediated EMT and fibroblast activation in mice, warranting the therapeutic potential of this drug for patients with <d>IPF</d>.
23815594|a|BACKGROUND: Studies have demonstrated associations between cytokine gene polymorphisms and the risk of <d>idiopathic pulmonary fibrosis</d> IPF. We therefore examined polymorphisms in the genes encoding interleukin IL-6, IL-10, interferon gamma IFN-y, tumor necrosis factor alpha TNF-a, and transforming growth factor-beta 1 TGF-b1, and compared the serum levels of these cytokines in IPF patients and healthy controls. Furthermore, we examined the association of the studied genotypes and serum cytokine levels with physiological parameters and the extent of parenchymal involvement determined by high-resolution computed tomography HRCT. METHODS: Sixty patients with IPF and 150 healthy controls were included. Cytokine genotyping was performed using the polymerase chain reaction sequence specific primer PCR-SSP method. In a subset of patients and controls, serum cytokine levels were determined by enzyme-linked immunosorbent assay. RESULTS: There was no difference between IPF patients and controls in the genotype and allele distributions of polymorphisms in TNF-a, IFN-y, IL-6, IL-10, and TGF-b1 all p > 0.05. The TNF-a -308 GG, IL-6 -174 GG and CG, and IL-10 -1082, -819, -592 ACC ATA genotypes were significantly associated with HRCT scores all p < 0.05. IL-10 -1082, -819, -592 ACC haplotype was associated with the diffusion capacity of the lung for carbon monoxide, and ATA haplotype was associated with the partial pressure of oxygen PaO2 all p < 0.05. The TGF-b1 codons 10 and 25 TC GG, TC GC, CC GG and CC GC genotypes were significantly associated with the PaO2 and HRCT scores p < 0.05. The TGF-b1 codons 10 and 25 CC GG genotype 5 patients was significantly associated with higher PaO2 value and less parenchymal involvement i.e., a lower total extent score compared to the other TGF-b1 genotypes 81.5    11.8 mm Hg vs. 67.4    11.1 mm Hg, p = 0.009 and 5.60    1.3 vs. 8.51    2.9, p = 0.037, respectively. Significant differences were noted between patients n = 38 and controls n = 36 in the serum levels of IL-6 and IL-10 both, p < 0.0001, but not in the levels of TNF-a and TGF-b1 both, p > 0.05. CONCLUSION: The studied genotypes and alleles do not predispose to the development of IPF but appear to play an important role in disease severity. Our results suggest that the TGF-b1 codons 10 and 25 CC GG genotype could be a useful genetic marker for identifying a subset of IPF patients with a favorable prognosis; however, validation in a larger sample is required.
23815594|a|BACKGROUND: Studies have demonstrated associations between cytokine gene polymorphisms and the risk of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. We therefore examined polymorphisms in the genes encoding interleukin IL-6, IL-10, interferon gamma IFN-y, tumor necrosis factor alpha TNF-a, and transforming growth factor-beta 1 TGF-b1, and compared the serum levels of these cytokines in <d>IPF</d> patients and healthy controls. Furthermore, we examined the association of the studied genotypes and serum cytokine levels with physiological parameters and the extent of parenchymal involvement determined by high-resolution computed tomography HRCT. METHODS: Sixty patients with <d>IPF</d> and 150 healthy controls were included. Cytokine genotyping was performed using the polymerase chain reaction sequence specific primer PCR-SSP method. In a subset of patients and controls, serum cytokine levels were determined by enzyme-linked immunosorbent assay. RESULTS: There was no difference between <d>IPF</d> patients and controls in the genotype and allele distributions of polymorphisms in TNF-a, IFN-y, IL-6, IL-10, and TGF-b1 all p > 0.05. The TNF-a -308 GG, IL-6 -174 GG and CG, and IL-10 -1082, -819, -592 ACC ATA genotypes were significantly associated with HRCT scores all p < 0.05. IL-10 -1082, -819, -592 ACC haplotype was associated with the diffusion capacity of the lung for carbon monoxide, and ATA haplotype was associated with the partial pressure of oxygen PaO2 all p < 0.05. The TGF-b1 codons 10 and 25 TC GG, TC GC, CC GG and CC GC genotypes were significantly associated with the PaO2 and HRCT scores p < 0.05. The TGF-b1 codons 10 and 25 CC GG genotype 5 patients was significantly associated with higher PaO2 value and less parenchymal involvement i.e., a lower total extent score compared to the other TGF-b1 genotypes 81.5    11.8 mm Hg vs. 67.4    11.1 mm Hg, p = 0.009 and 5.60    1.3 vs. 8.51    2.9, p = 0.037, respectively. Significant differences were noted between patients n = 38 and controls n = 36 in the serum levels of IL-6 and IL-10 both, p < 0.0001, but not in the levels of TNF-a and TGF-b1 both, p > 0.05. CONCLUSION: The studied genotypes and alleles do not predispose to the development of <d>IPF</d> but appear to play an important role in disease severity. Our results suggest that the TGF-b1 codons 10 and 25 CC GG genotype could be a useful genetic marker for identifying a subset of <d>IPF</d> patients with a favorable prognosis; however, validation in a larger sample is required.
23817018|a|BACKGROUND: <g>Transforming growth factor-b1</g> <g>TGF-b1</g>-induced epithelial-mesenchymal transition EMT of alveolar epithelial cells AEC may contribute to <d>idiopathic pulmonary fibrosis</d> IPF. <g>TGF-b1</g>-induced EMT in A549 cells a human AEC cell line resulted in the adoption of mesenchymal responses that were predominantly mediated via the <g>TGF-b1</g>-Smad2/3 signaling pathway. Simvastatin Sim, a 3-hydroxy-3-methylglutaryl CoA HMG-CoA reductase inhibitor, has been previously reported to inhibit EMT in human proximal tubular epithelial cells and porcine lens epithelial cells and to suppress Smad2/3 phosphorylation in animal models. However, whether Sim can attenuate <g>TGF-b1</g>-induced EMT in A549 cells and its underlying mechanisms remains unknown. METHODS: Cells were incubated with <g>TGF-b1</g> in the presence or absence of Sim. The epithelial marker E-cadherin E-Cad and the mesenchymal markers, a-smooth muscle actin a-SMA, vimentin Vi and fibronectin FN, were detected using western blotting analyses and immunofluorescence. Phosphorylated Smad2 and Smad3 levels and connective tissue growth factor CTGF were analyzed using western blotting. In addition, a cell migration assay was performed. Moreover, the levels of matrix metalloproteinase MMP-2 and -9 in the culture medium were examined using ELISA. RESULTS: Sim significantly attenuated the <g>TGF-b1</g>-induced decrease in E-Cad levels and elevated the levels of a-SMA, Vi and FN via the suppression of Smad2 and Smad3 phosphorylation. Furthermore, Sim inhibited the mesenchymal-like responses in A549 cells, including cell migration, CTGF expression and secretion of MMP-2 and -9. However, Sim failed to reverse the cell morphologial changes induced by <g>TGF-b1</g> in A549 cells. CONCLUSION: Sim attenuated <g>TGF-b1</g>-induced EMT in A549 cells and might be a promising therapeutic agent for treating IPF.
23817018|a|BACKGROUND: <g>Transforming growth factor-b1</g> <g>TGF-b1</g>-induced epithelial-mesenchymal transition EMT of alveolar epithelial cells AEC may contribute to <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. <g>TGF-b1</g>-induced EMT in A549 cells a human AEC cell line resulted in the adoption of mesenchymal responses that were predominantly mediated via the <g>TGF-b1</g>-Smad2/3 signaling pathway. Simvastatin Sim, a 3-hydroxy-3-methylglutaryl CoA HMG-CoA reductase inhibitor, has been previously reported to inhibit EMT in human proximal tubular epithelial cells and porcine lens epithelial cells and to suppress Smad2/3 phosphorylation in animal models. However, whether Sim can attenuate <g>TGF-b1</g>-induced EMT in A549 cells and its underlying mechanisms remains unknown. METHODS: Cells were incubated with <g>TGF-b1</g> in the presence or absence of Sim. The epithelial marker E-cadherin E-Cad and the mesenchymal markers, a-smooth muscle actin a-SMA, vimentin Vi and fibronectin FN, were detected using western blotting analyses and immunofluorescence. Phosphorylated Smad2 and Smad3 levels and connective tissue growth factor CTGF were analyzed using western blotting. In addition, a cell migration assay was performed. Moreover, the levels of matrix metalloproteinase MMP-2 and -9 in the culture medium were examined using ELISA. RESULTS: Sim significantly attenuated the <g>TGF-b1</g>-induced decrease in E-Cad levels and elevated the levels of a-SMA, Vi and FN via the suppression of Smad2 and Smad3 phosphorylation. Furthermore, Sim inhibited the mesenchymal-like responses in A549 cells, including cell migration, CTGF expression and secretion of MMP-2 and -9. However, Sim failed to reverse the cell morphologial changes induced by <g>TGF-b1</g> in A549 cells. CONCLUSION: Sim attenuated <g>TGF-b1</g>-induced EMT in A549 cells and might be a promising therapeutic agent for treating <d>IPF</d>.
23911740|a|AIMS: We studied the influence of <g>IL-4</g> gene polymorphisms on the <d>IPF</d> phenotype, i.e., extent of radiological changes HRCT interstitial IS and alveolar AS score and histopathological markers from lung biopsies. PATIENTS AND METHODS: 46 <d>IPF</d> patients underwent genotyping, 43 of them had HRCT and 14 patients had a surgical lung biopsy. The HRCT scans were evaluated for AS and IS. The histopathological evaluation comprised myofibroblast foci MF, intensity of inflammation and fibrosis Ashcroft score and numbers of eosinophils and granulomas. For immunohistochemical evaluation primary antibodies against PAR-2, CD124, TGF beta, YY-1 and TSLP were used. The <g>IL-4</g> and <g>IL-4</g> R alpha gene polymorphisms were characterized. RESULTS: We found a correlation between eosinophils in lung biopsies and AS. The Ashcroft score was higher in <g>IL-4</g> HA 2 GCC and MF were more frequent in <g>IL-4</g> HA 2 TCC carriers. A relationship was found between <g>IL-4</g> -1098 A2 T and PAR-2 expression and <g>IL-4</g> -590 A1 T, <g>IL-4</g> HA1TTT and CD124 expression. AS was lower in <g>IL-4</g> -590 A1 C, in <g>IL-4</g> HA1 TCC and in <g>IL-4</g>RA +1902 A1 A carriers. CONCLUSIONS: We suggest that the polymorphisms of <g>IL-4</g> genes might influence the phenotype of <d>IPF</d> reflected by histopathological changes in lung biopsies and HRCT score.
23911740|a|AIMS: We studied the influence of <g>IL-4</g> gene polymorphisms on the <d>IPF</d> phenotype, i.e., extent of radiological changes HRCT interstitial IS and alveolar <d>AS</d> score and histopathological markers from lung biopsies. PATIENTS AND METHODS: 46 <d>IPF</d> patients underwent genotyping, 43 of them had HRCT and 14 patients had a surgical lung biopsy. The HRCT scans were evaluated for <d>AS</d> and IS. The histopathological evaluation comprised myofibroblast foci MF, intensity of inflammation and fibrosis Ashcroft score and numbers of eosinophils and granulomas. For immunohistochemical evaluation primary antibodies against PAR-2, CD124, TGF beta, YY-1 and TSLP were used. The <g>IL-4</g> and <g>IL-4</g> R alpha gene polymorphisms were characterized. RESULTS: We found a correlation between eosinophils in lung biopsies and <d>AS</d>. The Ashcroft score was higher in <g>IL-4</g> HA 2 GCC and MF were more frequent in <g>IL-4</g> HA 2 TCC carriers. A relationship was found between <g>IL-4</g> -1098 A2 T and PAR-2 expression and <g>IL-4</g> -590 A1 T, <g>IL-4</g> HA1TTT and CD124 expression. <d>AS</d> was lower in <g>IL-4</g> -590 A1 C, in <g>IL-4</g> HA1 TCC and in <g>IL-4</g>RA +1902 A1 A carriers. CONCLUSIONS: We suggest that the polymorphisms of <g>IL-4</g> genes might influence the phenotype of <d>IPF</d> reflected by histopathological changes in lung biopsies and HRCT score.
23911740|a|AIMS: We studied the influence of <g>IL-4</g> gene polymorphisms on the <d>IPF</d> phenotype, i.e., extent of radiological changes HRCT interstitial IS and alveolar <d>AS</d> score and histopathological markers from lung biopsies. PATIENTS AND METHODS: 46 <d>IPF</d> patients underwent genotyping, 43 of them had HRCT and 14 patients had a surgical lung biopsy. The HRCT scans were evaluated for <d>AS</d> and IS. The histopathological evaluation comprised <d>myofibroblast foci</d> MF, intensity of inflammation and fibrosis Ashcroft score and numbers of eosinophils and granulomas. For immunohistochemical evaluation primary antibodies against PAR-2, CD124, TGF beta, YY-1 and TSLP were used. The <g>IL-4</g> and <g>IL-4</g> R alpha gene polymorphisms were characterized. RESULTS: We found a correlation between eosinophils in lung biopsies and <d>AS</d>. The Ashcroft score was higher in <g>IL-4</g> HA 2 GCC and MF were more frequent in <g>IL-4</g> HA 2 TCC carriers. A relationship was found between <g>IL-4</g> -1098 A2 T and PAR-2 expression and <g>IL-4</g> -590 A1 T, <g>IL-4</g> HA1TTT and CD124 expression. <d>AS</d> was lower in <g>IL-4</g> -590 A1 C, in <g>IL-4</g> HA1 TCC and in <g>IL-4</g>RA +1902 A1 A carriers. CONCLUSIONS: We suggest that the polymorphisms of <g>IL-4</g> genes might influence the phenotype of <d>IPF</d> reflected by histopathological changes in lung biopsies and HRCT score.
23911740|a|AIMS: We studied the influence of <g>IL-4</g> gene polymorphisms on the <d>IPF</d> phenotype, i.e., extent of radiological changes HRCT interstitial IS and alveolar <d>AS</d> score and histopathological markers from lung biopsies. PATIENTS AND METHODS: 46 <d>IPF</d> patients underwent genotyping, 43 of them had HRCT and 14 patients had a surgical lung biopsy. The HRCT scans were evaluated for <d>AS</d> and IS. The histopathological evaluation comprised <d>myofibroblast foci</d> <d>MF</d>, intensity of inflammation and fibrosis Ashcroft score and numbers of eosinophils and granulomas. For immunohistochemical evaluation primary antibodies against PAR-2, CD124, TGF beta, YY-1 and TSLP were used. The <g>IL-4</g> and <g>IL-4</g> R alpha gene polymorphisms were characterized. RESULTS: We found a correlation between eosinophils in lung biopsies and <d>AS</d>. The Ashcroft score was higher in <g>IL-4</g> HA 2 GCC and <d>MF</d> were more frequent in <g>IL-4</g> HA 2 TCC carriers. A relationship was found between <g>IL-4</g> -1098 A2 T and PAR-2 expression and <g>IL-4</g> -590 A1 T, <g>IL-4</g> HA1TTT and CD124 expression. <d>AS</d> was lower in <g>IL-4</g> -590 A1 C, in <g>IL-4</g> HA1 TCC and in <g>IL-4</g>RA +1902 A1 A carriers. CONCLUSIONS: We suggest that the polymorphisms of <g>IL-4</g> genes might influence the phenotype of <d>IPF</d> reflected by histopathological changes in lung biopsies and HRCT score.
23911740|a|AIMS: We studied the influence of <g>IL-4</g> gene polymorphisms on the <d>IPF</d> phenotype, i.e., extent of radiological changes HRCT interstitial IS and alveolar <d>AS</d> score and histopathological markers from lung biopsies. PATIENTS AND METHODS: 46 <d>IPF</d> patients underwent genotyping, 43 of them had HRCT and 14 patients had a surgical lung biopsy. The HRCT scans were evaluated for <d>AS</d> and IS. The histopathological evaluation comprised <d>myofibroblast foci</d> <d>MF</d>, intensity of <d>inflammation</d> and fibrosis Ashcroft score and numbers of eosinophils and granulomas. For immunohistochemical evaluation primary antibodies against PAR-2, CD124, TGF beta, YY-1 and TSLP were used. The <g>IL-4</g> and <g>IL-4</g> R alpha gene polymorphisms were characterized. RESULTS: We found a correlation between eosinophils in lung biopsies and <d>AS</d>. The Ashcroft score was higher in <g>IL-4</g> HA 2 GCC and <d>MF</d> were more frequent in <g>IL-4</g> HA 2 TCC carriers. A relationship was found between <g>IL-4</g> -1098 A2 T and PAR-2 expression and <g>IL-4</g> -590 A1 T, <g>IL-4</g> HA1TTT and CD124 expression. <d>AS</d> was lower in <g>IL-4</g> -590 A1 C, in <g>IL-4</g> HA1 TCC and in <g>IL-4</g>RA +1902 A1 A carriers. CONCLUSIONS: We suggest that the polymorphisms of <g>IL-4</g> genes might influence the phenotype of <d>IPF</d> reflected by histopathological changes in lung biopsies and HRCT score.
23911740|a|AIMS: We studied the influence of <g>IL-4</g> gene polymorphisms on the <d>IPF</d> phenotype, i.e., extent of radiological changes HRCT interstitial IS and alveolar <d>AS</d> score and histopathological markers from lung biopsies. PATIENTS AND METHODS: 46 <d>IPF</d> patients underwent genotyping, 43 of them had HRCT and 14 patients had a surgical lung biopsy. The HRCT scans were evaluated for <d>AS</d> and IS. The histopathological evaluation comprised <d>myofibroblast foci</d> <d>MF</d>, intensity of <d>inflammation</d> and <d>fibrosis</d> Ashcroft score and numbers of eosinophils and granulomas. For immunohistochemical evaluation primary antibodies against PAR-2, CD124, TGF beta, YY-1 and TSLP were used. The <g>IL-4</g> and <g>IL-4</g> R alpha gene polymorphisms were characterized. RESULTS: We found a correlation between eosinophils in lung biopsies and <d>AS</d>. The Ashcroft score was higher in <g>IL-4</g> HA 2 GCC and <d>MF</d> were more frequent in <g>IL-4</g> HA 2 TCC carriers. A relationship was found between <g>IL-4</g> -1098 A2 T and PAR-2 expression and <g>IL-4</g> -590 A1 T, <g>IL-4</g> HA1TTT and CD124 expression. <d>AS</d> was lower in <g>IL-4</g> -590 A1 C, in <g>IL-4</g> HA1 TCC and in <g>IL-4</g>RA +1902 A1 A carriers. CONCLUSIONS: We suggest that the polymorphisms of <g>IL-4</g> genes might influence the phenotype of <d>IPF</d> reflected by histopathological changes in lung biopsies and HRCT score.
23911740|a|AIMS: We studied the influence of <g>IL-4</g> gene polymorphisms on the <d>IPF</d> phenotype, i.e., extent of radiological changes HRCT interstitial IS and alveolar <d>AS</d> score and histopathological markers from lung biopsies. PATIENTS AND METHODS: 46 <d>IPF</d> patients underwent genotyping, 43 of them had HRCT and 14 patients had a surgical lung biopsy. The HRCT scans were evaluated for <d>AS</d> and IS. The histopathological evaluation comprised <d>myofibroblast foci</d> <d>MF</d>, intensity of <d>inflammation</d> and <d>fibrosis</d> Ashcroft score and numbers of eosinophils and <d>granulomas</d>. For immunohistochemical evaluation primary antibodies against PAR-2, CD124, TGF beta, YY-1 and TSLP were used. The <g>IL-4</g> and <g>IL-4</g> R alpha gene polymorphisms were characterized. RESULTS: We found a correlation between eosinophils in lung biopsies and <d>AS</d>. The Ashcroft score was higher in <g>IL-4</g> HA 2 GCC and <d>MF</d> were more frequent in <g>IL-4</g> HA 2 TCC carriers. A relationship was found between <g>IL-4</g> -1098 A2 T and PAR-2 expression and <g>IL-4</g> -590 A1 T, <g>IL-4</g> HA1TTT and CD124 expression. <d>AS</d> was lower in <g>IL-4</g> -590 A1 C, in <g>IL-4</g> HA1 TCC and in <g>IL-4</g>RA +1902 A1 A carriers. CONCLUSIONS: We suggest that the polymorphisms of <g>IL-4</g> genes might influence the phenotype of <d>IPF</d> reflected by histopathological changes in lung biopsies and HRCT score.
23915349|a|BACKGROUND: <d>Interstitial lung disease</d> is a major cause of morbidity and mortality in systemic sclerosis SSc, with insufficiently effective treatment options. Progression of pulmonary fibrosis involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of SSc lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from SSc lung biopsies at the time of diagnosis, compared with those from control lungs. METHODS: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with pulmonary fibrosis associated with SSc SSc-ILD, with those from control lung tissue peripheral to resected cancer n=10. Fibroblast cultures from 3 patients with idiopathic pulmonary fibrosis IPF were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis. RESULTS: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from SSc-ILD and/or IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-b response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group. CONCLUSIONS: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in pulmonary fibrosis that requires further investigation.
23915349|a|BACKGROUND: <d>Interstitial lung disease</d> is a major cause of morbidity and mortality in <d>systemic sclerosis</d> SSc, with insufficiently effective treatment options. Progression of pulmonary fibrosis involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of SSc lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from SSc lung biopsies at the time of diagnosis, compared with those from control lungs. METHODS: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with pulmonary fibrosis associated with SSc SSc-ILD, with those from control lung tissue peripheral to resected cancer n=10. Fibroblast cultures from 3 patients with idiopathic pulmonary fibrosis IPF were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis. RESULTS: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from SSc-ILD and/or IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-b response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group. CONCLUSIONS: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in pulmonary fibrosis that requires further investigation.
23915349|a|BACKGROUND: <d>Interstitial lung disease</d> is a major cause of morbidity and mortality in <d>systemic sclerosis</d> <d>SSc</d>, with insufficiently effective treatment options. Progression of pulmonary fibrosis involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of <d>SSc</d> lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from <d>SSc</d> lung biopsies at the time of diagnosis, compared with those from control lungs. METHODS: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with pulmonary fibrosis associated with <d>SSc</d> <d>SSc</d>-ILD, with those from control lung tissue peripheral to resected cancer n=10. Fibroblast cultures from 3 patients with idiopathic pulmonary fibrosis IPF were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis. RESULTS: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from <d>SSc</d>-ILD and/or IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-b response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group. CONCLUSIONS: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in pulmonary fibrosis that requires further investigation.
23915349|a|BACKGROUND: <d>Interstitial lung disease</d> is a major cause of morbidity and mortality in <d>systemic sclerosis</d> <d>SSc</d>, with insufficiently effective treatment options. Progression of <d>pulmonary fibrosis</d> involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of <d>SSc</d> lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from <d>SSc</d> lung biopsies at the time of diagnosis, compared with those from control lungs. METHODS: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with <d>pulmonary fibrosis</d> associated with <d>SSc</d> <d>SSc</d>-ILD, with those from control lung tissue peripheral to resected cancer n=10. Fibroblast cultures from 3 patients with idiopathic <d>pulmonary fibrosis</d> IPF were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis. RESULTS: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from <d>SSc</d>-ILD and/or IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-b response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group. CONCLUSIONS: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in <d>pulmonary fibrosis</d> that requires further investigation.
23915349|a|BACKGROUND: <d>Interstitial lung disease</d> is a major cause of morbidity and mortality in <d>systemic sclerosis</d> <d>SSc</d>, with insufficiently effective treatment options. Progression of <d>pulmonary fibrosis</d> involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of <d>SSc</d> lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from <d>SSc</d> lung biopsies at the time of diagnosis, compared with those from control lungs. METHODS: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with <d>pulmonary fibrosis</d> associated with <d>SSc</d> <d>SSc</d>-ILD, with those from control lung tissue peripheral to resected <d>cancer</d> n=10. Fibroblast cultures from 3 patients with idiopathic <d>pulmonary fibrosis</d> IPF were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis. RESULTS: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from <d>SSc</d>-ILD and/or IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-b response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group. CONCLUSIONS: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in <d>pulmonary fibrosis</d> that requires further investigation.
23915349|a|BACKGROUND: <d>Interstitial lung disease</d> is a major cause of morbidity and mortality in <d>systemic sclerosis</d> <d>SSc</d>, with insufficiently effective treatment options. Progression of <d>pulmonary fibrosis</d> involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of <d>SSc</d> lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from <d>SSc</d> lung biopsies at the time of diagnosis, compared with those from control lungs. METHODS: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with <d>pulmonary fibrosis</d> associated with <d>SSc</d> <d>SSc</d>-ILD, with those from control lung tissue peripheral to resected <d>cancer</d> n=10. Fibroblast cultures from 3 patients with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis. RESULTS: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from <d>SSc</d>-ILD and/or <d>IPF</d> compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-b response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group. CONCLUSIONS: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in <d>pulmonary fibrosis</d> that requires further investigation.
23915349|a|BACKGROUND: <d>Interstitial lung disease</d> is a major cause of morbidity and mortality in <d>systemic sclerosis</d> <d>SSc</d>, with insufficiently effective treatment options. Progression of <d>pulmonary <d>fibrosis</d></d> involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of <d>SSc</d> lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from <d>SSc</d> lung biopsies at the time of diagnosis, compared with those from control lungs. METHODS: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with <d>pulmonary <d>fibrosis</d></d> associated with <d>SSc</d> <d>SSc</d>-ILD, with those from control lung tissue peripheral to resected <d>cancer</d> n=10. Fibroblast cultures from 3 patients with idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis. RESULTS: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from <d>SSc</d>-ILD and/or <d>IPF</d> compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a <g>TGF-b</g> response signature including <d>fibrosis</d> associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group. CONCLUSIONS: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in <d>pulmonary <d>fibrosis</d></d> that requires further investigation.
23924348|a|RATIONALE: Alveolar transforming growth factor <g>TGF-b1</g> signaling and expression of <g>TGF-b1</g> target genes are increased in patients with <d>idiopathic pulmonary fibrosis</d> IPF and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-b receptor TbRI inhibits TGF-b signaling and could attenuate development of experimental lung fibrosis. OBJECTIVES: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting <g>TGF-b1</g> signaling in alveolar epithelial cells. METHODS: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with IPF versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell <g>TGF-b1</g> signaling, <g>TGF-b1</g>, and TbRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury. MEASUREMENTS AND MAIN RESULTS: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with IPF. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting <g>TGF-b1</g> signaling and downstream expression of <g>TGF-b1</g> target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted <g>caveolin-1</g>-dependent internalization of <g>TGF-b1</g> and TbRI in alveolar epithelial cells, which inhibited <g>TGF-b1</g> signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice. CONCLUSIONS: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting <g>caveolin-1</g>-dependent <g>TGF-b1</g> and TbRI internalization and inhibiting <g>TGF-b1</g> signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.
23924348|a|RATIONALE: Alveolar transforming growth factor <g>TGF-b1</g> signaling and expression of <g>TGF-b1</g> target genes are increased in patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-b receptor TbRI inhibits TGF-b signaling and could attenuate development of experimental lung fibrosis. OBJECTIVES: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting <g>TGF-b1</g> signaling in alveolar epithelial cells. METHODS: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with <d>IPF</d> versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell <g>TGF-b1</g> signaling, <g>TGF-b1</g>, and TbRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury. MEASUREMENTS AND MAIN RESULTS: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with <d>IPF</d>. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting <g>TGF-b1</g> signaling and downstream expression of <g>TGF-b1</g> target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted <g>caveolin-1</g>-dependent internalization of <g>TGF-b1</g> and TbRI in alveolar epithelial cells, which inhibited <g>TGF-b1</g> signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice. CONCLUSIONS: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting <g>caveolin-1</g>-dependent <g>TGF-b1</g> and TbRI internalization and inhibiting <g>TGF-b1</g> signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.
23924348|a|RATIONALE: Alveolar transforming growth factor <g>TGF-b1</g> signaling and expression of <g>TGF-b1</g> target genes are increased in patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> and in animal models of <d>pulmonary fibrosis</d>. Internalization and degradation of TGF-b receptor TbRI inhibits TGF-b signaling and could attenuate development of experimental lung fibrosis. OBJECTIVES: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting <g>TGF-b1</g> signaling in alveolar epithelial cells. METHODS: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with <d>IPF</d> versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell <g>TGF-b1</g> signaling, <g>TGF-b1</g>, and TbRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury. MEASUREMENTS AND MAIN RESULTS: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with <d>IPF</d>. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting <g>TGF-b1</g> signaling and downstream expression of <g>TGF-b1</g> target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted <g>caveolin-1</g>-dependent internalization of <g>TGF-b1</g> and TbRI in alveolar epithelial cells, which inhibited <g>TGF-b1</g> signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice. CONCLUSIONS: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting <g>caveolin-1</g>-dependent <g>TGF-b1</g> and TbRI internalization and inhibiting <g>TGF-b1</g> signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for <d>pulmonary fibrosis</d>.
23924348|a|RATIONALE: Alveolar transforming growth factor <g><g>TGF-b</g>1</g> signaling and expression of <g><g>TGF-b</g>1</g> target genes are increased in patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> and in animal models of <d>pulmonary fibrosis</d>. Internalization and degradation of <g>TGF-b</g> receptor TbRI inhibits <g>TGF-b</g> signaling and could attenuate development of <d>experimental lung fibrosis</d>. OBJECTIVES: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting <g><g>TGF-b</g>1</g> signaling in alveolar epithelial cells. METHODS: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with <d>IPF</d> versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell <g><g>TGF-b</g>1</g> signaling, <g><g>TGF-b</g>1</g>, and TbRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury. MEASUREMENTS AND MAIN RESULTS: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with <d>IPF</d>. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting <g><g>TGF-b</g>1</g> signaling and downstream expression of <g><g>TGF-b</g>1</g> target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted <g>caveolin-1</g>-dependent internalization of <g><g>TGF-b</g>1</g> and TbRI in alveolar epithelial cells, which inhibited <g><g>TGF-b</g>1</g> signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice. CONCLUSIONS: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting <g>caveolin-1</g>-dependent <g><g>TGF-b</g>1</g> and TbRI internalization and inhibiting <g><g>TGF-b</g>1</g> signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for <d>pulmonary fibrosis</d>.
23924348|a|RATIONALE: Alveolar transforming growth factor <g><g>TGF-b</g>1</g> signaling and expression of <g><g>TGF-b</g>1</g> target genes are increased in patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> and in animal models of <d>pulmonary fibrosis</d>. Internalization and degradation of <g>TGF-b</g> receptor TbRI inhibits <g>TGF-b</g> signaling and could attenuate development of <d>experimental lung fibrosis</d>. OBJECTIVES: To demonstrate that after experimental <d>lung injury</d>, human syndecan-2 confers antifibrotic effects by inhibiting <g><g>TGF-b</g>1</g> signaling in alveolar epithelial cells. METHODS: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with <d>IPF</d> versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell <g><g>TGF-b</g>1</g> signaling, <g><g>TGF-b</g>1</g>, and TbRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced <d>lung injury</d>. MEASUREMENTS AND MAIN RESULTS: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with <d>IPF</d>. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after <d>lung injury</d> by inhibiting <g><g>TGF-b</g>1</g> signaling and downstream expression of <g><g>TGF-b</g>1</g> target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted <g>caveolin-1</g>-dependent internalization of <g><g>TGF-b</g>1</g> and TbRI in alveolar epithelial cells, which inhibited <g><g>TGF-b</g>1</g> signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice. CONCLUSIONS: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting <g>caveolin-1</g>-dependent <g><g>TGF-b</g>1</g> and TbRI internalization and inhibiting <g><g>TGF-b</g>1</g> signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for <d>pulmonary fibrosis</d>.
23924348|a|RATIONALE: Alveolar transforming growth factor <g><g>TGF-b</g>1</g> signaling and expression of <g><g>TGF-b</g>1</g> target genes are increased in patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> and in animal models of <d>pulmonary fibrosis</d>. Internalization and degradation of <g>TGF-b</g> receptor TbRI inhibits <g>TGF-b</g> signaling and could attenuate development of <d>experimental lung fibrosis</d>. OBJECTIVES: To demonstrate that after experimental <d>lung injury</d>, human <g>syndecan-2</g> confers antifibrotic effects by inhibiting <g><g>TGF-b</g>1</g> signaling in alveolar epithelial cells. METHODS: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with <d>IPF</d> versus control subjects. Transgenic mice that constitutively overexpress human <g>syndecan-2</g> in macrophages were developed to test the antifibrotic properties of <g>syndecan-2</g>. In vitro assays were performed to determine <g>syndecan-2</g>-dependent changes in epithelial cell <g><g>TGF-b</g>1</g> signaling, <g><g>TGF-b</g>1</g>, and TbRI internalization and apoptosis. Wild-type mice were treated with recombinant human <g>syndecan-2</g> during the fibrotic phase of bleomycin-induced <d>lung injury</d>. MEASUREMENTS AND MAIN RESULTS: We observed significant increases in alveolar macrophage <g>syndecan-2</g> levels in patients with <d>IPF</d>. Macrophage-specific overexpression of human <g>syndecan-2</g> in transgenic mice conferred antifibrotic effects after <d>lung injury</d> by inhibiting <g><g>TGF-b</g>1</g> signaling and downstream expression of <g><g>TGF-b</g>1</g> target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, <g>syndecan-2</g> promoted <g>caveolin-1</g>-dependent internalization of <g><g>TGF-b</g>1</g> and TbRI in alveolar epithelial cells, which inhibited <g><g>TGF-b</g>1</g> signaling and epithelial cell apoptosis. Therapeutic administration of human <g>syndecan-2</g> <d>abrogated lung fibrosis</d> in mice. CONCLUSIONS: Alveolar macrophage <g>syndecan-2</g> exerts antifibrotic effects by promoting <g>caveolin-1</g>-dependent <g><g>TGF-b</g>1</g> and TbRI internalization and inhibiting <g><g>TGF-b</g>1</g> signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for <d>pulmonary fibrosis</d>.
23962103|a|Heparan sulfate proteoglycans HSPGs are integral components of the lung. Changes in HSPGs have been documented in <d>idiopathic pulmonary fibrosis</d> IPF. Many of the biological functions of HSPGs are mediated by heparan sulfate HS side chains, and little is understood about these side chains in the pathogenesis of IPF. The aims of this study were to compare HS structure between normal and IPF lungs and to examine how changes in HS regulate the fibrotic process. HS disaccharide analysis revealed that HS 6-O-sulfation was significantly increased in IPF lungs compared with normal lungs, concomitant with overexpression of HS 6-O-sulfotransferases 1 and 2 HS6ST1/2 mRNA. Immunohistochemistry revealed that HS6ST2 was specifically expressed in bronchial epithelial cells, including those lining the honeycomb cysts in IPF lungs, whereas HS6ST1 had a broad expression pattern. Lung fibroblasts in the fibroblastic foci of IPF lungs expressed HS6ST1, and overexpression of HS6ST1 mRNA was observed in primary lung fibroblasts isolated from IPF lungs compared with those from normal lungs. In vitro, small interference RNA-mediated silencing of HS6ST1 in primary normal lung fibroblasts resulted in reduced Smad2 expression and activation and in reduced expression of collagen I and a-smooth muscle actin after TGF-b1 stimulation. Similar results were obtained in primary IPF lung fibroblasts. Furthermore, silencing of HS6ST1 in normal and IPF lung fibroblasts resulted in significant down-regulation of TbRIII betaglycan. In summary, HS 6-O-sulfation is up-regulated in IPF with overexpression of HS6ST1 and HS6ST2, and overexpression of HS6ST1 in lung fibroblasts may regulate their fibrotic responses to TGF-b1.
23962103|a|Heparan sulfate proteoglycans HSPGs are integral components of the lung. Changes in HSPGs have been documented in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Many of the biological functions of HSPGs are mediated by heparan sulfate HS side chains, and little is understood about these side chains in the pathogenesis of <d>IPF</d>. The aims of this study were to compare HS structure between normal and <d>IPF</d> lungs and to examine how changes in HS regulate the fibrotic process. HS disaccharide analysis revealed that HS 6-O-sulfation was significantly increased in <d>IPF</d> lungs compared with normal lungs, concomitant with overexpression of HS 6-O-sulfotransferases 1 and 2 HS6ST1/2 mRNA. Immunohistochemistry revealed that HS6ST2 was specifically expressed in bronchial epithelial cells, including those lining the honeycomb cysts in <d>IPF</d> lungs, whereas HS6ST1 had a broad expression pattern. Lung fibroblasts in the fibroblastic foci of <d>IPF</d> lungs expressed HS6ST1, and overexpression of HS6ST1 mRNA was observed in primary lung fibroblasts isolated from <d>IPF</d> lungs compared with those from normal lungs. In vitro, small interference RNA-mediated silencing of HS6ST1 in primary normal lung fibroblasts resulted in reduced Smad2 expression and activation and in reduced expression of collagen I and a-smooth muscle actin after TGF-b1 stimulation. Similar results were obtained in primary <d>IPF</d> lung fibroblasts. Furthermore, silencing of HS6ST1 in normal and <d>IPF</d> lung fibroblasts resulted in significant down-regulation of TbRIII betaglycan. In summary, HS 6-O-sulfation is up-regulated in <d>IPF</d> with overexpression of HS6ST1 and HS6ST2, and overexpression of HS6ST1 in lung fibroblasts may regulate their fibrotic responses to TGF-b1.
23967091|a|Abnormal TGF-b1/Smad3 activation plays an important role in the pathogenesis of <d>pulmonary fibrosis</d>, which can be prevented by paclitaxel PTX. This study aimed to investigate an antifibrotic effect of the low-dose PTX 10 to 50 nM in vitro, and 0.6 mg/kg in vivo. PTX treatment resulted in phenotype reversion of epithelial-mesenchymal transition EMT in alveolar epithelial cells AECs with increase of miR-140. PTX resulted in an amelioration of bleomycin BLM-induced <d>pulmonary fibrosis</d> in rats with reduction of the wet lung weight to body weight ratios and the collagen deposition. Our results further demonstrated that PTX inhibited the effect of TGF-b1 on regulating the expression of Smad3 and phosphorylated Smad3 p-Smad3, and restored the levels of E-cadherin, vimentin and a-SMA. Moreover, lower miR-140 levels were found in idiopathic <d>pulmonary fibrosis</d> IPF patients, TGF-b1-treated AECs and BLM-instilled rat lungs. Through decreasing Smad3/p-Smad3 expression and upregulating miR-140, PTX treatment could significantly reverse the EMT of AECs and prevent <d>pulmonary fibrosis</d> of rats. The action of PTX to ameliorate TGF-b1-induced EMT was promoted by miR-140, which increased E-cadherin levels and reduced the expression of vimentin, Smad3 and p-Smad3. Collectively, our results demonstrate that low-dose PTX prevents <d>pulmonary fibrosis</d> by suppressing the TGF-b1/Smad3 pathway via upregulating miR-140.
23967091|a|Abnormal <g>TGF-b1</g>/<g>Smad3</g> activation plays an important role in the pathogenesis of <d>pulmonary fibrosis</d>, which can be prevented by paclitaxel PTX. This study aimed to investigate an antifibrotic effect of the low-dose PTX 10 to 50 nM in vitro, and 0.6 mg/kg in vivo. PTX treatment resulted in phenotype reversion of epithelial-mesenchymal transition EMT in alveolar epithelial cells AECs with increase of <g>miR-140</g>. PTX resulted in an amelioration of bleomycin BLM-induced <d>pulmonary fibrosis</d> in rats with reduction of the wet lung weight to body weight ratios and the collagen deposition. Our results further demonstrated that PTX inhibited the effect of <g>TGF-b1</g> on regulating the expression of <g>Smad3</g> and phosphorylated <g>Smad3</g> p-<g>Smad3</g>, and restored the levels of <g>E-cadherin</g>, <g>vimentin</g> and a-SMA. Moreover, lower <g>miR-140</g> levels were found in idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> patients, <g>TGF-b1</g>-treated AECs and BLM-instilled rat lungs. Through decreasing <g>Smad3</g>/p-<g>Smad3</g> expression and upregulating <g>miR-140</g>, PTX treatment could significantly reverse the EMT of AECs and prevent <d>pulmonary fibrosis</d> of rats. The action of PTX to ameliorate <g>TGF-b1</g>-induced EMT was promoted by <g>miR-140</g>, which increased <g>E-cadherin</g> levels and reduced the expression of <g>vimentin</g>, <g>Smad3</g> and p-<g>Smad3</g>. Collectively, our results demonstrate that low-dose PTX prevents <d>pulmonary fibrosis</d> by suppressing the <g>TGF-b1</g>/<g>Smad3</g> pathway via upregulating <g>miR-140</g>.
23977848|a|Idiopathic <d>pulmonary fibrosis</d> is a chronic progressive disease of increasing prevalence for which there is no effective therapy. Increased oxidative stress associated with an oxidant-antioxidant imbalance is thought to contribute to disease progression. NADPH oxidases Nox are a primary source of reactive oxygen species within the lung and cardiovascular system. We demonstrate that the Nox4 isoform is up-regulated in the lungs of patients with IPF and in a rodent model of bleomycin-induced <d>pulmonary fibrosis</d> and vascular remodeling. Nox4 is constitutively active, and therefore increased expression levels are likely to contribute to disease pathology. Using a small molecule Nox4/Nox1 inhibitor, we demonstrate that targeting Nox4 results in attenuation of an established fibrotic response, with reductions in gene transcripts for the extracellular matrix components collagen 1a1, collagen 3a1, and fibronectin and in principle pathway components associated with <d>pulmonary fibrosis</d> and hypoxia-mediated vascular remodeling: transforming growth factor TGF-b1, plasminogen activator inhibitor-1, hypoxia-inducible factor, and Nox4. TGF-b1 is a principle fibrotic mediator responsible for inducing up-regulation of profibrotic pathways associated with disease pathology. Using normal human lung-derived primary fibroblasts, we demonstrate that inhibition of Nox4 activity using a small molecule antagonist attenuates TGF-b1-mediated up-regulation in expression of profibrotic genes and inhibits the differentiation of fibroblast to myofibroblasts, that is associated with up-regulation in smooth muscle actin and acquisition of a contractile phenotype. These studies support the view that targeting Nox4 may provide a therapeutic approach for attenuating <d>pulmonary fibrosis</d>.
23977848|a|Idiopathic <d>pulmonary fibrosis</d> is a chronic progressive disease of increasing prevalence for which there is no effective therapy. Increased oxidative stress associated with an oxidant-antioxidant imbalance is thought to contribute to disease progression. NADPH oxidases Nox are a primary source of reactive oxygen species within the lung and cardiovascular system. We demonstrate that the <g>Nox4</g> isoform is up-regulated in the lungs of patients with <d>IPF</d> and in a rodent model of bleomycin-induced <d>pulmonary fibrosis</d> and vascular remodeling. <g>Nox4</g> is constitutively active, and therefore increased expression levels are likely to contribute to disease pathology. Using a small molecule <g>Nox4</g>/Nox1 inhibitor, we demonstrate that targeting <g>Nox4</g> results in attenuation of an established fibrotic response, with reductions in gene transcripts for the extracellular matrix components collagen 1a1, collagen 3a1, and fibronectin and in principle pathway components associated with <d>pulmonary fibrosis</d> and hypoxia-mediated vascular remodeling: transforming growth factor TGF-b1, plasminogen activator inhibitor-1, hypoxia-inducible factor, and <g>Nox4</g>. TGF-b1 is a principle fibrotic mediator responsible for inducing up-regulation of profibrotic pathways associated with disease pathology. Using normal human lung-derived primary fibroblasts, we demonstrate that inhibition of <g>Nox4</g> activity using a small molecule antagonist attenuates TGF-b1-mediated up-regulation in expression of profibrotic genes and inhibits the differentiation of fibroblast to myofibroblasts, that is associated with up-regulation in smooth muscle actin and acquisition of a contractile phenotype. These studies support the view that targeting <g>Nox4</g> may provide a therapeutic approach for attenuating <d>pulmonary fibrosis</d>.
23977848|a|Idiopathic <d>pulmonary fibrosis</d> is a chronic progressive disease of increasing prevalence for which there is no effective therapy. Increased oxidative stress associated with an oxidant-antioxidant imbalance is thought to contribute to disease progression. NADPH oxidases Nox are a primary source of reactive oxygen species within the lung and cardiovascular system. We demonstrate that the <g>Nox4</g> isoform is up-regulated in the lungs of patients with <d>IPF</d> and in a rodent model of bleomycin-induced <d>pulmonary fibrosis</d> and vascular remodeling. <g>Nox4</g> is constitutively active, and therefore increased expression levels are likely to contribute to disease pathology. Using a small molecule <g>Nox4</g>/<g>Nox1</g> inhibitor, we demonstrate that targeting <g>Nox4</g> results in attenuation of an established fibrotic response, with reductions in gene transcripts for the extracellular matrix components collagen 1a1, collagen 3a1, and <g>fibronectin</g> and in principle pathway components associated with <d>pulmonary fibrosis</d> and <d>hypoxia</d>-mediated vascular remodeling: transforming growth factor TGF-b1, plasminogen activator inhibitor-1, <d>hypoxia</d>-inducible factor, and <g>Nox4</g>. TGF-b1 is a principle fibrotic mediator responsible for inducing up-regulation of profibrotic pathways associated with disease pathology. Using normal human lung-derived primary fibroblasts, we demonstrate that inhibition of <g>Nox4</g> activity using a small molecule antagonist attenuates TGF-b1-mediated up-regulation in expression of profibrotic genes and inhibits the differentiation of fibroblast to myofibroblasts, that is associated with up-regulation in smooth muscle actin and acquisition of a contractile phenotype. These studies support the view that targeting <g>Nox4</g> may provide a therapeutic approach for attenuating <d>pulmonary fibrosis</d>.
23986222|a|The pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF remains largely unknown. It is believed that IPF is mainly driven by activated alveolar epithelial cells that have a compromised migration capacity, and that also produce substances such as connective tissue growth factor, CTGF that contribute to fibroblast activation and matrix protein accumulation. Because the mechanisms regulating these processes are unclear, the aim of this study was to determine the role of rapamycin in regulating epithelial cell migration and CTGF expression. Transformed epithelial cell line A549 and normal human pulmonary alveolar or bronchial epithelial cells were cultured in regular medium or medium containing rapamycin. Real time reverse transcriptase polymerase chain reaction was employed to determine CTGF mRNA expression. Western blotting and an enzyme-linked immunosorbent assay were used for detecting CTGF protein. Wound healing and migration assays were used to determine the cell migration potential. Transforming growth factor TGF-b type I receptor TbRI inhibitor, SB431542 and phosphoinositide 3-kinase PI3K inhibitor, LY294002 were used to determine rapamycin's mechanism of action. It was found that treatment of A549 and normal human alveolar or bronchial epithelial cells with rapamycin significantly promoted basal or TGF-b1 induced CTGF expression. LY294002, not SB431542 attenuated the promotional effect of rapamycin on CTGF expression. Cell mobility was not affected by rapamycin in wound healing and migration assays. These data suggest rapamycin has a profibrotic effect in vitro and underscore the potential of combined therapeutic approach with PI3K and mammalian target of rapamycin inhibitors for the treatment of animal or human lung fibrosis.
23986222|a|The pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> remains largely unknown. It is believed that <d>IPF</d> is mainly driven by activated alveolar epithelial cells that have a compromised migration capacity, and that also produce substances such as connective tissue growth factor, CTGF that contribute to fibroblast activation and matrix protein accumulation. Because the mechanisms regulating these processes are unclear, the aim of this study was to determine the role of rapamycin in regulating epithelial cell migration and CTGF expression. Transformed epithelial cell line A549 and normal human pulmonary alveolar or bronchial epithelial cells were cultured in regular medium or medium containing rapamycin. Real time reverse transcriptase polymerase chain reaction was employed to determine CTGF mRNA expression. Western blotting and an enzyme-linked immunosorbent assay were used for detecting CTGF protein. Wound healing and migration assays were used to determine the cell migration potential. Transforming growth factor TGF-b type I receptor TbRI inhibitor, SB431542 and phosphoinositide 3-kinase PI3K inhibitor, LY294002 were used to determine rapamycin's mechanism of action. It was found that treatment of A549 and normal human alveolar or bronchial epithelial cells with rapamycin significantly promoted basal or TGF-b1 induced CTGF expression. LY294002, not SB431542 attenuated the promotional effect of rapamycin on CTGF expression. Cell mobility was not affected by rapamycin in wound healing and migration assays. These data suggest rapamycin has a profibrotic effect in vitro and underscore the potential of combined therapeutic approach with PI3K and mammalian target of rapamycin inhibitors for the treatment of animal or human lung fibrosis.
23986222|a|The pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> remains largely unknown. It is believed that <d>IPF</d> is mainly driven by activated alveolar epithelial cells that have a compromised migration capacity, and that also produce substances such as connective tissue growth factor, <g>CTGF</g> that contribute to fibroblast activation and matrix protein accumulation. Because the mechanisms regulating these processes are unclear, the aim of this study was to determine the role of rapamycin in regulating epithelial cell migration and <g>CTGF</g> expression. Transformed epithelial cell line A549 and normal human <d>pulmonary alveolar</d> or bronchial epithelial cells were cultured in regular medium or medium containing rapamycin. Real time reverse transcriptase polymerase chain reaction was employed to determine <g>CTGF</g> mRNA expression. Western blotting and an enzyme-linked immunosorbent assay were used for detecting <g>CTGF</g> protein. Wound healing and migration assays were used to determine the cell migration potential. Transforming growth factor TGF-b type I receptor TbRI inhibitor, SB431542 and phosphoinositide 3-kinase PI3K inhibitor, LY294002 were used to determine rapamycin's mechanism of action. It was found that treatment of A549 and normal human alveolar or bronchial epithelial cells with rapamycin significantly promoted basal or TGF-b1 induced <g>CTGF</g> expression. LY294002, not SB431542 attenuated the promotional effect of rapamycin on <g>CTGF</g> expression. Cell mobility was not affected by rapamycin in wound healing and migration assays. These data suggest rapamycin has a profibrotic effect in vitro and underscore the potential of combined therapeutic approach with PI3K and mammalian target of rapamycin inhibitors for the treatment of animal or human lung fibrosis.
23986222|a|The pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> remains largely unknown. It is believed that <d>IPF</d> is mainly driven by activated alveolar epithelial cells that have a compromised migration capacity, and that also produce substances such as connective tissue growth factor, <g>CTGF</g> that contribute to fibroblast activation and matrix protein accumulation. Because the mechanisms regulating these processes are unclear, the aim of this study was to determine the role of rapamycin in regulating epithelial cell migration and <g>CTGF</g> expression. Transformed epithelial cell line A549 and normal human <d>pulmonary alveolar</d> or bronchial epithelial cells were cultured in regular medium or medium containing rapamycin. Real time reverse transcriptase polymerase chain reaction was employed to determine <g>CTGF</g> mRNA expression. Western blotting and an enzyme-linked immunosorbent assay were used for detecting <g>CTGF</g> protein. Wound healing and migration assays were used to determine the cell migration potential. Transforming growth factor TGF-b type I receptor TbRI inhibitor, SB431542 and phosphoinositide 3-kinase PI3K inhibitor, LY294002 were used to determine rapamycin's mechanism of action. It was found that treatment of A549 and normal human alveolar or bronchial epithelial cells with rapamycin significantly promoted basal or <g>TGF-b1</g> induced <g>CTGF</g> expression. LY294002, not SB431542 attenuated the promotional effect of rapamycin on <g>CTGF</g> expression. Cell mobility was not affected by rapamycin in wound healing and migration assays. These data suggest rapamycin has a profibrotic effect in vitro and underscore the potential of combined therapeutic approach with PI3K and mammalian target of rapamycin inhibitors for the treatment of animal or human <d>lung fibrosis</d>.
24050627|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated.
24050627|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of <d>IPF</d> is incomplete, recent advances delineating specific clinical and pathologic features of <d>IPF</d> have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to <d>IPF</d> and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within <d>IPF</d> fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated.
24050627|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fibrosing <d>interstitial lung disease</d> associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of <d>IPF</d> is incomplete, recent advances delineating specific clinical and pathologic features of <d>IPF</d> have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to <d>IPF</d> and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within <d>IPF</d> fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated.
24050627|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fibrosing <d>interstitial lung disease</d> associated with aging that is characterized by the histopathological pattern of usual <d>interstitial pneumonia</d>. Although an understanding of the pathogenesis of <d>IPF</d> is incomplete, recent advances delineating specific clinical and pathologic features of <d>IPF</d> have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to <d>IPF</d> and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within <d>IPF</d> fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated.
24088250|a|Pirfenidone PFD is the first and only clinically used antifibrotic drug for the treatment of <d>idiopathic pulmonary fibrosis</d> IPF. This study evaluated the antifibrotic effects of two metabolites of PFD, 5-hydroxypirfenidone PFD-OH and 5-carboxypirfenidone PFD-COOH, on WI-38 cells in an in vitro lung fibroblast model. The inhibitory effects of PFD-OH and PFD-COOH on transforming growth factor-b1 TGF-b1-induced collagen synthesis in WI-38 cells were evaluated by measuring intracellular hydroxyproline, a major component of the protein collagen. PFD-OH and PFD-COOH at 300 and 1000   M concentrations significantly decreased the TGF-b1-induced hydroxyproline content in WI-38 cells. These results indicate that PFD-OH and PFD-COOH have antifibrotic activities, which inhibit collagen synthesis in fibroblasts. This study suggests that the concentrations of PFD and its metabolites should be considered in clinical therapy for IPF.
24088250|a|Pirfenidone PFD is the first and only clinically used antifibrotic drug for the treatment of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. This study evaluated the antifibrotic effects of two metabolites of PFD, 5-hydroxypirfenidone PFD-OH and 5-carboxypirfenidone PFD-COOH, on WI-38 cells in an in vitro lung fibroblast model. The inhibitory effects of PFD-OH and PFD-COOH on transforming growth factor-b1 TGF-b1-induced collagen synthesis in WI-38 cells were evaluated by measuring intracellular hydroxyproline, a major component of the protein collagen. PFD-OH and PFD-COOH at 300 and 1000   M concentrations significantly decreased the TGF-b1-induced hydroxyproline content in WI-38 cells. These results indicate that PFD-OH and PFD-COOH have antifibrotic activities, which inhibit collagen synthesis in fibroblasts. This study suggests that the concentrations of PFD and its metabolites should be considered in clinical therapy for <d>IPF</d>.
24140943|a|Our objective was to investigate the pathogenesis pathways of <d>idiopathic pulmonary fibrosis</d> IPF. Bleomycin BLM induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-b1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-b1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-b1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-b, IL-31 and JAKs/STATs pathway.
24140943|a|Our objective was to investigate the pathogenesis pathways of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Bleomycin BLM induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-b1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-b1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-b1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-b, IL-31 and JAKs/STATs pathway.
24140943|a|Our objective was to investigate the pathogenesis pathways of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Bleomycin BLM induced animal models of <d>experimental lung fibrosis</d> were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-b1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-b1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-b1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-b, IL-31 and JAKs/STATs pathway.
24140943|a|Our objective was to investigate the pathogenesis pathways of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Bleomycin BLM induced animal models of <d>experimental lung fibrosis</d> were used. CHIP assay was executed to find the link between <g>Smad3</g> and <g>IL-31</g>, and the expressions of <g>TGF-b1</g>, <g>Smad3</g>, <g>IL-31</g> and <g>STAT1</g> were detected to find whether they were similar with each other. We found that in the early <d>injury or inflammation</d> of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of <g>TGF-b1</g> and <g>Smad3</g> increased. Activated <g>Smad3</g> bound to the <g>IL-31</g> promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of <g>TGF-b1</g> receptor decreased the <g>IL-31</g> expression and knocking-down of <g>IL-31</g> also decreased the <g>STAT1</g> expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-b, <g>IL-31</g> and JAKs/STATs pathway.
24140943|a|Our objective was to investigate the pathogenesis pathways of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Bleomycin BLM induced animal models of <d>experimental lung fibrosis</d> were used. CHIP assay was executed to find the link between <g>Smad3</g> and <g>IL-31</g>, and the expressions of <g>TGF-b1</g>, <g>Smad3</g>, <g>IL-31</g> and <g>STAT1</g> were detected to find whether they were similar with each other. We found that in the early <d>injury or <d>inflammation</d></d> of the animal model, BLM promoted the development of <d>inflammation</d>, leading to severe pulmonary fibrosis. Then the expression of <g>TGF-b1</g> and <g>Smad3</g> increased. Activated <g>Smad3</g> bound to the <g>IL-31</g> promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of <g>TGF-b1</g> receptor decreased the <g>IL-31</g> expression and knocking-down of <g>IL-31</g> also decreased the <g>STAT1</g> expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-b, <g>IL-31</g> and JAKs/STATs pathway.
24140943|a|Our objective was to investigate the pathogenesis pathways of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. Bleomycin BLM induced animal models of <d>experimental lung fibrosis</d> were used. CHIP assay was executed to find the link between <g>Smad3</g> and <g>IL-31</g>, and the expressions of <g>TGF-b1</g>, <g>Smad3</g>, <g>IL-31</g> and <g>STAT1</g> were detected to find whether they were similar with each other. We found that in the early <d>injury or <d>inflammation</d></d> of the animal model, BLM promoted the development of <d>inflammation</d>, leading to severe <d>pulmonary fibrosis</d>. Then the expression of <g>TGF-b1</g> and <g>Smad3</g> increased. Activated <g>Smad3</g> bound to the <g>IL-31</g> promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of <g>TGF-b1</g> receptor decreased the <g>IL-31</g> expression and knocking-down of <g>IL-31</g> also decreased the <g>STAT1</g> expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-b, <g>IL-31</g> and JAKs/STATs pathway.
24204629|a|RATIONALE: Idiopathic <d>pulmonary fibrosis</d> IPF is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in IPF pathogenesis. We have reported anti-colV immunity in IPF patients. The objective of our study was to determine the specificity of colV expression profile and anti-colV immunity relative to colI in clinical IPF and the efficacy of nebulized colV in pre-clinical IPF models. METHODS: ColV and colI expression profile was analyzed in normal human and IPF tissues. C57-BL6 mice were intratracheally instilled with bleomycin 0.025 U followed by colV nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses. RESULTS: Compared to normal lungs, IPF lungs had higher protein and transcript expression of the alpha 1 chain of colV and colI. Systemic anti-colV antibody concentrations, but not of anti-colI, were higher in IPF patients. Nebulized colV, but not colI, prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. ColV treatment suppressed systemic levels of anti-colV antibodies, IL-6 and TNF-a; and local Il-17a transcripts. Compared to controls, nebulized colV-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-a and IFN-y. In a clinically relevant established fibrosis model, nebulized colV decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis Tgf-b, Il-1b, Pdgfb, matrix Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3 and members of the <g>TGF-b</g> superfamily Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb. CONCLUSIONS: Anti-colV immunity is pathogenic in IPF, and colV-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- b-related signaling pathways.
24204629|a|RATIONALE: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in <d>IPF</d> pathogenesis. We have reported anti-colV immunity in <d>IPF</d> patients. The objective of our study was to determine the specificity of colV expression profile and anti-colV immunity relative to colI in clinical <d>IPF</d> and the efficacy of nebulized colV in pre-clinical <d>IPF</d> models. METHODS: ColV and colI expression profile was analyzed in normal human and <d>IPF</d> tissues. C57-BL6 mice were intratracheally instilled with bleomycin 0.025 U followed by colV nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses. RESULTS: Compared to normal lungs, <d>IPF</d> lungs had higher protein and transcript expression of the alpha 1 chain of colV and colI. Systemic anti-colV antibody concentrations, but not of anti-colI, were higher in <d>IPF</d> patients. Nebulized colV, but not colI, prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. ColV treatment suppressed systemic levels of anti-colV antibodies, IL-6 and TNF-a; and local Il-17a transcripts. Compared to controls, nebulized colV-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-a and IFN-y. In a clinically relevant established fibrosis model, nebulized colV decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis Tgf-b, Il-1b, Pdgfb, matrix Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3 and members of the <g>TGF-b</g> superfamily Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb. CONCLUSIONS: Anti-colV immunity is pathogenic in <d>IPF</d>, and colV-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- b-related signaling pathways.
24204629|a|RATIONALE: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a fatal <d>interstitial lung disease</d> characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in <d>IPF</d> pathogenesis. We have reported anti-colV immunity in <d>IPF</d> patients. The objective of our study was to determine the specificity of colV expression profile and anti-colV immunity relative to colI in clinical <d>IPF</d> and the efficacy of nebulized colV in pre-clinical <d>IPF</d> models. METHODS: ColV and colI expression profile was analyzed in normal human and <d>IPF</d> tissues. C57-BL6 mice were intratracheally instilled with bleomycin 0.025 U followed by colV nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses. RESULTS: Compared to normal lungs, <d>IPF</d> lungs had higher protein and transcript expression of the alpha 1 chain of colV and colI. Systemic anti-colV antibody concentrations, but not of anti-colI, were higher in <d>IPF</d> patients. Nebulized colV, but not colI, prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. ColV treatment suppressed systemic levels of anti-colV antibodies, IL-6 and TNF-a; and local Il-17a transcripts. Compared to controls, nebulized colV-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-a and IFN-y. In a clinically relevant established fibrosis model, nebulized colV decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis Tgf-b, Il-1b, Pdgfb, matrix Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3 and members of the <g>TGF-b</g> superfamily Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb. CONCLUSIONS: Anti-colV immunity is pathogenic in <d>IPF</d>, and colV-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- b-related signaling pathways.
24204629|a|RATIONALE: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a fatal <d>interstitial lung disease</d> characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in <d>IPF</d> pathogenesis. We have reported anti-colV immunity in <d>IPF</d> patients. The objective of our study was to determine the specificity of colV expression profile and anti-colV immunity relative to colI in clinical <d>IPF</d> and the efficacy of nebulized colV in pre-clinical <d>IPF</d> models. METHODS: ColV and colI expression profile was analyzed in normal human and <d>IPF</d> tissues. C57-BL6 mice were intratracheally instilled with bleomycin 0.025 U followed by colV nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses. RESULTS: Compared to normal lungs, <d>IPF</d> lungs had higher protein and transcript expression of the alpha 1 chain of colV and colI. Systemic anti-colV antibody concentrations, but not of anti-colI, were higher in <d>IPF</d> patients. Nebulized colV, but not colI, prevented bleomycin-induced <d>fibrosis</d>, collagen deposition, and myofibroblast differentiation. ColV treatment suppressed systemic levels of anti-colV antibodies, IL-6 and TNF-a; and local Il-17a transcripts. Compared to controls, nebulized colV-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-a and IFN-y. In a clinically relevant established <d>fibrosis</d> model, nebulized colV decreased collagen deposition. mRNA array revealed downregulation of genes specific to <d>fibrosis</d> Tgf-b, Il-1b, Pdgfb, matrix Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3 and members of the <g>TGF-b</g> superfamily Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb. CONCLUSIONS: Anti-colV immunity is pathogenic in <d>IPF</d>, and colV-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- b-related signaling pathways.
24265486|a|Pleural mesothelial cells PMCs, which are derived from the mesoderm, exhibit an extraordinary capacity to undergo phenotypic changes during development and disease. PMC transformation and trafficking has a newly defined role in <d>idiopathic pulmonary fibrosis</d> IPF; however, the contribution of <g>Wilms' tumor 1</g> <g>Wt1</g>-positive PMCs to the generation of pathognomonic myofibroblasts remains unclear. PMCs were obtained from IPF lung explants and healthy donor lungs that were not used for transplantation. Short hairpin <g>Wt1</g>-knockdown PMCs sh <g>Wt1</g> were generated with <g>Wt1</g> shRNA, and morphologic and functional assays were performed in vitro. Loss of <g>Wt1</g> abrogated the PMC phenotype and showed evidence of mesothelial-to-mesenchymal transition MMT, with a reduced expression of E-cadherin and an increase in the profibrotic markers a-smooth muscle actin a-SMA and fibronectin, along with increased migration and contractility, compared with that of the control. Migration of PMCs in response to active transforming growth factor TGF-b1 was assessed by live-cell imaging with 2-photon microscopy and 3D imaging, of <g>Wt1</g>-EGFP transgenic mice. Lineage-tracing experiments to map the fate of <g>Wt1</g>+ PMCs in mouse lung in response to TGF-b1 were also performed by using a Cre-loxP system. Our results, for the first time, demonstrate that <g>Wt1</g> is necessary for the morphologic integrity of pleural membrane and that loss of <g>Wt1</g> contributes to IPF via MMT of PMCs into a myofibroblast phenotype.
24265486|a|Pleural mesothelial cells PMCs, which are derived from the mesoderm, exhibit an extraordinary capacity to undergo phenotypic changes during development and disease. PMC transformation and trafficking has a newly defined role in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>; however, the contribution of <g>Wilms' tumor 1</g> <g>Wt1</g>-positive PMCs to the generation of pathognomonic myofibroblasts remains unclear. PMCs were obtained from <d>IPF</d> lung explants and healthy donor lungs that were not used for transplantation. Short hairpin <g>Wt1</g>-knockdown PMCs sh <g>Wt1</g> were generated with <g>Wt1</g> shRNA, and morphologic and functional assays were performed in vitro. Loss of <g>Wt1</g> abrogated the PMC phenotype and showed evidence of mesothelial-to-mesenchymal transition MMT, with a reduced expression of E-cadherin and an increase in the profibrotic markers a-smooth muscle actin a-SMA and fibronectin, along with increased migration and contractility, compared with that of the control. Migration of PMCs in response to active transforming growth factor TGF-b1 was assessed by live-cell imaging with 2-photon microscopy and 3D imaging, of <g>Wt1</g>-EGFP transgenic mice. Lineage-tracing experiments to map the fate of <g>Wt1</g>+ PMCs in mouse lung in response to TGF-b1 were also performed by using a Cre-loxP system. Our results, for the first time, demonstrate that <g>Wt1</g> is necessary for the morphologic integrity of pleural membrane and that loss of <g>Wt1</g> contributes to <d>IPF</d> via MMT of PMCs into a myofibroblast phenotype.
24276150|a|Idiopathic pulmonary fibrosis IPF is a chronic and progressive interstitial lung disease with unknown etiology and undefined treatment modality. Fibroblasts are regarded as the major cell type that mediates the onset and progression of <d>lung fibrosis</d> by secreting large amounts of extracellular matrix ECM proteins, such as connective tissue growth factor CTGF/CCN2. Current knowledge confers a crucial role of CCN2 in <d>lung fibrosis</d>. <g>CCN5</g>, another member of the CCN family, has been suggested to play an inhibitory role in some fibrotic diseases, such as cardiac fibrosis. However, the role of <g>CCN5</g> in the process of IPF remains unknown. In the present study, using western blot analysis, we demonstrate that CCN2 is highly expressed in fibroblasts derived from IPF tissue, but is only slightly expressed in normal human lung fibroblasts. However, <g>CCN5</g> was weakly expressed in all the above cells. qRT-PCR revealed that transforming growth factor TGF-b1 stimulation increased CCN2 expression in the IPF-derived cultures of primary human lung fibroblasts PIFs in a time- and concentration-dependent manner, but only slightly affected the expression of <g>CCN5</g>. The overexpression of <g>CCN5</g> induced by the transfection of PIFs with recombinant plasmid did not affect cell viability, proliferation and apoptosis; however, it significantly suppressed the expression of CCN2, a-smooth muscle actin a-SMA and collagen type I. The TGF-b1-induced upregulation of the phosphorylation of Akt was reversed by <g>CCN5</g> overexpression. Our results also demonstrated that adenovirus-mediated <g>CCN5</g> overexpression in a mouse model of bleomycin-induced IPF significantly decreased the hydroxyproline content in the lungs, as well as TGF-b1 expression in bronchoalveolar lavage fluid. Taken together, our data demonstrate that <g>CCN5</g> exerts an inhibitory effect on the fibrotic phenotypes of pulmonary fibroblasts in vitro and in vivo, and as such may be a promising target for the treatment of IPF.
24276150|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic and progressive interstitial lung disease with unknown etiology and undefined treatment modality. Fibroblasts are regarded as the major cell type that mediates the onset and progression of <d>lung fibrosis</d> by secreting large amounts of extracellular matrix ECM proteins, such as connective tissue growth factor CTGF/CCN2. Current knowledge confers a crucial role of CCN2 in <d>lung fibrosis</d>. <g>CCN5</g>, another member of the CCN family, has been suggested to play an inhibitory role in some fibrotic diseases, such as cardiac fibrosis. However, the role of <g>CCN5</g> in the process of IPF remains unknown. In the present study, using western blot analysis, we demonstrate that CCN2 is highly expressed in fibroblasts derived from IPF tissue, but is only slightly expressed in normal human lung fibroblasts. However, <g>CCN5</g> was weakly expressed in all the above cells. qRT-PCR revealed that transforming growth factor TGF-b1 stimulation increased CCN2 expression in the IPF-derived cultures of primary human lung fibroblasts PIFs in a time- and concentration-dependent manner, but only slightly affected the expression of <g>CCN5</g>. The overexpression of <g>CCN5</g> induced by the transfection of PIFs with recombinant plasmid did not affect cell viability, proliferation and apoptosis; however, it significantly suppressed the expression of CCN2, a-smooth muscle actin a-SMA and collagen type I. The TGF-b1-induced upregulation of the phosphorylation of Akt was reversed by <g>CCN5</g> overexpression. Our results also demonstrated that adenovirus-mediated <g>CCN5</g> overexpression in a mouse model of bleomycin-induced IPF significantly decreased the hydroxyproline content in the lungs, as well as TGF-b1 expression in bronchoalveolar lavage fluid. Taken together, our data demonstrate that <g>CCN5</g> exerts an inhibitory effect on the fibrotic phenotypes of pulmonary fibroblasts in vitro and in vivo, and as such may be a promising target for the treatment of IPF.
24276150|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and progressive interstitial lung disease with unknown etiology and undefined treatment modality. Fibroblasts are regarded as the major cell type that mediates the onset and progression of <d>lung fibrosis</d> by secreting large amounts of extracellular matrix ECM proteins, such as connective tissue growth factor CTGF/CCN2. Current knowledge confers a crucial role of CCN2 in <d>lung fibrosis</d>. <g>CCN5</g>, another member of the CCN family, has been suggested to play an inhibitory role in some fibrotic diseases, such as cardiac fibrosis. However, the role of <g>CCN5</g> in the process of <d>IPF</d> remains unknown. In the present study, using western blot analysis, we demonstrate that CCN2 is highly expressed in fibroblasts derived from <d>IPF</d> tissue, but is only slightly expressed in normal human lung fibroblasts. However, <g>CCN5</g> was weakly expressed in all the above cells. qRT-PCR revealed that transforming growth factor TGF-b1 stimulation increased CCN2 expression in the <d>IPF</d>-derived cultures of primary human lung fibroblasts PIFs in a time- and concentration-dependent manner, but only slightly affected the expression of <g>CCN5</g>. The overexpression of <g>CCN5</g> induced by the transfection of PIFs with recombinant plasmid did not affect cell viability, proliferation and apoptosis; however, it significantly suppressed the expression of CCN2, a-smooth muscle actin a-SMA and collagen type I. The TGF-b1-induced upregulation of the phosphorylation of Akt was reversed by <g>CCN5</g> overexpression. Our results also demonstrated that adenovirus-mediated <g>CCN5</g> overexpression in a mouse model of bleomycin-induced <d>IPF</d> significantly decreased the hydroxyproline content in the lungs, as well as TGF-b1 expression in bronchoalveolar lavage fluid. Taken together, our data demonstrate that <g>CCN5</g> exerts an inhibitory effect on the fibrotic phenotypes of pulmonary fibroblasts in vitro and in vivo, and as such may be a promising target for the treatment of <d>IPF</d>.
24276150|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and progressive <d>interstitial lung disease</d> with unknown etiology and undefined treatment modality. Fibroblasts are regarded as the major cell type that mediates the onset and progression of <d>lung fibrosis</d> by secreting large amounts of extracellular matrix ECM proteins, such as connective tissue growth factor CTGF/CCN2. Current knowledge confers a crucial role of CCN2 in <d>lung fibrosis</d>. <g>CCN5</g>, another member of the CCN family, has been suggested to play an inhibitory role in some fibrotic diseases, such as cardiac fibrosis. However, the role of <g>CCN5</g> in the process of <d>IPF</d> remains unknown. In the present study, using western blot analysis, we demonstrate that CCN2 is highly expressed in fibroblasts derived from <d>IPF</d> tissue, but is only slightly expressed in normal human lung fibroblasts. However, <g>CCN5</g> was weakly expressed in all the above cells. qRT-PCR revealed that transforming growth factor TGF-b1 stimulation increased CCN2 expression in the <d>IPF</d>-derived cultures of primary human lung fibroblasts PIFs in a time- and concentration-dependent manner, but only slightly affected the expression of <g>CCN5</g>. The overexpression of <g>CCN5</g> induced by the transfection of PIFs with recombinant plasmid did not affect cell viability, proliferation and apoptosis; however, it significantly suppressed the expression of CCN2, a-smooth muscle actin a-SMA and collagen type I. The TGF-b1-induced upregulation of the phosphorylation of Akt was reversed by <g>CCN5</g> overexpression. Our results also demonstrated that adenovirus-mediated <g>CCN5</g> overexpression in a mouse model of bleomycin-induced <d>IPF</d> significantly decreased the hydroxyproline content in the lungs, as well as TGF-b1 expression in bronchoalveolar lavage fluid. Taken together, our data demonstrate that <g>CCN5</g> exerts an inhibitory effect on the fibrotic phenotypes of pulmonary fibroblasts in vitro and in vivo, and as such may be a promising target for the treatment of <d>IPF</d>.
24276150|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and progressive <d>interstitial lung disease</d> with unknown etiology and undefined treatment modality. Fibroblasts are regarded as the major cell type that mediates the onset and progression of <d>lung fibrosis</d> by secreting large amounts of extracellular matrix ECM proteins, such as connective tissue growth factor <g>CTGF</g>/<g>CCN2</g>. Current knowledge confers a crucial role of <g>CCN2</g> in <d>lung fibrosis</d>. <g>CCN5</g>, another member of the CCN family, has been suggested to play an inhibitory role in some <d>fibrotic diseases</d>, such as cardiac fibrosis. However, the role of <g>CCN5</g> in the process of <d>IPF</d> remains unknown. In the present study, using western blot analysis, we demonstrate that <g>CCN2</g> is highly expressed in fibroblasts derived from <d>IPF</d> tissue, but is only slightly expressed in normal human lung fibroblasts. However, <g>CCN5</g> was weakly expressed in all the above cells. qRT-PCR revealed that transforming growth factor TGF-b1 stimulation increased <g>CCN2</g> expression in the <d>IPF</d>-derived cultures of primary human lung fibroblasts PIFs in a time- and concentration-dependent manner, but only slightly affected the expression of <g>CCN5</g>. The overexpression of <g>CCN5</g> induced by the transfection of PIFs with recombinant plasmid did not affect cell viability, proliferation and apoptosis; however, it significantly suppressed the expression of <g>CCN2</g>, a-smooth muscle actin a-SMA and collagen type I. The TGF-b1-induced upregulation of the phosphorylation of Akt was reversed by <g>CCN5</g> overexpression. Our results also demonstrated that adenovirus-mediated <g>CCN5</g> overexpression in a mouse model of bleomycin-induced <d>IPF</d> significantly decreased the hydroxyproline content in the lungs, as well as TGF-b1 expression in bronchoalveolar lavage fluid. Taken together, our data demonstrate that <g>CCN5</g> exerts an inhibitory effect on the fibrotic phenotypes of pulmonary fibroblasts in vitro and in vivo, and as such may be a promising target for the treatment of <d>IPF</d>.
24276150|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and progressive <d>interstitial lung disease</d> with unknown etiology and undefined treatment modality. Fibroblasts are regarded as the major cell type that mediates the onset and progression of <d>lung fibrosis</d> by secreting large amounts of extracellular matrix ECM proteins, such as connective tissue growth factor <g>CTGF</g>/<g>CCN2</g>. Current knowledge confers a crucial role of <g>CCN2</g> in <d>lung fibrosis</d>. <g>CCN5</g>, another member of the CCN family, has been suggested to play an inhibitory role in some <d>fibrotic diseases</d>, such as <d>cardiac fibrosis</d>. However, the role of <g>CCN5</g> in the process of <d>IPF</d> remains unknown. In the present study, using western blot analysis, we demonstrate that <g>CCN2</g> is highly expressed in fibroblasts derived from <d>IPF</d> tissue, but is only slightly expressed in normal human lung fibroblasts. However, <g>CCN5</g> was weakly expressed in all the above cells. qRT-PCR revealed that transforming growth factor TGF-b1 stimulation increased <g>CCN2</g> expression in the <d>IPF</d>-derived cultures of primary human lung fibroblasts PIFs in a time- and concentration-dependent manner, but only slightly affected the expression of <g>CCN5</g>. The overexpression of <g>CCN5</g> induced by the transfection of PIFs with recombinant plasmid did not affect cell viability, proliferation and apoptosis; however, it significantly suppressed the expression of <g>CCN2</g>, a-smooth muscle actin a-SMA and collagen type I. The TGF-b1-induced upregulation of the phosphorylation of Akt was reversed by <g>CCN5</g> overexpression. Our results also demonstrated that adenovirus-mediated <g>CCN5</g> overexpression in a mouse model of bleomycin-induced <d>IPF</d> significantly decreased the hydroxyproline content in the lungs, as well as TGF-b1 expression in bronchoalveolar lavage fluid. Taken together, our data demonstrate that <g>CCN5</g> exerts an inhibitory effect on the fibrotic phenotypes of pulmonary fibroblasts in vitro and in vivo, and as such may be a promising target for the treatment of <d>IPF</d>.
24279676|a|Repairing damaged tissues is an essential homeostatic mechanism that enables clearance of dead or damaged cells after injury, and the maintenance of tissue integrity. However, exaggeration of this process in the lung can lead to the development of fibrotic scar tissue. This is characterized by excessive accumulation of extracellular matrix ECM components such as fibronectin, proteoglycans, hyaluronic acid, and interstitial collagens. After tissue injury, or a breakdown of tissue integrity, a cascade of events unfolds to maintain normal tissue homeostasis. Inflammatory mediators are released from injured epithelium, leading to both platelet activation and inflammatory cell migration. Inflammatory cells are capable of releasing multiple pro-inflammatory and fibrogenic mediators such as transforming growth factor TGFb and interleukin IL-13, which can trigger myofibroblast proliferation and recruitment. The myofibroblast population is also expanded as a result of epithelial cells undergoing epithelial-to-mesenchymal transition and of the activation of resident fibroblasts, leading to ECM deposition and tissue remodeling. In the healthy lung, wound healing then proceeds to restore the normal architecture of the lung; however, fibrosis can develop when the wound is severe, the tissue injury persists, or the repair process becomes dysregulated. Understanding the processes regulating aberrant wound healing and the matrix in the chronic fibrotic lung disease <d>idiopathic pulmonary fibrosis</d> IPF, is key to identifying new treatments for this chronic debilitating disease. This review focuses primarily on the emerging role of enzymes in the lungs of patients with IPF. Elevated expression of a number of enzymes that can directly modulate the ECM has been reported, and recent data indicates that modulating the activity of these enzymes can have a downstream effect on fibrotic tissue remodeling.
24279676|a|Repairing damaged tissues is an essential homeostatic mechanism that enables clearance of dead or damaged cells after injury, and the maintenance of tissue integrity. However, exaggeration of this process in the lung can lead to the development of <d>fibrotic scar tissue</d>. This is characterized by excessive accumulation of extracellular matrix ECM components such as fibronectin, proteoglycans, hyaluronic acid, and interstitial collagens. After tissue injury, or a breakdown of tissue integrity, a cascade of events unfolds to maintain normal tissue homeostasis. Inflammatory mediators are released from injured epithelium, leading to both platelet activation and inflammatory cell migration. Inflammatory cells are capable of releasing multiple pro-inflammatory and fibrogenic mediators such as transforming growth factor TGFb and interleukin IL-13, which can trigger myofibroblast proliferation and recruitment. The myofibroblast population is also expanded as a result of epithelial cells undergoing epithelial-to-mesenchymal transition and of the activation of resident fibroblasts, leading to ECM deposition and tissue remodeling. In the healthy lung, wound healing then proceeds to restore the normal architecture of the lung; however, fibrosis can develop when the wound is severe, the tissue injury persists, or the repair process becomes dysregulated. Understanding the processes regulating aberrant wound healing and the matrix in the chronic fibrotic lung disease <d>idiopathic pulmonary fibrosis</d> IPF, is key to identifying new treatments for this chronic debilitating disease. This review focuses primarily on the emerging role of enzymes in the lungs of patients with IPF. Elevated expression of a number of enzymes that can directly modulate the ECM has been reported, and recent data indicates that modulating the activity of these enzymes can have a downstream effect on fibrotic tissue remodeling.
24279676|a|Repairing damaged tissues is an essential homeostatic mechanism that enables clearance of dead or damaged cells after injury, and the maintenance of tissue integrity. However, exaggeration of this process in the lung can lead to the development of <d>fibrotic scar tissue</d>. This is characterized by excessive accumulation of extracellular matrix ECM components such as <g>fibronectin</g>, proteoglycans, hyaluronic acid, and interstitial collagens. After tissue injury, or a breakdown of tissue integrity, a cascade of events unfolds to maintain normal tissue homeostasis. Inflammatory mediators are released from injured epithelium, leading to both platelet activation and inflammatory cell migration. Inflammatory cells are capable of releasing multiple pro-inflammatory and fibrogenic mediators such as transforming growth factor TGFb and <g>interleukin IL-13</g>, which can trigger myofibroblast proliferation and recruitment. The myofibroblast population is also expanded as a result of epithelial cells undergoing epithelial-to-mesenchymal transition and of the activation of resident fibroblasts, leading to ECM deposition and tissue remodeling. In the healthy lung, wound healing then proceeds to restore the normal architecture of the lung; however, <d>fibrosis</d> can develop when the wound is severe, the tissue injury persists, or the repair process becomes dysregulated. Understanding the processes regulating aberrant wound healing and the matrix in the chronic fibrotic lung disease <d>idiopathic pulmonary <d>fibrosis</d></d> IPF, is key to identifying new treatments for this chronic debilitating disease. This review focuses primarily on the emerging role of enzymes in the lungs of patients with IPF. Elevated expression of a number of enzymes that can directly modulate the ECM has been reported, and recent data indicates that modulating the activity of these enzymes can have a downstream effect on fibrotic tissue remodeling.
24279676|a|Repairing damaged tissues is an essential homeostatic mechanism that enables clearance of dead or damaged cells after injury, and the maintenance of tissue integrity. However, exaggeration of this process in the lung can lead to the development of <d>fibrotic scar tissue</d>. This is characterized by excessive accumulation of extracellular matrix ECM components such as <g>fibronectin</g>, proteoglycans, hyaluronic acid, and interstitial collagens. After tissue injury, or a breakdown of tissue integrity, a cascade of events unfolds to maintain normal tissue homeostasis. Inflammatory mediators are released from injured epithelium, leading to both platelet activation and inflammatory cell migration. Inflammatory cells are capable of releasing multiple pro-inflammatory and fibrogenic mediators such as transforming growth factor TGFb and <g>interleukin IL-13</g>, which can trigger myofibroblast proliferation and recruitment. The myofibroblast population is also expanded as a result of epithelial cells undergoing epithelial-to-mesenchymal transition and of the activation of resident fibroblasts, leading to ECM deposition and tissue remodeling. In the healthy lung, wound healing then proceeds to restore the normal architecture of the lung; however, <d>fibrosis</d> can develop when the wound is severe, the tissue injury persists, or the repair process becomes dysregulated. Understanding the processes regulating aberrant wound healing and the matrix in the chronic <d>fibrotic lung</d> disease <d>idiopathic pulmonary <d>fibrosis</d></d> IPF, is key to identifying new treatments for this chronic debilitating disease. This review focuses primarily on the emerging role of enzymes in the lungs of patients with IPF. Elevated expression of a number of enzymes that can directly modulate the ECM has been reported, and recent data indicates that modulating the activity of these enzymes can have a downstream effect on fibrotic tissue remodeling.
24279676|a|Repairing damaged tissues is an essential homeostatic mechanism that enables clearance of dead or damaged cells after injury, and the maintenance of tissue integrity. However, exaggeration of this process in the lung can lead to the development of <d>fibrotic scar tissue</d>. This is characterized by excessive accumulation of extracellular matrix ECM components such as <g>fibronectin</g>, proteoglycans, hyaluronic acid, and interstitial collagens. After tissue injury, or a breakdown of tissue integrity, a cascade of events unfolds to maintain normal tissue homeostasis. Inflammatory mediators are released from injured epithelium, leading to both platelet activation and inflammatory cell migration. Inflammatory cells are capable of releasing multiple pro-inflammatory and fibrogenic mediators such as transforming growth factor TGFb and <g>interleukin IL-13</g>, which can trigger myofibroblast proliferation and recruitment. The myofibroblast population is also expanded as a result of epithelial cells undergoing epithelial-to-mesenchymal transition and of the activation of resident fibroblasts, leading to ECM deposition and tissue remodeling. In the healthy lung, wound healing then proceeds to restore the normal architecture of the lung; however, <d>fibrosis</d> can develop when the wound is severe, the tissue injury persists, or the repair process becomes dysregulated. Understanding the processes regulating aberrant wound healing and the matrix in the chronic <d>fibrotic lung</d> disease <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, is key to identifying new treatments for this chronic debilitating disease. This review focuses primarily on the emerging role of enzymes in the lungs of patients with <d>IPF</d>. Elevated expression of a number of enzymes that can directly modulate the ECM has been reported, and recent data indicates that modulating the activity of these enzymes can have a downstream effect on fibrotic tissue remodeling.
24279830|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a fatal disorder resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor TGF-b has a well-established role in lung fibrosis, clinical experience with neutralizing antibodies to TGF-b has been disappointing, and strategies to directly suppress TGF-b1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-b1 regulation and to validate the role of miR-326 in <d>pulmonary fibrosis</d>.We show that hsa-miR-326 regulates TGF-b1 expression and that hsa-miR-326 levels are inversely correlated to TGF-b1 protein levels in multiple human cell lines. The increase in TGF-b1 expression during the progression of bleomycin-induced lung fibrosis in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-b1 expression and attenuate the fibrotic response. Moreover, human IPF lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-b signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-b1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis.
24279830|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a fatal disorder resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor TGF-b has a well-established role in lung fibrosis, clinical experience with neutralizing antibodies to TGF-b has been disappointing, and strategies to directly suppress TGF-b1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-b1 regulation and to validate the role of miR-326 in <d>pulmonary fibrosis</d>.We show that hsa-miR-326 regulates TGF-b1 expression and that hsa-miR-326 levels are inversely correlated to TGF-b1 protein levels in multiple human cell lines. The increase in TGF-b1 expression during the progression of bleomycin-induced lung fibrosis in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-b1 expression and attenuate the fibrotic response. Moreover, human <d>IPF</d> lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-b signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-b1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis.
24279830|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a <d>fatal disorder</d> resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor TGF-b has a well-established role in lung fibrosis, clinical experience with neutralizing antibodies to TGF-b has been disappointing, and strategies to directly suppress TGF-b1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-b1 regulation and to validate the role of miR-326 in <d>pulmonary fibrosis</d>.We show that hsa-miR-326 regulates TGF-b1 expression and that hsa-miR-326 levels are inversely correlated to TGF-b1 protein levels in multiple human cell lines. The increase in TGF-b1 expression during the progression of bleomycin-induced lung fibrosis in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-b1 expression and attenuate the fibrotic response. Moreover, human <d>IPF</d> lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-b signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-b1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis.
24279830|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a <d>fatal disorder</d> resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor TGF-b has a well-established role in <d>lung fibrosis</d>, clinical experience with neutralizing antibodies to TGF-b has been disappointing, and strategies to directly suppress TGF-b1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-b1 regulation and to validate the role of miR-326 in <d>pulmonary fibrosis</d>.We show that hsa-miR-326 regulates TGF-b1 expression and that hsa-miR-326 levels are inversely correlated to TGF-b1 protein levels in multiple human cell lines. The increase in TGF-b1 expression during the progression of bleomycin-induced <d>lung fibrosis</d> in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-b1 expression and attenuate the fibrotic response. Moreover, human <d>IPF</d> lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-b signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-b1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating <d>lung fibrosis</d>.
24279830|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>fatal disorder</d> resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor <g>TGF-b</g> has a well-established role in <d>lung <d>fibrosis</d></d>, clinical experience with neutralizing antibodies to <g>TGF-b</g> has been disappointing, and strategies to directly suppress <g>TGF-b</g>1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in <g>TGF-b</g>1 regulation and to validate the role of <g>miR-326</g> in <d>pulmonary <d>fibrosis</d></d>.We show that hsa-<g>miR-326</g> regulates <g>TGF-b</g>1 expression and that hsa-<g>miR-326</g> levels are inversely correlated to <g>TGF-b</g>1 protein levels in multiple human cell lines. The increase in <g>TGF-b</g>1 expression during the progression of bleomycin-induced <d>lung <d>fibrosis</d></d> in mice was associated with loss of mmu-<g>miR-326</g>. Restoration of mmu-<g>miR-326</g> levels by intranasal delivery of <g>miR-326</g> mimics was sufficient to inhibit <g>TGF-b</g>1 expression and attenuate the fibrotic response. Moreover, human <d>IPF</d> lung specimens had markedly diminished <g>miR-326</g> expression as compared with nonfibrotic lungs. Additional targets of <g>miR-326</g> controlling <g>TGF-b</g> signaling and <d>fibrosis</d>-related pathways were identified, and <g>miR-326</g> was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that <g>miR-326</g> plays a key role in regulating <g>TGF-b</g>1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating <d>lung <d>fibrosis</d></d>.
24300094|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition EMT, apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-kB NF-kB is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced <d>pulmonary fibrosis</d>. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-a in bronchoalveolar lavage fluid BALF were measured. HE staining and Masson's trichrome MT staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-b1 and a-SMA mRNA and protein were analyzed. Activation of NF-kB was determined by western blotting and electrophoretic mobility shift assay EMSA. On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-a in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-b1 and a-SMA mRNA and protein expression in bleomycin-induced <d>pulmonary fibrosis</d>. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-kB p65/total NF-kB p65 and NF-kB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-kB. Andrographolide holds promise as a novel drug to treat the devastating disease of <d>pulmonary fibrosis</d>.
24300094|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition EMT, apoptosis, and oxidative stress, are involved in the pathogenesis of <d>IPF</d>. Recent findings suggested that nuclear factor-kB NF-kB is constitutively activated in <d>IPF</d> and acts as a central regulator in the pathogenesis of <d>IPF</d>. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced <d>pulmonary fibrosis</d>. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-a in bronchoalveolar lavage fluid BALF were measured. HE staining and Masson's trichrome MT staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-b1 and a-SMA mRNA and protein were analyzed. Activation of NF-kB was determined by western blotting and electrophoretic mobility shift assay EMSA. On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-a in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-b1 and a-SMA mRNA and protein expression in bleomycin-induced <d>pulmonary fibrosis</d>. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-kB p65/total NF-kB p65 and NF-kB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-kB. Andrographolide holds promise as a novel drug to treat the devastating disease of <d>pulmonary fibrosis</d>.
24300094|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic devastating disease with poor prognosis. Multiple pathological processes, including <d>inflammation</d>, epithelial mesenchymal transition EMT, apoptosis, and oxidative stress, are involved in the pathogenesis of <d>IPF</d>. Recent findings suggested that nuclear factor-kB NF-kB is constitutively activated in <d>IPF</d> and acts as a central regulator in the pathogenesis of <d>IPF</d>. The aim of our study was to reveal the value of andrographolide on bleomycin-induced <d>inflammation</d> and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced <d>pulmonary fibrosis</d>. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-a in bronchoalveolar lavage fluid BALF were measured. HE staining and Masson's trichrome MT staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-b1 and a-SMA mRNA and protein were analyzed. Activation of NF-kB was determined by western blotting and electrophoretic mobility shift assay EMSA. On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-a in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-b1 and a-SMA mRNA and protein expression in bleomycin-induced <d>pulmonary fibrosis</d>. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-kB p65/total NF-kB p65 and NF-kB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary <d>inflammation</d> and fibrosis possibly through inactivation of NF-kB. Andrographolide holds promise as a novel drug to treat the devastating disease of <d>pulmonary fibrosis</d>.
24300094|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic devastating disease with poor prognosis. Multiple pathological processes, including <d>inflammation</d>, epithelial mesenchymal transition EMT, apoptosis, and oxidative stress, are involved in the pathogenesis of <d>IPF</d>. Recent findings suggested that nuclear factor-kB NF-kB is constitutively activated in <d>IPF</d> and acts as a central regulator in the pathogenesis of <d>IPF</d>. The aim of our study was to reveal the value of andrographolide on bleomycin-induced <d>inflammation</d> and <d>fibrosis</d> in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-a in bronchoalveolar lavage fluid BALF were measured. HE staining and Masson's trichrome MT staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-b1 and a-SMA mRNA and protein were analyzed. Activation of NF-kB was determined by western blotting and electrophoretic mobility shift assay EMSA. On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-a in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-b1 and a-SMA mRNA and protein expression in bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-kB p65/total NF-kB p65 and NF-kB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary <d>inflammation</d> and <d>fibrosis</d> possibly through inactivation of NF-kB. Andrographolide holds promise as a novel drug to treat the devastating disease of <d>pulmonary <d>fibrosis</d></d>.
24307592|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix ECM in the lungs. TGF-b1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. aB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of aB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that aB-crystallin is strongly expressed in fibrotic lung tissue from IPF patients and in vivo rodent models of <d>pulmonary fibrosis</d>. We also show that aB-crystallin-deficient mice are protected from bleomycin-induced fibrosis. Similar protection from fibrosis was observed in aB-crystallin KO mice after transient adenoviral-mediated over-expression of IL-1b or TGF-b1. We show in vitro in primary epithelial cells and fibroblasts that aB-crystallin increases the nuclear localization of <g>Smad4</g>, thereby enhancing the TGF-b1-Smad pathway and the consequent activation of TGF-b1 downstream genes. aB-crystallin over-expression disrupts <g>Smad4</g> mono-ubiquitination by interacting with its E3-ubiquitin ligase, TIF1y, thus limiting its nuclear export. Conversely, in the absence of aB-crystallin, TIF1y can freely interact with <g>Smad4</g>. Consequently, <g>Smad4</g> mono-ubiquitination and nuclear export are favoured and thus TGF-b1-<g>Smad4</g> pro-fibrotic activity is inhibited. This study demonstrates that aB-crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases.
24307592|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix ECM in the lungs. TGF-b1 is the major profibrotic cytokine involved in <d>IPF</d> and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. aB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of aB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that aB-crystallin is strongly expressed in fibrotic lung tissue from <d>IPF</d> patients and in vivo rodent models of <d>pulmonary fibrosis</d>. We also show that aB-crystallin-deficient mice are protected from bleomycin-induced fibrosis. Similar protection from fibrosis was observed in aB-crystallin KO mice after transient adenoviral-mediated over-expression of IL-1b or TGF-b1. We show in vitro in primary epithelial cells and fibroblasts that aB-crystallin increases the nuclear localization of <g>Smad4</g>, thereby enhancing the TGF-b1-Smad pathway and the consequent activation of TGF-b1 downstream genes. aB-crystallin over-expression disrupts <g>Smad4</g> mono-ubiquitination by interacting with its E3-ubiquitin ligase, TIF1y, thus limiting its nuclear export. Conversely, in the absence of aB-crystallin, TIF1y can freely interact with <g>Smad4</g>. Consequently, <g>Smad4</g> mono-ubiquitination and nuclear export are favoured and thus TGF-b1-<g>Smad4</g> pro-fibrotic activity is inhibited. This study demonstrates that aB-crystallin may be a key target for the development of specific drugs in the treatment of <d>IPF</d> or other fibrotic diseases.
24307592|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix ECM in the lungs. <g>TGF-b1</g> is the major profibrotic cytokine involved in <d>IPF</d> and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. aB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of aB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that aB-crystallin is strongly expressed in fibrotic lung tissue from <d>IPF</d> patients and in vivo rodent models of <d>pulmonary <d>fibrosis</d></d>. We also show that aB-crystallin-deficient mice are protected from bleomycin-induced <d>fibrosis</d>. Similar protection from <d>fibrosis</d> was observed in aB-crystallin KO mice after transient adenoviral-mediated over-expression of IL-1b or <g>TGF-b1</g>. We show in vitro in primary epithelial cells and fibroblasts that aB-crystallin increases the nuclear localization of <g>Smad4</g>, thereby enhancing the <g>TGF-b1</g>-Smad pathway and the consequent activation of <g>TGF-b1</g> downstream genes. aB-crystallin over-expression disrupts <g>Smad4</g> mono-ubiquitination by interacting with its E3-ubiquitin ligase, TIF1y, thus limiting its nuclear export. Conversely, in the absence of aB-crystallin, TIF1y can freely interact with <g>Smad4</g>. Consequently, <g>Smad4</g> mono-ubiquitination and nuclear export are favoured and thus <g>TGF-b1</g>-<g>Smad4</g> pro-fibrotic activity is inhibited. This study demonstrates that aB-crystallin may be a key target for the development of specific drugs in the treatment of <d>IPF</d> or other fibrotic diseases.
24307592|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix ECM in the lungs. <g>TGF-b1</g> is the major profibrotic cytokine involved in <d>IPF</d> and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. aB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of aB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that aB-crystallin is strongly expressed in fibrotic lung tissue from <d>IPF</d> patients and in vivo rodent models of <d>pulmonary <d>fibrosis</d></d>. We also show that aB-crystallin-deficient mice are protected from bleomycin-induced <d>fibrosis</d>. Similar protection from <d>fibrosis</d> was observed in aB-crystallin KO mice after transient adenoviral-mediated over-expression of <g>IL-1b</g> or <g>TGF-b1</g>. We show in vitro in primary epithelial cells and fibroblasts that aB-crystallin increases the nuclear localization of <g>Smad4</g>, thereby enhancing the <g>TGF-b1</g>-Smad pathway and the consequent activation of <g>TGF-b1</g> downstream genes. aB-crystallin over-expression disrupts <g>Smad4</g> mono-ubiquitination by interacting with its E3-ubiquitin ligase, TIF1y, thus limiting its nuclear export. Conversely, in the absence of aB-crystallin, TIF1y can freely interact with <g>Smad4</g>. Consequently, <g>Smad4</g> mono-ubiquitination and nuclear export are favoured and thus <g>TGF-b1</g>-<g>Smad4</g> pro-fibrotic activity is inhibited. This study demonstrates that aB-crystallin may be a key target for the development of specific drugs in the treatment of <d>IPF</d> or other <d>fibrotic diseases</d>.
24344132|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic and fatal lung disease characterized by the overgrowth, hardening, and scarring of lung tissue. The exact mechanisms of how IPF develops and progresses are unknown. IPF is characterized by extracellular matrix remodeling and accumulation of active TGFb, which promotes collagen expression and the differentiation of smooth muscle a-actin SMA-positive myofibroblasts. <g>Aortic carboxypeptidase-like protein</g> <g>ACLP</g> is an extracellular matrix protein secreted by fibroblasts and myofibroblasts and is expressed in fibrotic human lung tissue and in mice with bleomycin-induced fibrosis. Importantly, <g>ACLP</g> knockout mice are significantly protected from bleomycin-induced fibrosis. The goal of this study was to identify the mechanisms of <g>ACLP</g> action on fibroblast differentiation. As primary lung fibroblasts differentiated into myofibroblasts, <g>ACLP</g> expression preceded SMA and collagen expression. Recombinant <g>ACLP</g> induced SMA and collagen expression in mouse and human lung fibroblasts. Knockdown of <g>ACLP</g> slowed the fibroblast-to-myofibroblast transition and partially reverted differentiated myofibroblasts by reducing SMA expression. We hypothesized that <g>ACLP</g> stimulates myofibroblast formation partly through activating TGFb signaling. Treatment of fibroblasts with recombinant <g>ACLP</g> induced phosphorylation and nuclear translocation of Smad3. This phosphorylation and induction of SMA was dependent on TGFb receptor binding and kinase activity. <g>ACLP</g>-induced collagen expression was independent of interaction with the TGFb receptor. These findings indicate that <g>ACLP</g> stimulates the fibroblast-to-myofibroblast transition by promoting SMA expression via TGFb signaling and promoting collagen expression through a TGFb receptor-independent pathway.
24344132|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and fatal lung disease characterized by the overgrowth, hardening, and scarring of lung tissue. The exact mechanisms of how <d>IPF</d> develops and progresses are unknown. <d>IPF</d> is characterized by extracellular matrix remodeling and accumulation of active TGFb, which promotes collagen expression and the differentiation of smooth muscle a-actin SMA-positive myofibroblasts. <g>Aortic carboxypeptidase-like protein</g> <g>ACLP</g> is an extracellular matrix protein secreted by fibroblasts and myofibroblasts and is expressed in fibrotic human lung tissue and in mice with bleomycin-induced fibrosis. Importantly, <g>ACLP</g> knockout mice are significantly protected from bleomycin-induced fibrosis. The goal of this study was to identify the mechanisms of <g>ACLP</g> action on fibroblast differentiation. As primary lung fibroblasts differentiated into myofibroblasts, <g>ACLP</g> expression preceded SMA and collagen expression. Recombinant <g>ACLP</g> induced SMA and collagen expression in mouse and human lung fibroblasts. Knockdown of <g>ACLP</g> slowed the fibroblast-to-myofibroblast transition and partially reverted differentiated myofibroblasts by reducing SMA expression. We hypothesized that <g>ACLP</g> stimulates myofibroblast formation partly through activating TGFb signaling. Treatment of fibroblasts with recombinant <g>ACLP</g> induced phosphorylation and nuclear translocation of Smad3. This phosphorylation and induction of SMA was dependent on TGFb receptor binding and kinase activity. <g>ACLP</g>-induced collagen expression was independent of interaction with the TGFb receptor. These findings indicate that <g>ACLP</g> stimulates the fibroblast-to-myofibroblast transition by promoting SMA expression via TGFb signaling and promoting collagen expression through a TGFb receptor-independent pathway.
24344132|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and <d>fatal lung disease</d> characterized by the overgrowth, hardening, and scarring of lung tissue. The exact mechanisms of how <d>IPF</d> develops and progresses are unknown. <d>IPF</d> is characterized by extracellular matrix remodeling and accumulation of active TGFb, which promotes collagen expression and the differentiation of smooth muscle a-actin SMA-positive myofibroblasts. <g>Aortic carboxypeptidase-like protein</g> <g>ACLP</g> is an extracellular matrix protein secreted by fibroblasts and myofibroblasts and is expressed in fibrotic human lung tissue and in mice with bleomycin-induced fibrosis. Importantly, <g>ACLP</g> knockout mice are significantly protected from bleomycin-induced fibrosis. The goal of this study was to identify the mechanisms of <g>ACLP</g> action on fibroblast differentiation. As primary lung fibroblasts differentiated into myofibroblasts, <g>ACLP</g> expression preceded SMA and collagen expression. Recombinant <g>ACLP</g> induced SMA and collagen expression in mouse and human lung fibroblasts. Knockdown of <g>ACLP</g> slowed the fibroblast-to-myofibroblast transition and partially reverted differentiated myofibroblasts by reducing SMA expression. We hypothesized that <g>ACLP</g> stimulates myofibroblast formation partly through activating TGFb signaling. Treatment of fibroblasts with recombinant <g>ACLP</g> induced phosphorylation and nuclear translocation of Smad3. This phosphorylation and induction of SMA was dependent on TGFb receptor binding and kinase activity. <g>ACLP</g>-induced collagen expression was independent of interaction with the TGFb receptor. These findings indicate that <g>ACLP</g> stimulates the fibroblast-to-myofibroblast transition by promoting SMA expression via TGFb signaling and promoting collagen expression through a TGFb receptor-independent pathway.
24344132|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic and <d>fatal lung disease</d> characterized by the overgrowth, hardening, and scarring of lung tissue. The exact mechanisms of how <d>IPF</d> develops and progresses are unknown. <d>IPF</d> is characterized by extracellular matrix remodeling and accumulation of active <g>TGFb</g>, which promotes collagen expression and the differentiation of <g>smooth muscle a-actin</g> <g>SMA</g>-positive myofibroblasts. <g>Aortic carboxypeptidase-like protein</g> <g>ACLP</g> is an extracellular matrix protein secreted by fibroblasts and myofibroblasts and is expressed in fibrotic human lung tissue and in mice with bleomycin-induced <d>fibrosis</d>. Importantly, <g>ACLP</g> knockout mice are significantly protected from bleomycin-induced <d>fibrosis</d>. The goal of this study was to identify the mechanisms of <g>ACLP</g> action on fibroblast differentiation. As primary lung fibroblasts differentiated into myofibroblasts, <g>ACLP</g> expression preceded <g>SMA</g> and collagen expression. Recombinant <g>ACLP</g> induced <g>SMA</g> and collagen expression in mouse and human lung fibroblasts. Knockdown of <g>ACLP</g> slowed the fibroblast-to-myofibroblast transition and partially reverted differentiated myofibroblasts by reducing <g>SMA</g> expression. We hypothesized that <g>ACLP</g> stimulates myofibroblast formation partly through activating <g>TGFb</g> signaling. Treatment of fibroblasts with recombinant <g>ACLP</g> induced phosphorylation and nuclear translocation of Smad3. This phosphorylation and induction of <g>SMA</g> was dependent on <g>TGFb</g> receptor binding and kinase activity. <g>ACLP</g>-induced collagen expression was independent of interaction with the <g>TGFb</g> receptor. These findings indicate that <g>ACLP</g> stimulates the fibroblast-to-myofibroblast transition by promoting <g>SMA</g> expression via <g>TGFb</g> signaling and promoting collagen expression through a <g>TGFb</g> receptor-independent pathway.
24376648|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and life threatening disease with median survival of 2.5-3 years. The IPF lung is characterized by abnormal lung remodeling, epithelial cell hyperplasia, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that cartilage oligomeric matrix protein COMP, a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes Fold change 13, p-value <0.05 in IPF lungs. This finding was confirmed at the mRNA level by nCounter   expression analysis in additional 115 IPF lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that COMP was expressed in dense fibrotic regions of IPF lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with TGF-b1 induced an increase in COMP mRNA and protein expression. Silencing COMP in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of TGF-b1 on COL1A1 and PAI1. COMP protein concentration measured by ELISA assay was significantly increased in serum of IPF patients compared to controls. Analysis of serum COMP concentrations in 23 patients who had prospective blood draws revealed that COMP levels increased in a time dependent fashion and correlated with declines in force vital capacity FVC. Taken together, our results should encourage more research into the potential use of COMP as a biomarker for disease activity and TGF-b1 activity in patients with IPF. Hence, studies that explore modalities that affect COMP expression, alleviate extracellular matrix rigidity and lung restriction in IPF and interfere with the amplification of TGF-b1 signaling should be persuaded.
24376648|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and life threatening disease with median survival of 2.5-3 years. The <d>IPF</d> lung is characterized by abnormal lung remodeling, epithelial cell hyperplasia, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that cartilage oligomeric matrix protein COMP, a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes Fold change 13, p-value <0.05 in <d>IPF</d> lungs. This finding was confirmed at the mRNA level by nCounter   expression analysis in additional 115 <d>IPF</d> lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that COMP was expressed in dense fibrotic regions of <d>IPF</d> lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with TGF-b1 induced an increase in COMP mRNA and protein expression. Silencing COMP in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of TGF-b1 on COL1A1 and PAI1. COMP protein concentration measured by ELISA assay was significantly increased in serum of <d>IPF</d> patients compared to controls. Analysis of serum COMP concentrations in 23 patients who had prospective blood draws revealed that COMP levels increased in a time dependent fashion and correlated with declines in force vital capacity FVC. Taken together, our results should encourage more research into the potential use of COMP as a biomarker for disease activity and TGF-b1 activity in patients with <d>IPF</d>. Hence, studies that explore modalities that affect COMP expression, alleviate extracellular matrix rigidity and lung restriction in <d>IPF</d> and interfere with the amplification of TGF-b1 signaling should be persuaded.
24376648|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and life threatening disease with median survival of 2.5-3 years. The <d>IPF</d> lung is characterized by abnormal lung remodeling, epithelial cell <d>hyperplasia</d>, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that cartilage oligomeric matrix protein COMP, a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes Fold change 13, p-value <0.05 in <d>IPF</d> lungs. This finding was confirmed at the mRNA level by nCounter   expression analysis in additional 115 <d>IPF</d> lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that COMP was expressed in dense fibrotic regions of <d>IPF</d> lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with TGF-b1 induced an increase in COMP mRNA and protein expression. Silencing COMP in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of TGF-b1 on COL1A1 and PAI1. COMP protein concentration measured by ELISA assay was significantly increased in serum of <d>IPF</d> patients compared to controls. Analysis of serum COMP concentrations in 23 patients who had prospective blood draws revealed that COMP levels increased in a time dependent fashion and correlated with declines in force vital capacity FVC. Taken together, our results should encourage more research into the potential use of COMP as a biomarker for disease activity and TGF-b1 activity in patients with <d>IPF</d>. Hence, studies that explore modalities that affect COMP expression, alleviate extracellular matrix rigidity and lung restriction in <d>IPF</d> and interfere with the amplification of TGF-b1 signaling should be persuaded.
24376648|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and life threatening disease with median survival of 2.5-3 years. The <d>IPF</d> lung is characterized by abnormal lung remodeling, epithelial cell <d>hyperplasia</d>, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that <g>cartilage oligomeric matrix protein</g> <g>COMP</g>, a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes Fold change 13, p-value <0.05 in <d>IPF</d> lungs. This finding was confirmed at the mRNA level by nCounter   expression analysis in additional 115 <d>IPF</d> lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that <g>COMP</g> was expressed in dense fibrotic regions of <d>IPF</d> lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with <g>TGF-b1</g> induced an increase in <g>COMP</g> mRNA and protein expression. Silencing <g>COMP</g> in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of <g>TGF-b1</g> on <g>COL1A1</g> and <g>PAI1</g>. <g>COMP</g> protein concentration measured by ELISA assay was significantly increased in serum of <d>IPF</d> patients compared to controls. Analysis of serum <g>COMP</g> concentrations in 23 patients who had prospective blood draws revealed that <g>COMP</g> levels increased in a time dependent fashion and correlated with declines in force vital capacity FVC. Taken together, our results should encourage more research into the potential use of <g>COMP</g> as a biomarker for disease activity and <g>TGF-b1</g> activity in patients with <d>IPF</d>. Hence, studies that explore modalities that affect <g>COMP</g> expression, alleviate extracellular matrix <d>rigidity</d> and lung restriction in <d>IPF</d> and interfere with the amplification of <g>TGF-b1</g> signaling should be persuaded.
24392001|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that <g>KCa3.1</g> K+ channel-dependent cell processes contribute to IPF pathophysiology. METHODS: <g>KCa3.1</g> expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of <g>KCa3.1</g> channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct <g>KCa3.1</g> blockers TRAM-34 and ICA-17043 [Senicapoc]. RESULTS: Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed <g>KCa3.1</g> channel mRNA and protein. <g>KCa3.1</g> ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. <g>KCa3.1</g> currents were increased in myofibroblasts by TGFb1 and basic FGF. <g>KCa3.1</g> was expressed strongly in IPF tissue. <g>KCa3.1</g> pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFb1-dependent increases in intracellular free Ca2+. CONCLUSIONS: <g>KCa3.1</g> activity promotes pro-fibrotic human lung myofibroblast function. Blocking <g>KCa3.1</g> may offer a novel approach to treating IPF with the potential for rapid translation to the clinic.
24392001|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that <g>KCa3.1</g> K+ channel-dependent cell processes contribute to <d>IPF</d> pathophysiology. METHODS: <g>KCa3.1</g> expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of <g>KCa3.1</g> channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct <g>KCa3.1</g> blockers TRAM-34 and ICA-17043 [Senicapoc]. RESULTS: Both healthy non fibrotic control and <d>IPF</d>-derived human lung myofibroblasts expressed <g>KCa3.1</g> channel mRNA and protein. <g>KCa3.1</g> ion currents were elicited more frequently and were larger in <d>IPF</d>-derived myofibroblasts compared to controls. <g>KCa3.1</g> currents were increased in myofibroblasts by TGFb1 and basic FGF. <g>KCa3.1</g> was expressed strongly in <d>IPF</d> tissue. <g>KCa3.1</g> pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFb1-dependent increases in intracellular free Ca2+. CONCLUSIONS: <g>KCa3.1</g> activity promotes pro-fibrotic human lung myofibroblast function. Blocking <g>KCa3.1</g> may offer a novel approach to treating <d>IPF</d> with the potential for rapid translation to the clinic.
24392001|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a common, progressive and invariably lethal <d>interstitial lung disease</d> with no effective therapy. We hypothesised that <g>KCa3.1</g> K+ channel-dependent cell processes contribute to <d>IPF</d> pathophysiology. METHODS: <g>KCa3.1</g> expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of <g>KCa3.1</g> channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct <g>KCa3.1</g> blockers TRAM-34 and ICA-17043 [Senicapoc]. RESULTS: Both healthy non fibrotic control and <d>IPF</d>-derived human lung myofibroblasts expressed <g>KCa3.1</g> channel mRNA and protein. <g>KCa3.1</g> ion currents were elicited more frequently and were larger in <d>IPF</d>-derived myofibroblasts compared to controls. <g>KCa3.1</g> currents were increased in myofibroblasts by TGFb1 and basic FGF. <g>KCa3.1</g> was expressed strongly in <d>IPF</d> tissue. <g>KCa3.1</g> pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFb1-dependent increases in intracellular free Ca2+. CONCLUSIONS: <g>KCa3.1</g> activity promotes pro-fibrotic human lung myofibroblast function. Blocking <g>KCa3.1</g> may offer a novel approach to treating <d>IPF</d> with the potential for rapid translation to the clinic.
24418172|a|The immune response plays an unsettled role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF, the contribution of inflammation being controversial as well. Emerging novel T cell sub-populations including regulatory T lymphocytes Treg and interleukin IL-17 secreting T helper cells Th17 may exert antithetical actions in this scenario. Phenotype and frequency of circulating immune cell subsets were assessed by multi-parametric flow cytometry in 29 clinically stable IPF patients and 17 healthy controls. The interplay between Treg lymphocytes expressing transforming growth factor TGF-b and Th17 cells was also investigated. Proportion and absolute number of natural killer NK cells were significantly reduced in IPF patients in comparison with controls p<0.001. Conversely, the proportion and absolute number of CD3+CD4+CD25highFoxp-3+ cells were significantly increased in IPF patients p=0.000. As in controls, almost the totality of cells >90% expressed TGF-b upon stimulation. Interestingly, the frequency of Th17 cells was significantly compromised in IPF patients p=0.000 leading to an increased TGF-b/IL-17 ratio 4.2  2.3 vs 0.5  0.3 in controls, p=0.000. Depletion of NK and Th17 cells along with a not compromised Treg compartment delineate the existence of an "immune profile" that argue against the recent hypothesis of IPF as an autoimmune disease. Our findings along with the imbalance of the Treg/Th17 axis more closely suggest these immune perturbations to be similar to those observed in cancer. Clinical relevance, limitations and perspectives for future research are discussed.
24418172|a|The immune response plays an unsettled role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, the contribution of inflammation being controversial as well. Emerging novel T cell sub-populations including regulatory T lymphocytes Treg and interleukin IL-17 secreting T helper cells Th17 may exert antithetical actions in this scenario. Phenotype and frequency of circulating immune cell subsets were assessed by multi-parametric flow cytometry in 29 clinically stable <d>IPF</d> patients and 17 healthy controls. The interplay between Treg lymphocytes expressing transforming growth factor TGF-b and Th17 cells was also investigated. Proportion and absolute number of natural killer NK cells were significantly reduced in <d>IPF</d> patients in comparison with controls p<0.001. Conversely, the proportion and absolute number of CD3+CD4+CD25highFoxp-3+ cells were significantly increased in <d>IPF</d> patients p=0.000. As in controls, almost the totality of cells >90% expressed TGF-b upon stimulation. Interestingly, the frequency of Th17 cells was significantly compromised in <d>IPF</d> patients p=0.000 leading to an increased TGF-b/IL-17 ratio 4.2  2.3 vs 0.5  0.3 in controls, p=0.000. Depletion of NK and Th17 cells along with a not compromised Treg compartment delineate the existence of an "immune profile" that argue against the recent hypothesis of <d>IPF</d> as an autoimmune disease. Our findings along with the imbalance of the Treg/Th17 axis more closely suggest these immune perturbations to be similar to those observed in cancer. Clinical relevance, limitations and perspectives for future research are discussed.
24418172|a|The immune response plays an unsettled role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, the contribution of <d>inflammation</d> being controversial as well. Emerging novel T cell sub-populations including regulatory T lymphocytes Treg and interleukin IL-17 secreting T helper cells Th17 may exert antithetical actions in this scenario. Phenotype and frequency of circulating immune cell subsets were assessed by multi-parametric flow cytometry in 29 clinically stable <d>IPF</d> patients and 17 healthy controls. The interplay between Treg lymphocytes expressing transforming growth factor TGF-b and Th17 cells was also investigated. Proportion and absolute number of natural killer NK cells were significantly reduced in <d>IPF</d> patients in comparison with controls p<0.001. Conversely, the proportion and absolute number of CD3+CD4+CD25highFoxp-3+ cells were significantly increased in <d>IPF</d> patients p=0.000. As in controls, almost the totality of cells >90% expressed TGF-b upon stimulation. Interestingly, the frequency of Th17 cells was significantly compromised in <d>IPF</d> patients p=0.000 leading to an increased TGF-b/IL-17 ratio 4.2  2.3 vs 0.5  0.3 in controls, p=0.000. Depletion of NK and Th17 cells along with a not compromised Treg compartment delineate the existence of an "immune profile" that argue against the recent hypothesis of <d>IPF</d> as an autoimmune disease. Our findings along with the imbalance of the Treg/Th17 axis more closely suggest these immune perturbations to be similar to those observed in cancer. Clinical relevance, limitations and perspectives for future research are discussed.
24418172|a|The immune response plays an unsettled role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, the contribution of <d>inflammation</d> being controversial as well. Emerging novel T cell sub-populations including regulatory T lymphocytes Treg and <g>interleukin <g>IL-17</g></g> secreting T helper cells Th17 may exert antithetical actions in this scenario. Phenotype and frequency of circulating immune cell subsets were assessed by multi-parametric flow cytometry in 29 clinically stable <d>IPF</d> patients and 17 healthy controls. The interplay between Treg lymphocytes expressing transforming growth factor <g>TGF-b</g> and Th17 cells was also investigated. Proportion and absolute number of natural killer NK cells were significantly reduced in <d>IPF</d> patients in comparison with controls p<0.001. Conversely, the proportion and absolute number of CD3+CD4+CD25high<g>Foxp-3</g>+ cells were significantly increased in <d>IPF</d> patients p=0.000. As in controls, almost the totality of cells >90% expressed <g>TGF-b</g> upon stimulation. Interestingly, the frequency of Th17 cells was significantly compromised in <d>IPF</d> patients p=0.000 leading to an increased <g>TGF-b</g>/<g>IL-17</g> ratio 4.2  2.3 vs 0.5  0.3 in controls, p=0.000. Depletion of NK and Th17 cells along with a not compromised Treg compartment delineate the existence of an "immune profile" that argue against the recent hypothesis of <d>IPF</d> as an <d>autoimmune disease</d>. Our findings along with the imbalance of the Treg/Th17 axis more closely suggest these immune perturbations to be similar to those observed in cancer. Clinical relevance, limitations and perspectives for future research are discussed.
24418172|a|The immune response plays an unsettled role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, the contribution of <d>inflammation</d> being controversial as well. Emerging novel T cell sub-populations including regulatory T lymphocytes Treg and <g>interleukin <g>IL-17</g></g> secreting T helper cells Th17 may exert antithetical actions in this scenario. Phenotype and frequency of circulating immune cell subsets were assessed by multi-parametric flow cytometry in 29 clinically stable <d>IPF</d> patients and 17 healthy controls. The interplay between Treg lymphocytes expressing transforming growth factor <g>TGF-b</g> and Th17 cells was also investigated. Proportion and absolute number of natural killer NK cells were significantly reduced in <d>IPF</d> patients in comparison with controls p<0.001. Conversely, the proportion and absolute number of CD3+CD4+CD25high<g>Foxp-3</g>+ cells were significantly increased in <d>IPF</d> patients p=0.000. As in controls, almost the totality of cells >90% expressed <g>TGF-b</g> upon stimulation. Interestingly, the frequency of Th17 cells was significantly compromised in <d>IPF</d> patients p=0.000 leading to an increased <g>TGF-b</g>/<g>IL-17</g> ratio 4.2  2.3 vs 0.5  0.3 in controls, p=0.000. Depletion of NK and Th17 cells along with a not compromised Treg compartment delineate the existence of an "immune profile" that argue against the recent hypothesis of <d>IPF</d> as an <d>autoimmune disease</d>. Our findings along with the imbalance of the Treg/Th17 axis more closely suggest these immune perturbations to be similar to those observed in <d>cancer</d>. Clinical relevance, limitations and perspectives for future research are discussed.
24478701|a|Idiopathic pulmonary fibrosis IPF is a fatal lung disorder of unknown etiology characterized by accumulation of lung fibroblasts and extracellular matrix deposition, ultimately leading to compromised tissue architecture and lung function capacity. IPF has a heterogeneous clinical course; however the median survival after diagnosis is only 3-5 years. The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for IPF, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of IPF. The precise link between inflammation and fibrosis remains unclear, but it appears that immune cells can promote fibrosis by releasing fibrogenic factors. So far, however, therapeutic approaches targeting macrophages, neutrophils, or lymphocytes have failed to alter disease pathogenesis. A new cell to garner research interest in fibrosis is the mast cell. Increased numbers of mast cells have long been known to be present in pulmonary fibrosis and clinically correlations between mast cells and fibrosis have been reported. More recent data suggests that mast cells may contribute to the fibrotic process by stimulating fibroblasts resident in the lung, thus driving the pathogenesis of the disease. In this review, we will discuss the mast cell and its physiological role in tissue repair and remodeling, as well as its pathological role in <d>fibrotic diseases</d> such as IPF, where the process of tissue repair and remodeling is thought to be dysregulated.
24478701|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a fatal lung disorder of unknown etiology characterized by accumulation of lung fibroblasts and extracellular matrix deposition, ultimately leading to compromised tissue architecture and lung function capacity. IPF has a heterogeneous clinical course; however the median survival after diagnosis is only 3-5 years. The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for IPF, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of IPF. The precise link between inflammation and fibrosis remains unclear, but it appears that immune cells can promote fibrosis by releasing fibrogenic factors. So far, however, therapeutic approaches targeting macrophages, neutrophils, or lymphocytes have failed to alter disease pathogenesis. A new cell to garner research interest in fibrosis is the mast cell. Increased numbers of mast cells have long been known to be present in pulmonary fibrosis and clinically correlations between mast cells and fibrosis have been reported. More recent data suggests that mast cells may contribute to the fibrotic process by stimulating fibroblasts resident in the lung, thus driving the pathogenesis of the disease. In this review, we will discuss the mast cell and its physiological role in tissue repair and remodeling, as well as its pathological role in <d>fibrotic diseases</d> such as IPF, where the process of tissue repair and remodeling is thought to be dysregulated.
24478701|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a fatal lung disorder of unknown etiology characterized by accumulation of lung fibroblasts and extracellular matrix deposition, ultimately leading to compromised tissue architecture and lung function capacity. <d>IPF</d> has a heterogeneous clinical course; however the median survival after diagnosis is only 3-5 years. The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for <d>IPF</d>, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of <d>IPF</d>. The precise link between inflammation and fibrosis remains unclear, but it appears that immune cells can promote fibrosis by releasing fibrogenic factors. So far, however, therapeutic approaches targeting macrophages, neutrophils, or lymphocytes have failed to alter disease pathogenesis. A new cell to garner research interest in fibrosis is the mast cell. Increased numbers of mast cells have long been known to be present in pulmonary fibrosis and clinically correlations between mast cells and fibrosis have been reported. More recent data suggests that mast cells may contribute to the fibrotic process by stimulating fibroblasts resident in the lung, thus driving the pathogenesis of the disease. In this review, we will discuss the mast cell and its physiological role in tissue repair and remodeling, as well as its pathological role in <d>fibrotic diseases</d> such as <d>IPF</d>, where the process of tissue repair and remodeling is thought to be dysregulated.
24478701|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>fatal lung disorder</d> of unknown etiology characterized by accumulation of lung fibroblasts and extracellular matrix deposition, ultimately leading to compromised tissue architecture and lung function capacity. <d>IPF</d> has a heterogeneous clinical course; however the median survival after diagnosis is only 3-5 years. The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for <d>IPF</d>, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of <d>IPF</d>. The precise link between inflammation and fibrosis remains unclear, but it appears that immune cells can promote fibrosis by releasing fibrogenic factors. So far, however, therapeutic approaches targeting macrophages, neutrophils, or lymphocytes have failed to alter disease pathogenesis. A new cell to garner research interest in fibrosis is the mast cell. Increased numbers of mast cells have long been known to be present in pulmonary fibrosis and clinically correlations between mast cells and fibrosis have been reported. More recent data suggests that mast cells may contribute to the fibrotic process by stimulating fibroblasts resident in the lung, thus driving the pathogenesis of the disease. In this review, we will discuss the mast cell and its physiological role in tissue repair and remodeling, as well as its pathological role in <d>fibrotic diseases</d> such as <d>IPF</d>, where the process of tissue repair and remodeling is thought to be dysregulated.
24478701|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>fatal lung disorder</d> of unknown etiology characterized by accumulation of lung fibroblasts and extracellular matrix deposition, ultimately leading to compromised tissue architecture and lung function capacity. <d>IPF</d> has a heterogeneous clinical course; however the median survival after diagnosis is only 3-5 years. The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for <d>IPF</d>, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of <d>IPF</d>. The precise link between <d>inflammation</d> and fibrosis remains unclear, but it appears that immune cells can promote fibrosis by releasing fibrogenic factors. So far, however, therapeutic approaches targeting macrophages, neutrophils, or lymphocytes have failed to alter disease pathogenesis. A new cell to garner research interest in fibrosis is the mast cell. Increased numbers of mast cells have long been known to be present in pulmonary fibrosis and clinically correlations between mast cells and fibrosis have been reported. More recent data suggests that mast cells may contribute to the fibrotic process by stimulating fibroblasts resident in the lung, thus driving the pathogenesis of the disease. In this review, we will discuss the mast cell and its physiological role in tissue repair and remodeling, as well as its pathological role in <d>fibrotic diseases</d> such as <d>IPF</d>, where the process of tissue repair and remodeling is thought to be dysregulated.
24478701|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>fatal lung disorder</d> of unknown etiology characterized by accumulation of lung fibroblasts and extracellular matrix deposition, ultimately leading to compromised tissue architecture and lung function capacity. <d>IPF</d> has a heterogeneous clinical course; however the median survival after diagnosis is only 3-5 years. The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for <d>IPF</d>, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of <d>IPF</d>. The precise link between <d>inflammation</d> and <d>fibrosis</d> remains unclear, but it appears that immune cells can promote <d>fibrosis</d> by releasing fibrogenic factors. So far, however, therapeutic approaches targeting macrophages, neutrophils, or lymphocytes have failed to alter disease pathogenesis. A new cell to garner research interest in <d>fibrosis</d> is the mast cell. Increased numbers of mast cells have long been known to be present in pulmonary <d>fibrosis</d> and clinically correlations between mast cells and <d>fibrosis</d> have been reported. More recent data suggests that mast cells may contribute to the fibrotic process by stimulating fibroblasts resident in the lung, thus driving the pathogenesis of the disease. In this review, we will discuss the mast cell and its physiological role in tissue repair and remodeling, as well as its pathological role in <d>fibrotic diseases</d> such as <d>IPF</d>, where the process of tissue repair and remodeling is thought to be dysregulated.
24515257|a|<g>Vascular endothelial growth factor</g> <g>VEGF</g>-D, a member of the <g>VEGF</g> family, induces both angiogenesis and lymphangiogenesis by activating <g>VEGF</g> receptor-2 <g>VEGF</g>R-2 and <g>VEGF</g>R-3 on the surface of endothelial cells. <g>Transforming growth factor <g>TGF-b1</g></g> has been shown to stimulate <g>VEGF</g>-A expression in human lung fibroblast via the <g>Smad3</g> signaling pathway and to induce <g>VEGF</g>-C in human proximal tubular epithelial cells. However, the effects of <g>TGF-b1</g> on <g>VEGF</g>-D regulation are unknown. To investigate the regulation of <g>VEGF</g>-D, human lung fibroblasts were studied under pro-fibrotic conditions in vitro and in <d>idiopathic pulmonary fibrosis</d> IPF lung tissue. We demonstrate that <g>TGF-b1</g> downregulates <g>VEGF</g>-D expression in a dose- and time-dependent manner in human lung fibroblasts. This <g>TGF-b1</g> effect can be abolished by inhibitors of TGF-b type I receptor kinase and <g>Jun NH2-terminal kinase</g> JNK, but not by <g>Smad3</g> knockdown. In addition, <g>VEGF</g>-D knockdown in human lung fibroblasts induces G1/S transition and promotes cell proliferation. Importantly, <g>VEGF</g>-D protein expression is decreased in lung homogenates from IPF patients compared with control lung. In IPF lung sections, fibroblastic foci show very weak <g>VEGF</g>-D immunoreactivity, whereas <g>VEGF</g>-D is abundantly expressed within alveolar interstitial cells in control lung. Taken together, our data identify a novel mechanism for downstream signal transduction induced by <g>TGF-b1</g> in lung fibroblasts, through which they may mediate tissue remodeling in IPF.
24515257|a|<g>Vascular endothelial growth factor</g> <g>VEGF</g>-D, a member of the <g>VEGF</g> family, induces both angiogenesis and lymphangiogenesis by activating <g>VEGF</g> receptor-2 <g>VEGF</g>R-2 and <g>VEGF</g>R-3 on the surface of endothelial cells. <g>Transforming growth factor <g>TGF-b1</g></g> has been shown to stimulate <g>VEGF</g>-A expression in human lung fibroblast via the <g>Smad3</g> signaling pathway and to induce <g>VEGF</g>-C in human proximal tubular epithelial cells. However, the effects of <g>TGF-b1</g> on <g>VEGF</g>-D regulation are unknown. To investigate the regulation of <g>VEGF</g>-D, human lung fibroblasts were studied under pro-fibrotic conditions in vitro and in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> lung tissue. We demonstrate that <g>TGF-b1</g> downregulates <g>VEGF</g>-D expression in a dose- and time-dependent manner in human lung fibroblasts. This <g>TGF-b1</g> effect can be abolished by inhibitors of TGF-b type I receptor kinase and <g>Jun NH2-terminal kinase</g> JNK, but not by <g>Smad3</g> knockdown. In addition, <g>VEGF</g>-D knockdown in human lung fibroblasts induces G1/S transition and promotes cell proliferation. Importantly, <g>VEGF</g>-D protein expression is decreased in lung homogenates from <d>IPF</d> patients compared with control lung. In <d>IPF</d> lung sections, fibroblastic foci show very weak <g>VEGF</g>-D immunoreactivity, whereas <g>VEGF</g>-D is abundantly expressed within alveolar interstitial cells in control lung. Taken together, our data identify a novel mechanism for downstream signal transduction induced by <g>TGF-b1</g> in lung fibroblasts, through which they may mediate tissue remodeling in <d>IPF</d>.
24529509|a|Activation of transforming growth factor TGF-b is a key event in the progression of <d>fibrosis</d> in human lung tissue. Idiopathic pulmonary <d>fibrosis</d> IPF in West Highland white terriers WHWTs shares histopathological features of human usual interstitial pneumonia UIP, the histopathological counterpart of IPF and non-specific interstitial pneumonia NSIP. The aim of the present immunohistochemical study was to investigate TGF-b signalling activity and its known extracellular matrix ECM regulatory proteins, latent TGF-b binding protein LTBP-1 and fibrillin-2, in lung tissue of WHWTs with IPF and healthy WHWTs and to compare these with findings in human UIP and NSIP. P-Smad2 immunoreactivity, indicating TGF-b signalling activity, was increased in WHWTs with IPF relative to healthy WHWTs and expression was localized predominantly in the altered alveolar epithelium, as seen in both UIP and NSIP. Increased peribronchial and perivascular LTBP-1 immunoreactivity was seen in WHWTs with IPF compared with controls, possibly indicating the importance of the small airways in the canine disease. Alveolar LTPB-1 immunolabelling in diseased WHWTs was seen mainly in the altered alveolar epithelium, resembling more closely the labelling in UIP than in NSIP. Alveolar interstitial fibrillin-2 immunoreactivity, which is up-regulated in the lungs of people with UIP, was also detected in the lungs of WHWTs with IPF and people with NSIP. However, no significant difference was seen between WHWTs with IPF and control WHWTs. The results suggest that increased TGF-b signalling and expression of the ECM regulatory proteins LTBP-1 and fibrillin-2 are part of the molecular pathophysiology of canine IPF.
24529509|a|Activation of transforming growth factor TGF-b is a key event in the progression of <d>fibrosis</d> in human lung tissue. Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> in West Highland white terriers WHWTs shares histopathological features of human usual interstitial pneumonia UIP, the histopathological counterpart of <d>IPF</d> and non-specific interstitial pneumonia NSIP. The aim of the present immunohistochemical study was to investigate TGF-b signalling activity and its known extracellular matrix ECM regulatory proteins, latent TGF-b binding protein LTBP-1 and fibrillin-2, in lung tissue of WHWTs with <d>IPF</d> and healthy WHWTs and to compare these with findings in human UIP and NSIP. P-Smad2 immunoreactivity, indicating TGF-b signalling activity, was increased in WHWTs with <d>IPF</d> relative to healthy WHWTs and expression was localized predominantly in the altered alveolar epithelium, as seen in both UIP and NSIP. Increased peribronchial and perivascular LTBP-1 immunoreactivity was seen in WHWTs with <d>IPF</d> compared with controls, possibly indicating the importance of the small airways in the canine disease. Alveolar LTPB-1 immunolabelling in diseased WHWTs was seen mainly in the altered alveolar epithelium, resembling more closely the labelling in UIP than in NSIP. Alveolar interstitial fibrillin-2 immunoreactivity, which is up-regulated in the lungs of people with UIP, was also detected in the lungs of WHWTs with <d>IPF</d> and people with NSIP. However, no significant difference was seen between WHWTs with <d>IPF</d> and control WHWTs. The results suggest that increased TGF-b signalling and expression of the ECM regulatory proteins LTBP-1 and fibrillin-2 are part of the molecular pathophysiology of canine <d>IPF</d>.
24529509|a|Activation of transforming growth factor TGF-b is a key event in the progression of <d>fibrosis</d> in human lung tissue. Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> in West Highland white terriers WHWTs shares histopathological features of human <d>usual interstitial pneumonia</d> UIP, the histopathological counterpart of <d>IPF</d> and non-specific interstitial pneumonia NSIP. The aim of the present immunohistochemical study was to investigate TGF-b signalling activity and its known extracellular matrix ECM regulatory proteins, latent TGF-b binding protein LTBP-1 and fibrillin-2, in lung tissue of WHWTs with <d>IPF</d> and healthy WHWTs and to compare these with findings in human UIP and NSIP. P-Smad2 immunoreactivity, indicating TGF-b signalling activity, was increased in WHWTs with <d>IPF</d> relative to healthy WHWTs and expression was localized predominantly in the altered alveolar epithelium, as seen in both UIP and NSIP. Increased peribronchial and perivascular LTBP-1 immunoreactivity was seen in WHWTs with <d>IPF</d> compared with controls, possibly indicating the importance of the small airways in the canine disease. Alveolar LTPB-1 immunolabelling in diseased WHWTs was seen mainly in the altered alveolar epithelium, resembling more closely the labelling in UIP than in NSIP. Alveolar interstitial fibrillin-2 immunoreactivity, which is up-regulated in the lungs of people with UIP, was also detected in the lungs of WHWTs with <d>IPF</d> and people with NSIP. However, no significant difference was seen between WHWTs with <d>IPF</d> and control WHWTs. The results suggest that increased TGF-b signalling and expression of the ECM regulatory proteins LTBP-1 and fibrillin-2 are part of the molecular pathophysiology of canine <d>IPF</d>.
24529509|a|Activation of transforming growth factor TGF-b is a key event in the progression of <d>fibrosis</d> in human lung tissue. Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> in West Highland white terriers WHWTs shares histopathological features of human <d>usual interstitial pneumonia</d> <d>UIP</d>, the histopathological counterpart of <d>IPF</d> and non-specific interstitial pneumonia NSIP. The aim of the present immunohistochemical study was to investigate TGF-b signalling activity and its known extracellular matrix ECM regulatory proteins, latent TGF-b binding protein LTBP-1 and fibrillin-2, in lung tissue of WHWTs with <d>IPF</d> and healthy WHWTs and to compare these with findings in human <d>UIP</d> and NSIP. P-Smad2 immunoreactivity, indicating TGF-b signalling activity, was increased in WHWTs with <d>IPF</d> relative to healthy WHWTs and expression was localized predominantly in the altered alveolar epithelium, as seen in both <d>UIP</d> and NSIP. Increased peribronchial and perivascular LTBP-1 immunoreactivity was seen in WHWTs with <d>IPF</d> compared with controls, possibly indicating the importance of the small airways in the canine disease. Alveolar LTPB-1 immunolabelling in diseased WHWTs was seen mainly in the altered alveolar epithelium, resembling more closely the labelling in <d>UIP</d> than in NSIP. Alveolar interstitial fibrillin-2 immunoreactivity, which is up-regulated in the lungs of people with <d>UIP</d>, was also detected in the lungs of WHWTs with <d>IPF</d> and people with NSIP. However, no significant difference was seen between WHWTs with <d>IPF</d> and control WHWTs. The results suggest that increased TGF-b signalling and expression of the ECM regulatory proteins LTBP-1 and fibrillin-2 are part of the molecular pathophysiology of canine <d>IPF</d>.
24529509|a|Activation of transforming growth factor TGF-b is a key event in the progression of <d>fibrosis</d> in human lung tissue. Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> in West Highland white terriers WHWTs shares histopathological features of human <d>usual interstitial pneumonia</d> <d>UIP</d>, the histopathological counterpart of <d>IPF</d> and <d>non-specific interstitial pneumonia</d> NSIP. The aim of the present immunohistochemical study was to investigate TGF-b signalling activity and its known extracellular matrix ECM regulatory proteins, latent TGF-b binding protein LTBP-1 and fibrillin-2, in lung tissue of WHWTs with <d>IPF</d> and healthy WHWTs and to compare these with findings in human <d>UIP</d> and NSIP. P-Smad2 immunoreactivity, indicating TGF-b signalling activity, was increased in WHWTs with <d>IPF</d> relative to healthy WHWTs and expression was localized predominantly in the altered alveolar epithelium, as seen in both <d>UIP</d> and NSIP. Increased peribronchial and perivascular LTBP-1 immunoreactivity was seen in WHWTs with <d>IPF</d> compared with controls, possibly indicating the importance of the small airways in the canine disease. Alveolar LTPB-1 immunolabelling in diseased WHWTs was seen mainly in the altered alveolar epithelium, resembling more closely the labelling in <d>UIP</d> than in NSIP. Alveolar interstitial fibrillin-2 immunoreactivity, which is up-regulated in the lungs of people with <d>UIP</d>, was also detected in the lungs of WHWTs with <d>IPF</d> and people with NSIP. However, no significant difference was seen between WHWTs with <d>IPF</d> and control WHWTs. The results suggest that increased TGF-b signalling and expression of the ECM regulatory proteins LTBP-1 and fibrillin-2 are part of the molecular pathophysiology of canine <d>IPF</d>.
24529509|a|Activation of transforming growth factor TGF-b is a key event in the progression of <d>fibrosis</d> in human lung tissue. Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> in West Highland white terriers WHWTs shares histopathological features of human <d>usual interstitial pneumonia</d> <d>UIP</d>, the histopathological counterpart of <d>IPF</d> and <d>non-specific interstitial pneumonia</d> <d>NSIP</d>. The aim of the present immunohistochemical study was to investigate TGF-b signalling activity and its known extracellular matrix ECM regulatory proteins, latent TGF-b binding protein LTBP-1 and fibrillin-2, in lung tissue of WHWTs with <d>IPF</d> and healthy WHWTs and to compare these with findings in human <d>UIP</d> and <d>NSIP</d>. P-Smad2 immunoreactivity, indicating TGF-b signalling activity, was increased in WHWTs with <d>IPF</d> relative to healthy WHWTs and expression was localized predominantly in the altered alveolar epithelium, as seen in both <d>UIP</d> and <d>NSIP</d>. Increased peribronchial and perivascular LTBP-1 immunoreactivity was seen in WHWTs with <d>IPF</d> compared with controls, possibly indicating the importance of the small airways in the canine disease. Alveolar LTPB-1 immunolabelling in diseased WHWTs was seen mainly in the altered alveolar epithelium, resembling more closely the labelling in <d>UIP</d> than in <d>NSIP</d>. Alveolar interstitial fibrillin-2 immunoreactivity, which is up-regulated in the lungs of people with <d>UIP</d>, was also detected in the lungs of WHWTs with <d>IPF</d> and people with <d>NSIP</d>. However, no significant difference was seen between WHWTs with <d>IPF</d> and control WHWTs. The results suggest that increased TGF-b signalling and expression of the ECM regulatory proteins LTBP-1 and fibrillin-2 are part of the molecular pathophysiology of canine <d>IPF</d>.
24594795|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic, progressive, and high-lethality fibrotic lung disease characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, loss of lung function. Although dysregulation of some microRNAs miRs has been shown to play important roles in the pathophysiological processes of IPF, the role of miRs in fibrotic lung diseases is not well understood. In this study, we found downregulation of miR-26a in the lungs of mice with experimental pulmonary fibrosis and in IPF, which resulted in posttranscriptional derepression of connective tissue growth factor CTGF, and induced collagen production. More importantly, inhibition of miR-26a in the lungs caused pulmonary fibrosis in vivo, whereas overexpression of miR-26a repressed transforming growth factor TGF-b1-induced fibrogenesis in MRC-5 cells and attenuated experimental pulmonary fibrosis in mice. Our study showed that miR-26a was downregulated by TGF-b1-mediated phosphorylation of Smad3. Moreover, miR-26a inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of miR-26a in fibrotic lung diseases and suggested a new strategy for the prevention and treatment of IPF using miR-26a. The current study also uncovered a novel positive feedback loop between miR-26a and p-Smad3, which is involved in pulmonary fibrosis.
24594795|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and high-lethality fibrotic lung disease characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, loss of lung function. Although dysregulation of some microRNAs miRs has been shown to play important roles in the pathophysiological processes of <d>IPF</d>, the role of miRs in fibrotic lung diseases is not well understood. In this study, we found downregulation of miR-26a in the lungs of mice with experimental pulmonary fibrosis and in <d>IPF</d>, which resulted in posttranscriptional derepression of connective tissue growth factor CTGF, and induced collagen production. More importantly, inhibition of miR-26a in the lungs caused pulmonary fibrosis in vivo, whereas overexpression of miR-26a repressed transforming growth factor TGF-b1-induced fibrogenesis in MRC-5 cells and attenuated experimental pulmonary fibrosis in mice. Our study showed that miR-26a was downregulated by TGF-b1-mediated phosphorylation of Smad3. Moreover, miR-26a inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of miR-26a in fibrotic lung diseases and suggested a new strategy for the prevention and treatment of <d>IPF</d> using miR-26a. The current study also uncovered a novel positive feedback loop between miR-26a and p-Smad3, which is involved in pulmonary fibrosis.
24594795|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and high-lethality <d>fibrotic lung disease</d> characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, loss of lung function. Although dysregulation of some microRNAs miRs has been shown to play important roles in the pathophysiological processes of <d>IPF</d>, the role of miRs in <d>fibrotic lung disease</d>s is not well understood. In this study, we found downregulation of miR-26a in the lungs of mice with experimental pulmonary fibrosis and in <d>IPF</d>, which resulted in posttranscriptional derepression of connective tissue growth factor CTGF, and induced collagen production. More importantly, inhibition of miR-26a in the lungs caused pulmonary fibrosis in vivo, whereas overexpression of miR-26a repressed transforming growth factor TGF-b1-induced fibrogenesis in MRC-5 cells and attenuated experimental pulmonary fibrosis in mice. Our study showed that miR-26a was downregulated by TGF-b1-mediated phosphorylation of Smad3. Moreover, miR-26a inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of miR-26a in <d>fibrotic lung disease</d>s and suggested a new strategy for the prevention and treatment of <d>IPF</d> using miR-26a. The current study also uncovered a novel positive feedback loop between miR-26a and p-Smad3, which is involved in pulmonary fibrosis.
24594795|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and high-lethality <d>fibrotic lung disease</d> characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, <d>loss of lung function</d>. Although dysregulation of some microRNAs miRs has been shown to play important roles in the pathophysiological processes of <d>IPF</d>, the role of miRs in <d>fibrotic lung disease</d>s is not well understood. In this study, we found downregulation of miR-26a in the lungs of mice with experimental pulmonary fibrosis and in <d>IPF</d>, which resulted in posttranscriptional derepression of connective tissue growth factor CTGF, and induced collagen production. More importantly, inhibition of miR-26a in the lungs caused pulmonary fibrosis in vivo, whereas overexpression of miR-26a repressed transforming growth factor TGF-b1-induced fibrogenesis in MRC-5 cells and attenuated experimental pulmonary fibrosis in mice. Our study showed that miR-26a was downregulated by TGF-b1-mediated phosphorylation of Smad3. Moreover, miR-26a inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of miR-26a in <d>fibrotic lung disease</d>s and suggested a new strategy for the prevention and treatment of <d>IPF</d> using miR-26a. The current study also uncovered a novel positive feedback loop between miR-26a and p-Smad3, which is involved in pulmonary fibrosis.
24594795|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and high-lethality <d>fibrotic lung disease</d> characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, <d>loss of lung function</d>. Although dysregulation of some microRNAs miRs has been shown to play important roles in the pathophysiological processes of <d>IPF</d>, the role of miRs in <d>fibrotic lung disease</d>s is not well understood. In this study, we found downregulation of <g>miR-26a</g> in the lungs of mice with <d>experimental pulmonary fibrosis</d> and in <d>IPF</d>, which resulted in posttranscriptional derepression of connective tissue growth factor CTGF, and induced collagen production. More importantly, inhibition of <g>miR-26a</g> in the lungs caused pulmonary fibrosis in vivo, whereas overexpression of <g>miR-26a</g> repressed transforming growth factor TGF-b1-induced fibrogenesis in MRC-5 cells and attenuated <d>experimental pulmonary fibrosis</d> in mice. Our study showed that <g>miR-26a</g> was downregulated by TGF-b1-mediated phosphorylation of Smad3. Moreover, <g>miR-26a</g> inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of <g>miR-26a</g> in <d>fibrotic lung disease</d>s and suggested a new strategy for the prevention and treatment of <d>IPF</d> using <g>miR-26a</g>. The current study also uncovered a novel positive feedback loop between <g>miR-26a</g> and p-Smad3, which is involved in pulmonary fibrosis.
24594795|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a chronic, progressive, and high-lethality <d>fibrotic lung disease</d> characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, <d>loss of lung function</d>. Although dysregulation of some microRNAs miRs has been shown to play important roles in the pathophysiological processes of <d>IPF</d>, the role of miRs in <d>fibrotic lung disease</d>s is not well understood. In this study, we found downregulation of <g>miR-26a</g> in the lungs of mice with <d>experimental <d>pulmonary fibrosis</d></d> and in <d>IPF</d>, which resulted in posttranscriptional derepression of <g>connective tissue growth factor</g> <g>CTGF</g>, and induced collagen production. More importantly, inhibition of <g>miR-26a</g> in the lungs caused <d>pulmonary fibrosis</d> in vivo, whereas overexpression of <g>miR-26a</g> repressed transforming growth factor TGF-b1-induced fibrogenesis in MRC-5 cells and attenuated <d>experimental <d>pulmonary fibrosis</d></d> in mice. Our study showed that <g>miR-26a</g> was downregulated by TGF-b1-mediated phosphorylation of Smad3. Moreover, <g>miR-26a</g> inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of <g>miR-26a</g> in <d>fibrotic lung disease</d>s and suggested a new strategy for the prevention and treatment of <d>IPF</d> using <g>miR-26a</g>. The current study also uncovered a novel positive feedback loop between <g>miR-26a</g> and p-Smad3, which is involved in <d>pulmonary fibrosis</d>.
24613900|a|Pirfenidone is an orally active small molecule that has been shown to inhibit the progression of <d>fibrosis</d> in animal models and in patients with idiopathic pulmonary <d>fibrosis</d>. Although pirfenidone exhibits well documented antifibrotic and antiinflammatory activities, in vitro and in vivo, its molecular targets and mechanisms of action have not been elucidated. In this study, we investigated the effects of pirfenidone on proliferation, <g>TGF-b</g>-induced differentiation and fibrogenic activity of primary human lung fibroblasts HLFs. Pirfenidone reduced fibroblast proliferation and attenuated <g>TGF-b</g>-induced a-smooth muscle actin SMA and pro-collagen Col-I mRNA and protein levels. Importantly, pirfenidone inhibited <g>TGF-b</g>-induced phosphorylation of Smad3, p38, and Akt, key factors in the <g>TGF-b</g> pathway. Together, these results demonstrate that pirfenidone modulates HLF proliferation and <g>TGF-b</g>-mediated differentiation into myofibroblasts by attenuating key <g>TGF-b</g>-induced signaling pathways.
24625972|a|Endoplasmic reticulum ER stress is considered one of the pathological mechanisms of idiopathic <d>pulmonary fibrosis</d> IPF. Therefore, we examined whether an ER stress regulator, Bax inhibitor-1 BI-1, regulates collagen accumulation, which is both a marker of fibrosis and a pathological mechanism of fibrosis. The presence of BI-1 inhibited the transforming growth factor-b1-induced epithelial-mesenchymal transition of epithelial pulmonary cells and bleomycin-induced <d>pulmonary fibrosis</d> in a mouse model by enhancing collagen degradation, most likely by enhanced activation of the lysosomal <g>V-ATPase</g> through glycosylation. We also found a correlation between post-translational glycosylation of the <g>V-ATPase</g> and its associated chaperone, calnexin, in BI-1-overexpressing cells. BI-1-induced degradation of collagen through lysosomal <g>V-ATPase</g> glycosylation and the involvement of calnexin were confirmed in a bleomycin-induced fibrosis mouse model. These results highlight the regulatory role of BI-1 in IPF and reveal for the first time the role of lysosomal <g>V-ATPase</g> glycosylation in IPF.
24625972|a|Endoplasmic reticulum ER stress is considered one of the pathological mechanisms of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. Therefore, we examined whether an ER stress regulator, Bax inhibitor-1 BI-1, regulates collagen accumulation, which is both a marker of fibrosis and a pathological mechanism of fibrosis. The presence of BI-1 inhibited the transforming growth factor-b1-induced epithelial-mesenchymal transition of epithelial pulmonary cells and bleomycin-induced <d>pulmonary fibrosis</d> in a mouse model by enhancing collagen degradation, most likely by enhanced activation of the lysosomal <g>V-ATPase</g> through glycosylation. We also found a correlation between post-translational glycosylation of the <g>V-ATPase</g> and its associated chaperone, calnexin, in BI-1-overexpressing cells. BI-1-induced degradation of collagen through lysosomal <g>V-ATPase</g> glycosylation and the involvement of calnexin were confirmed in a bleomycin-induced fibrosis mouse model. These results highlight the regulatory role of BI-1 in <d>IPF</d> and reveal for the first time the role of lysosomal <g>V-ATPase</g> glycosylation in <d>IPF</d>.
24625972|a|Endoplasmic reticulum ER stress is considered one of the pathological mechanisms of idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Therefore, we examined whether an ER stress regulator, <g>Bax inhibitor-1</g> <g>BI-1</g>, regulates collagen accumulation, which is both a marker of <d>fibrosis</d> and a pathological mechanism of <d>fibrosis</d>. The presence of <g>BI-1</g> inhibited the transforming growth factor-b1-induced epithelial-mesenchymal transition of epithelial pulmonary cells and bleomycin-induced <d>pulmonary <d>fibrosis</d></d> in a mouse model by enhancing collagen degradation, most likely by enhanced activation of the lysosomal <g>V-ATPase</g> through glycosylation. We also found a correlation between post-translational glycosylation of the <g>V-ATPase</g> and its associated chaperone, calnexin, in <g>BI-1</g>-overexpressing cells. <g>BI-1</g>-induced degradation of collagen through lysosomal <g>V-ATPase</g> glycosylation and the involvement of calnexin were confirmed in a bleomycin-induced <d>fibrosis</d> mouse model. These results highlight the regulatory role of <g>BI-1</g> in <d>IPF</d> and reveal for the first time the role of lysosomal <g>V-ATPase</g> glycosylation in <d>IPF</d>.
24641440|a|BACKGROUND AND PURPOSE: Idiopathic pulmonary fibrosis IPF is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of <d>pulmonary hypertension</d> PH; the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. EXPERIMENTAL APPROACH: Pulmonary haemodynamics, right ventricular function and markers of lung fibrosis were determined in wild-type WT and natriuretic peptide receptor NPR-A knockout KO mice exposed to bleomycin 1 mg  kg-1 . Human myofibroblast differentiation was studied in vitro. KEY RESULTS: Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels ecadotril and potentiated natriuretic peptide-dependent signalling sildenafil reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFb-induced human myofibroblast differentiation, a key driver of remodelling in IPF patients. CONCLUSIONS AND IMPLICATIONS: These data highlight an endogenous host-defence capacity of natriuretic peptides in lung fibrosis and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.
24641440|a|BACKGROUND AND PURPOSE: Idiopathic pulmonary fibrosis IPF is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of <d>pulmonary hypertension</d> PH; the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. EXPERIMENTAL APPROACH: Pulmonary haemodynamics, right ventricular function and markers of <d>lung fibrosis</d> were determined in wild-type WT and natriuretic peptide receptor NPR-A knockout KO mice exposed to bleomycin 1 mg  kg-1 . Human myofibroblast differentiation was studied in vitro. KEY RESULTS: Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels ecadotril and potentiated natriuretic peptide-dependent signalling sildenafil reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFb-induced human myofibroblast differentiation, a key driver of remodelling in IPF patients. CONCLUSIONS AND IMPLICATIONS: These data highlight an endogenous host-defence capacity of natriuretic peptides in <d>lung fibrosis</d> and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.
24641440|a|BACKGROUND AND PURPOSE: <d>Idiopathic pulmonary fibrosis</d> IPF is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of <d>pulmonary hypertension</d> PH; the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. EXPERIMENTAL APPROACH: Pulmonary haemodynamics, right ventricular function and markers of <d>lung fibrosis</d> were determined in wild-type WT and natriuretic peptide receptor NPR-A knockout KO mice exposed to bleomycin 1 mg  kg-1 . Human myofibroblast differentiation was studied in vitro. KEY RESULTS: Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels ecadotril and potentiated natriuretic peptide-dependent signalling sildenafil reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFb-induced human myofibroblast differentiation, a key driver of remodelling in IPF patients. CONCLUSIONS AND IMPLICATIONS: These data highlight an endogenous host-defence capacity of natriuretic peptides in <d>lung fibrosis</d> and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.
24641440|a|BACKGROUND AND PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of <d>pulmonary hypertension</d> PH; the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. EXPERIMENTAL APPROACH: Pulmonary haemodynamics, right ventricular function and markers of <d>lung fibrosis</d> were determined in wild-type WT and natriuretic peptide receptor NPR-A knockout KO mice exposed to bleomycin 1 mg  kg-1 . Human myofibroblast differentiation was studied in vitro. KEY RESULTS: Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels ecadotril and potentiated natriuretic peptide-dependent signalling sildenafil reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFb-induced human myofibroblast differentiation, a key driver of remodelling in <d>IPF</d> patients. CONCLUSIONS AND IMPLICATIONS: These data highlight an endogenous host-defence capacity of natriuretic peptides in <d>lung fibrosis</d> and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with <d>IPF</d>.
24641440|a|BACKGROUND AND PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibro-proliferative disorder</d> refractory to current therapy commonly complicated by the development of <d>pulmonary hypertension</d> PH; the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. EXPERIMENTAL APPROACH: Pulmonary haemodynamics, right ventricular function and markers of <d>lung fibrosis</d> were determined in wild-type WT and natriuretic peptide receptor NPR-A knockout KO mice exposed to bleomycin 1 mg  kg-1 . Human myofibroblast differentiation was studied in vitro. KEY RESULTS: Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels ecadotril and potentiated natriuretic peptide-dependent signalling sildenafil reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFb-induced human myofibroblast differentiation, a key driver of remodelling in <d>IPF</d> patients. CONCLUSIONS AND IMPLICATIONS: These data highlight an endogenous host-defence capacity of natriuretic peptides in <d>lung fibrosis</d> and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with <d>IPF</d>.
24641440|a|BACKGROUND AND PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibro-proliferative disorder</d> refractory to current therapy commonly complicated by the development of <d>pulmonary hypertension</d> <d>PH</d>; the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated <d>PH</d>, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. EXPERIMENTAL APPROACH: Pulmonary haemodynamics, right ventricular function and markers of <d>lung fibrosis</d> were determined in wild-type WT and natriuretic peptide receptor NPR-A knockout KO mice exposed to bleomycin 1 mg  kg-1 . Human myofibroblast differentiation was studied in vitro. KEY RESULTS: Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels ecadotril and potentiated natriuretic peptide-dependent signalling sildenafil reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFb-induced human myofibroblast differentiation, a key driver of remodelling in <d>IPF</d> patients. CONCLUSIONS AND IMPLICATIONS: These data highlight an endogenous host-defence capacity of natriuretic peptides in <d>lung fibrosis</d> and <d>PH</d>. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with <d>IPF</d>.
24641440|a|BACKGROUND AND PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibro-proliferative disorder</d> refractory to current therapy commonly complicated by the development of <d>pulmonary hypertension</d> <d>PH</d>; the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and <d>myocardial fibrosis</d>. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated <d>PH</d>, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. EXPERIMENTAL APPROACH: Pulmonary haemodynamics, right ventricular function and markers of <d>lung fibrosis</d> were determined in wild-type WT and natriuretic peptide receptor NPR-A knockout KO mice exposed to bleomycin 1 mg  kg-1 . Human myofibroblast differentiation was studied in vitro. KEY RESULTS: Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels ecadotril and potentiated natriuretic peptide-dependent signalling sildenafil reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFb-induced human myofibroblast differentiation, a key driver of remodelling in <d>IPF</d> patients. CONCLUSIONS AND IMPLICATIONS: These data highlight an endogenous host-defence capacity of natriuretic peptides in <d>lung fibrosis</d> and <d>PH</d>. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with <d>IPF</d>.
24641440|a|BACKGROUND AND PURPOSE: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive <d>fibro-proliferative disorder</d> refractory to current therapy commonly complicated by the development of <d>pulmonary hypertension</d> <d>PH</d>; the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and <d>myocardial fibrosis</d>. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of <d>pulmonary fibrosis</d> and associated <d>PH</d>, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. EXPERIMENTAL APPROACH: Pulmonary haemodynamics, right ventricular function and markers of <d>lung fibrosis</d> were determined in wild-type WT and natriuretic peptide receptor NPR-A knockout KO mice exposed to bleomycin 1 mg  kg-1 . Human myofibroblast differentiation was studied in vitro. KEY RESULTS: Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels ecadotril and potentiated natriuretic peptide-dependent signalling sildenafil reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFb-induced human myofibroblast differentiation, a key driver of remodelling in <d>IPF</d> patients. CONCLUSIONS AND IMPLICATIONS: These data highlight an endogenous host-defence capacity of natriuretic peptides in <d>lung fibrosis</d> and <d>PH</d>. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with <d>IPF</d>.
24641440|a|BACKGROUND AND PURPOSE: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive <d>fibro-proliferative disorder</d> refractory to current therapy commonly complicated by the development of <d>pulmonary hypertension</d> <d>PH</d>; the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and <d>myocardial fibrosis</d>. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of <d>pulmonary fibrosis</d> and associated <d>PH</d>, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. EXPERIMENTAL APPROACH: Pulmonary haemodynamics, right ventricular function and markers of <d>lung fibrosis</d> were determined in wild-type WT and natriuretic peptide receptor NPR-A knockout KO mice exposed to bleomycin 1 mg  kg-1 . Human myofibroblast differentiation was studied in vitro. KEY RESULTS: Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels ecadotril and potentiated natriuretic peptide-dependent signalling sildenafil reduced indices of disease progression, whether administered prophylactically or to animals with <d>established lung disease</d>. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFb-induced human myofibroblast differentiation, a key driver of remodelling in <d>IPF</d> patients. CONCLUSIONS AND IMPLICATIONS: These data highlight an endogenous host-defence capacity of natriuretic peptides in <d>lung fibrosis</d> and <d>PH</d>. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with <d>IPF</d>.
24669082|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a debilitating lung disease of unknown etiology. Its pathogenesis remains poorly elucidated but aberrant wound healing is central to its pathology. It has a median survival time of 3 to 5 years. None of the treatment modality or drugs tried in its management has so far changed the overall outcome. Recent in vitro and experimental studies have shown that ambroxol hydrochloride exerts several newer actions, namely the surfactant stimulatory, anti-imflammatory and anti-oxidant actions, in addition to its being a secrrtolytic and mucokinetic agent. The anti inflammatory and anti-fibrotic properties of the drug are due to its ability to block the release of oxidant stress markers, cytokines, leukotrienes, MPO activity, hydroxyproline content, nitic oxide and/or collagen I _ III mRNA in the local milieu while preserving the SOD and GSH-PX activities. In human studies also, the agent was able to block the expression of TGF-beta and TNF-alpha in plasma and preserving the carbon monoxide diffusion capacity of the lungs in lung cancer patients on radiation therapy. Thus, ambroxol may have the potential to check the dysregulated healing process that is typical of IPF. This, coupled with its safety profile for human use, warrants clinical trials of the drug in the management of IPF.
24669082|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a debilitating lung disease of unknown etiology. Its pathogenesis remains poorly elucidated but aberrant wound healing is central to its pathology. It has a median survival time of 3 to 5 years. None of the treatment modality or drugs tried in its management has so far changed the overall outcome. Recent in vitro and experimental studies have shown that ambroxol hydrochloride exerts several newer actions, namely the surfactant stimulatory, anti-imflammatory and anti-oxidant actions, in addition to its being a secrrtolytic and mucokinetic agent. The anti inflammatory and anti-fibrotic properties of the drug are due to its ability to block the release of oxidant stress markers, cytokines, leukotrienes, MPO activity, hydroxyproline content, nitic oxide and/or collagen I _ III mRNA in the local milieu while preserving the SOD and GSH-PX activities. In human studies also, the agent was able to block the expression of TGF-beta and TNF-alpha in plasma and preserving the carbon monoxide diffusion capacity of the lungs in lung cancer patients on radiation therapy. Thus, ambroxol may have the potential to check the dysregulated healing process that is typical of <d>IPF</d>. This, coupled with its safety profile for human use, warrants clinical trials of the drug in the management of <d>IPF</d>.
24669082|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a debilitating lung disease of unknown etiology. Its pathogenesis remains poorly elucidated but aberrant wound healing is central to its pathology. It has a median survival time of 3 to 5 years. None of the treatment modality or drugs tried in its management has so far changed the overall outcome. Recent in vitro and experimental studies have shown that ambroxol hydrochloride exerts several newer actions, namely the surfactant stimulatory, anti-imflammatory and anti-oxidant actions, in addition to its being a secrrtolytic and mucokinetic agent. The anti inflammatory and anti-fibrotic properties of the drug are due to its ability to block the release of oxidant stress markers, cytokines, leukotrienes, MPO activity, hydroxyproline content, nitic oxide and/or collagen I _ III mRNA in the local milieu while preserving the SOD and GSH-PX activities. In human studies also, the agent was able to block the expression of <g>TGF-beta</g> and <g>TNF-alpha</g> in plasma and preserving the carbon monoxide diffusion capacity of the lungs in <d>lung cancer</d> patients on radiation therapy. Thus, ambroxol may have the potential to check the dysregulated healing process that is typical of <d>IPF</d>. This, coupled with its safety profile for human use, warrants clinical trials of the drug in the management of <d>IPF</d>.
24756129|a|Microsomal prostaglandin E2 synthase-1 mPGES-1, an inducible enzyme that converts prostaglandin H2 PGH2 to prostaglandin E2 PGE2, plays an important role in a variety of diseases. So far, the role of mPGES-1 in idiopathic <d>pulmonary fibrosis</d> IPF remained unknown. The current study aimed to investigate the role of mPGES-1 in <d>pulmonary fibrosis</d> induced by bleomycin in mice. We found that mPGES-1 deficient mPGES-1-/- mice exhibited more severe fibrotic lesions with a decrease in PGE2 content in lungs after bleomycin treatment when compared with wild type mPGES-1+/+ mice. The mPGES-1 expression levels and PGE2 content were also decreased in bleomycin-treated mPGES-1+/+ mice compared to saline-treated mPGES-1+/+ mice. Moreover, in both mPGES-1-/- and mPGES-1+/+ mice, bleomycin treatment reduced the expression levels of E prostanoid receptor 2 EP2 and EP4 receptor in lungs, whereas had little effect on EP1 and EP3. In cultured human lung fibroblast cells MRC-5, siRNA-mediated knockdown of mPGES-1 augmented transforming growth factor-b1 TGF-b1-induced a-smooth muscle actin a-SMA protein expression, and the increase was reversed by treatment of PGE2, selective EP2 agonist and focal adhesion kinase FAK inhibitor. In conclusion, these findings revealed mPGES-1 exerts an essential effect against pulmonary fibrogenesis via EP2-mediated signaling transduction, and activation of mPGES-1-PGE2-EP2-FAK signaling pathway may represent a new therapeutic strategy for treatment of IPF patients.
24756129|a|Microsomal prostaglandin E2 synthase-1 <g>mPGES-1</g>, an inducible enzyme that converts prostaglandin H2 PGH2 to prostaglandin E2 PGE2, plays an important role in a variety of diseases. So far, the role of <g>mPGES-1</g> in idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> remained unknown. The current study aimed to investigate the role of <g>mPGES-1</g> in <d>pulmonary fibrosis</d> induced by bleomycin in mice. We found that <g>mPGES-1</g> deficient <g>mPGES-1</g>-/- mice exhibited more severe fibrotic lesions with a decrease in PGE2 content in lungs after bleomycin treatment when compared with wild type <g>mPGES-1</g>+/+ mice. The <g>mPGES-1</g> expression levels and PGE2 content were also decreased in bleomycin-treated <g>mPGES-1</g>+/+ mice compared to saline-treated <g>mPGES-1</g>+/+ mice. Moreover, in both <g>mPGES-1</g>-/- and <g>mPGES-1</g>+/+ mice, bleomycin treatment reduced the expression levels of E prostanoid receptor 2 EP2 and EP4 receptor in lungs, whereas had little effect on EP1 and EP3. In cultured human lung fibroblast cells MRC-5, siRNA-mediated knockdown of <g>mPGES-1</g> augmented transforming growth factor-b1 TGF-b1-induced a-smooth muscle actin a-SMA protein expression, and the increase was reversed by treatment of PGE2, selective EP2 agonist and focal adhesion kinase FAK inhibitor. In conclusion, these findings revealed <g>mPGES-1</g> exerts an essential effect against pulmonary fibrogenesis via EP2-mediated signaling transduction, and activation of <g>mPGES-1</g>-PGE2-EP2-FAK signaling pathway may represent a new therapeutic strategy for treatment of <d>IPF</d> patients.
24756129|a|Microsomal prostaglandin E2 synthase-1 <g>mPGES-1</g>, an inducible enzyme that converts prostaglandin H2 PGH2 to prostaglandin E2 PGE2, plays an important role in a variety of diseases. So far, the role of <g>mPGES-1</g> in idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> remained unknown. The current study aimed to investigate the role of <g>mPGES-1</g> in <d>pulmonary fibrosis</d> induced by bleomycin in mice. We found that <g>mPGES-1</g> deficient <g>mPGES-1</g>-/- mice exhibited more severe <d>fibrotic lesions</d> with a decrease in PGE2 content in lungs after bleomycin treatment when compared with wild type <g>mPGES-1</g>+/+ mice. The <g>mPGES-1</g> expression levels and PGE2 content were also decreased in bleomycin-treated <g>mPGES-1</g>+/+ mice compared to saline-treated <g>mPGES-1</g>+/+ mice. Moreover, in both <g>mPGES-1</g>-/- and <g>mPGES-1</g>+/+ mice, bleomycin treatment reduced the expression levels of E prostanoid receptor 2 EP2 and EP4 receptor in lungs, whereas had little effect on EP1 and EP3. In cultured human lung fibroblast cells MRC-5, siRNA-mediated knockdown of <g>mPGES-1</g> augmented transforming growth factor-b1 TGF-b1-induced a-smooth muscle actin a-SMA protein expression, and the increase was reversed by treatment of PGE2, selective EP2 agonist and focal adhesion kinase FAK inhibitor. In conclusion, these findings revealed <g>mPGES-1</g> exerts an essential effect against pulmonary fibrogenesis via EP2-mediated signaling transduction, and activation of <g>mPGES-1</g>-PGE2-EP2-FAK signaling pathway may represent a new therapeutic strategy for treatment of <d>IPF</d> patients.
24762191|a|BACKGROUND: Idiopathic pulmonary fibrosis IPF is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-b1 is expressed in fibrotic lung and promotes <d>fibroblast to myofibroblast differentiation</d> FMD as well as matrix deposition. METHODS: To identify the mechanism of Arsenic trioxide's ATO's anti-fibrotic effect in vitro, normal human lung fibroblasts NHLFs were treated with ATO for 24  hours and were then exposed to TGF-b1 1  ng/ml before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung fibrosis in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14  days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as a-smooth muscle actin a-SMA and a-1 type I collagen. RESULTS: Treatment of NHLFs with ATO at very low concentrations 10-20nM inhibits TGF-b1-induced a-smooth muscle actin a-SMA and a-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-b1-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-b1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia PML nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts MEFs showed decreased fibronectin and PAI-1 expression in response to TGF-b1. Daily intraperitoneal injection of ATO 1  mg/kg in C57BL/6 mice inhibits bleomycin induced lung a-1 type I collagen mRNA and protein expression. CONCLUSIONS: In summary, these data indicate that low concentrations of ATO inhibit TGF-b1-induced <d>fibroblast to myofibroblast differentiation</d> and decreases bleomycin induced pulmonary fibrosis.
24762191|a|BACKGROUND: Idiopathic pulmonary <d>fibrosis</d> IPF is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-b1 is expressed in fibrotic lung and promotes <d>fibroblast to myofibroblast differentiation</d> FMD as well as matrix deposition. METHODS: To identify the mechanism of Arsenic trioxide's ATO's anti-fibrotic effect in vitro, normal human lung fibroblasts NHLFs were treated with ATO for 24  hours and were then exposed to TGF-b1 1  ng/ml before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung <d>fibrosis</d> in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14  days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as a-smooth muscle actin a-SMA and a-1 type I collagen. RESULTS: Treatment of NHLFs with ATO at very low concentrations 10-20nM inhibits TGF-b1-induced a-smooth muscle actin a-SMA and a-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-b1-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-b1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia PML nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts MEFs showed decreased fibronectin and PAI-1 expression in response to TGF-b1. Daily intraperitoneal injection of ATO 1  mg/kg in C57BL/6 mice inhibits bleomycin induced lung a-1 type I collagen mRNA and protein expression. CONCLUSIONS: In summary, these data indicate that low concentrations of ATO inhibit TGF-b1-induced <d>fibroblast to myofibroblast differentiation</d> and decreases bleomycin induced pulmonary <d>fibrosis</d>.
24762191|a|BACKGROUND: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in <d>IPF</d>. TGF-b1 is expressed in fibrotic lung and promotes <d>fibroblast to myofibroblast differentiation</d> FMD as well as matrix deposition. METHODS: To identify the mechanism of Arsenic trioxide's ATO's anti-fibrotic effect in vitro, normal human lung fibroblasts NHLFs were treated with ATO for 24  hours and were then exposed to TGF-b1 1  ng/ml before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung <d>fibrosis</d> in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14  days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as a-smooth muscle actin a-SMA and a-1 type I collagen. RESULTS: Treatment of NHLFs with ATO at very low concentrations 10-20nM inhibits TGF-b1-induced a-smooth muscle actin a-SMA and a-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-b1-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-b1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia PML nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts MEFs showed decreased fibronectin and PAI-1 expression in response to TGF-b1. Daily intraperitoneal injection of ATO 1  mg/kg in C57BL/6 mice inhibits bleomycin induced lung a-1 type I collagen mRNA and protein expression. CONCLUSIONS: In summary, these data indicate that low concentrations of ATO inhibit TGF-b1-induced <d>fibroblast to myofibroblast differentiation</d> and decreases bleomycin induced pulmonary <d>fibrosis</d>.
24762191|a|BACKGROUND: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive disease of insidious onset, and is responsible for up to 30,000 <d>deaths</d> per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in <d>IPF</d>. TGF-b1 is expressed in fibrotic lung and promotes <d>fibroblast to myofibroblast differentiation</d> FMD as well as matrix deposition. METHODS: To identify the mechanism of Arsenic trioxide's ATO's anti-fibrotic effect in vitro, normal human lung fibroblasts NHLFs were treated with ATO for 24  hours and were then exposed to TGF-b1 1  ng/ml before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung <d>fibrosis</d> in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14  days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as a-smooth muscle actin a-SMA and a-1 type I collagen. RESULTS: Treatment of NHLFs with ATO at very low concentrations 10-20nM inhibits TGF-b1-induced a-smooth muscle actin a-SMA and a-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-b1-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-b1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia PML nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts MEFs showed decreased fibronectin and PAI-1 expression in response to TGF-b1. Daily intraperitoneal injection of ATO 1  mg/kg in C57BL/6 mice inhibits bleomycin induced lung a-1 type I collagen mRNA and protein expression. CONCLUSIONS: In summary, these data indicate that low concentrations of ATO inhibit TGF-b1-induced <d>fibroblast to myofibroblast differentiation</d> and decreases bleomycin induced pulmonary <d>fibrosis</d>.
24762191|a|BACKGROUND: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive disease of insidious onset, and is responsible for up to 30,000 <d>deaths</d> per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in <d>IPF</d>. <g>TGF-b1</g> is expressed in fibrotic lung and promotes <d>fibroblast to myofibroblast differentiation</d> <d>FMD</d> as well as matrix deposition. METHODS: To identify the mechanism of Arsenic trioxide's ATO's anti-fibrotic effect in vitro, normal human lung fibroblasts NHLFs were treated with ATO for 24  hours and were then exposed to <g>TGF-b1</g> 1  ng/ml before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung <d>fibrosis</d> in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14  days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as a-smooth muscle actin a-SMA and a-1 type I collagen. RESULTS: Treatment of NHLFs with ATO at very low concentrations 10-20nM inhibits <g>TGF-b1</g>-induced a-smooth muscle actin a-SMA and a-1 type I collagen mRNA and protein expression. ATO also diminishes the <g>TGF-b1</g>-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. <g>TGF-b1</g>-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia PML nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts MEFs showed decreased fibronectin and PAI-1 expression in response to <g>TGF-b1</g>. Daily intraperitoneal injection of ATO 1  mg/kg in C57BL/6 mice inhibits bleomycin induced lung a-1 type I collagen mRNA and protein expression. CONCLUSIONS: In summary, these data indicate that low concentrations of ATO inhibit <g>TGF-b1</g>-induced <d>fibroblast to myofibroblast differentiation</d> and decreases bleomycin induced pulmonary <d>fibrosis</d>.
24762191|a|BACKGROUND: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive disease of insidious onset, and is responsible for up to 30,000 <d>deaths</d> per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in <d>IPF</d>. <g>TGF-b1</g> is expressed in fibrotic lung and promotes <d>fibroblast to myofibroblast differentiation</d> <d>FMD</d> as well as matrix deposition. METHODS: To identify the mechanism of Arsenic trioxide's ATO's anti-fibrotic effect in vitro, normal human lung fibroblasts NHLFs were treated with ATO for 24  hours and were then exposed to <g>TGF-b1</g> 1  ng/ml before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung <d>fibrosis</d> in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14  days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as a-smooth muscle actin <g>a-SMA</g> and a-1 type I collagen. RESULTS: Treatment of NHLFs with ATO at very low concentrations 10-20nM inhibits <g>TGF-b1</g>-induced a-smooth muscle actin <g>a-SMA</g> and a-1 type I collagen mRNA and protein expression. ATO also diminishes the <g>TGF-b1</g>-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of <g>Akt</g>, as well as <g>Smad2</g>/<g>Smad3</g> phosphorylation. <g>TGF-b1</g>-induced H2O2 and <g>NOX-4</g> mRNA expression are also blocked by ATO. ATO-mediated reduction in <g>Smad3</g> phosphorylation correlated with a <d>reduction of promyelocytic leukemia</d> PML nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts MEFs showed decreased fibronectin and PAI-1 expression in response to <g>TGF-b1</g>. Daily intraperitoneal injection of ATO 1  mg/kg in C57BL/6 mice inhibits bleomycin induced lung a-1 type I collagen mRNA and protein expression. CONCLUSIONS: In summary, these data indicate that low concentrations of ATO inhibit <g>TGF-b1</g>-induced <d>fibroblast to myofibroblast differentiation</d> and decreases bleomycin induced pulmonary <d>fibrosis</d>.
24811261|a|Carbon monoxide CO has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles CO-HbV. We hypothesized that CO-HbV could have a therapeutic effect on idiopathic <d>pulmonary fibrosis</d> IPF, an incurable lung fibrosis, that is thought to involve inflammation and the production of reactive oxygen species ROS. Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on <d>pulmonary fibrosis</d> can be attributed to a decrease in ROS generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-b in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of <d>pulmonary fibrosis</d> via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV has the potential for use in the treatment of, not only IPF, but also a variety of other ROS and inflammation-related disorders.
24811261|a|Carbon monoxide CO has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles CO-HbV. We hypothesized that CO-HbV could have a therapeutic effect on idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, an incurable lung fibrosis, that is thought to involve inflammation and the production of reactive oxygen species ROS. Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on <d>pulmonary fibrosis</d> can be attributed to a decrease in ROS generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-b in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of <d>pulmonary fibrosis</d> via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV has the potential for use in the treatment of, not only <d>IPF</d>, but also a variety of other ROS and inflammation-related disorders.
24811261|a|Carbon monoxide CO has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles CO-HbV. We hypothesized that CO-HbV could have a therapeutic effect on idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, an incurable <d>lung fibrosis</d>, that is thought to involve inflammation and the production of reactive oxygen species ROS. Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on <d>pulmonary fibrosis</d> can be attributed to a decrease in ROS generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-b in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of <d>pulmonary fibrosis</d> via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV has the potential for use in the treatment of, not only <d>IPF</d>, but also a variety of other ROS and inflammation-related disorders.
24811261|a|Carbon monoxide CO has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles CO-HbV. We hypothesized that CO-HbV could have a therapeutic effect on idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, an incurable <d>lung fibrosis</d>, that is thought to involve <d>inflammation</d> and the production of reactive oxygen species ROS. Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on <d>pulmonary fibrosis</d> can be attributed to a decrease in ROS generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-b in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of <d>pulmonary fibrosis</d> via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV has the potential for use in the treatment of, not only <d>IPF</d>, but also a variety of other ROS and <d>inflammation</d>-related disorders.
24811261|a|Carbon monoxide CO has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles CO-HbV. We hypothesized that CO-HbV could have a therapeutic effect on idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, an incurable <d>lung fibrosis</d>, that is thought to involve <d>inflammation</d> and the production of <d>reactive oxygen species</d> ROS. Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on <d>pulmonary fibrosis</d> can be attributed to a decrease in ROS generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-b in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of <d>pulmonary fibrosis</d> via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV has the potential for use in the treatment of, not only <d>IPF</d>, but also a variety of other ROS and <d>inflammation</d>-related disorders.
24811261|a|Carbon monoxide CO has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles CO-HbV. We hypothesized that CO-HbV could have a therapeutic effect on idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, an incurable <d>lung fibrosis</d>, that is thought to involve <d>inflammation</d> and the production of <d>reactive oxygen species</d> <d>ROS</d>. Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on <d>pulmonary fibrosis</d> can be attributed to a decrease in <d>ROS</d> generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-b in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of <d>pulmonary fibrosis</d> via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced <d>pulmonary fibrosis</d> mice model. CO-HbV has the potential for use in the treatment of, not only <d>IPF</d>, but also a variety of other <d>ROS</d> and <d>inflammation</d>-related disorders.
24853416|a|<d>Idiopathic Pulmonary Fibrosis</d> IPF is a chronic, progressive, and highly lethal fibrotic lung disease with poor treatment and unknown etiology. Emerging evidence suggests that epithelial-mesenchymal transition EMT has an important role in repair and scar formation following epithelial injury during pulmonary fibrosis. Although some miRNAs have been shown to be dysregulated in the pathophysiological processes of IPF, limited studies have payed attention on the participation of miRNAs in EMT in lung fibrosis. In our study, we identified and constructed a regulation network of differentially expressed IPF miRNAs and EMT genes. Additionally, we found the downregulation of miR-26a in mice with experimental pulmonary fibrosis. Further studies showed that miR-26a regulated HMGA2, which is a key factor in the process of EMT and had the maximum number of regulating miRNAs in the regulation network. More importantly, inhibition of miR-26a resulted in lung epithelial cells transforming into myofibroblasts in vitro and in vivo, whereas forced expression of miR-26a alleviated TGF-b1- and BLM-induced EMT in A549 cells and in mice, respectively. Taken together, our study deciphered the essential role of miR-26a in the pathogenesis of EMT in pulmonary fibrosis, and suggests that miR-26a may be a potential therapeutic target for IPF.
24853416|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a chronic, progressive, and highly lethal fibrotic lung disease with poor treatment and unknown etiology. Emerging evidence suggests that epithelial-mesenchymal transition EMT has an important role in repair and scar formation following epithelial injury during pulmonary fibrosis. Although some miRNAs have been shown to be dysregulated in the pathophysiological processes of <d>IPF</d>, limited studies have payed attention on the participation of miRNAs in EMT in lung fibrosis. In our study, we identified and constructed a regulation network of differentially expressed <d>IPF</d> miRNAs and EMT genes. Additionally, we found the downregulation of miR-26a in mice with experimental pulmonary fibrosis. Further studies showed that miR-26a regulated HMGA2, which is a key factor in the process of EMT and had the maximum number of regulating miRNAs in the regulation network. More importantly, inhibition of miR-26a resulted in lung epithelial cells transforming into myofibroblasts in vitro and in vivo, whereas forced expression of miR-26a alleviated TGF-b1- and BLM-induced EMT in A549 cells and in mice, respectively. Taken together, our study deciphered the essential role of miR-26a in the pathogenesis of EMT in pulmonary fibrosis, and suggests that miR-26a may be a potential therapeutic target for <d>IPF</d>.
24853416|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a chronic, progressive, and highly lethal <d>fibrotic lung disease</d> with poor treatment and unknown etiology. Emerging evidence suggests that epithelial-mesenchymal transition EMT has an important role in repair and scar formation following epithelial injury during pulmonary fibrosis. Although some miRNAs have been shown to be dysregulated in the pathophysiological processes of <d>IPF</d>, limited studies have payed attention on the participation of miRNAs in EMT in lung fibrosis. In our study, we identified and constructed a regulation network of differentially expressed <d>IPF</d> miRNAs and EMT genes. Additionally, we found the downregulation of miR-26a in mice with experimental pulmonary fibrosis. Further studies showed that miR-26a regulated HMGA2, which is a key factor in the process of EMT and had the maximum number of regulating miRNAs in the regulation network. More importantly, inhibition of miR-26a resulted in lung epithelial cells transforming into myofibroblasts in vitro and in vivo, whereas forced expression of miR-26a alleviated TGF-b1- and BLM-induced EMT in A549 cells and in mice, respectively. Taken together, our study deciphered the essential role of miR-26a in the pathogenesis of EMT in pulmonary fibrosis, and suggests that miR-26a may be a potential therapeutic target for <d>IPF</d>.
24853416|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a chronic, progressive, and highly lethal <d>fibrotic lung disease</d> with poor treatment and unknown etiology. Emerging evidence suggests that epithelial-mesenchymal transition EMT has an important role in repair and scar formation following epithelial injury during <d>pulmonary fibrosis</d>. Although some miRNAs have been shown to be dysregulated in the pathophysiological processes of <d>IPF</d>, limited studies have payed attention on the participation of miRNAs in EMT in lung fibrosis. In our study, we identified and constructed a regulation network of differentially expressed <d>IPF</d> miRNAs and EMT genes. Additionally, we found the downregulation of miR-26a in mice with experimental <d>pulmonary fibrosis</d>. Further studies showed that miR-26a regulated HMGA2, which is a key factor in the process of EMT and had the maximum number of regulating miRNAs in the regulation network. More importantly, inhibition of miR-26a resulted in lung epithelial cells transforming into myofibroblasts in vitro and in vivo, whereas forced expression of miR-26a alleviated TGF-b1- and BLM-induced EMT in A549 cells and in mice, respectively. Taken together, our study deciphered the essential role of miR-26a in the pathogenesis of EMT in <d>pulmonary fibrosis</d>, and suggests that miR-26a may be a potential therapeutic target for <d>IPF</d>.
24853416|a|<d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a chronic, progressive, and highly lethal <d>fibrotic lung disease</d> with poor treatment and unknown etiology. Emerging evidence suggests that epithelial-mesenchymal transition EMT has an important role in repair and scar formation following epithelial injury during <d>pulmonary fibrosis</d>. Although some miRNAs have been shown to be dysregulated in the pathophysiological processes of <d>IPF</d>, limited studies have payed attention on the participation of miRNAs in <d>EMT in lung fibrosis</d>. In our study, we identified and constructed a regulation network of differentially expressed <d>IPF</d> miRNAs and EMT genes. Additionally, we found the downregulation of miR-26a in mice with experimental <d>pulmonary fibrosis</d>. Further studies showed that miR-26a regulated HMGA2, which is a key factor in the process of EMT and had the maximum number of regulating miRNAs in the regulation network. More importantly, inhibition of miR-26a resulted in lung epithelial cells transforming into myofibroblasts in vitro and in vivo, whereas forced expression of miR-26a alleviated TGF-b1- and BLM-induced EMT in A549 cells and in mice, respectively. Taken together, our study deciphered the essential role of miR-26a in the pathogenesis of EMT in <d>pulmonary fibrosis</d>, and suggests that miR-26a may be a potential therapeutic target for <d>IPF</d>.
24879051|a|Patients with <d>idiopathic pulmonary fibrosis</d> IPF often do worse following infection, but the cause of the decline is not fully understood. We previously demonstrated that infection with a murine gamma herpes virus yHV-68 could exacerbate established lung fibrosis following administration of fluorescein isothiocyanate McMillan et al. Am J Respir Crit Care Med 177: 771-780, 2008. In the present study, we anesthetized mice and injected saline or bleomycin intratracheally on day 0. On day 14, mice were anesthetized again and infected with either a Gram-negative bacteria Pseudomonas aeruginosa, or with H1N1 or yHV-68 viruses. Measurements were then made on days 15, 21, or 35. We demonstrate that infection with P. aeruginosa does not exacerbate extracellular matrix deposition post-bleomycin. Furthermore, fibrotic mice are effectively able to clear P. aeruginosa infection. In contrast, bleomycin-treated mice develop worse lung fibrosis when infected with yHV-68, but not when infected with H1N1. The differential ability of yHV-68 to cause increased collagen deposition could not be explained by differences in inflammatory cell recruitment or whole lung chemokine and cytokine responses. Alveolar epithelial cells from yHV-68-infected mice displayed increased expression of TGFb receptor 1, increased SMAD3 phosphorylation, and evidence of apoptosis measured by cleaved poly-ADP ribose polymerase PARP. The ability of yHV-68 to augment fibrosis required the ability of the virus to reactivate from latency. This property appears unique to yHV-68, as the b-herpes virus, cytomegalovirus, did not have the same effect.
24879051|a|Patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> often do worse following infection, but the cause of the decline is not fully understood. We previously demonstrated that infection with a murine gamma herpes virus yHV-68 could exacerbate established lung fibrosis following administration of fluorescein isothiocyanate McMillan et al. Am J Respir Crit Care Med 177: 771-780, 2008. In the present study, we anesthetized mice and injected saline or bleomycin intratracheally on day 0. On day 14, mice were anesthetized again and infected with either a Gram-negative bacteria Pseudomonas aeruginosa, or with H1N1 or yHV-68 viruses. Measurements were then made on days 15, 21, or 35. We demonstrate that infection with P. aeruginosa does not exacerbate extracellular matrix deposition post-bleomycin. Furthermore, fibrotic mice are effectively able to clear P. aeruginosa infection. In contrast, bleomycin-treated mice develop worse lung fibrosis when infected with yHV-68, but not when infected with H1N1. The differential ability of yHV-68 to cause increased collagen deposition could not be explained by differences in inflammatory cell recruitment or whole lung chemokine and cytokine responses. Alveolar epithelial cells from yHV-68-infected mice displayed increased expression of TGFb receptor 1, increased SMAD3 phosphorylation, and evidence of apoptosis measured by cleaved poly-ADP ribose polymerase PARP. The ability of yHV-68 to augment fibrosis required the ability of the virus to reactivate from latency. This property appears unique to yHV-68, as the b-herpes virus, cytomegalovirus, did not have the same effect.
24879051|a|Patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> often do worse following infection, but the cause of the decline is not fully understood. We previously demonstrated that infection with a murine gamma herpes virus yHV-68 could exacerbate <d>established lung fibrosis</d> following administration of fluorescein isothiocyanate McMillan et al. Am J Respir Crit Care Med 177: 771-780, 2008. In the present study, we anesthetized mice and injected saline or bleomycin intratracheally on day 0. On day 14, mice were anesthetized again and infected with either a Gram-negative bacteria Pseudomonas aeruginosa, or with H1N1 or yHV-68 viruses. Measurements were then made on days 15, 21, or 35. We demonstrate that infection with P. aeruginosa does not exacerbate extracellular matrix deposition post-bleomycin. Furthermore, fibrotic mice are effectively able to clear P. aeruginosa infection. In contrast, bleomycin-treated mice develop worse lung fibrosis when infected with yHV-68, but not when infected with H1N1. The differential ability of yHV-68 to cause increased collagen deposition could not be explained by differences in inflammatory cell recruitment or whole lung chemokine and cytokine responses. Alveolar epithelial cells from yHV-68-infected mice displayed increased expression of TGFb receptor 1, increased SMAD3 phosphorylation, and evidence of apoptosis measured by cleaved poly-ADP ribose polymerase PARP. The ability of yHV-68 to augment fibrosis required the ability of the virus to reactivate from latency. This property appears unique to yHV-68, as the b-herpes virus, cytomegalovirus, did not have the same effect.
24879051|a|Patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> often do worse following infection, but the cause of the decline is not fully understood. We previously demonstrated that infection with a murine gamma herpes virus yHV-68 could exacerbate <d>established lung fibrosis</d> following administration of fluorescein isothiocyanate McMillan et al. Am J Respir Crit Care Med 177: 771-780, 2008. In the present study, we anesthetized mice and injected saline or bleomycin intratracheally on day 0. On day 14, mice were anesthetized again and infected with either a Gram-negative bacteria Pseudomonas aeruginosa, or with H1N1 or yHV-68 viruses. Measurements were then made on days 15, 21, or 35. We demonstrate that infection with P. aeruginosa does not exacerbate extracellular matrix deposition post-bleomycin. Furthermore, fibrotic mice are effectively able to clear P. aeruginosa infection. In contrast, bleomycin-treated mice develop <d>worse lung fibrosis</d> when infected with yHV-68, but not when infected with H1N1. The differential ability of yHV-68 to cause increased collagen deposition could not be explained by differences in inflammatory cell recruitment or whole lung chemokine and cytokine responses. Alveolar epithelial cells from yHV-68-infected mice displayed increased expression of TGFb receptor 1, increased SMAD3 phosphorylation, and evidence of apoptosis measured by cleaved poly-ADP ribose polymerase PARP. The ability of yHV-68 to augment fibrosis required the ability of the virus to reactivate from latency. This property appears unique to yHV-68, as the b-herpes virus, cytomegalovirus, did not have the same effect.
24879051|a|Patients with <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> often do worse following infection, but the cause of the decline is not fully understood. We previously demonstrated that infection with a murine gamma herpes virus yHV-68 could exacerbate <d>established lung <d>fibrosis</d></d> following administration of fluorescein isothiocyanate McMillan et al. Am J Respir Crit Care Med 177: 771-780, 2008. In the present study, we anesthetized mice and injected saline or bleomycin intratracheally on day 0. On day 14, mice were anesthetized again and infected with either a Gram-negative bacteria Pseudomonas aeruginosa, or with H1N1 or yHV-68 viruses. Measurements were then made on days 15, 21, or 35. We demonstrate that infection with P. aeruginosa does not exacerbate extracellular matrix deposition post-bleomycin. Furthermore, fibrotic mice are effectively able to clear P. aeruginosa infection. In contrast, bleomycin-treated mice develop <d>worse lung <d>fibrosis</d></d> when infected with yHV-68, but not when infected with H1N1. The differential ability of yHV-68 to cause increased collagen deposition could not be explained by differences in inflammatory cell recruitment or whole lung chemokine and cytokine responses. Alveolar epithelial cells from yHV-68-infected mice displayed increased expression of TGFb receptor 1, increased <g>SMAD3</g> phosphorylation, and evidence of apoptosis measured by cleaved <g>poly-ADP ribose polymerase</g> <g>PARP</g>. The ability of yHV-68 to augment <d>fibrosis</d> required the ability of the virus to reactivate from latency. This property appears unique to yHV-68, as the b-herpes virus, cytomegalovirus, did not have the same effect.
24879051|a|Patients with <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> often do worse following infection, but the cause of the decline is not fully understood. We previously demonstrated that infection with a murine gamma herpes virus yHV-68 could exacerbate <d>established lung <d>fibrosis</d></d> following administration of fluorescein isothiocyanate McMillan et al. Am J Respir Crit Care Med 177: 771-780, 2008. In the present study, we anesthetized mice and injected saline or bleomycin intratracheally on day 0. On day 14, mice were anesthetized again and infected with either a Gram-negative bacteria Pseudomonas aeruginosa, or with H1N1 or yHV-68 viruses. Measurements were then made on days 15, 21, or 35. We demonstrate that infection with P. aeruginosa does not exacerbate extracellular matrix deposition post-bleomycin. Furthermore, fibrotic mice are effectively able to clear P. aeruginosa infection. In contrast, bleomycin-treated mice develop <d>worse lung <d>fibrosis</d></d> when infected with yHV-68, but not when infected with H1N1. The differential ability of yHV-68 to cause increased collagen deposition could not be explained by differences in inflammatory cell recruitment or whole lung chemokine and cytokine responses. Alveolar epithelial cells from yHV-68-infected mice displayed increased expression of TGFb receptor 1, increased <g>SMAD3</g> phosphorylation, and evidence of apoptosis measured by cleaved <g>poly-ADP ribose polymerase</g> <g>PARP</g>. The ability of yHV-68 to augment <d>fibrosis</d> required the ability of the virus to reactivate from latency. This property appears unique to yHV-68, as the b-herpes virus, <d>cytomegalovirus</d>, did not have the same effect.
24886817|a|Idiopathic pulmonary fibrosis IPF is a progressing lethal disease with few clinically effective therapies. Corilagin is a tannin derivative which shows anti-inflammatory and antifibrotics properties and is potentiated in treating IPF. Here, we investigated the effect of corilagin on <d>lung injury</d> following bleomycin exposure in an animal model of pulmonary fibrosis. Corilagin abrogated bleomycin-induced lung fibrosis as assessed by H_E; Masson's trichrome staining and lung hydroxyproline content in lung tissue. Corilagin reduced the number of apoptotic lung cells and prevented lung epithelial cells from membrane breakdown, effluence of lamellar bodies and thickening of the respiratory membrane. Bleomycin exposure induced expression of MDA, IKKa, phosphorylated IKKa p-IKKa, NF-kB P65, TNF-a and IL-1b, and reduced I-kB expression in mice lung tissue or in BALF. These changes were reversed by high-dose corilagin 100 mg/kg i.p more dramatically than by low dose 10 mg/kg i.p. Last, corilagin inhibits TGF-b1 production and a-SMA expression in lung tissue samples. Taken together, these findings confirmed that corilagin attenuates bleomycin-induced epithelial injury and fibrosis via inactivation of oxidative stress, proinflammatory cytokine release and NF-kB and TGF-b1 signaling. Corilagin may serve as a promising therapeutic agent for pulmonary fibrosis.
24886817|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressing lethal disease with few clinically effective therapies. Corilagin is a tannin derivative which shows anti-inflammatory and antifibrotics properties and is potentiated in treating IPF. Here, we investigated the effect of corilagin on <d>lung injury</d> following bleomycin exposure in an animal model of pulmonary fibrosis. Corilagin abrogated bleomycin-induced lung fibrosis as assessed by H_E; Masson's trichrome staining and lung hydroxyproline content in lung tissue. Corilagin reduced the number of apoptotic lung cells and prevented lung epithelial cells from membrane breakdown, effluence of lamellar bodies and thickening of the respiratory membrane. Bleomycin exposure induced expression of MDA, IKKa, phosphorylated IKKa p-IKKa, NF-kB P65, TNF-a and IL-1b, and reduced I-kB expression in mice lung tissue or in BALF. These changes were reversed by high-dose corilagin 100 mg/kg i.p more dramatically than by low dose 10 mg/kg i.p. Last, corilagin inhibits TGF-b1 production and a-SMA expression in lung tissue samples. Taken together, these findings confirmed that corilagin attenuates bleomycin-induced epithelial injury and fibrosis via inactivation of oxidative stress, proinflammatory cytokine release and NF-kB and TGF-b1 signaling. Corilagin may serve as a promising therapeutic agent for pulmonary fibrosis.
24886817|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressing lethal disease with few clinically effective therapies. Corilagin is a tannin derivative which shows anti-inflammatory and antifibrotics properties and is potentiated in treating <d>IPF</d>. Here, we investigated the effect of corilagin on <d>lung injury</d> following bleomycin exposure in an animal model of pulmonary fibrosis. Corilagin abrogated bleomycin-induced lung fibrosis as assessed by H_E; Masson's trichrome staining and lung hydroxyproline content in lung tissue. Corilagin reduced the number of apoptotic lung cells and prevented lung epithelial cells from membrane breakdown, effluence of lamellar bodies and thickening of the respiratory membrane. Bleomycin exposure induced expression of MDA, IKKa, phosphorylated IKKa p-IKKa, NF-kB P65, TNF-a and IL-1b, and reduced I-kB expression in mice lung tissue or in BALF. These changes were reversed by high-dose corilagin 100 mg/kg i.p more dramatically than by low dose 10 mg/kg i.p. Last, corilagin inhibits TGF-b1 production and a-SMA expression in lung tissue samples. Taken together, these findings confirmed that corilagin attenuates bleomycin-induced epithelial injury and fibrosis via inactivation of oxidative stress, proinflammatory cytokine release and NF-kB and TGF-b1 signaling. Corilagin may serve as a promising therapeutic agent for pulmonary fibrosis.
24886817|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressing lethal disease with few clinically effective therapies. Corilagin is a tannin derivative which shows anti-inflammatory and antifibrotics properties and is potentiated in treating <d>IPF</d>. Here, we investigated the effect of corilagin on <d>lung injury</d> following bleomycin exposure in an animal model of <d>pulmonary fibrosis</d>. Corilagin abrogated bleomycin-induced lung fibrosis as assessed by H_E; Masson's trichrome staining and lung hydroxyproline content in lung tissue. Corilagin reduced the number of apoptotic lung cells and prevented lung epithelial cells from membrane breakdown, effluence of lamellar bodies and thickening of the respiratory membrane. Bleomycin exposure induced expression of MDA, IKKa, phosphorylated IKKa p-IKKa, NF-kB P65, TNF-a and IL-1b, and reduced I-kB expression in mice lung tissue or in BALF. These changes were reversed by high-dose corilagin 100 mg/kg i.p more dramatically than by low dose 10 mg/kg i.p. Last, corilagin inhibits TGF-b1 production and a-SMA expression in lung tissue samples. Taken together, these findings confirmed that corilagin attenuates bleomycin-induced epithelial injury and fibrosis via inactivation of oxidative stress, proinflammatory cytokine release and NF-kB and TGF-b1 signaling. Corilagin may serve as a promising therapeutic agent for <d>pulmonary fibrosis</d>.
24886817|a|<d>Idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d> is a progressing lethal disease with few clinically effective therapies. Corilagin is a tannin derivative which shows anti-inflammatory and antifibrotics properties and is potentiated in treating <d>IPF</d>. Here, we investigated the effect of corilagin on <d>lung injury</d> following bleomycin exposure in an animal model of <d>pulmonary <d>fibrosis</d></d>. Corilagin abrogated bleomycin-induced lung <d>fibrosis</d> as assessed by H_E; Masson's trichrome staining and lung hydroxyproline content in lung tissue. Corilagin reduced the number of apoptotic lung cells and prevented lung epithelial cells from membrane breakdown, effluence of lamellar bodies and thickening of the respiratory membrane. Bleomycin exposure induced expression of MDA, IKKa, phosphorylated IKKa p-IKKa, NF-kB P65, TNF-a and IL-1b, and reduced I-kB expression in mice lung tissue or in BALF. These changes were reversed by high-dose corilagin 100 mg/kg i.p more dramatically than by low dose 10 mg/kg i.p. Last, corilagin inhibits TGF-b1 production and a-SMA expression in lung tissue samples. Taken together, these findings confirmed that corilagin attenuates bleomycin-induced epithelial injury and <d>fibrosis</d> via inactivation of oxidative stress, proinflammatory cytokine release and NF-kB and TGF-b1 signaling. Corilagin may serve as a promising therapeutic agent for <d>pulmonary <d>fibrosis</d></d>.
24886817|a|<d>Idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d> is a progressing lethal disease with few clinically effective therapies. Corilagin is a tannin derivative which shows anti-inflammatory and antifibrotics properties and is potentiated in treating <d>IPF</d>. Here, we investigated the effect of corilagin on <d>lung injury</d> following bleomycin exposure in an animal model of <d>pulmonary <d>fibrosis</d></d>. Corilagin abrogated bleomycin-induced lung <d>fibrosis</d> as assessed by H_E; Masson's trichrome staining and lung hydroxyproline content in lung tissue. Corilagin reduced the number of apoptotic lung cells and prevented lung epithelial cells from membrane breakdown, effluence of lamellar bodies and thickening of the respiratory membrane. Bleomycin exposure induced expression of MDA, <g>IKKa</g>, phosphorylated <g>IKKa</g> p-<g>IKKa</g>, NF-kB P65, <g>TNF-a</g> and <g>IL-1b</g>, and reduced I-kB expression in mice lung tissue or in BALF. These changes were reversed by high-dose corilagin 100 mg/kg i.p more dramatically than by low dose 10 mg/kg i.p. Last, corilagin inhibits <g>TGF-b1</g> production and <g>a-SMA</g> expression in lung tissue samples. Taken together, these findings confirmed that corilagin attenuates bleomycin-induced <d>epithelial injury</d> and <d>fibrosis</d> via inactivation of oxidative stress, proinflammatory cytokine release and NF-kB and <g>TGF-b1</g> signaling. Corilagin may serve as a promising therapeutic agent for <d>pulmonary <d>fibrosis</d></d>.
24890164|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a progressive diffuse parenchymal disease with a poor prognosis. A variety of cytokines and chemokines are involved in its pathophysiology. The aim of this study was to evaluate the clinical features in IPF patients with the expression of <g>suppressor of cytokine signaling 1</g> SOCS-1, which acts as a negative regulator of cytokine signaling. METHODS: IPF patients n = 20 and healthy controls n = 16 were included in this study. The expression of SOCS-1 was analyzed in peripheral blood mononuclear cells PBMC of subjects using RT-PCR. Interleukin 4 IL-4, transforming growth factor b1 TGF-b1 and type I collagen expression were also analyzed in each individual using enzyme-linked immunosorbent assay ELISA. The clinical characteristics of IPF patients were delineated. These results were analyzed by SPSS13.0 statistics software. RESULTS: SOCS-1 mRNA expression was significantly decreased in the PBMC of IPF patients compared with healthy controls; serum levels of IL-4 and TGF-b1 were higher in IPF patients. The patients with lower expression of SOCS-1 developed lower percentage of forced vital capacity FVC% and DLCO/VA. A patients' SOCS-1 mRNA level was negatively correlated with serum levels of IL-4, and negatively correlated with their high-resolution computed tomography HRCT scores. CONCLUSIONS: SOCS-1 mRNA can be detected in PBMC, and it is down-regulated in IPF patients. The expression of SOCS-1 is associated with the severity of IPF patients' symptoms, so it might be the predictor of disease severity. SOCS-1 might play an important role in IPF by reducing the expression of the T helper type 2 Th2 cell-related cytokine IL-4.
24890164|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive diffuse parenchymal disease with a poor prognosis. A variety of cytokines and chemokines are involved in its pathophysiology. The aim of this study was to evaluate the clinical features in <d>IPF</d> patients with the expression of <g>suppressor of cytokine signaling 1</g> SOCS-1, which acts as a negative regulator of cytokine signaling. METHODS: <d>IPF</d> patients n = 20 and healthy controls n = 16 were included in this study. The expression of SOCS-1 was analyzed in peripheral blood mononuclear cells PBMC of subjects using RT-PCR. Interleukin 4 IL-4, transforming growth factor b1 TGF-b1 and type I collagen expression were also analyzed in each individual using enzyme-linked immunosorbent assay ELISA. The clinical characteristics of <d>IPF</d> patients were delineated. These results were analyzed by SPSS13.0 statistics software. RESULTS: SOCS-1 mRNA expression was significantly decreased in the PBMC of <d>IPF</d> patients compared with healthy controls; serum levels of IL-4 and TGF-b1 were higher in <d>IPF</d> patients. The patients with lower expression of SOCS-1 developed lower percentage of forced vital capacity FVC% and DLCO/VA. A patients' SOCS-1 mRNA level was negatively correlated with serum levels of IL-4, and negatively correlated with their high-resolution computed tomography HRCT scores. CONCLUSIONS: SOCS-1 mRNA can be detected in PBMC, and it is down-regulated in <d>IPF</d> patients. The expression of SOCS-1 is associated with the severity of <d>IPF</d> patients' symptoms, so it might be the predictor of disease severity. SOCS-1 might play an important role in <d>IPF</d> by reducing the expression of the T helper type 2 Th2 cell-related cytokine IL-4.
24921217|a|RATIONALE: Wnt/b-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. OBJECTIVES: To determine whether the Wnt coreceptor <g>Lrp5</g> drives pulmonary fibrosis in mice and is predictive of disease severity in humans. METHODS: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor <g>Lrp5</g> in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of transforming growth factor TGF-b. We also analyzed gene expression in peripheral blood mononuclear cells PBMC from patients with <d>idiopathic pulmonary fibrosis</d> IPF. MEASUREMENTS AND MAIN RESULTS: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, <g>Lrp5</g> and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. <g>Lrp5</g> null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of b-catenin signaling by the small molecular inhibitor of b-catenin responsive transcription. Transplantation of <g>Lrp5</g> null bone marrow cells into wild-type mice did not limit fibrosis. Instead, <g>Lrp5</g> loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes. Consistent with a role of <g>Lrp5</g> in the activation of TGF-b, <g>Lrp5</g> null mice were not protected against lung fibrosis induced by TGF-b. CONCLUSIONS: We show that the Wnt coreceptor, <g>Lrp5</g>, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-b signaling can override a loss in <g>Lrp5</g> has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.
24921217|a|RATIONALE: Wnt/<g>b-catenin</g> signaling has been implicated in <d>lung fibrosis</d>, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. OBJECTIVES: To determine whether the Wnt coreceptor <g>Lrp5</g> drives pulmonary fibrosis in mice and is predictive of disease severity in humans. METHODS: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor <g>Lrp5</g> in models of <d>lung fibrosis</d> induced by bleomycin or an adenovirus encoding an active form of transforming growth factor TGF-b. We also analyzed gene expression in peripheral blood mononuclear cells PBMC from patients with <d>idiopathic pulmonary fibrosis</d> IPF. MEASUREMENTS AND MAIN RESULTS: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, <g>Lrp5</g> and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. <g>Lrp5</g> null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of <g>b-catenin</g> signaling by the small molecular inhibitor of <g>b-catenin</g> responsive transcription. Transplantation of <g>Lrp5</g> null bone marrow cells into wild-type mice did not limit fibrosis. Instead, <g>Lrp5</g> loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes. Consistent with a role of <g>Lrp5</g> in the activation of TGF-b, <g>Lrp5</g> null mice were not protected against <d>lung fibrosis</d> induced by TGF-b. CONCLUSIONS: We show that the Wnt coreceptor, <g>Lrp5</g>, is a genetic driver of <d>lung fibrosis</d> in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-b signaling can override a loss in <g>Lrp5</g> has implications for patient selection and timing of Wnt pathway inhibitors in <d>lung fibrosis</d>.
24921217|a|RATIONALE: Wnt/<g>b-catenin</g> signaling has been implicated in <d>lung fibrosis</d>, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. OBJECTIVES: To determine whether the Wnt coreceptor <g>Lrp5</g> drives <d>pulmonary fibrosis</d> in mice and is predictive of disease severity in humans. METHODS: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor <g>Lrp5</g> in models of <d>lung fibrosis</d> induced by bleomycin or an adenovirus encoding an active form of transforming growth factor TGF-b. We also analyzed gene expression in peripheral blood mononuclear cells PBMC from patients with <d>idiopathic <d>pulmonary fibrosis</d></d> IPF. MEASUREMENTS AND MAIN RESULTS: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, <g>Lrp5</g> and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. <g>Lrp5</g> null mice were protected against bleomycin-induced <d>pulmonary fibrosis</d>, an effect that was phenocopied by direct inhibition of <g>b-catenin</g> signaling by the small molecular inhibitor of <g>b-catenin</g> responsive transcription. Transplantation of <g>Lrp5</g> null bone marrow cells into wild-type mice did not limit fibrosis. Instead, <g>Lrp5</g> loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes. Consistent with a role of <g>Lrp5</g> in the activation of TGF-b, <g>Lrp5</g> null mice were not protected against <d>lung fibrosis</d> induced by TGF-b. CONCLUSIONS: We show that the Wnt coreceptor, <g>Lrp5</g>, is a genetic driver of <d>lung fibrosis</d> in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-b signaling can override a loss in <g>Lrp5</g> has implications for patient selection and timing of Wnt pathway inhibitors in <d>lung fibrosis</d>.
24921217|a|RATIONALE: Wnt/<g>b-catenin</g> signaling has been implicated in <d>lung fibrosis</d>, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. OBJECTIVES: To determine whether the Wnt coreceptor <g>Lrp5</g> drives <d>pulmonary fibrosis</d> in mice and is predictive of disease severity in humans. METHODS: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor <g>Lrp5</g> in models of <d>lung fibrosis</d> induced by bleomycin or an adenovirus encoding an active form of transforming growth factor TGF-b. We also analyzed gene expression in peripheral blood mononuclear cells PBMC from patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. MEASUREMENTS AND MAIN RESULTS: In patients with <d>IPF</d>, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, <g>Lrp5</g> and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with <d>IPF</d>. <g>Lrp5</g> null mice were protected against bleomycin-induced <d>pulmonary fibrosis</d>, an effect that was phenocopied by direct inhibition of <g>b-catenin</g> signaling by the small molecular inhibitor of <g>b-catenin</g> responsive transcription. Transplantation of <g>Lrp5</g> null bone marrow cells into wild-type mice did not limit fibrosis. Instead, <g>Lrp5</g> loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes. Consistent with a role of <g>Lrp5</g> in the activation of TGF-b, <g>Lrp5</g> null mice were not protected against <d>lung fibrosis</d> induced by TGF-b. CONCLUSIONS: We show that the Wnt coreceptor, <g>Lrp5</g>, is a genetic driver of <d>lung fibrosis</d> in mice and a marker of disease progression and severity in humans with <d>IPF</d>. Evidence that TGF-b signaling can override a loss in <g>Lrp5</g> has implications for patient selection and timing of Wnt pathway inhibitors in <d>lung fibrosis</d>.
24921217|a|RATIONALE: Wnt/<g>b-catenin</g> signaling has been implicated in <d>lung <d>fibrosis</d></d>, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. OBJECTIVES: To determine whether the Wnt coreceptor <g>Lrp5</g> drives <d>pulmonary <d>fibrosis</d></d> in mice and is predictive of disease severity in humans. METHODS: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor <g>Lrp5</g> in models of <d>lung <d>fibrosis</d></d> induced by bleomycin or an adenovirus encoding an active form of transforming growth factor TGF-b. We also analyzed gene expression in peripheral blood mononuclear cells PBMC from patients with <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d>. MEASUREMENTS AND MAIN RESULTS: In patients with <d>IPF</d>, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, <g>Lrp5</g> and 6, was independently associated with disease progression. <g>LRP5</g> was also associated with disease severity at presentation in an additional cohort of patients with <d>IPF</d>. <g>Lrp5</g> null mice were protected against bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, an effect that was phenocopied by direct inhibition of <g>b-catenin</g> signaling by the small molecular inhibitor of <g>b-catenin</g> responsive transcription. Transplantation of <g>Lrp5</g> null bone marrow cells into wild-type mice did not limit <d>fibrosis</d>. Instead, <g>Lrp5</g> loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes. Consistent with a role of <g>Lrp5</g> in the activation of TGF-b, <g>Lrp5</g> null mice were not protected against <d>lung <d>fibrosis</d></d> induced by TGF-b. CONCLUSIONS: We show that the Wnt coreceptor, <g>Lrp5</g>, is a genetic driver of <d>lung <d>fibrosis</d></d> in mice and a marker of disease progression and severity in humans with <d>IPF</d>. Evidence that TGF-b signaling can override a loss in <g>Lrp5</g> has implications for patient selection and timing of Wnt pathway inhibitors in <d>lung <d>fibrosis</d></d>.
24953558|a|Idiopathic <d>pulmonary fibrosis</d> IPF is the most common and fatal form of idiopathic interstitial pneumonia. MicroRNAs miRNAs, short, single-stranded RNAs that regulate protein expression in a post-transcriptional manner, have recently been demonstrated to contribute to IPF pathogenesis. We have previously identified WNT1-inducible signaling pathway protein 1 <g>WISP1</g> as a highly expressed pro-fibrotic mediator in IPF, but the underlying mechanisms resulting in increased <g>WISP1</g> expression, remain elusive. Here, we investigated whether <g>WISP1</g> is a target of miRNA regulation. We applied a novel supervised machine learning approach, which predicted miR-30a/d and miR-92a target sites in regions of the human <g>WISP1</g> 3'UTR preferentially bound by the miRNA ribonucleoprotein complex. Both miRNAs were decreased in IPF samples, whereas <g>WISP1</g> protein was increased. We demonstrated further that transforming growth factor <g>TGF-b1</g>-induced <g>WISP1</g> expression in primary lung fibroblasts in vitro and lung homogenates in vivo. Notably, miR-30a and miR-92a reversed <g>TGF-b1</g>-induced <g>WISP1</g> mRNA expression in lung fibroblasts. Moreover, miR-92a inhibition increased <g>WISP1</g> protein expression in lung fibroblasts. An inverse relationship for <g>WISP1</g> and miR-92a was found in a <g>TGF-b1</g> dependent lung fibrosis model in vivo. Finally, we found significantly increased <g>WISP1</g> expression in primary IPF fibroblasts, which negatively correlated with miR-92a level ex vivo. Altogether, our findings indicate a regulatory role of miR-92a for <g>WISP1</g> expression in <d>pulmonary fibrosis</d>.
24953558|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is the most common and fatal form of idiopathic interstitial pneumonia. MicroRNAs miRNAs, short, single-stranded RNAs that regulate protein expression in a post-transcriptional manner, have recently been demonstrated to contribute to <d>IPF</d> pathogenesis. We have previously identified WNT1-inducible signaling pathway protein 1 <g>WISP1</g> as a highly expressed pro-fibrotic mediator in <d>IPF</d>, but the underlying mechanisms resulting in increased <g>WISP1</g> expression, remain elusive. Here, we investigated whether <g>WISP1</g> is a target of miRNA regulation. We applied a novel supervised machine learning approach, which predicted miR-30a/d and miR-92a target sites in regions of the human <g>WISP1</g> 3'UTR preferentially bound by the miRNA ribonucleoprotein complex. Both miRNAs were decreased in <d>IPF</d> samples, whereas <g>WISP1</g> protein was increased. We demonstrated further that transforming growth factor <g>TGF-b1</g>-induced <g>WISP1</g> expression in primary lung fibroblasts in vitro and lung homogenates in vivo. Notably, miR-30a and miR-92a reversed <g>TGF-b1</g>-induced <g>WISP1</g> mRNA expression in lung fibroblasts. Moreover, miR-92a inhibition increased <g>WISP1</g> protein expression in lung fibroblasts. An inverse relationship for <g>WISP1</g> and miR-92a was found in a <g>TGF-b1</g> dependent lung fibrosis model in vivo. Finally, we found significantly increased <g>WISP1</g> expression in primary <d>IPF</d> fibroblasts, which negatively correlated with miR-92a level ex vivo. Altogether, our findings indicate a regulatory role of miR-92a for <g>WISP1</g> expression in <d>pulmonary fibrosis</d>.
24953558|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is the most common and fatal form of <d>idiopathic interstitial pneumonia</d>. MicroRNAs miRNAs, short, single-stranded RNAs that regulate protein expression in a post-transcriptional manner, have recently been demonstrated to contribute to <d>IPF</d> pathogenesis. We have previously identified WNT1-inducible signaling pathway protein 1 <g>WISP1</g> as a highly expressed pro-fibrotic mediator in <d>IPF</d>, but the underlying mechanisms resulting in increased <g>WISP1</g> expression, remain elusive. Here, we investigated whether <g>WISP1</g> is a target of miRNA regulation. We applied a novel supervised machine learning approach, which predicted miR-30a/d and miR-92a target sites in regions of the human <g>WISP1</g> 3'UTR preferentially bound by the miRNA ribonucleoprotein complex. Both miRNAs were decreased in <d>IPF</d> samples, whereas <g>WISP1</g> protein was increased. We demonstrated further that transforming growth factor <g>TGF-b1</g>-induced <g>WISP1</g> expression in primary lung fibroblasts in vitro and lung homogenates in vivo. Notably, miR-30a and miR-92a reversed <g>TGF-b1</g>-induced <g>WISP1</g> mRNA expression in lung fibroblasts. Moreover, miR-92a inhibition increased <g>WISP1</g> protein expression in lung fibroblasts. An inverse relationship for <g>WISP1</g> and miR-92a was found in a <g>TGF-b1</g> dependent lung fibrosis model in vivo. Finally, we found significantly increased <g>WISP1</g> expression in primary <d>IPF</d> fibroblasts, which negatively correlated with miR-92a level ex vivo. Altogether, our findings indicate a regulatory role of miR-92a for <g>WISP1</g> expression in <d>pulmonary fibrosis</d>.
24953558|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is the most common and fatal form of <d>idiopathic interstitial pneumonia</d>. MicroRNAs miRNAs, short, single-stranded RNAs that regulate protein expression in a post-transcriptional manner, have recently been demonstrated to contribute to <d>IPF</d> pathogenesis. We have previously identified <g>WNT1-inducible signaling pathway protein 1</g> <g>WISP1</g> as a highly expressed pro-fibrotic mediator in <d>IPF</d>, but the underlying mechanisms resulting in increased <g>WISP1</g> expression, remain elusive. Here, we investigated whether <g>WISP1</g> is a target of miRNA regulation. We applied a novel supervised machine learning approach, which predicted <g>miR-30a</g>/d and miR-92a target sites in regions of the human <g>WISP1</g> 3'UTR preferentially bound by the miRNA ribonucleoprotein complex. Both miRNAs were decreased in <d>IPF</d> samples, whereas <g>WISP1</g> protein was increased. We demonstrated further that transforming growth factor <g>TGF-b1</g>-induced <g>WISP1</g> expression in primary lung fibroblasts in vitro and lung homogenates in vivo. Notably, <g>miR-30a</g> and miR-92a reversed <g>TGF-b1</g>-induced <g>WISP1</g> mRNA expression in lung fibroblasts. Moreover, miR-92a inhibition increased <g>WISP1</g> protein expression in lung fibroblasts. An inverse relationship for <g>WISP1</g> and miR-92a was found in a <g>TGF-b1</g> dependent lung <d>fibrosis</d> model in vivo. Finally, we found significantly increased <g>WISP1</g> expression in primary <d>IPF</d> fibroblasts, which negatively correlated with miR-92a level ex vivo. Altogether, our findings indicate a regulatory role of miR-92a for <g>WISP1</g> expression in <d>pulmonary <d>fibrosis</d></d>.
24958208|a|The epithelial complement inhibitory proteins CIPs cluster of differentiation 46 and 55 CD46 and CD55 regulate circulating immune complex-mediated complement activation in idiopathic pulmonary fibrosis IPF. Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor b1 <g>TGF-b1</g> and down-regulates CIPs. In the current study, we examined the mechanistic role of <g>TGF-b1</g> in complement activation-mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a C3a and C5a, locally and systemically. In normal primary human small airway epithelial cells SAECs treated with <g>TGF-b1</g> 10 ng/ml, C3a, or C5a 100 nM, we observed loss of CIPs and increased polyADP-ribose polymerase PARP activation [also observed with RNA interference RNAi of CD46/CD55]. <g>TGF-b1</g>-mediated loss of CIPs and Snail induction [SNAI1; a transcriptional repressor of E-cadherin E-CAD] was blocked by inhibiting mitogen-activated protein kinase p38MAPK; SB203580 and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of CIPs was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 negative regulator of TGF-b, and whereas <g>TGF-b1</g> induced C3a/C5a receptor C3aR/C5aR expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of CIPs. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of <g>TGF-b1</g>-induced loss of CIPs leading to complement activation that down-regulates CIPs and induces <g>TGF-b1</g> expression.-Gu, H., Mickler, E. A., Cummings, O. W, Sandusky, G. E., Weber, D. J., Gracon, A., Woodruff, T., Wilkes, D. S., Vittal, R. Crosstalk between <g>TGF-b1</g> and complement activation augments epithelial <d>injury in pulmonary fibrosis</d>.
24958208|a|The epithelial <d>complement inhibitory proteins</d> CIPs cluster of differentiation 46 and 55 CD46 and CD55 regulate circulating immune complex-mediated complement activation in idiopathic pulmonary fibrosis IPF. Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor b1 <g>TGF-b1</g> and down-regulates CIPs. In the current study, we examined the mechanistic role of <g>TGF-b1</g> in complement activation-mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a C3a and C5a, locally and systemically. In normal primary human small airway epithelial cells SAECs treated with <g>TGF-b1</g> 10 ng/ml, C3a, or C5a 100 nM, we observed loss of CIPs and increased polyADP-ribose polymerase PARP activation [also observed with RNA interference RNAi of CD46/CD55]. <g>TGF-b1</g>-mediated loss of CIPs and Snail induction [SNAI1; a transcriptional repressor of E-cadherin E-CAD] was blocked by inhibiting mitogen-activated protein kinase p38MAPK; SB203580 and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of CIPs was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 negative regulator of TGF-b, and whereas <g>TGF-b1</g> induced C3a/C5a receptor C3aR/C5aR expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of CIPs. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of <g>TGF-b1</g>-induced loss of CIPs leading to complement activation that down-regulates CIPs and induces <g>TGF-b1</g> expression.-Gu, H., Mickler, E. A., Cummings, O. W, Sandusky, G. E., Weber, D. J., Gracon, A., Woodruff, T., Wilkes, D. S., Vittal, R. Crosstalk between <g>TGF-b1</g> and complement activation augments epithelial <d>injury in pulmonary fibrosis</d>.
24958208|a|The epithelial <d>complement inhibitory proteins</d> <d>CIPs</d> cluster of differentiation 46 and 55 CD46 and CD55 regulate circulating immune complex-mediated complement activation in idiopathic pulmonary fibrosis IPF. Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor b1 <g>TGF-b1</g> and down-regulates <d>CIPs</d>. In the current study, we examined the mechanistic role of <g>TGF-b1</g> in complement activation-mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a C3a and C5a, locally and systemically. In normal primary human small airway epithelial cells SAECs treated with <g>TGF-b1</g> 10 ng/ml, C3a, or C5a 100 nM, we observed loss of <d>CIPs</d> and increased polyADP-ribose polymerase PARP activation [also observed with RNA interference RNAi of CD46/CD55]. <g>TGF-b1</g>-mediated loss of <d>CIPs</d> and Snail induction [SNAI1; a transcriptional repressor of E-cadherin E-CAD] was blocked by inhibiting mitogen-activated protein kinase p38MAPK; SB203580 and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of <d>CIPs</d> was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 negative regulator of TGF-b, and whereas <g>TGF-b1</g> induced C3a/C5a receptor C3aR/C5aR expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of <d>CIPs</d>. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of <g>TGF-b1</g>-induced loss of <d>CIPs</d> leading to complement activation that down-regulates <d>CIPs</d> and induces <g>TGF-b1</g> expression.-Gu, H., Mickler, E. A., Cummings, O. W, Sandusky, G. E., Weber, D. J., Gracon, A., Woodruff, T., Wilkes, D. S., Vittal, R. Crosstalk between <g>TGF-b1</g> and complement activation augments epithelial <d>injury in pulmonary fibrosis</d>.
24958208|a|The epithelial <d>complement inhibitory proteins</d> <d>CIPs</d> cluster of differentiation 46 and 55 <g>CD46</g> and <g>CD55</g> regulate circulating immune complex-mediated complement activation in <d>idiopathic pulmonary fibrosis</d> IPF. Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor b1 <g>TGF-b1</g> and down-regulates <d>CIPs</d>. In the current study, we examined the mechanistic role of <g>TGF-b1</g> in complement activation-mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a C3a and C5a, locally and systemically. In normal primary human small airway epithelial cells SAECs treated with <g>TGF-b1</g> 10 ng/ml, C3a, or C5a 100 nM, we observed loss of <d>CIPs</d> and increased polyADP-ribose polymerase PARP activation [also observed with RNA interference RNAi of <g>CD46</g>/<g>CD55</g>]. <g>TGF-b1</g>-mediated loss of <d>CIPs</d> and Snail induction [SNAI1; a transcriptional repressor of E-cadherin E-CAD] was blocked by inhibiting mitogen-activated protein kinase p38MAPK; SB203580 and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of <d>CIPs</d> was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 negative regulator of TGF-b, and whereas <g>TGF-b1</g> induced C3a/C5a receptor C3aR/C5aR expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of <d>CIPs</d>. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of <g>TGF-b1</g>-induced loss of <d>CIPs</d> leading to complement activation that down-regulates <d>CIPs</d> and induces <g>TGF-b1</g> expression.-Gu, H., Mickler, E. A., Cummings, O. W, Sandusky, G. E., Weber, D. J., Gracon, A., Woodruff, T., Wilkes, D. S., Vittal, R. Crosstalk between <g>TGF-b1</g> and complement activation augments epithelial <d>injury in pulmonary fibrosis</d>.
24958208|a|The epithelial <d>complement inhibitory proteins</d> <d>CIPs</d> cluster of differentiation 46 and 55 <g>CD46</g> and <g>CD55</g> regulate circulating immune complex-mediated complement activation in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor b1 <g>TGF-b1</g> and down-regulates <d>CIPs</d>. In the current study, we examined the mechanistic role of <g>TGF-b1</g> in complement activation-mediated airway epithelial injury in <d>IPF</d> pathogenesis. We observed lower epithelial CIP expression in <d>IPF</d> lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a C3a and C5a, locally and systemically. In normal primary human small airway epithelial cells SAECs treated with <g>TGF-b1</g> 10 ng/ml, C3a, or C5a 100 nM, we observed loss of <d>CIPs</d> and increased polyADP-ribose polymerase PARP activation [also observed with RNA interference RNAi of <g>CD46</g>/<g>CD55</g>]. <g>TGF-b1</g>-mediated loss of <d>CIPs</d> and Snail induction [SNAI1; a transcriptional repressor of E-cadherin E-CAD] was blocked by inhibiting mitogen-activated protein kinase p38MAPK; SB203580 and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of <d>CIPs</d> was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 negative regulator of TGF-b, and whereas <g>TGF-b1</g> induced C3a/C5a receptor C3aR/C5aR expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of <d>CIPs</d>. Taken together, our results suggest that epithelial injury in <d>IPF</d> can be collectively amplified as a result of <g>TGF-b1</g>-induced loss of <d>CIPs</d> leading to complement activation that down-regulates <d>CIPs</d> and induces <g>TGF-b1</g> expression.-Gu, H., Mickler, E. A., Cummings, O. W, Sandusky, G. E., Weber, D. J., Gracon, A., Woodruff, T., Wilkes, D. S., Vittal, R. Crosstalk between <g>TGF-b1</g> and complement activation augments epithelial <d>injury in pulmonary fibrosis</d>.
24958208|a|The epithelial <d>complement inhibitory proteins</d> <d>CIPs</d> cluster of differentiation 46 and 55 <g>CD46</g> and <g>CD55</g> regulate circulating immune complex-mediated complement activation in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Our previous studies demonstrated that <g>IL-17A</g> mediates <d>epithelial injury</d> via transforming growth factor b1 <g>TGF-b1</g> and down-regulates <d>CIPs</d>. In the current study, we examined the mechanistic role of <g>TGF-b1</g> in complement activation-mediated airway <d>epithelial injury</d> in <d>IPF</d> pathogenesis. We observed lower epithelial CIP expression in <d>IPF</d> lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a C3a and C5a, locally and systemically. In normal primary human small airway epithelial cells SAECs treated with <g>TGF-b1</g> 10 ng/ml, C3a, or C5a 100 nM, we observed loss of <d>CIPs</d> and increased polyADP-ribose polymerase PARP activation [also observed with RNA interference RNAi of <g>CD46</g>/<g>CD55</g>]. <g>TGF-b1</g>-mediated loss of <d>CIPs</d> and Snail induction [SNAI1; a transcriptional repressor of E-cadherin E-CAD] was blocked by inhibiting mitogen-activated protein kinase p38MAPK; SB203580 and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of <d>CIPs</d> was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 negative regulator of TGF-b, and whereas <g>TGF-b1</g> induced C3a/C5a receptor C3aR/C5aR expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of <d>CIPs</d>. Taken together, our results suggest that <d>epithelial injury</d> in <d>IPF</d> can be collectively amplified as a result of <g>TGF-b1</g>-induced loss of <d>CIPs</d> leading to complement activation that down-regulates <d>CIPs</d> and induces <g>TGF-b1</g> expression.-Gu, H., Mickler, E. A., Cummings, O. W, Sandusky, G. E., Weber, D. J., Gracon, A., Woodruff, T., Wilkes, D. S., Vittal, R. Crosstalk between <g>TGF-b1</g> and complement activation augments epithelial <d>injury in pulmonary fibrosis</d>.
25032514|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a devastating disease characterized by myofibroblasts proliferation and extracellular-matrix accumulation. IPF typically starts in subpleural lung regions and recent studies suggest that pleural mesothelial cells play a role in the onset of the disease. The transition of mesothelial cells into myofibroblasts [Mesothelio-Mesenchymal Transition MMT] is induced by the profibrotic cytokine transforming growth factor TGF-b1 and is thought to play a role in the development and progression of IPF. The Smad-dependent pathway is the main TGF-b1 pathway involved in fibrosis. aB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperon and is known to play a role in cell cytoskeleton architecture. We recently showed that the lack of aB-crystallin hampered TGF-b1 signaling by favoring Smad4 monoubiquitination and nuclear export. We demonstrate here for the first time that aB-crystallin is strongly overexpressed in the pleura of fibrotic lungs from IPF patients and in rodent models of pleural/subpleural fibrosis. aB-crystallin-deficient mice are protected from pleural/subpleural fibrosis induced by the transient adenoviral-mediated overexpression of TGF-b1 or the intrapleural injection of bleomycin combined with carbon particles. We show that aB-crystallin inhibition hampers Smad4 nuclear localization in pleural mesothelial cells and the consequent characteristics of MMT. aB-crystallin-deficient mesothelial cells fail to acquire the properties of myofibroblasts thus limiting their migration in vivo and the progression of fibrosis in the lung parenchyma. In conclusion, our work demonstrates that aB-crystallin may be a key target for the development of specific drugs in the treatment of IPF.
25032514|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating disease characterized by myofibroblasts proliferation and extracellular-matrix accumulation. <d>IPF</d> typically starts in subpleural lung regions and recent studies suggest that pleural mesothelial cells play a role in the onset of the disease. The transition of mesothelial cells into myofibroblasts [Mesothelio-Mesenchymal Transition MMT] is induced by the profibrotic cytokine transforming growth factor TGF-b1 and is thought to play a role in the development and progression of <d>IPF</d>. The Smad-dependent pathway is the main TGF-b1 pathway involved in fibrosis. aB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperon and is known to play a role in cell cytoskeleton architecture. We recently showed that the lack of aB-crystallin hampered TGF-b1 signaling by favoring Smad4 monoubiquitination and nuclear export. We demonstrate here for the first time that aB-crystallin is strongly overexpressed in the pleura of fibrotic lungs from <d>IPF</d> patients and in rodent models of pleural/subpleural fibrosis. aB-crystallin-deficient mice are protected from pleural/subpleural fibrosis induced by the transient adenoviral-mediated overexpression of TGF-b1 or the intrapleural injection of bleomycin combined with carbon particles. We show that aB-crystallin inhibition hampers Smad4 nuclear localization in pleural mesothelial cells and the consequent characteristics of MMT. aB-crystallin-deficient mesothelial cells fail to acquire the properties of myofibroblasts thus limiting their migration in vivo and the progression of fibrosis in the lung parenchyma. In conclusion, our work demonstrates that aB-crystallin may be a key target for the development of specific drugs in the treatment of <d>IPF</d>.
25032514|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating disease characterized by myofibroblasts proliferation and extracellular-matrix accumulation. <d>IPF</d> typically starts in subpleural lung regions and recent studies suggest that pleural mesothelial cells play a role in the onset of the disease. The transition of mesothelial cells into myofibroblasts [Mesothelio-Mesenchymal Transition MMT] is induced by the profibrotic cytokine transforming growth factor <g>TGF-b1</g> and is thought to play a role in the development and progression of <d>IPF</d>. The Smad-dependent pathway is the main <g>TGF-b1</g> pathway involved in <d>fibrosis</d>. aB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperon and is known to play a role in cell cytoskeleton architecture. We recently showed that the lack of aB-crystallin hampered <g>TGF-b1</g> signaling by favoring Smad4 monoubiquitination and nuclear export. We demonstrate here for the first time that aB-crystallin is strongly overexpressed in the pleura of fibrotic lungs from <d>IPF</d> patients and in rodent models of pleural/subpleural <d>fibrosis</d>. aB-crystallin-deficient mice are protected from pleural/subpleural <d>fibrosis</d> induced by the transient adenoviral-mediated overexpression of <g>TGF-b1</g> or the intrapleural injection of bleomycin combined with carbon particles. We show that aB-crystallin inhibition hampers Smad4 nuclear localization in pleural mesothelial cells and the consequent characteristics of MMT. aB-crystallin-deficient mesothelial cells fail to acquire the properties of myofibroblasts thus limiting their migration in vivo and the progression of <d>fibrosis</d> in the lung parenchyma. In conclusion, our work demonstrates that aB-crystallin may be a key target for the development of specific drugs in the treatment of <d>IPF</d>.
25032514|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating disease characterized by myofibroblasts proliferation and extracellular-matrix accumulation. <d>IPF</d> typically starts in subpleural lung regions and recent studies suggest that pleural mesothelial cells play a role in the onset of the disease. The transition of mesothelial cells into myofibroblasts [Mesothelio-Mesenchymal Transition MMT] is induced by the profibrotic cytokine transforming growth factor <g>TGF-b1</g> and is thought to play a role in the development and progression of <d>IPF</d>. The Smad-dependent pathway is the main <g>TGF-b1</g> pathway involved in <d>fibrosis</d>. aB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperon and is known to play a role in cell cytoskeleton architecture. We recently showed that the lack of aB-crystallin hampered <g>TGF-b1</g> signaling by favoring <g>Smad4</g> monoubiquitination and nuclear export. We demonstrate here for the first time that aB-crystallin is strongly overexpressed in the pleura of fibrotic lungs from <d>IPF</d> patients and in rodent models of pleural/subpleural <d>fibrosis</d>. <d>aB-crystallin-deficient</d> mice are protected from pleural/subpleural <d>fibrosis</d> induced by the transient adenoviral-mediated overexpression of <g>TGF-b1</g> or the intrapleural injection of bleomycin combined with carbon particles. We show that aB-crystallin inhibition hampers <g>Smad4</g> nuclear localization in pleural mesothelial cells and the consequent characteristics of MMT. <d>aB-crystallin-deficient</d> mesothelial cells fail to acquire the properties of myofibroblasts thus limiting their migration in vivo and the progression of <d>fibrosis</d> in the lung parenchyma. In conclusion, our work demonstrates that aB-crystallin may be a key target for the development of specific drugs in the treatment of <d>IPF</d>.
25064447|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a progressive parenchymal lung disease of unknown aetiology and poor prognosis, characterized by altered tissue repair and fibrosis. The extracellular matrix ECM is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in IPF lungs. METHODS: ECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary fibrosis IPF, hypersensitivity pneumonitis HP, categorized as chronic cHP and subacute saHP, and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate <g>tenascin-C</g> TNC synthesis. RESULTS: A total of 20 ECM proteins were upregulated and 6 proteins downregulated in IPF. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs IPF and cHP compared to saHP. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in cHP lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from IPF patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and a-sma was induced by TGF-b1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased a-sma mRNA. CONCLUSIONS: The difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung fibrosis. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing.
25064447|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive parenchymal lung disease of unknown aetiology and poor prognosis, characterized by altered tissue repair and fibrosis. The extracellular matrix ECM is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in <d>IPF</d> lungs. METHODS: ECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary fibrosis <d>IPF</d>, hypersensitivity pneumonitis HP, categorized as chronic cHP and subacute saHP, and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate <g>tenascin-C</g> TNC synthesis. RESULTS: A total of 20 ECM proteins were upregulated and 6 proteins downregulated in <d>IPF</d>. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs <d>IPF</d> and cHP compared to saHP. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in cHP lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from <d>IPF</d> patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and a-sma was induced by TGF-b1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased a-sma mRNA. CONCLUSIONS: The difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung fibrosis. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing.
25064447|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>parenchymal lung disease</d> of unknown aetiology and poor prognosis, characterized by altered tissue repair and fibrosis. The extracellular matrix ECM is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in <d>IPF</d> lungs. METHODS: ECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary fibrosis <d>IPF</d>, hypersensitivity pneumonitis HP, categorized as chronic cHP and subacute saHP, and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate <g>tenascin-C</g> TNC synthesis. RESULTS: A total of 20 ECM proteins were upregulated and 6 proteins downregulated in <d>IPF</d>. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs <d>IPF</d> and cHP compared to saHP. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in cHP lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from <d>IPF</d> patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and a-sma was induced by TGF-b1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased a-sma mRNA. CONCLUSIONS: The difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung fibrosis. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing.
25064447|a|BACKGROUND: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive <d>parenchymal lung disease</d> of unknown aetiology and poor prognosis, characterized by altered tissue repair and <d>fibrosis</d>. The extracellular matrix ECM is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in <d>IPF</d> lungs. METHODS: ECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, hypersensitivity pneumonitis HP, categorized as chronic cHP and subacute saHP, and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate <g>tenascin-C</g> TNC synthesis. RESULTS: A total of 20 ECM proteins were upregulated and 6 proteins downregulated in <d>IPF</d>. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs <d>IPF</d> and cHP compared to saHP. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in cHP lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from <d>IPF</d> patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and a-sma was induced by TGF-b1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased a-sma mRNA. CONCLUSIONS: The difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung <d>fibrosis</d>. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing.
25064447|a|BACKGROUND: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive <d>parenchymal lung disease</d> of unknown aetiology and poor prognosis, characterized by altered tissue repair and <d>fibrosis</d>. The extracellular matrix ECM is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in <d>IPF</d> lungs. METHODS: ECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, <d>hypersensitivity pneumonitis</d> HP, categorized as chronic cHP and subacute saHP, and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate <g>tenascin-C</g> TNC synthesis. RESULTS: A total of 20 ECM proteins were upregulated and 6 proteins downregulated in <d>IPF</d>. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs <d>IPF</d> and cHP compared to saHP. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in cHP lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from <d>IPF</d> patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and a-sma was induced by TGF-b1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased a-sma mRNA. CONCLUSIONS: The difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung <d>fibrosis</d>. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing.
25064447|a|BACKGROUND: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive <d>parenchymal lung disease</d> of unknown aetiology and poor prognosis, characterized by altered tissue repair and <d>fibrosis</d>. The extracellular matrix ECM is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in <d>IPF</d> lungs. METHODS: ECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, <d>hypersensitivity pneumonitis</d> <d>HP</d>, categorized as chronic c<d>HP</d> and subacute sa<d>HP</d>, and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate <g>tenascin-C</g> TNC synthesis. RESULTS: A total of 20 ECM proteins were upregulated and 6 proteins downregulated in <d>IPF</d>. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs <d>IPF</d> and c<d>HP</d> compared to sa<d>HP</d>. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in c<d>HP</d> lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from <d>IPF</d> patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and a-sma was induced by TGF-b1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased a-sma mRNA. CONCLUSIONS: The difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung <d>fibrosis</d>. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing.
25064447|a|BACKGROUND: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive <d>parenchymal lung disease</d> of unknown aetiology and poor prognosis, characterized by altered tissue repair and <d>fibrosis</d>. The extracellular matrix ECM is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in <d>IPF</d> lungs. METHODS: ECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, <d>hypersensitivity pneumonitis</d> <d>HP</d>, categorized as chronic c<d>HP</d> and subacute sa<d>HP</d>, and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate <g>tenascin-C</g> <g>TNC</g> synthesis. RESULTS: A total of 20 ECM proteins were upregulated and 6 proteins downregulated in <d>IPF</d>. <g>TNC</g> was almost undetected in normal lungs and significantly upregulated in fibrotic lungs <d>IPF</d> and c<d>HP</d> compared to sa<d>HP</d>. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. <g>TNC</g> levels were correlated with fibroblastic foci content in c<d>HP</d> lungs. Versican and fibronectin glycoproteins were associated with <g>TNC</g>, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from <d>IPF</d> patients constitutively synthesized higher levels of <g>TNC</g> than normal fibroblasts. <g>TNC</g> and a-sma was induced by TGF-b1 in both fibrotic and normal fibroblasts. <g>TNC</g> treatment of normal and fibrotic fibroblasts induced a non-significant increased a-sma mRNA. CONCLUSIONS: The difference in ECM glycoprotein content in <d>interstitial lung diseases</d> could contribute to the development of lung <d>fibrosis</d>. The increase of <g>TNC</g> in interstitial areas of fibrotic activity could play a key role in the altered wound healing.
25111852|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive lung disease with high mortality and poor prognosis. Previous studies confirmed that NF-kB plays a critical role in the pathogenesis of <d>pulmonary fibrosis</d> and glucagon like peptide-1 GLP-1 has a property of anti-inflammation by inactivation of NF-kB. Furthermore, the GLP-1 receptor was detected in the lung tissues. Our aim was to investigate the potential value and mechanisms of GLP-1 on BLM-induced <d>pulmonary fibrosis</d> in mice. Mice with BLM-induced <d>pulmonary fibrosis</d> were treated with or without GLP-1 administration. 28 days after BLM infusion, the number of total cells, macrophages, neutrophils, lymphocytes, and the content of TGF-b1 in BALF were measured. Hematoxylin-eosin HE staining and Masson's trichrome MT staining were performed. The Ashcroft score and hydroxyproline content were analyzed. RT-qPCR and western blot were used to evaluate the expression of a-SMA and VCAM-1. The phosphorylation of NF-kB p65 was also assessed by western blot. DNA binding of NF-kB p65 was measured through TransAM p65 transcription factor ELISA kit. GLP-1 reduced inflammatory cell infiltration and the content of TGF-b1 in BLAF in mice with BLM injection. The Ashcroft score and hydroxyproline content were decreased by GLP-1 administration. Meanwhile, BLM-induced overexpression of a-SMA and VCAM-1 were blocked by GLP-1 treatment in mice. GLP-1 also reduced the ratio of phosphor-NF-kB p65/total-NF-kB p65 and NF-kB p65 DNA binding activity in BLM-induced <d>pulmonary fibrosis</d> in mice. Our data found that BLM-induced lung inflammation and <d>pulmonary fibrosis</d> were significantly alleviated by GLP-1 treatment in mice, possibly through inactivation of NF-kB.
25111852|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive lung disease with high mortality and poor prognosis. Previous studies confirmed that NF-kB plays a critical role in the pathogenesis of <d>pulmonary fibrosis</d> and glucagon like peptide-1 GLP-1 has a property of anti-inflammation by inactivation of NF-kB. Furthermore, the GLP-1 receptor was detected in the lung tissues. Our aim was to investigate the potential value and mechanisms of GLP-1 on BLM-induced <d>pulmonary fibrosis</d> in mice. Mice with BLM-induced <d>pulmonary fibrosis</d> were treated with or without GLP-1 administration. 28 days after BLM infusion, the number of total cells, macrophages, neutrophils, lymphocytes, and the content of TGF-b1 in BALF were measured. Hematoxylin-eosin HE staining and Masson's trichrome MT staining were performed. The Ashcroft score and hydroxyproline content were analyzed. RT-qPCR and western blot were used to evaluate the expression of a-SMA and VCAM-1. The phosphorylation of NF-kB p65 was also assessed by western blot. DNA binding of NF-kB p65 was measured through TransAM p65 transcription factor ELISA kit. GLP-1 reduced inflammatory cell infiltration and the content of TGF-b1 in BLAF in mice with BLM injection. The Ashcroft score and hydroxyproline content were decreased by GLP-1 administration. Meanwhile, BLM-induced overexpression of a-SMA and VCAM-1 were blocked by GLP-1 treatment in mice. GLP-1 also reduced the ratio of phosphor-NF-kB p65/total-NF-kB p65 and NF-kB p65 DNA binding activity in BLM-induced <d>pulmonary fibrosis</d> in mice. Our data found that BLM-induced lung inflammation and <d>pulmonary fibrosis</d> were significantly alleviated by GLP-1 treatment in mice, possibly through inactivation of NF-kB.
25111852|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>lung disease</d> with high mortality and poor prognosis. Previous studies confirmed that NF-kB plays a critical role in the pathogenesis of <d>pulmonary fibrosis</d> and glucagon like peptide-1 GLP-1 has a property of anti-inflammation by inactivation of NF-kB. Furthermore, the GLP-1 receptor was detected in the lung tissues. Our aim was to investigate the potential value and mechanisms of GLP-1 on BLM-induced <d>pulmonary fibrosis</d> in mice. Mice with BLM-induced <d>pulmonary fibrosis</d> were treated with or without GLP-1 administration. 28 days after BLM infusion, the number of total cells, macrophages, neutrophils, lymphocytes, and the content of TGF-b1 in BALF were measured. Hematoxylin-eosin HE staining and Masson's trichrome MT staining were performed. The Ashcroft score and hydroxyproline content were analyzed. RT-qPCR and western blot were used to evaluate the expression of a-SMA and VCAM-1. The phosphorylation of NF-kB p65 was also assessed by western blot. DNA binding of NF-kB p65 was measured through TransAM p65 transcription factor ELISA kit. GLP-1 reduced inflammatory cell infiltration and the content of TGF-b1 in BLAF in mice with BLM injection. The Ashcroft score and hydroxyproline content were decreased by GLP-1 administration. Meanwhile, BLM-induced overexpression of a-SMA and VCAM-1 were blocked by GLP-1 treatment in mice. GLP-1 also reduced the ratio of phosphor-NF-kB p65/total-NF-kB p65 and NF-kB p65 DNA binding activity in BLM-induced <d>pulmonary fibrosis</d> in mice. Our data found that BLM-induced lung inflammation and <d>pulmonary fibrosis</d> were significantly alleviated by GLP-1 treatment in mice, possibly through inactivation of NF-kB.
25111852|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>lung disease</d> with high mortality and poor prognosis. Previous studies confirmed that NF-kB plays a critical role in the pathogenesis of <d>pulmonary fibrosis</d> and <g>glucagon like peptide-1</g> <g>GLP-1</g> has a property of anti-<d>inflammation</d> by inactivation of NF-kB. Furthermore, the <g>GLP-1</g> receptor was detected in the lung tissues. Our aim was to investigate the potential value and mechanisms of <g>GLP-1</g> on BLM-induced <d>pulmonary fibrosis</d> in mice. Mice with BLM-induced <d>pulmonary fibrosis</d> were treated with or without <g>GLP-1</g> administration. 28 days after BLM infusion, the number of total cells, macrophages, neutrophils, lymphocytes, and the content of TGF-b1 in BALF were measured. Hematoxylin-eosin HE staining and Masson's trichrome MT staining were performed. The Ashcroft score and hydroxyproline content were analyzed. RT-qPCR and western blot were used to evaluate the expression of a-SMA and VCAM-1. The phosphorylation of NF-kB p65 was also assessed by western blot. DNA binding of NF-kB p65 was measured through TransAM p65 transcription factor ELISA kit. <g>GLP-1</g> reduced inflammatory cell infiltration and the content of TGF-b1 in BLAF in mice with BLM injection. The Ashcroft score and hydroxyproline content were decreased by <g>GLP-1</g> administration. Meanwhile, BLM-induced overexpression of a-SMA and VCAM-1 were blocked by <g>GLP-1</g> treatment in mice. <g>GLP-1</g> also reduced the ratio of phosphor-NF-kB p65/total-NF-kB p65 and NF-kB p65 DNA binding activity in BLM-induced <d>pulmonary fibrosis</d> in mice. Our data found that BLM-induced lung <d>inflammation</d> and <d>pulmonary fibrosis</d> were significantly alleviated by <g>GLP-1</g> treatment in mice, possibly through inactivation of NF-kB.
25162417|a|A characteristic of dysregulated wound healing in IPF is fibroblastic-mediated damage to lung epithelial cells within fibroblastic foci. In these foci, TGF-b and other growth factors activate fibroblasts that secrete growth factors and matrix regulatory proteins, which activate a fibrotic cascade. Our studies and those of others have revealed that Akt is activated in IPF fibroblasts and it mediates the activation by TGF-b of pro-fibrotic pathways. Recent studies show that <g>mTORC2</g>, a component of the mTOR pathway, mediates the activation of Akt. In this study we set out to determine if blocking <g>mTORC2</g> with MLN0128, an active site dual mTOR inhibitor, which blocks both mTORC1 and <g>mTORC2</g>, inhibits <d>lung fibrosis</d>. We examined the effect of MLN0128 on TGF-b-mediated induction of stromal proteins in IPF lung fibroblasts; also, we looked at its effect on TGF-b-mediated epithelial injury using a Transwell co-culture system. Additionally, we assessed MLN0128 in the murine bleomycin lung model. We found that TGF-b induces the Rictor component of <g>mTORC2</g> in IPF lung fibroblasts, which led to Akt activation, and that MLN0128 exhibited potent anti-fibrotic activity in vitro and in vivo. Also, we observed that Rictor induction is Akt-mediated. MLN0128 displays multiple anti-fibrotic and lung epithelial-protective activities; it 1 inhibited the expression of pro-fibrotic matrix-regulatory proteins in TGF-b-stimulated IPF fibroblasts; 2 inhibited fibrosis in a murine bleomycin lung model; and 3 protected lung epithelial cells from injury caused by TGF-b-stimulated IPF fibroblasts. Our findings support a role for <g>mTORC2</g> in the pathogenesis of <d>lung fibrosis</d> and for the potential of active site mTOR inhibitors in the treatment of IPF and other fibrotic lung diseases.
25162417|a|A characteristic of dysregulated wound healing in <d>IPF</d> is fibroblastic-mediated damage to lung epithelial cells within fibroblastic foci. In these foci, TGF-b and other growth factors activate fibroblasts that secrete growth factors and matrix regulatory proteins, which activate a fibrotic cascade. Our studies and those of others have revealed that Akt is activated in <d>IPF</d> fibroblasts and it mediates the activation by TGF-b of pro-fibrotic pathways. Recent studies show that <g>mTORC2</g>, a component of the mTOR pathway, mediates the activation of Akt. In this study we set out to determine if blocking <g>mTORC2</g> with MLN0128, an active site dual mTOR inhibitor, which blocks both mTORC1 and <g>mTORC2</g>, inhibits <d>lung fibrosis</d>. We examined the effect of MLN0128 on TGF-b-mediated induction of stromal proteins in <d>IPF</d> lung fibroblasts; also, we looked at its effect on TGF-b-mediated epithelial injury using a Transwell co-culture system. Additionally, we assessed MLN0128 in the murine bleomycin lung model. We found that TGF-b induces the Rictor component of <g>mTORC2</g> in <d>IPF</d> lung fibroblasts, which led to Akt activation, and that MLN0128 exhibited potent anti-fibrotic activity in vitro and in vivo. Also, we observed that Rictor induction is Akt-mediated. MLN0128 displays multiple anti-fibrotic and lung epithelial-protective activities; it 1 inhibited the expression of pro-fibrotic matrix-regulatory proteins in TGF-b-stimulated <d>IPF</d> fibroblasts; 2 inhibited fibrosis in a murine bleomycin lung model; and 3 protected lung epithelial cells from injury caused by TGF-b-stimulated <d>IPF</d> fibroblasts. Our findings support a role for <g>mTORC2</g> in the pathogenesis of <d>lung fibrosis</d> and for the potential of active site mTOR inhibitors in the treatment of <d>IPF</d> and other fibrotic lung diseases.
25162417|a|A characteristic of dysregulated wound healing in <d>IPF</d> is fibroblastic-mediated damage to lung epithelial cells within fibroblastic foci. In these foci, <g>TGF-b</g> and other growth factors activate fibroblasts that secrete growth factors and matrix regulatory proteins, which activate a fibrotic cascade. Our studies and those of others have revealed that <g>Akt</g> is activated in <d>IPF</d> fibroblasts and it mediates the activation by <g>TGF-b</g> of pro-fibrotic pathways. Recent studies show that <g><g>mTOR</g>C2</g>, a component of the <g>mTOR</g> pathway, mediates the activation of <g>Akt</g>. In this study we set out to determine if blocking <g><g>mTOR</g>C2</g> with MLN0128, an active site dual <g>mTOR</g> inhibitor, which blocks both <g>mTOR</g>C1 and <g><g>mTOR</g>C2</g>, inhibits <d>lung <d>fibrosis</d></d>. We examined the effect of MLN0128 on <g>TGF-b</g>-mediated induction of stromal proteins in <d>IPF</d> lung fibroblasts; also, we looked at its effect on <g>TGF-b</g>-mediated epithelial injury using a Transwell co-culture system. Additionally, we assessed MLN0128 in the murine bleomycin lung model. We found that <g>TGF-b</g> induces the <g>Rictor</g> component of <g><g>mTOR</g>C2</g> in <d>IPF</d> lung fibroblasts, which led to <g>Akt</g> activation, and that MLN0128 exhibited potent anti-fibrotic activity in vitro and in vivo. Also, we observed that <g>Rictor</g> induction is <g>Akt</g>-mediated. MLN0128 displays multiple anti-fibrotic and lung epithelial-protective activities; it 1 inhibited the expression of pro-fibrotic matrix-regulatory proteins in <g>TGF-b</g>-stimulated <d>IPF</d> fibroblasts; 2 inhibited <d>fibrosis</d> in a murine bleomycin lung model; and 3 protected lung epithelial cells from injury caused by <g>TGF-b</g>-stimulated <d>IPF</d> fibroblasts. Our findings support a role for <g><g>mTOR</g>C2</g> in the pathogenesis of <d>lung <d>fibrosis</d></d> and for the potential of active site <g>mTOR</g> inhibitors in the treatment of <d>IPF</d> and other fibrotic lung diseases.
25162417|a|A characteristic of dysregulated wound healing in <d>IPF</d> is fibroblastic-mediated damage to lung epithelial cells within fibroblastic foci. In these foci, <g>TGF-b</g> and other growth factors activate fibroblasts that secrete growth factors and matrix regulatory proteins, which activate a fibrotic cascade. Our studies and those of others have revealed that <g>Akt</g> is activated in <d>IPF</d> fibroblasts and it mediates the activation by <g>TGF-b</g> of pro-fibrotic pathways. Recent studies show that <g><g>mTOR</g>C2</g>, a component of the <g>mTOR</g> pathway, mediates the activation of <g>Akt</g>. In this study we set out to determine if blocking <g><g>mTOR</g>C2</g> with MLN0128, an active site dual <g>mTOR</g> inhibitor, which blocks both <g>mTOR</g>C1 and <g><g>mTOR</g>C2</g>, inhibits <d>lung <d>fibrosis</d></d>. We examined the effect of MLN0128 on <g>TGF-b</g>-mediated induction of stromal proteins in <d>IPF</d> lung fibroblasts; also, we looked at its effect on <g>TGF-b</g>-mediated epithelial injury using a Transwell co-culture system. Additionally, we assessed MLN0128 in the murine bleomycin lung model. We found that <g>TGF-b</g> induces the <g>Rictor</g> component of <g><g>mTOR</g>C2</g> in <d>IPF</d> lung fibroblasts, which led to <g>Akt</g> activation, and that MLN0128 exhibited potent anti-fibrotic activity in vitro and in vivo. Also, we observed that <g>Rictor</g> induction is <g>Akt</g>-mediated. MLN0128 displays multiple anti-fibrotic and lung epithelial-protective activities; it 1 inhibited the expression of pro-fibrotic matrix-regulatory proteins in <g>TGF-b</g>-stimulated <d>IPF</d> fibroblasts; 2 inhibited <d>fibrosis</d> in a murine bleomycin lung model; and 3 protected lung epithelial cells from injury caused by <g>TGF-b</g>-stimulated <d>IPF</d> fibroblasts. Our findings support a role for <g><g>mTOR</g>C2</g> in the pathogenesis of <d>lung <d>fibrosis</d></d> and for the potential of active site <g>mTOR</g> inhibitors in the treatment of <d>IPF</d> and other <d>fibrotic lung diseases</d>.
25182202|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive fibrosing disease with disappointing survival rate, and uneffective therapeutic progress has been made in the last few years, forcing the urgent need to improve research to this disease. The commonly accepted pathogenic hypothesis of IPF is the trigger from continuous alveolar epithelium microinjuries and in the following series events, many signaling pathways were reported to lead to abnormal tissue repair and lung structure derangement in IPF, such as TGF-b, wnt, VEGF and PI3K-Akt signaling pathways. Traditional research of IPF related signaling pathway always focus on the independent function of pathway and disease signals, but the crosstalks and interactions among them were rarely valued. In this review, we summarize the signaling pathways which were reported to play important roles in the pathologic changes of IPF and the synergistic effect among those pathways. Next we discuss the application of genomics research and bioinformatics tools on IPF related pathway analysis, and give a systems biology perspective by integrating multi-level disease related data. The novel prospective of pathway analysis could tease out the complex pathway interaction profiles of IPF, and is powerful to detect IPF related biomarkers for early diagnose and potential therapeutic targets.
25182202|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive fibrosing disease with disappointing survival rate, and uneffective therapeutic progress has been made in the last few years, forcing the urgent need to improve research to this disease. The commonly accepted pathogenic hypothesis of <d>IPF</d> is the trigger from continuous alveolar epithelium microinjuries and in the following series events, many signaling pathways were reported to lead to abnormal tissue repair and lung structure derangement in <d>IPF</d>, such as TGF-b, wnt, VEGF and PI3K-Akt signaling pathways. Traditional research of <d>IPF</d> related signaling pathway always focus on the independent function of pathway and disease signals, but the crosstalks and interactions among them were rarely valued. In this review, we summarize the signaling pathways which were reported to play important roles in the pathologic changes of <d>IPF</d> and the synergistic effect among those pathways. Next we discuss the application of genomics research and bioinformatics tools on <d>IPF</d> related pathway analysis, and give a systems biology perspective by integrating multi-level disease related data. The novel prospective of pathway analysis could tease out the complex pathway interaction profiles of <d>IPF</d>, and is powerful to detect <d>IPF</d> related biomarkers for early diagnose and potential therapeutic targets.
25182202|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrosing disease</d> with disappointing survival rate, and uneffective therapeutic progress has been made in the last few years, forcing the urgent need to improve research to this disease. The commonly accepted pathogenic hypothesis of <d>IPF</d> is the trigger from continuous alveolar epithelium microinjuries and in the following series events, many signaling pathways were reported to lead to abnormal tissue repair and lung structure derangement in <d>IPF</d>, such as TGF-b, wnt, VEGF and PI3K-Akt signaling pathways. Traditional research of <d>IPF</d> related signaling pathway always focus on the independent function of pathway and disease signals, but the crosstalks and interactions among them were rarely valued. In this review, we summarize the signaling pathways which were reported to play important roles in the pathologic changes of <d>IPF</d> and the synergistic effect among those pathways. Next we discuss the application of genomics research and bioinformatics tools on <d>IPF</d> related pathway analysis, and give a systems biology perspective by integrating multi-level disease related data. The novel prospective of pathway analysis could tease out the complex pathway interaction profiles of <d>IPF</d>, and is powerful to detect <d>IPF</d> related biomarkers for early diagnose and potential therapeutic targets.
25197006|a|Within the lungs, <d>fibrosis</d> can affect both the parenchyma and the airways. Fibrosis is a hallmark pathological change in the parenchyma in patients with idiopathic pulmonary <d>fibrosis</d> IPF, whilst in asthma or chronic obstructive pulmonary disease COPD <d>fibrosis</d> is a component of the remodelling of the airways. In the past decade, significant advances have been made in understanding the disease behaviour and pathogenesis of parenchymal and airway <d>fibrosis</d> and as a result a variety of novel therapeutic targets for slowing or preventing progression of these fibrotic changes have been identified. This review highlights a number of these targets and discusses the potential for treating parenchymal or airway <d>fibrosis</d> through these mediators/pathways in the future.
25197006|a|Within the lungs, <d>fibrosis</d> can affect both the parenchyma and the airways. <d>Fibrosis</d> is a hallmark pathological change in the parenchyma in patients with idiopathic pulmonary <d>fibrosis</d> IPF, whilst in asthma or chronic obstructive pulmonary disease COPD <d>fibrosis</d> is a component of the remodelling of the airways. In the past decade, significant advances have been made in understanding the disease behaviour and pathogenesis of parenchymal and airway <d>fibrosis</d> and as a result a variety of novel therapeutic targets for slowing or preventing progression of these fibrotic changes have been identified. This review highlights a number of these targets and discusses the potential for treating parenchymal or airway <d>fibrosis</d> through these mediators/pathways in the future.
25197006|a|Within the lungs, <d>fibrosis</d> can affect both the parenchyma and the airways. <d>Fibrosis</d> is a hallmark pathological change in the parenchyma in patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, whilst in asthma or chronic obstructive pulmonary disease COPD <d>fibrosis</d> is a component of the remodelling of the airways. In the past decade, significant advances have been made in understanding the disease behaviour and pathogenesis of parenchymal and airway <d>fibrosis</d> and as a result a variety of novel therapeutic targets for slowing or preventing progression of these fibrotic changes have been identified. This review highlights a number of these targets and discusses the potential for treating parenchymal or airway <d>fibrosis</d> through these mediators/pathways in the future.
25197006|a|Within the lungs, <d>fibrosis</d> can affect both the parenchyma and the airways. <d>Fibrosis</d> is a hallmark pathological change in the parenchyma in patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, whilst in <d>asthma</d> or chronic obstructive pulmonary disease COPD <d>fibrosis</d> is a component of the remodelling of the airways. In the past decade, significant advances have been made in understanding the disease behaviour and pathogenesis of parenchymal and airway <d>fibrosis</d> and as a result a variety of novel therapeutic targets for slowing or preventing progression of these fibrotic changes have been identified. This review highlights a number of these targets and discusses the potential for treating parenchymal or airway <d>fibrosis</d> through these mediators/pathways in the future.
25197006|a|Within the lungs, <d>fibrosis</d> can affect both the parenchyma and the airways. <d>Fibrosis</d> is a hallmark pathological change in the parenchyma in patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, whilst in <d>asthma</d> or <d>chronic obstructive pulmonary disease</d> COPD <d>fibrosis</d> is a component of the remodelling of the airways. In the past decade, significant advances have been made in understanding the disease behaviour and pathogenesis of parenchymal and airway <d>fibrosis</d> and as a result a variety of novel therapeutic targets for slowing or preventing progression of these fibrotic changes have been identified. This review highlights a number of these targets and discusses the potential for treating parenchymal or airway <d>fibrosis</d> through these mediators/pathways in the future.
25197006|a|Within the lungs, <d>fibrosis</d> can affect both the parenchyma and the airways. <d>Fibrosis</d> is a hallmark pathological change in the parenchyma in patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, whilst in <d>asthma</d> or <d>chronic obstructive pulmonary disease</d> <d>COPD</d> <d>fibrosis</d> is a component of the remodelling of the airways. In the past decade, significant advances have been made in understanding the disease behaviour and pathogenesis of parenchymal and airway <d>fibrosis</d> and as a result a variety of novel therapeutic targets for slowing or preventing progression of these fibrotic changes have been identified. This review highlights a number of these targets and discusses the potential for treating parenchymal or airway <d>fibrosis</d> through these mediators/pathways in the future.
25199049|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic diffuse lung disease characterized by an accumulation of excess fibrous material in the lung. Protease nexin-1 PN-1 is a tissue serpin produced by many cell types, including lung fibroblasts. PN-1 is capable of regulating proteases of both coagulation and fibrinolysis systems, by inhibiting, respectively, <g>thrombin</g> and plasminergic enzymes. PN-1 is thus a good candidate for regulating tissue remodeling occurring during IPF. We demonstrated a significant increase of PN-1 expression in lung tissue extracts, lung fibroblasts and bronchoalveolar lavage fluids of patients with IPF. The increase of PN-1 expression was reproduced after stimulation of control lung fibroblasts by transforming growth factor-b, a major pro-fibrotic cytokine involved in IPF. Another serpin, plasminogen activator inhibitor-1 PAI-1 is also overexpressed in fibrotic fibroblasts. Unlike PAI-1, cell-bound PN-1 as well as secreted PN-1 from IPF and stimulated fibroblasts were shown to inhibit efficiently <g>thrombin</g> activity, indicating that both serpins should exhibit complementary roles in IPF pathogenesis, via their different preferential antiprotease activities. Moreover, we observed that overexpression of PN-1 induced by transfection of control fibroblasts led to increased <g>fibronectin</g> expression, whereas PN-1 silencing induced in fibrotic fibroblasts led to decreased <g>fibronectin</g> expression. Overexpression of PN-1 lacking either its antiprotease activity or its binding capacity to glycosaminoglycans had no effect on <g>fibronectin</g> expression. These novel findings suggest that modulation of PN-1 expression in lung fibroblasts may also have a role in the development of IPF by directly influencing the expression of extracellular matrix proteins. Our data provide new insights into the role of PN-1 in the poorly understood pathological processes involved in IPF and could therefore give rise to new therapeutic approaches.
25199049|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic diffuse lung disease characterized by an accumulation of excess fibrous material in the lung. Protease nexin-1 PN-1 is a tissue serpin produced by many cell types, including lung fibroblasts. PN-1 is capable of regulating proteases of both coagulation and fibrinolysis systems, by inhibiting, respectively, <g>thrombin</g> and plasminergic enzymes. PN-1 is thus a good candidate for regulating tissue remodeling occurring during <d>IPF</d>. We demonstrated a significant increase of PN-1 expression in lung tissue extracts, lung fibroblasts and bronchoalveolar lavage fluids of patients with <d>IPF</d>. The increase of PN-1 expression was reproduced after stimulation of control lung fibroblasts by transforming growth factor-b, a major pro-fibrotic cytokine involved in <d>IPF</d>. Another serpin, plasminogen activator inhibitor-1 PAI-1 is also overexpressed in fibrotic fibroblasts. Unlike PAI-1, cell-bound PN-1 as well as secreted PN-1 from <d>IPF</d> and stimulated fibroblasts were shown to inhibit efficiently <g>thrombin</g> activity, indicating that both serpins should exhibit complementary roles in <d>IPF</d> pathogenesis, via their different preferential antiprotease activities. Moreover, we observed that overexpression of PN-1 induced by transfection of control fibroblasts led to increased <g>fibronectin</g> expression, whereas PN-1 silencing induced in fibrotic fibroblasts led to decreased <g>fibronectin</g> expression. Overexpression of PN-1 lacking either its antiprotease activity or its binding capacity to glycosaminoglycans had no effect on <g>fibronectin</g> expression. These novel findings suggest that modulation of PN-1 expression in lung fibroblasts may also have a role in the development of <d>IPF</d> by directly influencing the expression of extracellular matrix proteins. Our data provide new insights into the role of PN-1 in the poorly understood pathological processes involved in <d>IPF</d> and could therefore give rise to new therapeutic approaches.
25199049|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic <d>diffuse lung disease</d> characterized by an accumulation of excess fibrous material in the lung. Protease nexin-1 PN-1 is a tissue serpin produced by many cell types, including lung fibroblasts. PN-1 is capable of regulating proteases of both coagulation and fibrinolysis systems, by inhibiting, respectively, <g>thrombin</g> and plasminergic enzymes. PN-1 is thus a good candidate for regulating tissue remodeling occurring during <d>IPF</d>. We demonstrated a significant increase of PN-1 expression in lung tissue extracts, lung fibroblasts and bronchoalveolar lavage fluids of patients with <d>IPF</d>. The increase of PN-1 expression was reproduced after stimulation of control lung fibroblasts by transforming growth factor-b, a major pro-fibrotic cytokine involved in <d>IPF</d>. Another serpin, plasminogen activator inhibitor-1 PAI-1 is also overexpressed in fibrotic fibroblasts. Unlike PAI-1, cell-bound PN-1 as well as secreted PN-1 from <d>IPF</d> and stimulated fibroblasts were shown to inhibit efficiently <g>thrombin</g> activity, indicating that both serpins should exhibit complementary roles in <d>IPF</d> pathogenesis, via their different preferential antiprotease activities. Moreover, we observed that overexpression of PN-1 induced by transfection of control fibroblasts led to increased <g>fibronectin</g> expression, whereas PN-1 silencing induced in fibrotic fibroblasts led to decreased <g>fibronectin</g> expression. Overexpression of PN-1 lacking either its antiprotease activity or its binding capacity to glycosaminoglycans had no effect on <g>fibronectin</g> expression. These novel findings suggest that modulation of PN-1 expression in lung fibroblasts may also have a role in the development of <d>IPF</d> by directly influencing the expression of extracellular matrix proteins. Our data provide new insights into the role of PN-1 in the poorly understood pathological processes involved in <d>IPF</d> and could therefore give rise to new therapeutic approaches.
25214520|a|Idiopathic pulmonary fibrosis IPF is a chronic progressive interstitial lung disease, in which a decline in patient prognosis is frequently associated with the onset of pulmonary hypertension PH. Animal models exhibiting principle pathophysiological features of IPF and PH could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive <d>interstitial pulmonary fibrosis</d> and associated PH, as defined by the presence of fibrotic foci adjacent to areas of alveolar injury and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure mPAP >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, MMP-2, MMP-7, and MMP-12, TIMP-1, the chemoattractant and mitogen, PDGF-b, and the chemokines CCL2 and CXCL12, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator TGF-b1 and components of the TGF-b signaling pathway; PAI-1, Nox-4, and HIF-1a. Therapeutic treatment with the ALK-5/TGF-b RI inhibitor SB-525334 reversed established pulmonary fibrosis and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of mPAP. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis.
25214520|a|Idiopathic pulmonary fibrosis IPF is a chronic progressive interstitial lung disease, in which a decline in patient prognosis is frequently associated with the onset of <d>pulmonary hypertension</d> PH. Animal models exhibiting principle pathophysiological features of IPF and PH could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive <d>interstitial pulmonary fibrosis</d> and associated PH, as defined by the presence of fibrotic foci adjacent to areas of alveolar injury and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure mPAP >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, MMP-2, MMP-7, and MMP-12, TIMP-1, the chemoattractant and mitogen, PDGF-b, and the chemokines CCL2 and CXCL12, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator TGF-b1 and components of the TGF-b signaling pathway; PAI-1, Nox-4, and HIF-1a. Therapeutic treatment with the ALK-5/TGF-b RI inhibitor SB-525334 reversed established pulmonary fibrosis and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of mPAP. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis.
25214520|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic progressive interstitial lung disease, in which a decline in patient prognosis is frequently associated with the onset of <d>pulmonary hypertension</d> PH. Animal models exhibiting principle pathophysiological features of IPF and PH could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive <d>interstitial pulmonary fibrosis</d> and associated PH, as defined by the presence of fibrotic foci adjacent to areas of alveolar injury and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure mPAP >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, MMP-2, MMP-7, and MMP-12, TIMP-1, the chemoattractant and mitogen, PDGF-b, and the chemokines CCL2 and CXCL12, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator TGF-b1 and components of the TGF-b signaling pathway; PAI-1, Nox-4, and HIF-1a. Therapeutic treatment with the ALK-5/TGF-b RI inhibitor SB-525334 reversed established pulmonary fibrosis and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of mPAP. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis.
25214520|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive interstitial lung disease, in which a decline in patient prognosis is frequently associated with the onset of <d>pulmonary hypertension</d> PH. Animal models exhibiting principle pathophysiological features of <d>IPF</d> and PH could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive <d>interstitial pulmonary fibrosis</d> and associated PH, as defined by the presence of fibrotic foci adjacent to areas of alveolar injury and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure mPAP >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, MMP-2, MMP-7, and MMP-12, TIMP-1, the chemoattractant and mitogen, PDGF-b, and the chemokines CCL2 and CXCL12, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator TGF-b1 and components of the TGF-b signaling pathway; PAI-1, Nox-4, and HIF-1a. Therapeutic treatment with the ALK-5/TGF-b RI inhibitor SB-525334 reversed established pulmonary fibrosis and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of mPAP. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis.
25214520|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive <d>interstitial lung disease</d>, in which a decline in patient prognosis is frequently associated with the onset of <d>pulmonary hypertension</d> PH. Animal models exhibiting principle pathophysiological features of <d>IPF</d> and PH could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive <d>interstitial pulmonary fibrosis</d> and associated PH, as defined by the presence of fibrotic foci adjacent to areas of alveolar injury and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure mPAP >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, MMP-2, MMP-7, and MMP-12, TIMP-1, the chemoattractant and mitogen, PDGF-b, and the chemokines CCL2 and CXCL12, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator TGF-b1 and components of the TGF-b signaling pathway; PAI-1, Nox-4, and HIF-1a. Therapeutic treatment with the ALK-5/TGF-b RI inhibitor SB-525334 reversed established pulmonary fibrosis and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of mPAP. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis.
25214520|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive <d>interstitial lung disease</d>, in which a decline in patient prognosis is frequently associated with the onset of <d>pulmonary hypertension</d> <d>PH</d>. Animal models exhibiting principle pathophysiological features of <d>IPF</d> and <d>PH</d> could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive <d>interstitial pulmonary fibrosis</d> and associated <d>PH</d>, as defined by the presence of fibrotic foci adjacent to areas of alveolar injury and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure mPAP >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, MMP-2, MMP-7, and MMP-12, TIMP-1, the chemoattractant and mitogen, PDGF-b, and the chemokines CCL2 and CXCL12, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator TGF-b1 and components of the TGF-b signaling pathway; PAI-1, Nox-4, and HIF-1a. Therapeutic treatment with the ALK-5/TGF-b RI inhibitor SB-525334 reversed established pulmonary fibrosis and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of mPAP. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis.
25214520|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive <d>interstitial lung disease</d>, in which a decline in patient prognosis is frequently associated with the onset of <d>pulmonary hypertension</d> <d>PH</d>. Animal models exhibiting principle pathophysiological features of <d>IPF</d> and <d>PH</d> could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive <d>interstitial pulmonary fibrosis</d> and associated <d>PH</d>, as defined by the presence of fibrotic foci adjacent to areas of <d>alveolar injury</d> and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure mPAP >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, MMP-2, MMP-7, and MMP-12, TIMP-1, the chemoattractant and mitogen, PDGF-b, and the chemokines CCL2 and CXCL12, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator TGF-b1 and components of the TGF-b signaling pathway; PAI-1, Nox-4, and HIF-1a. Therapeutic treatment with the ALK-5/TGF-b RI inhibitor SB-525334 reversed established pulmonary fibrosis and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of mPAP. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis.
25214520|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive <d>interstitial lung disease</d>, in which a decline in patient prognosis is frequently associated with the onset of <d>pulmonary hypertension</d> <d>PH</d>. Animal models exhibiting principle pathophysiological features of <d>IPF</d> and <d>PH</d> could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive <d>interstitial pulmonary fibrosis</d> and associated <d>PH</d>, as defined by the presence of fibrotic foci adjacent to areas of <d>alveolar injury</d> and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure <g>mPAP</g> >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, <g>MMP-2</g>, <g>MMP-7</g>, and <g>MMP-12</g>, <g>TIMP-1</g>, the chemoattractant and mitogen, <g>PDGF-b</g>, and the chemokines <g>CCL2</g> and <g>CXCL12</g>, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator <g><g>TGF-b</g>1</g> and components of the <g>TGF-b</g> signaling pathway; <g>PAI-1</g>, <g>Nox-4</g>, and <g>HIF-1a</g>. Therapeutic treatment with the <g>ALK-5</g>/<g>TGF-b</g> RI inhibitor SB-525334 reversed <d>established pulmonary fibrosis</d> and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of <g>mPAP</g>. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis.
25252739|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive, fatal disease, thought to be largely transforming growth factor b TGFb driven, for which there is no effective therapy. We assessed the potential benefits in IPF of nitrated fatty acids NFAs, which are unique endogenous agonists of peroxisome proliferator-activated receptor y PPARy, a nuclear hormone receptor that exhibits wound-healing and antifibrotic properties potentially useful for IPF therapy. We found that pulmonary PPARy is down-regulated in patients with IPF. In vitro, knockdown or knockout of PPARy expression in isolated human and mouse lung fibroblasts induced a profibrotic phenotype, whereas treating human fibroblasts with NFAs up-regulated PPARy and blocked TGFb signaling and actions. NFAs also converted TGFb to inactive monomers in cell-free solution, suggesting an additional mechanism through which they may inhibit TGFb. In vivo, treating mice bearing experimental <d>pulmonary fibrosis</d> with NFAs reduced disease severity. Also, NFAs up-regulated the collagen-targeting factor milk fat globule-EGF factor 8 MFG-E8, stimulated collagen uptake and degradation by alveolar macrophages, and promoted myofibroblast dedifferentiation. Moreover, treating mice with established <d>pulmonary fibrosis</d> using NFAs reversed their existing myofibroblast differentiation and collagen deposition. These findings raise the prospect of treating IPF with NFAs to halt and perhaps even reverse the progress of IPF.-Reddy, A. T., Lakshmi, S. P., Zhang, Y., Reddy, R. C. Nitrated fatty acids reverse <d>pulmonary fibrosis</d> by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages.
25252739|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, fatal disease, thought to be largely transforming growth factor b TGFb driven, for which there is no effective therapy. We assessed the potential benefits in <d>IPF</d> of nitrated fatty acids NFAs, which are unique endogenous agonists of peroxisome proliferator-activated receptor y PPARy, a nuclear hormone receptor that exhibits wound-healing and antifibrotic properties potentially useful for <d>IPF</d> therapy. We found that pulmonary PPARy is down-regulated in patients with <d>IPF</d>. In vitro, knockdown or knockout of PPARy expression in isolated human and mouse lung fibroblasts induced a profibrotic phenotype, whereas treating human fibroblasts with NFAs up-regulated PPARy and blocked TGFb signaling and actions. NFAs also converted TGFb to inactive monomers in cell-free solution, suggesting an additional mechanism through which they may inhibit TGFb. In vivo, treating mice bearing experimental <d>pulmonary fibrosis</d> with NFAs reduced disease severity. Also, NFAs up-regulated the collagen-targeting factor milk fat globule-EGF factor 8 MFG-E8, stimulated collagen uptake and degradation by alveolar macrophages, and promoted myofibroblast dedifferentiation. Moreover, treating mice with established <d>pulmonary fibrosis</d> using NFAs reversed their existing myofibroblast differentiation and collagen deposition. These findings raise the prospect of treating <d>IPF</d> with NFAs to halt and perhaps even reverse the progress of <d>IPF</d>.-Reddy, A. T., Lakshmi, S. P., Zhang, Y., Reddy, R. C. Nitrated fatty acids reverse <d>pulmonary fibrosis</d> by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages.
25252739|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, <d>fatal disease</d>, thought to be largely transforming growth factor b TGFb driven, for which there is no effective therapy. We assessed the potential benefits in <d>IPF</d> of nitrated fatty acids NFAs, which are unique endogenous agonists of peroxisome proliferator-activated receptor y PPARy, a nuclear hormone receptor that exhibits wound-healing and antifibrotic properties potentially useful for <d>IPF</d> therapy. We found that pulmonary PPARy is down-regulated in patients with <d>IPF</d>. In vitro, knockdown or knockout of PPARy expression in isolated human and mouse lung fibroblasts induced a profibrotic phenotype, whereas treating human fibroblasts with NFAs up-regulated PPARy and blocked TGFb signaling and actions. NFAs also converted TGFb to inactive monomers in cell-free solution, suggesting an additional mechanism through which they may inhibit TGFb. In vivo, treating mice bearing experimental <d>pulmonary fibrosis</d> with NFAs reduced disease severity. Also, NFAs up-regulated the collagen-targeting factor milk fat globule-EGF factor 8 MFG-E8, stimulated collagen uptake and degradation by alveolar macrophages, and promoted myofibroblast dedifferentiation. Moreover, treating mice with established <d>pulmonary fibrosis</d> using NFAs reversed their existing myofibroblast differentiation and collagen deposition. These findings raise the prospect of treating <d>IPF</d> with NFAs to halt and perhaps even reverse the progress of <d>IPF</d>.-Reddy, A. T., Lakshmi, S. P., Zhang, Y., Reddy, R. C. Nitrated fatty acids reverse <d>pulmonary fibrosis</d> by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages.
25252739|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, <d>fatal disease</d>, thought to be largely <g>transforming growth factor b</g> <g>TGFb</g> driven, for which there is no effective therapy. We assessed the potential benefits in <d>IPF</d> of <d>nitrated fatty acids</d> NFAs, which are unique endogenous agonists of peroxisome proliferator-activated receptor y PPARy, a nuclear hormone receptor that exhibits wound-healing and antifibrotic properties potentially useful for <d>IPF</d> therapy. We found that pulmonary PPARy is down-regulated in patients with <d>IPF</d>. In vitro, knockdown or knockout of PPARy expression in isolated human and mouse lung fibroblasts induced a profibrotic phenotype, whereas treating human fibroblasts with NFAs up-regulated PPARy and blocked <g>TGFb</g> signaling and actions. NFAs also converted <g>TGFb</g> to inactive monomers in cell-free solution, suggesting an additional mechanism through which they may inhibit <g>TGFb</g>. In vivo, treating mice bearing experimental <d>pulmonary fibrosis</d> with NFAs reduced disease severity. Also, NFAs up-regulated the collagen-targeting factor milk fat globule-EGF factor 8 MFG-E8, stimulated collagen uptake and degradation by alveolar macrophages, and promoted myofibroblast dedifferentiation. Moreover, treating mice with established <d>pulmonary fibrosis</d> using NFAs reversed their existing myofibroblast differentiation and collagen deposition. These findings raise the prospect of treating <d>IPF</d> with NFAs to halt and perhaps even reverse the progress of <d>IPF</d>.-Reddy, A. T., Lakshmi, S. P., Zhang, Y., Reddy, R. C. Nitrated fatty acids reverse <d>pulmonary fibrosis</d> by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages.
25252739|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, <d>fatal disease</d>, thought to be largely <g>transforming growth factor b</g> <g>TGFb</g> driven, for which there is no effective therapy. We assessed the potential benefits in <d>IPF</d> of <d>nitrated fatty acids</d> <d>NFAs</d>, which are unique endogenous agonists of peroxisome proliferator-activated receptor y PPARy, a nuclear hormone receptor that exhibits wound-healing and antifibrotic properties potentially useful for <d>IPF</d> therapy. We found that pulmonary PPARy is down-regulated in patients with <d>IPF</d>. In vitro, knockdown or knockout of PPARy expression in isolated human and mouse lung fibroblasts induced a profibrotic phenotype, whereas treating human fibroblasts with <d>NFAs</d> up-regulated PPARy and blocked <g>TGFb</g> signaling and actions. <d>NFAs</d> also converted <g>TGFb</g> to inactive monomers in cell-free solution, suggesting an additional mechanism through which they may inhibit <g>TGFb</g>. In vivo, treating mice bearing experimental <d>pulmonary fibrosis</d> with <d>NFAs</d> reduced disease severity. Also, <d>NFAs</d> up-regulated the collagen-targeting factor milk fat globule-EGF factor 8 MFG-E8, stimulated collagen uptake and degradation by alveolar macrophages, and promoted myofibroblast dedifferentiation. Moreover, treating mice with established <d>pulmonary fibrosis</d> using <d>NFAs</d> reversed their existing myofibroblast differentiation and collagen deposition. These findings raise the prospect of treating <d>IPF</d> with <d>NFAs</d> to halt and perhaps even reverse the progress of <d>IPF</d>.-Reddy, A. T., Lakshmi, S. P., Zhang, Y., Reddy, R. C. Nitrated fatty acids reverse <d>pulmonary fibrosis</d> by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages.
25260753|a|Aberrant expression of master phenotype regulators by lung fibroblasts may play a central role in <d>idiopathic pulmonary fibrosis</d> IPF. Interrogating IPF fibroblast transcriptome datasets, we identified <g>Forkhead Box F1</g> <g>FOXF1</g>, a DNA-binding protein required for lung development, as a candidate actor in IPF. Thus, we determined <g>FOXF1</g> expression levels in fibroblasts cultured from normal or IPF lungs in vitro, and explored <g>FOXF1</g> functions in these cells using transient and stable loss-of-function and gain-of-function models. <g>FOXF1</g> mRNA and protein were expressed at higher levels in IPF compared with controls. In normal lung fibroblasts, <g>FOXF1</g> repressed key fibroblast functions such as proliferation, survival, and expression of collagen-1 COL1 and actin related protein 2/3 complex, subunit 2 <g>ARPC2</g>. <g>ARPC2</g> knockdown mimicked <g>FOXF1</g> overexpression with regard to proliferation and COL1 expression. <g>FOXF1</g> expression was induced by the antifibrotic mediator prostaglandin E2 PGE2. Ex vivo, <g>FOXF1</g> knockdown conferred CCL-210 lung fibroblasts the ability to implant and survive in uninjured mouse lungs. In IPF lung fibroblasts, <g>FOXF1</g> regulated COL1 but not <g>ARPC2</g> expression. In conclusion, <g>FOXF1</g> functions and regulation were consistent with an antifibrotic role in lung fibroblasts. Higher <g>FOXF1</g> levels in IPF fibroblasts may thus participate in a compensatory response to fibrogenesis.
25260753|a|Aberrant expression of master phenotype regulators by lung fibroblasts may play a central role in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Interrogating <d>IPF</d> fibroblast transcriptome datasets, we identified <g>Forkhead Box F1</g> <g>FOXF1</g>, a DNA-binding protein required for lung development, as a candidate actor in <d>IPF</d>. Thus, we determined <g>FOXF1</g> expression levels in fibroblasts cultured from normal or <d>IPF</d> lungs in vitro, and explored <g>FOXF1</g> functions in these cells using transient and stable loss-of-function and gain-of-function models. <g>FOXF1</g> mRNA and protein were expressed at higher levels in <d>IPF</d> compared with controls. In normal lung fibroblasts, <g>FOXF1</g> repressed key fibroblast functions such as proliferation, survival, and expression of collagen-1 COL1 and actin related protein 2/3 complex, subunit 2 <g>ARPC2</g>. <g>ARPC2</g> knockdown mimicked <g>FOXF1</g> overexpression with regard to proliferation and COL1 expression. <g>FOXF1</g> expression was induced by the antifibrotic mediator prostaglandin E2 PGE2. Ex vivo, <g>FOXF1</g> knockdown conferred CCL-210 lung fibroblasts the ability to implant and survive in uninjured mouse lungs. In <d>IPF</d> lung fibroblasts, <g>FOXF1</g> regulated COL1 but not <g>ARPC2</g> expression. In conclusion, <g>FOXF1</g> functions and regulation were consistent with an antifibrotic role in lung fibroblasts. Higher <g>FOXF1</g> levels in <d>IPF</d> fibroblasts may thus participate in a compensatory response to fibrogenesis.
25331544|a|BACKGROUND: The pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF in dogs is poorly understood. In human, transforming growth factor b1 TGF-b1 is considered central in the pathogenesis. OBJECTIVES: To investigate TGF-b1 pathway in IPF. ANIMALS: Lung tissues from 12 affected and 11 control dogs. Serum from 16 affected West Highland white Terriers WHWTs and healthy dogs from predisposed 13 WHWTs, 12 Scottish Terriers and 13 Bichons Frise and nonpredisposed breeds 10 Whippets, 10 Belgian shepherds, 8 Labradors. METHODS: In this prospective study, immunohistochemistry was used to evaluate expression and localization of TGF-b1 protein and proteins involved in TGF-b1 signaling TGF-b receptor type I and phospho-Smad2/3. Pulmonary expression of TGF-b1 and molecules involved in its storage latent TGF-b binding proteins [LTBP] 1, 2, and 4, activation a  b6 and a  b8 integrins, thrombospondin-1 and signal inhibition Smad 7 was analyzed by quantitative reverse transcriptase PCR. Circulating TGF-b1 concentration was measured by ELISA. RESULTS: In IPF, high level of TGF-b1 protein was found in areas of fibrosis, epithelial cells had strong expression of TGF-b receptor type 1 and phospho-Smad2/3, gene expression was decreased for LTBP 4 P  =  .009 and b8 integrin P  <  .001 and increased for thrombospondin-1 P  =  .016; no difference was seen for Smad7, LTBP1 and 2. Serum TGF-b1 concentration was higher in predisposed compared with nonpredisposed breeds P  <  .0001. CONCLUSIONS AND CLINICAL IMPORTANCE: This study identified an enhanced TGF-b1 signaling activity in IPF. TGF-b1 storage and activation proteins with altered expression represent potential therapeutic targets. Higher circulating TGF-b1 concentration in predisposed breeds might partly explain their susceptibility for IPF.
25331544|a|BACKGROUND: The pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> in dogs is poorly understood. In human, transforming growth factor b1 TGF-b1 is considered central in the pathogenesis. OBJECTIVES: To investigate TGF-b1 pathway in <d>IPF</d>. ANIMALS: Lung tissues from 12 affected and 11 control dogs. Serum from 16 affected West Highland white Terriers WHWTs and healthy dogs from predisposed 13 WHWTs, 12 Scottish Terriers and 13 Bichons Frise and nonpredisposed breeds 10 Whippets, 10 Belgian shepherds, 8 Labradors. METHODS: In this prospective study, immunohistochemistry was used to evaluate expression and localization of TGF-b1 protein and proteins involved in TGF-b1 signaling TGF-b receptor type I and phospho-Smad2/3. Pulmonary expression of TGF-b1 and molecules involved in its storage latent TGF-b binding proteins [LTBP] 1, 2, and 4, activation a  b6 and a  b8 integrins, thrombospondin-1 and signal inhibition Smad 7 was analyzed by quantitative reverse transcriptase PCR. Circulating TGF-b1 concentration was measured by ELISA. RESULTS: In <d>IPF</d>, high level of TGF-b1 protein was found in areas of fibrosis, epithelial cells had strong expression of TGF-b receptor type 1 and phospho-Smad2/3, gene expression was decreased for LTBP 4 P  =  .009 and b8 integrin P  <  .001 and increased for thrombospondin-1 P  =  .016; no difference was seen for Smad7, LTBP1 and 2. Serum TGF-b1 concentration was higher in predisposed compared with nonpredisposed breeds P  <  .0001. CONCLUSIONS AND CLINICAL IMPORTANCE: This study identified an enhanced TGF-b1 signaling activity in <d>IPF</d>. TGF-b1 storage and activation proteins with altered expression represent potential therapeutic targets. Higher circulating TGF-b1 concentration in predisposed breeds might partly explain their susceptibility for <d>IPF</d>.
25331544|a|BACKGROUND: The pathogenesis of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> in dogs is poorly understood. In human, <g>transforming growth factor b1</g> <g>TGF-b1</g> is considered central in the pathogenesis. OBJECTIVES: To investigate <g>TGF-b1</g> pathway in <d>IPF</d>. ANIMALS: Lung tissues from 12 affected and 11 control dogs. Serum from 16 affected West Highland white Terriers WHWTs and healthy dogs from predisposed 13 WHWTs, 12 Scottish Terriers and 13 Bichons Frise and nonpredisposed breeds 10 Whippets, 10 Belgian shepherds, 8 Labradors. METHODS: In this prospective study, immunohistochemistry was used to evaluate expression and localization of <g>TGF-b1</g> protein and proteins involved in <g>TGF-b1</g> signaling TGF-b receptor type I and phospho-Smad2/3. Pulmonary expression of <g>TGF-b1</g> and molecules involved in its storage latent TGF-b binding proteins [<g>LTBP] 1, 2, and 4</g>, activation a  b6 and a  b8 integrins, <g>thrombospondin-1</g> and signal inhibition <g>Smad 7</g> was analyzed by quantitative reverse transcriptase PCR. Circulating <g>TGF-b1</g> concentration was measured by ELISA. RESULTS: In <d>IPF</d>, high level of <g>TGF-b1</g> protein was found in areas of <d>fibrosis</d>, epithelial cells had strong expression of TGF-b receptor type 1 and phospho-Smad2/3, gene expression was decreased for LTBP 4 P  =  .009 and b8 integrin P  <  .001 and increased for <g>thrombospondin-1</g> P  =  .016; no difference was seen for Smad7, LTBP1 and 2. Serum <g>TGF-b1</g> concentration was higher in predisposed compared with nonpredisposed breeds P  <  .0001. CONCLUSIONS AND CLINICAL IMPORTANCE: This study identified an enhanced <g>TGF-b1</g> signaling activity in <d>IPF</d>. <g>TGF-b1</g> storage and activation proteins with altered expression represent potential therapeutic targets. Higher circulating <g>TGF-b1</g> concentration in predisposed breeds might partly explain their susceptibility for <d>IPF</d>.
25361680|a|BACKGROUND: Activins are members of the TGF-   superfamily of growth factors. First, we identified by expression array screening that <g>activin</g>-B and <g>follistatin</g> are upregulated in human idiopathic <d>pulmonary fibrosis</d> IPF. Next, we wanted to clarify their specific role in lung fibrosis formation. METHODS: We used specific antibodies for <g>activin</g>-A and -B subunits and <g>follistatin</g> to measure and localize their levels in idiopathic <d>pulmonary fibrosis</d> and control lung biopsies. To inhibit <g>activin</g> signaling, we used soluble <g>activin</g> type IIB receptor fused to the Fc portion of human IgG1 sActRIIB-Fc in two different mouse models of <d>pulmonary fibrosis</d>. RESULTS: Activin-B and <g>follistatin</g> mRNA levels were elevated in the human IPF lung. Immunoreactivity to <g>activin</g>-A, -B and <g>follistatin</g> localized predominantly to the hyperplastic, activated alveolar epithelium, but was also seen in inflammatory cells. Mice treated with sActRIIB-Fc showed increased skeletal muscle mass and a clear reduction in alveolar cell counts in bronchoalveolar lavage fluid, but no significant antifibrotic effect in the lung was observed. CONCLUSIONS: The upregulation of <g>activin</g>-B and <g>follistatin</g> in IPF is a novel finding. Our results indicate that <g>activin</g> inhibition is not an efficient tool for antifibrotic therapy, but could be useful in reducing alveolar cellular response to injury. Activin-B and <g>follistatin</g> levels may be useful as biomarkers of IPF.
25361680|a|BACKGROUND: Activins are members of the TGF-   superfamily of growth factors. First, we identified by expression array screening that <g>activin</g>-B and <g>follistatin</g> are upregulated in human idiopathic <d>pulmonary <d>fibrosis</d></d> IPF. Next, we wanted to clarify their specific role in lung <d>fibrosis</d> formation. METHODS: We used specific antibodies for <g>activin</g>-A and -B subunits and <g>follistatin</g> to measure and localize their levels in idiopathic <d>pulmonary <d>fibrosis</d></d> and control lung biopsies. To inhibit <g>activin</g> signaling, we used soluble <g>activin</g> type IIB receptor fused to the Fc portion of human IgG1 sActRIIB-Fc in two different mouse models of <d>pulmonary <d>fibrosis</d></d>. RESULTS: Activin-B and <g>follistatin</g> mRNA levels were elevated in the human IPF lung. Immunoreactivity to <g>activin</g>-A, -B and <g>follistatin</g> localized predominantly to the hyperplastic, activated alveolar epithelium, but was also seen in inflammatory cells. Mice treated with sActRIIB-Fc showed increased skeletal muscle mass and a clear reduction in alveolar cell counts in bronchoalveolar lavage fluid, but no significant antifibrotic effect in the lung was observed. CONCLUSIONS: The upregulation of <g>activin</g>-B and <g>follistatin</g> in IPF is a novel finding. Our results indicate that <g>activin</g> inhibition is not an efficient tool for antifibrotic therapy, but could be useful in reducing alveolar cellular response to injury. Activin-B and <g>follistatin</g> levels may be useful as biomarkers of IPF.
25361680|a|BACKGROUND: Activins are members of the TGF-   superfamily of growth factors. First, we identified by expression array screening that <g>activin</g>-B and <g>follistatin</g> are upregulated in human idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Next, we wanted to clarify their specific role in lung <d>fibrosis</d> formation. METHODS: We used specific antibodies for <g>activin</g>-A and -B subunits and <g>follistatin</g> to measure and localize their levels in idiopathic <d>pulmonary <d>fibrosis</d></d> and control lung biopsies. To inhibit <g>activin</g> signaling, we used soluble <g>activin</g> type IIB receptor fused to the Fc portion of human IgG1 sActRIIB-Fc in two different mouse models of <d>pulmonary <d>fibrosis</d></d>. RESULTS: Activin-B and <g>follistatin</g> mRNA levels were elevated in the human <d>IPF</d> lung. Immunoreactivity to <g>activin</g>-A, -B and <g>follistatin</g> localized predominantly to the hyperplastic, activated alveolar epithelium, but was also seen in inflammatory cells. Mice treated with sActRIIB-Fc showed increased skeletal muscle mass and a clear reduction in alveolar cell counts in bronchoalveolar lavage fluid, but no significant antifibrotic effect in the lung was observed. CONCLUSIONS: The upregulation of <g>activin</g>-B and <g>follistatin</g> in <d>IPF</d> is a novel finding. Our results indicate that <g>activin</g> inhibition is not an efficient tool for antifibrotic therapy, but could be useful in reducing alveolar cellular response to injury. Activin-B and <g>follistatin</g> levels may be useful as biomarkers of <d>IPF</d>.
25361680|a|BACKGROUND: <g>Activin</g>s are members of the TGF-   superfamily of growth factors. First, we identified by expression array screening that <g>activin</g>-B and <g>follistatin</g> are upregulated in human idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Next, we wanted to clarify their specific role in lung <d>fibrosis</d> formation. METHODS: We used specific antibodies for <g>activin</g>-A and -B subunits and <g>follistatin</g> to measure and localize their levels in idiopathic <d>pulmonary <d>fibrosis</d></d> and control lung biopsies. To inhibit <g>activin</g> signaling, we used soluble <g>activin</g> type IIB receptor fused to the Fc portion of human <g>IgG1</g> sActRIIB-Fc in two different mouse models of <d>pulmonary <d>fibrosis</d></d>. RESULTS: <g>Activin</g>-B and <g>follistatin</g> mRNA levels were elevated in the human <d>IPF</d> lung. Immunoreactivity to <g>activin</g>-A, -B and <g>follistatin</g> localized predominantly to the <d>hyperplastic</d>, activated alveolar epithelium, but was also seen in inflammatory cells. Mice treated with sActRIIB-Fc showed increased skeletal muscle mass and a clear reduction in alveolar cell counts in bronchoalveolar lavage fluid, but no significant antifibrotic effect in the lung was observed. CONCLUSIONS: The upregulation of <g>activin</g>-B and <g>follistatin</g> in <d>IPF</d> is a novel finding. Our results indicate that <g>activin</g> inhibition is not an efficient tool for antifibrotic therapy, but could be useful in reducing alveolar cellular response to injury. <g>Activin</g>-B and <g>follistatin</g> levels may be useful as biomarkers of <d>IPF</d>.
25365224|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a fatal fibrotic lung disorder with no effective medical treatments available. The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated TGF-b; however, it is not clear how fibroblasts sense and transmit the mechanical signals that promote differentiation into myofibroblasts. As transient receptor potential vanilloid 4 <g>TRPV4</g> channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether <g>TRPV4</g> contributes to generation of myofibroblasts and/or experimental lung fibrosis. We determined that <g>TRPV4</g> activity is upregulated in lung fibroblasts derived from patients with IPF. Moreover, <g>TRPV4</g>-deficient mice were protected from fibrosis. Furthermore, genetic ablation or pharmacological inhibition of <g>TRPV4</g> function abrogated myofibroblast differentiation, which was restored by <g>TRPV4</g> reintroduction. <g>TRPV4</g> channel activity was elevated when cells were plated on matrices of increasing stiffness or on fibrotic lung tissue, and matrix stiffness-dependent myofibroblast differentiation was reduced in response to TRVP4 inhibition. <g>TRPV4</g> activity modulated TGF-b1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the a-SMA transcription coactivator MRTF-A. Together, these data indicate that <g>TRPV4</g> activity mediates pulmonary fibrogenesis and suggest that manipulation of <g>TRPV4</g> channel activity has potential as a therapeutic approach for fibrotic diseases.
25365224|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a fatal fibrotic lung disorder with no effective medical treatments available. The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated TGF-b; however, it is not clear how fibroblasts sense and transmit the mechanical signals that promote differentiation into myofibroblasts. As transient receptor potential vanilloid 4 <g>TRPV4</g> channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether <g>TRPV4</g> contributes to generation of myofibroblasts and/or experimental lung fibrosis. We determined that <g>TRPV4</g> activity is upregulated in lung fibroblasts derived from patients with <d>IPF</d>. Moreover, <g>TRPV4</g>-deficient mice were protected from fibrosis. Furthermore, genetic ablation or pharmacological inhibition of <g>TRPV4</g> function abrogated myofibroblast differentiation, which was restored by <g>TRPV4</g> reintroduction. <g>TRPV4</g> channel activity was elevated when cells were plated on matrices of increasing stiffness or on fibrotic lung tissue, and matrix stiffness-dependent myofibroblast differentiation was reduced in response to TRVP4 inhibition. <g>TRPV4</g> activity modulated TGF-b1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the a-SMA transcription coactivator MRTF-A. Together, these data indicate that <g>TRPV4</g> activity mediates pulmonary fibrogenesis and suggest that manipulation of <g>TRPV4</g> channel activity has potential as a therapeutic approach for fibrotic diseases.
25365224|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a fatal <d>fibrotic lung disorder</d> with no effective medical treatments available. The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated TGF-b; however, it is not clear how fibroblasts sense and transmit the mechanical signals that promote differentiation into myofibroblasts. As transient receptor potential vanilloid 4 <g>TRPV4</g> channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether <g>TRPV4</g> contributes to generation of myofibroblasts and/or experimental lung fibrosis. We determined that <g>TRPV4</g> activity is upregulated in lung fibroblasts derived from patients with <d>IPF</d>. Moreover, <g>TRPV4</g>-deficient mice were protected from fibrosis. Furthermore, genetic ablation or pharmacological inhibition of <g>TRPV4</g> function abrogated myofibroblast differentiation, which was restored by <g>TRPV4</g> reintroduction. <g>TRPV4</g> channel activity was elevated when cells were plated on matrices of increasing stiffness or on fibrotic lung tissue, and matrix stiffness-dependent myofibroblast differentiation was reduced in response to TRVP4 inhibition. <g>TRPV4</g> activity modulated TGF-b1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the a-SMA transcription coactivator MRTF-A. Together, these data indicate that <g>TRPV4</g> activity mediates pulmonary fibrogenesis and suggest that manipulation of <g>TRPV4</g> channel activity has potential as a therapeutic approach for fibrotic diseases.
25365224|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a fatal <d>fibrotic lung disorder</d> with no effective medical treatments available. The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated <g>TGF-b</g>; however, it is not clear how fibroblasts sense and transmit the mechanical signals that promote differentiation into myofibroblasts. As <g>transient receptor potential vanilloid 4</g> <g>TRPV4</g> channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether <g>TRPV4</g> contributes to generation of myofibroblasts and/or experimental lung <d>fibrosis</d>. We determined that <g>TRPV4</g> activity is upregulated in lung fibroblasts derived from patients with <d>IPF</d>. Moreover, <g>TRPV4</g>-deficient mice were protected from <d>fibrosis</d>. Furthermore, genetic ablation or pharmacological inhibition of <g>TRPV4</g> function abrogated myofibroblast differentiation, which was restored by <g>TRPV4</g> reintroduction. <g>TRPV4</g> channel activity was elevated when cells were plated on matrices of increasing stiffness or on fibrotic lung tissue, and matrix stiffness-dependent myofibroblast differentiation was reduced in response to TRVP4 inhibition. <g>TRPV4</g> activity modulated <g>TGF-b</g>1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the a-SMA transcription coactivator MRTF-A. Together, these data indicate that <g>TRPV4</g> activity mediates pulmonary fibrogenesis and suggest that manipulation of <g>TRPV4</g> channel activity has potential as a therapeutic approach for fibrotic diseases.
25365224|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a fatal <d>fibrotic lung disorder</d> with no effective medical treatments available. The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated <g>TGF-b</g>; however, it is not clear how fibroblasts sense and transmit the mechanical signals that promote differentiation into myofibroblasts. As <g>transient receptor potential vanilloid 4</g> <g>TRPV4</g> channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether <g>TRPV4</g> contributes to generation of myofibroblasts and/or experimental lung <d>fibrosis</d>. We determined that <g>TRPV4</g> activity is upregulated in lung fibroblasts derived from patients with <d>IPF</d>. Moreover, <g>TRPV4</g>-deficient mice were protected from <d>fibrosis</d>. Furthermore, genetic ablation or pharmacological inhibition of <g>TRPV4</g> function abrogated myofibroblast differentiation, which was restored by <g>TRPV4</g> reintroduction. <g>TRPV4</g> channel activity was elevated when cells were plated on matrices of increasing stiffness or on fibrotic lung tissue, and matrix stiffness-dependent myofibroblast differentiation was reduced in response to TRVP4 inhibition. <g>TRPV4</g> activity modulated <g>TGF-b</g>1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the a-SMA transcription coactivator <g>MRTF-A</g>. Together, these data indicate that <g>TRPV4</g> activity mediates pulmonary fibrogenesis and suggest that manipulation of <g>TRPV4</g> channel activity has potential as a therapeutic approach for <d>fibrotic diseases</d>.
25373521|a|Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF. In these hypotheses, continuous TGF-b1 secretion by alveolar epithelial cells AECs in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells MSCs home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 <g>Stanniocalcin-1</g> secretion in a bleomycin-induced IPF model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-b1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum ER stress, and TGF-b1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 UCP2 and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial-mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for IPF.Molecular Therapy 2014; doi:10.1038/mt.2014.217.
25373521|a|Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. In these hypotheses, continuous TGF-b1 secretion by alveolar epithelial cells AECs in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells MSCs home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in <d>IPF</d>. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 <g>Stanniocalcin-1</g> secretion in a bleomycin-induced <d>IPF</d> model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-b1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum ER stress, and TGF-b1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 UCP2 and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial-mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for <d>IPF</d>.Molecular Therapy 2014; doi:10.1038/mt.2014.217.
25373521|a|Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. In these hypotheses, continuous <g>TGF-b1</g> secretion by alveolar epithelial cells AECs in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells MSCs home to the injury site and reduce <d>fibrosis</d> by secreting multifunctional antifibrotic humoral factors in <d>IPF</d>. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 <g>Stanniocalcin-1</g> secretion in a bleomycin-induced <d>IPF</d> model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the <d>fibrosis</d>. MSCs secrete large amounts of STC1 in response to <g>TGF-b1</g> in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum ER stress, and <g>TGF-b1</g> production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 UCP2 and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial-mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for <d>IPF</d>.Molecular Therapy 2014; doi:10.1038/mt.2014.217.
25373521|a|Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. In these hypotheses, continuous <g>TGF-b1</g> secretion by alveolar epithelial cells AECs in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells MSCs home to the injury site and reduce <d>fibrosis</d> by secreting multifunctional antifibrotic humoral factors in <d>IPF</d>. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through <g>STC1</g> <g>Stanniocalcin-1</g> secretion in a bleomycin-induced <d>IPF</d> model. Inhalation of recombinant <g>STC1</g> shows the same effects as the injection of MSCs. Using <g>STC1</g> plasmid, it was possible to enhance the ability of MSCs to ameliorate the <d>fibrosis</d>. MSCs secrete large amounts of <g>STC1</g> in response to <g>TGF-b1</g> in comparison to AECs and fibroblasts. The antifibrotic effects of <g>STC1</g> include reducing oxidative stress, <d>endoplasmic reticulum</d> ER stress, and <g>TGF-b1</g> production in AECs. The <g>STC1</g> effects can be controlled by blocking uncoupling protein 2 UCP2 and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that <g>STC1</g> tends to correct the inappropriate epithelial-mesenchymal relationships and that <g>STC1</g> plasmid transfected to MSCs or <g>STC1</g> inhalation could become promising treatments for <d>IPF</d>.Molecular Therapy 2014; doi:10.1038/mt.2014.217.
25373521|a|Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. In these hypotheses, continuous <g>TGF-b1</g> secretion by alveolar epithelial cells AECs in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells MSCs home to the injury site and reduce <d>fibrosis</d> by secreting multifunctional antifibrotic humoral factors in <d>IPF</d>. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through <g>STC1</g> <g>Stanniocalcin-1</g> secretion in a bleomycin-induced <d>IPF</d> model. Inhalation of recombinant <g>STC1</g> shows the same effects as the injection of MSCs. Using <g>STC1</g> plasmid, it was possible to enhance the ability of MSCs to ameliorate the <d>fibrosis</d>. MSCs secrete large amounts of <g>STC1</g> in response to <g>TGF-b1</g> in comparison to AECs and fibroblasts. The antifibrotic effects of <g>STC1</g> include reducing oxidative stress, <d>endoplasmic reticulum</d> <d>ER</d> stress, and <g>TGF-b1</g> production in AECs. The <g>STC1</g> effects can be controlled by blocking uncoupling protein 2 UCP2 and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that <g>STC1</g> tends to correct the inappropriate epithelial-mesenchymal relationships and that <g>STC1</g> plasmid transfected to MSCs or <g>STC1</g> inhalation could become promising treatments for <d>IPF</d>.Molecular Therapy 2014; doi:10.1038/mt.2014.217.
25446881|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a devastating disease characterized by alveolar epithelial cell injury, accumulation of fibroblasts/myofibroblasts and deposition of extracellular matrix proteins. Levels of sphingosine-1-phosphate S1P, a naturally occurring bioactive lipid, are elevated in bronchoalveolar fluids and lung tissues from IPF patients and animal models of <d>pulmonary fibrosis</d>. However, the in  vivo contribution of S1P, regulated by its synthesis catalyzed by Sphingosine kinases SphKs 1 _ 2 and catabolism by S1P phosphatases and S1P lyase S1PL, in the pathogenesis of <d>pulmonary fibrosis</d> is not well defined. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1-, SphK2- or S1PL-knockout mice and SphK inhibitor were used to assess the role of S1P in fibrogenesis. The expression of SphK1 negatively correlated with lung function and survival of patients with IPF. Further, the expressions of SphK1 and S1PL were increased in lung tissues from patients with IPF and bleomycin-challenged mice. Genetic knockdown of SphK1, but not SphK2, ameliorated bleomycin-induced <d>pulmonary fibrosis</d> in mice while deletion of S1PL SGPL1+/- in mice potentiated fibrosis post-bleomycin challenge. TGF-b increased the expression of SphK1 and S1PL in human lung fibroblasts and knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-b mediated signal transduction. Over-expression of S1PL attenuated bleomycin-induced TGF-b secretion and S1P mediated differentiation of human lung fibroblasts through regulation of autophagy. Administration of SphK1 inhibitor 8 days post-bleomycin challenge reduced bleomycin-induced mortality and <d>pulmonary fibrosis</d>. Our results suggest that SphK1 and S1PL play critical roles in the pathology of lung fibrosis and may be novel therapeutic targets.
25446881|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a devastating disease characterized by alveolar epithelial cell injury, accumulation of fibroblasts/myofibroblasts and deposition of extracellular matrix proteins. Levels of sphingosine-1-phosphate S1P, a naturally occurring bioactive lipid, are elevated in bronchoalveolar fluids and lung tissues from <d>IPF</d> patients and animal models of <d>pulmonary fibrosis</d>. However, the in  vivo contribution of S1P, regulated by its synthesis catalyzed by Sphingosine kinases SphKs 1 _ 2 and catabolism by S1P phosphatases and S1P lyase S1PL, in the pathogenesis of <d>pulmonary fibrosis</d> is not well defined. Microarray analysis of blood mononuclear cells from patients with <d>IPF</d> and SphK1-, SphK2- or S1PL-knockout mice and SphK inhibitor were used to assess the role of S1P in fibrogenesis. The expression of SphK1 negatively correlated with lung function and survival of patients with <d>IPF</d>. Further, the expressions of SphK1 and S1PL were increased in lung tissues from patients with <d>IPF</d> and bleomycin-challenged mice. Genetic knockdown of SphK1, but not SphK2, ameliorated bleomycin-induced <d>pulmonary fibrosis</d> in mice while deletion of S1PL SGPL1+/- in mice potentiated fibrosis post-bleomycin challenge. TGF-b increased the expression of SphK1 and S1PL in human lung fibroblasts and knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-b mediated signal transduction. Over-expression of S1PL attenuated bleomycin-induced TGF-b secretion and S1P mediated differentiation of human lung fibroblasts through regulation of autophagy. Administration of SphK1 inhibitor 8 days post-bleomycin challenge reduced bleomycin-induced mortality and <d>pulmonary fibrosis</d>. Our results suggest that SphK1 and S1PL play critical roles in the pathology of lung fibrosis and may be novel therapeutic targets.
25446881|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating disease characterized by alveolar epithelial cell injury, accumulation of fibroblasts/myofibroblasts and deposition of extracellular matrix proteins. Levels of sphingosine-1-phosphate <g>S1P</g>, a naturally occurring bioactive lipid, are elevated in bronchoalveolar fluids and lung tissues from <d>IPF</d> patients and animal models of <d>pulmonary <d>fibrosis</d></d>. However, the in  vivo contribution of <g>S1P</g>, regulated by its synthesis catalyzed by Sphingosine kinases <g>SphK</g>s 1 _ 2 and catabolism by <g>S1P</g> phosphatases and <g>S1P</g> lyase <g>S1P</g>L, in the pathogenesis of <d>pulmonary <d>fibrosis</d></d> is not well defined. Microarray analysis of blood mononuclear cells from patients with <d>IPF</d> and <g><g>SphK</g>1</g>-, <g><g>SphK</g>2</g>- or <g>S1P</g>L-knockout mice and <g>SphK</g> inhibitor were used to assess the role of <g>S1P</g> in fibrogenesis. The expression of <g><g>SphK</g>1</g> negatively correlated with lung function and survival of patients with <d>IPF</d>. Further, the expressions of <g><g>SphK</g>1</g> and <g>S1P</g>L were increased in lung tissues from patients with <d>IPF</d> and bleomycin-challenged mice. Genetic knockdown of <g><g>SphK</g>1</g>, but not <g><g>SphK</g>2</g>, ameliorated bleomycin-induced <d>pulmonary <d>fibrosis</d></d> in mice while deletion of <g>S1P</g>L <g>SGPL1</g>+/- in mice potentiated <d>fibrosis</d> post-bleomycin challenge. TGF-b increased the expression of <g><g>SphK</g>1</g> and <g>S1P</g>L in human lung fibroblasts and knockdown of <g><g>SphK</g>1</g> or treatment with <g>SphK</g> inhibitor attenuated <g>S1P</g> generation and TGF-b mediated signal transduction. Over-expression of <g>S1P</g>L attenuated bleomycin-induced TGF-b secretion and <g>S1P</g> mediated differentiation of human lung fibroblasts through regulation of autophagy. Administration of <g><g>SphK</g>1</g> inhibitor 8 days post-bleomycin challenge reduced bleomycin-induced mortality and <d>pulmonary <d>fibrosis</d></d>. Our results suggest that <g><g>SphK</g>1</g> and <g>S1P</g>L play critical roles in the pathology of lung <d>fibrosis</d> and may be novel therapeutic targets.
25451236|a|Idiopathic pulmonary <d>fibrosis</d> IPF is a fatal lung disorder with unknown cause and no effective treatment. The incidence of and mortality from IPF increase with age, suggesting that advanced age is a major risk factor for IPF. The mechanism underlying the increased susceptibility of the elderly to IPF, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 PAI-1, a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung <d>fibrosis</d> as compared to young mice. Most interestingly, we show that fewer myofibroblasts underwent apoptosis and more myofibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-b1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-b1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-b1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung <d>fibrosis</d> in part by protecting fibroblasts from apoptosis.
25451236|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a fatal lung disorder with unknown cause and no effective treatment. The incidence of and mortality from <d>IPF</d> increase with age, suggesting that advanced age is a major risk factor for <d>IPF</d>. The mechanism underlying the increased susceptibility of the elderly to <d>IPF</d>, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 PAI-1, a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung <d>fibrosis</d> as compared to young mice. Most interestingly, we show that fewer myofibroblasts underwent apoptosis and more myofibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-b1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-b1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-b1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung <d>fibrosis</d> in part by protecting fibroblasts from apoptosis.
25451236|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a fatal <d>lung disorder</d> with unknown cause and no effective treatment. The incidence of and mortality from <d>IPF</d> increase with age, suggesting that advanced age is a major risk factor for <d>IPF</d>. The mechanism underlying the increased susceptibility of the elderly to <d>IPF</d>, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 PAI-1, a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung <d>fibrosis</d> as compared to young mice. Most interestingly, we show that fewer myofibroblasts underwent apoptosis and more myofibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-b1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-b1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-b1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung <d>fibrosis</d> in part by protecting fibroblasts from apoptosis.
25496490|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor VEGFR, platelet-derived growth factor receptor PDGFR and fibroblast growth factor receptor FGFR significantly reduced the rate of decline of forced vital capacity versus placebo. AIM: To determine the in vitro effect of nintedanib on primary human lung fibroblasts. METHODS: Fibroblasts were isolated from lungs of IPF patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF bFGF        nintedanib on: i expression/activation of VEGFR, PDGFR, and FGFR, ii cell proliferation, secretion of iii matrix metalloproteinases MMP, iv tissue inhibitor of metalloproteinase TIMP, and v collagen. RESULTS: IPF fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib. CONCLUSION: Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug's anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.
25496490|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor VEGFR, platelet-derived growth factor receptor PDGFR and fibroblast growth factor receptor FGFR significantly reduced the rate of decline of forced vital capacity versus placebo. AIM: To determine the in vitro effect of nintedanib on primary human lung fibroblasts. METHODS: Fibroblasts were isolated from lungs of <d>IPF</d> patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF bFGF        nintedanib on: i expression/activation of VEGFR, PDGFR, and FGFR, ii cell proliferation, secretion of iii matrix metalloproteinases MMP, iv tissue inhibitor of metalloproteinase TIMP, and v collagen. RESULTS: <d>IPF</d> fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib. CONCLUSION: Our data demonstrate a significant anti-fibrotic effect of nintedanib in <d>IPF</d> fibroblasts. This effect consists of the drug's anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.
25496490|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>lung disease</d> with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor VEGFR, platelet-derived growth factor receptor PDGFR and fibroblast growth factor receptor FGFR significantly reduced the rate of decline of forced vital capacity versus placebo. AIM: To determine the in vitro effect of nintedanib on primary human lung fibroblasts. METHODS: Fibroblasts were isolated from lungs of <d>IPF</d> patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF bFGF        nintedanib on: i expression/activation of VEGFR, PDGFR, and FGFR, ii cell proliferation, secretion of iii matrix metalloproteinases MMP, iv tissue inhibitor of metalloproteinase TIMP, and v collagen. RESULTS: <d>IPF</d> fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib. CONCLUSION: Our data demonstrate a significant anti-fibrotic effect of nintedanib in <d>IPF</d> fibroblasts. This effect consists of the drug's anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.
25505594|a|Transforming growth factor-b TGF-b plays an important role in the development of tissue <d>fibrosis</d>, and molecules inhibiting this pathway are attractive therapeutic targets for fibrotic diseases such as idiopathic pulmonary <d>fibrosis</d> IPF. Activation of TGF-b is the rate-limiting step in TGF-b bioavailability, and activation by the aVb6 integrin is important in <d>fibrosis</d> of the lung, liver, and kidney. Activation of TGF-b by aVb6 requires direct cell-cell contact and measurable release of active TGF-b in extracellular fluid compartments does not reflect tissue specific activation. The aim of this study was to determine the effect of antifibrotic compounds on both total, and specific aVb6 integrin-mediated TGF-b activity. Using a transformed mink lung cell TMLC TGF-b reporter, the effects of potential antifibrotic therapies including an activin-like kinase Alk5 inhibitor, Dexamethasone, Pirfenidone, N-acetylcysteine NAC, and BIBF1120 were assessed. Effects due to aVb6 integrin-mediated TGF-b activity were measured using reporter cells cocultured with cells expressing aVb6 integrins. These high-throughput studies were validated using a phosphorylated Smad2 Enzyme-Linked Immunosorbent Assay. Alk5 inhibitors are potent inhibitors of TGF-b activity, whereas the novel antifibrotics, Pirfenidone, BIBF1120, and NAC are only moderate inhibitors, and Dexamethasone does not specifically affect TGF-bactivity, but inhibits TGF-b-induced gene expression. None of the current small molecular inhibitors inhibit aVb6-mediated TGF-b activity. These results demonstrate the potential of this high-throughput assay of aVb6-specific TGF-b activity and illustrate that currently available antifibrotics have limited effects on aVb6 integrin-mediated TGF-b activity.
25505594|a|Transforming growth factor-b TGF-b plays an important role in the development of tissue <d>fibrosis</d>, and molecules inhibiting this pathway are attractive therapeutic targets for <d>fibrotic diseases</d> such as idiopathic pulmonary <d>fibrosis</d> IPF. Activation of TGF-b is the rate-limiting step in TGF-b bioavailability, and activation by the aVb6 integrin is important in <d>fibrosis</d> of the lung, liver, and kidney. Activation of TGF-b by aVb6 requires direct cell-cell contact and measurable release of active TGF-b in extracellular fluid compartments does not reflect tissue specific activation. The aim of this study was to determine the effect of antifibrotic compounds on both total, and specific aVb6 integrin-mediated TGF-b activity. Using a transformed mink lung cell TMLC TGF-b reporter, the effects of potential antifibrotic therapies including an activin-like kinase Alk5 inhibitor, Dexamethasone, Pirfenidone, N-acetylcysteine NAC, and BIBF1120 were assessed. Effects due to aVb6 integrin-mediated TGF-b activity were measured using reporter cells cocultured with cells expressing aVb6 integrins. These high-throughput studies were validated using a phosphorylated Smad2 Enzyme-Linked Immunosorbent Assay. Alk5 inhibitors are potent inhibitors of TGF-b activity, whereas the novel antifibrotics, Pirfenidone, BIBF1120, and NAC are only moderate inhibitors, and Dexamethasone does not specifically affect TGF-bactivity, but inhibits TGF-b-induced gene expression. None of the current small molecular inhibitors inhibit aVb6-mediated TGF-b activity. These results demonstrate the potential of this high-throughput assay of aVb6-specific TGF-b activity and illustrate that currently available antifibrotics have limited effects on aVb6 integrin-mediated TGF-b activity.
25505594|a|Transforming growth factor-b TGF-b plays an important role in the development of tissue <d>fibrosis</d>, and molecules inhibiting this pathway are attractive therapeutic targets for <d>fibrotic diseases</d> such as idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. Activation of TGF-b is the rate-limiting step in TGF-b bioavailability, and activation by the aVb6 integrin is important in <d>fibrosis</d> of the lung, liver, and kidney. Activation of TGF-b by aVb6 requires direct cell-cell contact and measurable release of active TGF-b in extracellular fluid compartments does not reflect tissue specific activation. The aim of this study was to determine the effect of antifibrotic compounds on both total, and specific aVb6 integrin-mediated TGF-b activity. Using a transformed mink lung cell TMLC TGF-b reporter, the effects of potential antifibrotic therapies including an activin-like kinase Alk5 inhibitor, Dexamethasone, Pirfenidone, N-acetylcysteine NAC, and BIBF1120 were assessed. Effects due to aVb6 integrin-mediated TGF-b activity were measured using reporter cells cocultured with cells expressing aVb6 integrins. These high-throughput studies were validated using a phosphorylated Smad2 Enzyme-Linked Immunosorbent Assay. Alk5 inhibitors are potent inhibitors of TGF-b activity, whereas the novel antifibrotics, Pirfenidone, BIBF1120, and NAC are only moderate inhibitors, and Dexamethasone does not specifically affect TGF-bactivity, but inhibits TGF-b-induced gene expression. None of the current small molecular inhibitors inhibit aVb6-mediated TGF-b activity. These results demonstrate the potential of this high-throughput assay of aVb6-specific TGF-b activity and illustrate that currently available antifibrotics have limited effects on aVb6 integrin-mediated TGF-b activity.
25524739|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> IPF is one of the most common and severe interstitial lung diseases. Epithelial-to-mesenchymal transition EMT is a process whereby epithelial cells undergo transition to a mesenchymal phenotype. This process has been shown to contribute to IPF. MicroRNAs miRNAs are small non-coding RNAs of 18-24 nucleotides in length which regulate gene expression. Several studies have implicated miRNAs in EMT; however, specific miRNAs that regulate EMT in IPF have not yet been identified. In this study, we identified 6 up-regulated and 3 down-regulated miRNAs in a human lung epithelial cell EMT model using miRNA microarray and real-time PCR. Overexpression of one of these up-regulated miRNAs, <g>miR-424</g>, increased the expression of a-smooth muscle actin, an indicator of myofibroblast differentiation, but had no effects on the epithelial or mesenchymal cell markers. <g>miR-424</g> enhanced the activity of the TGF-b signaling pathway, as demonstrated by a luciferase reporter assay. Further experiments showed that <g>miR-424</g> decreased the protein expression of Smurf2, a negative regulator of TGF-b signaling, indicating that <g>miR-424</g> exerts a forward regulatory loop in the TGF-b signaling pathway. Our results suggest that <g>miR-424</g> regulates the myofibroblast differentiation during EMT by potentiating the TGF-b signaling pathway, likely through Smurf2.
25524739|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is one of the most common and severe interstitial lung diseases. Epithelial-to-mesenchymal transition EMT is a process whereby epithelial cells undergo transition to a mesenchymal phenotype. This process has been shown to contribute to <d>IPF</d>. MicroRNAs miRNAs are small non-coding RNAs of 18-24 nucleotides in length which regulate gene expression. Several studies have implicated miRNAs in EMT; however, specific miRNAs that regulate EMT in <d>IPF</d> have not yet been identified. In this study, we identified 6 up-regulated and 3 down-regulated miRNAs in a human lung epithelial cell EMT model using miRNA microarray and real-time PCR. Overexpression of one of these up-regulated miRNAs, <g>miR-424</g>, increased the expression of a-smooth muscle actin, an indicator of myofibroblast differentiation, but had no effects on the epithelial or mesenchymal cell markers. <g>miR-424</g> enhanced the activity of the TGF-b signaling pathway, as demonstrated by a luciferase reporter assay. Further experiments showed that <g>miR-424</g> decreased the protein expression of Smurf2, a negative regulator of TGF-b signaling, indicating that <g>miR-424</g> exerts a forward regulatory loop in the TGF-b signaling pathway. Our results suggest that <g>miR-424</g> regulates the myofibroblast differentiation during EMT by potentiating the TGF-b signaling pathway, likely through Smurf2.
25524739|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is one of the most common and severe <d>interstitial lung diseases</d>. Epithelial-to-mesenchymal transition EMT is a process whereby epithelial cells undergo transition to a mesenchymal phenotype. This process has been shown to contribute to <d>IPF</d>. MicroRNAs miRNAs are small non-coding RNAs of 18-24 nucleotides in length which regulate gene expression. Several studies have implicated miRNAs in EMT; however, specific miRNAs that regulate EMT in <d>IPF</d> have not yet been identified. In this study, we identified 6 up-regulated and 3 down-regulated miRNAs in a human lung epithelial cell EMT model using miRNA microarray and real-time PCR. Overexpression of one of these up-regulated miRNAs, <g>miR-424</g>, increased the expression of a-smooth muscle actin, an indicator of myofibroblast differentiation, but had no effects on the epithelial or mesenchymal cell markers. <g>miR-424</g> enhanced the activity of the TGF-b signaling pathway, as demonstrated by a luciferase reporter assay. Further experiments showed that <g>miR-424</g> decreased the protein expression of Smurf2, a negative regulator of TGF-b signaling, indicating that <g>miR-424</g> exerts a forward regulatory loop in the TGF-b signaling pathway. Our results suggest that <g>miR-424</g> regulates the myofibroblast differentiation during EMT by potentiating the TGF-b signaling pathway, likely through Smurf2.
25533688|a|OBJECTIVE: To investigate the expressions of cytokines in <d>idiopathic pulmonary fibrosis</d> IPF and in idiopathic nonspecific interstitial pneumonia INSIP; To discuss expressions and meanings of bone morphogenetic protein 7 <g>BMP-7</g> and transforming growth factor beta <g>TGF-b</g> in IPF and IPF. METHODS: Selected 47 cases of idiopathic interstitial pneumonia IIP, which were diagnosed by clinical-radiologic-pathologic CRP, and classified into two groups which were group IPF 25 IPF and group INSIP 22 INSIP, including 6 cellular pattern and 16 fibrosing pattern. The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of <g>BMP-7</g> and <g>TGF-b</g> in both kinds of IIPs. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. RESULTS: According to gene microarray results, these two groups were up-expression in TGF family,IL family and TNF family. Most of BMP members were down-expression, in comparison with the control group, except BMP-5,BMP-8B and BMP-15. As the tissue microarray results demonstrated, compared with normal lung tissues,<g>BMP-7</g> expressed decreasingly in IPF and INSIP groups t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001. The expression of IPF were lower than INSIP t = 5.387, P < 0.05; In INSIP group, patients of cellular pattern expressed <g>BMP-7</g> more than fibrosing pattern's t = -5.341, P < 0.001. There were dramatically increasing expressions of <g>TGF-b</g> in IPF and INSIP, when compared with the control group t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001 and it presented negative correlation with <g>BMP-7</g>group IPF: r = -0.771, P < 0.001; group INSIP: r = -0.729, P < 0.001. 3 Clinical follow-up data showed, the stabilityimprovement, deterioration and death rates of the group IPF and the group INSIP were, respectively, 00%, 2 8%, 23 92% and 15 68.1%, 3 13.6%, 4 18.2%. The results were statistically significant all P < 0.05. The median survival time of the part with higher <g>BMP-7</g> expression and the part with relatively lower <g>BMP-7</g> expression, in the group IPF, were 110.8 and 66.4 months t = -2.686, P < 0.05; In the group INSIP, were 146.4 and 74.9 months t = -3.037, P < 0.05. CONCLUSIONS: Cellular cytokines presented different expression profiles in IPF and INSIP patients. Differently with highly activated <g>TGF-b</g>, <g>BMP-7</g> was inhibited in IIP patients, which would remind the degree of fibrosis and prognosis of IIP. <g>BMP-7</g> would be expected to be a novel target for IIP pathogenesis and prognostic research.
25533688|a|OBJECTIVE: To investigate the expressions of cytokines in <d>idiopathic pulmonary fibrosis</d> IPF and in <d>idiopathic nonspecific interstitial pneumonia</d> INSIP; To discuss expressions and meanings of bone morphogenetic protein 7 <g>BMP-7</g> and transforming growth factor beta <g>TGF-b</g> in IPF and IPF. METHODS: Selected 47 cases of idiopathic interstitial pneumonia IIP, which were diagnosed by clinical-radiologic-pathologic CRP, and classified into two groups which were group IPF 25 IPF and group INSIP 22 INSIP, including 6 cellular pattern and 16 fibrosing pattern. The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of <g>BMP-7</g> and <g>TGF-b</g> in both kinds of IIPs. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. RESULTS: According to gene microarray results, these two groups were up-expression in TGF family,IL family and TNF family. Most of BMP members were down-expression, in comparison with the control group, except BMP-5,BMP-8B and BMP-15. As the tissue microarray results demonstrated, compared with normal lung tissues,<g>BMP-7</g> expressed decreasingly in IPF and INSIP groups t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001. The expression of IPF were lower than INSIP t = 5.387, P < 0.05; In INSIP group, patients of cellular pattern expressed <g>BMP-7</g> more than fibrosing pattern's t = -5.341, P < 0.001. There were dramatically increasing expressions of <g>TGF-b</g> in IPF and INSIP, when compared with the control group t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001 and it presented negative correlation with <g>BMP-7</g>group IPF: r = -0.771, P < 0.001; group INSIP: r = -0.729, P < 0.001. 3 Clinical follow-up data showed, the stabilityimprovement, deterioration and death rates of the group IPF and the group INSIP were, respectively, 00%, 2 8%, 23 92% and 15 68.1%, 3 13.6%, 4 18.2%. The results were statistically significant all P < 0.05. The median survival time of the part with higher <g>BMP-7</g> expression and the part with relatively lower <g>BMP-7</g> expression, in the group IPF, were 110.8 and 66.4 months t = -2.686, P < 0.05; In the group INSIP, were 146.4 and 74.9 months t = -3.037, P < 0.05. CONCLUSIONS: Cellular cytokines presented different expression profiles in IPF and INSIP patients. Differently with highly activated <g>TGF-b</g>, <g>BMP-7</g> was inhibited in IIP patients, which would remind the degree of fibrosis and prognosis of IIP. <g>BMP-7</g> would be expected to be a novel target for IIP pathogenesis and prognostic research.
25533688|a|OBJECTIVE: To investigate the expressions of cytokines in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and in <d>idiopathic nonspecific interstitial pneumonia</d> INSIP; To discuss expressions and meanings of bone morphogenetic protein 7 <g>BMP-7</g> and transforming growth factor beta <g>TGF-b</g> in <d>IPF</d> and <d>IPF</d>. METHODS: Selected 47 cases of idiopathic interstitial pneumonia IIP, which were diagnosed by clinical-radiologic-pathologic CRP, and classified into two groups which were group <d>IPF</d> 25 <d>IPF</d> and group INSIP 22 INSIP, including 6 cellular pattern and 16 fibrosing pattern. The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of <g>BMP-7</g> and <g>TGF-b</g> in both kinds of IIPs. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. RESULTS: According to gene microarray results, these two groups were up-expression in TGF family,IL family and TNF family. Most of BMP members were down-expression, in comparison with the control group, except BMP-5,BMP-8B and BMP-15. As the tissue microarray results demonstrated, compared with normal lung tissues,<g>BMP-7</g> expressed decreasingly in <d>IPF</d> and INSIP groups t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001. The expression of <d>IPF</d> were lower than INSIP t = 5.387, P < 0.05; In INSIP group, patients of cellular pattern expressed <g>BMP-7</g> more than fibrosing pattern's t = -5.341, P < 0.001. There were dramatically increasing expressions of <g>TGF-b</g> in <d>IPF</d> and INSIP, when compared with the control group t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001 and it presented negative correlation with <g>BMP-7</g>group <d>IPF</d>: r = -0.771, P < 0.001; group INSIP: r = -0.729, P < 0.001. 3 Clinical follow-up data showed, the stabilityimprovement, deterioration and death rates of the group <d>IPF</d> and the group INSIP were, respectively, 00%, 2 8%, 23 92% and 15 68.1%, 3 13.6%, 4 18.2%. The results were statistically significant all P < 0.05. The median survival time of the part with higher <g>BMP-7</g> expression and the part with relatively lower <g>BMP-7</g> expression, in the group <d>IPF</d>, were 110.8 and 66.4 months t = -2.686, P < 0.05; In the group INSIP, were 146.4 and 74.9 months t = -3.037, P < 0.05. CONCLUSIONS: Cellular cytokines presented different expression profiles in <d>IPF</d> and INSIP patients. Differently with highly activated <g>TGF-b</g>, <g>BMP-7</g> was inhibited in IIP patients, which would remind the degree of fibrosis and prognosis of IIP. <g>BMP-7</g> would be expected to be a novel target for IIP pathogenesis and prognostic research.
25533688|a|OBJECTIVE: To investigate the expressions of cytokines in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and in <d>idiopathic nonspecific interstitial pneumonia</d> <d>INSIP</d>; To discuss expressions and meanings of bone morphogenetic protein 7 <g>BMP-7</g> and transforming growth factor beta <g>TGF-b</g> in <d>IPF</d> and <d>IPF</d>. METHODS: Selected 47 cases of idiopathic interstitial pneumonia IIP, which were diagnosed by clinical-radiologic-pathologic CRP, and classified into two groups which were group <d>IPF</d> 25 <d>IPF</d> and group <d>INSIP</d> 22 <d>INSIP</d>, including 6 cellular pattern and 16 fibrosing pattern. The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of <g>BMP-7</g> and <g>TGF-b</g> in both kinds of IIPs. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. RESULTS: According to gene microarray results, these two groups were up-expression in TGF family,IL family and TNF family. Most of BMP members were down-expression, in comparison with the control group, except BMP-5,BMP-8B and BMP-15. As the tissue microarray results demonstrated, compared with normal lung tissues,<g>BMP-7</g> expressed decreasingly in <d>IPF</d> and <d>INSIP</d> groups t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001. The expression of <d>IPF</d> were lower than <d>INSIP</d> t = 5.387, P < 0.05; In <d>INSIP</d> group, patients of cellular pattern expressed <g>BMP-7</g> more than fibrosing pattern's t = -5.341, P < 0.001. There were dramatically increasing expressions of <g>TGF-b</g> in <d>IPF</d> and <d>INSIP</d>, when compared with the control group t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001 and it presented negative correlation with <g>BMP-7</g>group <d>IPF</d>: r = -0.771, P < 0.001; group <d>INSIP</d>: r = -0.729, P < 0.001. 3 Clinical follow-up data showed, the stabilityimprovement, deterioration and death rates of the group <d>IPF</d> and the group <d>INSIP</d> were, respectively, 00%, 2 8%, 23 92% and 15 68.1%, 3 13.6%, 4 18.2%. The results were statistically significant all P < 0.05. The median survival time of the part with higher <g>BMP-7</g> expression and the part with relatively lower <g>BMP-7</g> expression, in the group <d>IPF</d>, were 110.8 and 66.4 months t = -2.686, P < 0.05; In the group <d>INSIP</d>, were 146.4 and 74.9 months t = -3.037, P < 0.05. CONCLUSIONS: Cellular cytokines presented different expression profiles in <d>IPF</d> and <d>INSIP</d> patients. Differently with highly activated <g>TGF-b</g>, <g>BMP-7</g> was inhibited in IIP patients, which would remind the degree of fibrosis and prognosis of IIP. <g>BMP-7</g> would be expected to be a novel target for IIP pathogenesis and prognostic research.
25533688|a|OBJECTIVE: To investigate the expressions of cytokines in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and in <d>idiopathic nonspecific interstitial pneumonia</d> <d>INSIP</d>; To discuss expressions and meanings of <g>bone morphogenetic protein 7</g> <g>BMP-7</g> and <g>transforming growth factor beta</g> <g>TGF-b</g> in <d>IPF</d> and <d>IPF</d>. METHODS: Selected 47 cases of <d>idiopathic interstitial pneumonia</d> IIP, which were diagnosed by clinical-radiologic-pathologic CRP, and classified into two groups which were group <d>IPF</d> 25 <d>IPF</d> and group <d>INSIP</d> 22 <d>INSIP</d>, including 6 cellular pattern and 16 fibrosing pattern. The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of <g>BMP-7</g> and <g>TGF-b</g> in both kinds of IIPs. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. RESULTS: According to gene microarray results, these two groups were up-expression in TGF family,IL family and TNF family. Most of BMP members were down-expression, in comparison with the control group, except BMP-5,BMP-8B and BMP-15. As the tissue microarray results demonstrated, compared with normal lung tissues,<g>BMP-7</g> expressed decreasingly in <d>IPF</d> and <d>INSIP</d> groups t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001. The expression of <d>IPF</d> were lower than <d>INSIP</d> t = 5.387, P < 0.05; In <d>INSIP</d> group, patients of cellular pattern expressed <g>BMP-7</g> more than fibrosing pattern's t = -5.341, P < 0.001. There were dramatically increasing expressions of <g>TGF-b</g> in <d>IPF</d> and <d>INSIP</d>, when compared with the control group t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001 and it presented negative correlation with <g>BMP-7</g>group <d>IPF</d>: r = -0.771, P < 0.001; group <d>INSIP</d>: r = -0.729, P < 0.001. 3 Clinical follow-up data showed, the stabilityimprovement, deterioration and death rates of the group <d>IPF</d> and the group <d>INSIP</d> were, respectively, 00%, 2 8%, 23 92% and 15 68.1%, 3 13.6%, 4 18.2%. The results were statistically significant all P < 0.05. The median survival time of the part with higher <g>BMP-7</g> expression and the part with relatively lower <g>BMP-7</g> expression, in the group <d>IPF</d>, were 110.8 and 66.4 months t = -2.686, P < 0.05; In the group <d>INSIP</d>, were 146.4 and 74.9 months t = -3.037, P < 0.05. CONCLUSIONS: Cellular cytokines presented different expression profiles in <d>IPF</d> and <d>INSIP</d> patients. Differently with highly activated <g>TGF-b</g>, <g>BMP-7</g> was inhibited in IIP patients, which would remind the degree of fibrosis and prognosis of IIP. <g>BMP-7</g> would be expected to be a novel target for IIP pathogenesis and prognostic research.
25533688|a|OBJECTIVE: To investigate the expressions of cytokines in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and in <d>idiopathic nonspecific interstitial pneumonia</d> <d>INSIP</d>; To discuss expressions and meanings of <g>bone morphogenetic protein 7</g> <g>BMP-7</g> and <g>transforming growth factor beta</g> <g>TGF-b</g> in <d>IPF</d> and <d>IPF</d>. METHODS: Selected 47 cases of <d>idiopathic interstitial pneumonia</d> <d>IIP</d>, which were diagnosed by clinical-radiologic-pathologic CRP, and classified into two groups which were group <d>IPF</d> 25 <d>IPF</d> and group <d>INSIP</d> 22 <d>INSIP</d>, including 6 cellular pattern and 16 fibrosing pattern. The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of <g>BMP-7</g> and <g>TGF-b</g> in both kinds of <d>IIP</d>s. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. RESULTS: According to gene microarray results, these two groups were up-expression in TGF family,IL family and TNF family. Most of BMP members were down-expression, in comparison with the control group, except BMP-5,BMP-8B and BMP-15. As the tissue microarray results demonstrated, compared with normal lung tissues,<g>BMP-7</g> expressed decreasingly in <d>IPF</d> and <d>INSIP</d> groups t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001. The expression of <d>IPF</d> were lower than <d>INSIP</d> t = 5.387, P < 0.05; In <d>INSIP</d> group, patients of cellular pattern expressed <g>BMP-7</g> more than fibrosing pattern's t = -5.341, P < 0.001. There were dramatically increasing expressions of <g>TGF-b</g> in <d>IPF</d> and <d>INSIP</d>, when compared with the control group t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001 and it presented negative correlation with <g>BMP-7</g>group <d>IPF</d>: r = -0.771, P < 0.001; group <d>INSIP</d>: r = -0.729, P < 0.001. 3 Clinical follow-up data showed, the stabilityimprovement, deterioration and death rates of the group <d>IPF</d> and the group <d>INSIP</d> were, respectively, 00%, 2 8%, 23 92% and 15 68.1%, 3 13.6%, 4 18.2%. The results were statistically significant all P < 0.05. The median survival time of the part with higher <g>BMP-7</g> expression and the part with relatively lower <g>BMP-7</g> expression, in the group <d>IPF</d>, were 110.8 and 66.4 months t = -2.686, P < 0.05; In the group <d>INSIP</d>, were 146.4 and 74.9 months t = -3.037, P < 0.05. CONCLUSIONS: Cellular cytokines presented different expression profiles in <d>IPF</d> and <d>INSIP</d> patients. Differently with highly activated <g>TGF-b</g>, <g>BMP-7</g> was inhibited in <d>IIP</d> patients, which would remind the degree of fibrosis and prognosis of <d>IIP</d>. <g>BMP-7</g> would be expected to be a novel target for <d>IIP</d> pathogenesis and prognostic research.
25533688|a|OBJECTIVE: To investigate the expressions of cytokines in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and in <d>idiopathic nonspecific interstitial pneumonia</d> <d>INSIP</d>; To discuss expressions and meanings of <g>bone morphogenetic protein 7</g> <g>BMP-7</g> and <g>transforming growth factor beta</g> <g>TGF-b</g> in <d>IPF</d> and <d>IPF</d>. METHODS: Selected 47 cases of <d>idiopathic interstitial pneumonia</d> <d>IIP</d>, which were diagnosed by clinical-radiologic-pathologic CRP, and classified into two groups which were group <d>IPF</d> 25 <d>IPF</d> and group <d>INSIP</d> 22 <d>INSIP</d>, including 6 cellular pattern and 16 fibrosing pattern. The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of <g>BMP-7</g> and <g>TGF-b</g> in both kinds of <d>IIP</d>s. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. RESULTS: According to gene microarray results, these two groups were up-expression in TGF family,IL family and <d>TNF</d> family. Most of BMP members were down-expression, in comparison with the control group, except BMP-5,BMP-8B and BMP-15. As the tissue microarray results demonstrated, compared with normal lung tissues,<g>BMP-7</g> expressed decreasingly in <d>IPF</d> and <d>INSIP</d> groups t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001. The expression of <d>IPF</d> were lower than <d>INSIP</d> t = 5.387, P < 0.05; In <d>INSIP</d> group, patients of cellular pattern expressed <g>BMP-7</g> more than fibrosing pattern's t = -5.341, P < 0.001. There were dramatically increasing expressions of <g>TGF-b</g> in <d>IPF</d> and <d>INSIP</d>, when compared with the control group t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001 and it presented negative correlation with <g>BMP-7</g>group <d>IPF</d>: r = -0.771, P < 0.001; group <d>INSIP</d>: r = -0.729, P < 0.001. 3 Clinical follow-up data showed, the stabilityimprovement, deterioration and death rates of the group <d>IPF</d> and the group <d>INSIP</d> were, respectively, 00%, 2 8%, 23 92% and 15 68.1%, 3 13.6%, 4 18.2%. The results were statistically significant all P < 0.05. The median survival time of the part with higher <g>BMP-7</g> expression and the part with relatively lower <g>BMP-7</g> expression, in the group <d>IPF</d>, were 110.8 and 66.4 months t = -2.686, P < 0.05; In the group <d>INSIP</d>, were 146.4 and 74.9 months t = -3.037, P < 0.05. CONCLUSIONS: Cellular cytokines presented different expression profiles in <d>IPF</d> and <d>INSIP</d> patients. Differently with highly activated <g>TGF-b</g>, <g>BMP-7</g> was inhibited in <d>IIP</d> patients, which would remind the degree of fibrosis and prognosis of <d>IIP</d>. <g>BMP-7</g> would be expected to be a novel target for <d>IIP</d> pathogenesis and prognostic research.
25533688|a|OBJECTIVE: To investigate the expressions of cytokines in <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> and in <d>idiopathic nonspecific interstitial pneumonia</d> <d>INSIP</d>; To discuss expressions and meanings of <g>bone morphogenetic protein 7</g> <g>BMP-7</g> and <g>transforming growth factor beta</g> <g>TGF-b</g> in <d>IPF</d> and <d>IPF</d>. METHODS: Selected 47 cases of <d>idiopathic interstitial pneumonia</d> <d>IIP</d>, which were diagnosed by clinical-radiologic-pathologic CRP, and classified into two groups which were group <d>IPF</d> 25 <d>IPF</d> and group <d>INSIP</d> 22 <d>INSIP</d>, including 6 cellular pattern and 16 fibrosing pattern. The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of <g>BMP-7</g> and <g>TGF-b</g> in both kinds of <d>IIP</d>s. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. RESULTS: According to gene microarray results, these two groups were up-expression in TGF family,IL family and <d>TNF</d> family. Most of BMP members were down-expression, in comparison with the control group, except <g>BMP-5</g>,<g>BMP-8B</g> and <g>BMP-15</g>. As the tissue microarray results demonstrated, compared with normal lung tissues,<g>BMP-7</g> expressed decreasingly in <d>IPF</d> and <d>INSIP</d> groups t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001. The expression of <d>IPF</d> were lower than <d>INSIP</d> t = 5.387, P < 0.05; In <d>INSIP</d> group, patients of cellular pattern expressed <g>BMP-7</g> more than fibrosing pattern's t = -5.341, P < 0.001. There were dramatically increasing expressions of <g>TGF-b</g> in <d>IPF</d> and <d>INSIP</d>, when compared with the control group t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001 and it presented negative correlation with <g>BMP-7</g>group <d>IPF</d>: r = -0.771, P < 0.001; group <d>INSIP</d>: r = -0.729, P < 0.001. 3 Clinical follow-up data showed, the stabilityimprovement, deterioration and death rates of the group <d>IPF</d> and the group <d>INSIP</d> were, respectively, 00%, 2 8%, 23 92% and 15 68.1%, 3 13.6%, 4 18.2%. The results were statistically significant all P < 0.05. The median survival time of the part with higher <g>BMP-7</g> expression and the part with relatively lower <g>BMP-7</g> expression, in the group <d>IPF</d>, were 110.8 and 66.4 months t = -2.686, P < 0.05; In the group <d>INSIP</d>, were 146.4 and 74.9 months t = -3.037, P < 0.05. CONCLUSIONS: Cellular cytokines presented different expression profiles in <d>IPF</d> and <d>INSIP</d> patients. Differently with highly activated <g>TGF-b</g>, <g>BMP-7</g> was inhibited in <d>IIP</d> patients, which would remind the degree of <d>fibrosis</d> and prognosis of <d>IIP</d>. <g>BMP-7</g> would be expected to be a novel target for <d>IIP</d> pathogenesis and prognostic research.
25555634|a|Activins, cytokines belonging to the transforming growth factor-b superfamily, have an important role in inflammation and fibrosis. Activin A has been suggested to participate in the pathophysiology of human <d>idiopathic pulmonary fibrosis</d> IPF, but studies on the role of activin B are sparse. Canine IPF CIPF is an incurable interstitial lung disease occurring particularly in West Highland white terriers WHWTs. During the disease course there are acute exacerbations AEs and the condition has a poor prognosis. Microscopically, AEs of CIPF are characterized by diffuse alveolar damage, which is also a key feature of acute respiratory distress syndrome ARDS. The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with CIPF and WHWTs with CIPF and concurrent AE, and dogs of various breeds with ARDS and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid BALF from WHWTs with CIPF and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with CIPF as well as in the lungs of dogs with ARDS. Activin B was detected in the BALF of WHWTs with CIPF, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of CIPF and might act as a marker of alveolar epithelial damage.
25555634|a|Activins, cytokines belonging to the transforming growth factor-b superfamily, have an important role in inflammation and fibrosis. Activin A has been suggested to participate in the pathophysiology of human <d>idiopathic pulmonary fibrosis</d> IPF, but studies on the role of activin B are sparse. Canine IPF CIPF is an incurable interstitial lung disease occurring particularly in West Highland white terriers WHWTs. During the disease course there are acute exacerbations AEs and the condition has a poor prognosis. Microscopically, AEs of CIPF are characterized by <d>diffuse alveolar damage</d>, which is also a key feature of acute respiratory distress syndrome ARDS. The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with CIPF and WHWTs with CIPF and concurrent AE, and dogs of various breeds with ARDS and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid BALF from WHWTs with CIPF and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with CIPF as well as in the lungs of dogs with ARDS. Activin B was detected in the BALF of WHWTs with CIPF, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of CIPF and might act as a marker of alveolar epithelial damage.
25555634|a|Activins, cytokines belonging to the transforming growth factor-b superfamily, have an important role in <d>inflammation</d> and fibrosis. Activin A has been suggested to participate in the pathophysiology of human <d>idiopathic pulmonary fibrosis</d> IPF, but studies on the role of activin B are sparse. Canine IPF CIPF is an incurable interstitial lung disease occurring particularly in West Highland white terriers WHWTs. During the disease course there are acute exacerbations AEs and the condition has a poor prognosis. Microscopically, AEs of CIPF are characterized by <d>diffuse alveolar damage</d>, which is also a key feature of acute respiratory distress syndrome ARDS. The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with CIPF and WHWTs with CIPF and concurrent AE, and dogs of various breeds with ARDS and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid BALF from WHWTs with CIPF and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with CIPF as well as in the lungs of dogs with ARDS. Activin B was detected in the BALF of WHWTs with CIPF, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of CIPF and might act as a marker of alveolar epithelial damage.
25555634|a|Activins, cytokines belonging to the transforming growth factor-b superfamily, have an important role in <d>inflammation</d> and <d>fibrosis</d>. Activin A has been suggested to participate in the pathophysiology of human <d>idiopathic pulmonary <d>fibrosis</d></d> IPF, but studies on the role of activin B are sparse. Canine IPF CIPF is an incurable interstitial lung disease occurring particularly in West Highland white terriers WHWTs. During the disease course there are acute exacerbations AEs and the condition has a poor prognosis. Microscopically, AEs of CIPF are characterized by <d>diffuse alveolar damage</d>, which is also a key feature of acute respiratory distress syndrome ARDS. The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with CIPF and WHWTs with CIPF and concurrent AE, and dogs of various breeds with ARDS and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid BALF from WHWTs with CIPF and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with CIPF as well as in the lungs of dogs with ARDS. Activin B was detected in the BALF of WHWTs with CIPF, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of CIPF and might act as a marker of alveolar epithelial damage.
25555634|a|Activins, cytokines belonging to the transforming growth factor-b superfamily, have an important role in <d>inflammation</d> and <d>fibrosis</d>. Activin A has been suggested to participate in the pathophysiology of human <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, but studies on the role of activin B are sparse. Canine <d>IPF</d> C<d>IPF</d> is an incurable interstitial lung disease occurring particularly in West Highland white terriers WHWTs. During the disease course there are acute exacerbations AEs and the condition has a poor prognosis. Microscopically, AEs of C<d>IPF</d> are characterized by <d>diffuse alveolar damage</d>, which is also a key feature of acute respiratory distress syndrome ARDS. The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with C<d>IPF</d> and WHWTs with C<d>IPF</d> and concurrent AE, and dogs of various breeds with ARDS and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid BALF from WHWTs with C<d>IPF</d> and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with C<d>IPF</d> as well as in the lungs of dogs with ARDS. Activin B was detected in the BALF of WHWTs with C<d>IPF</d>, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of C<d>IPF</d> and might act as a marker of alveolar epithelial damage.
25555634|a|Activins, cytokines belonging to the transforming growth factor-b superfamily, have an important role in <d>inflammation</d> and <d>fibrosis</d>. Activin A has been suggested to participate in the pathophysiology of human <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, but studies on the role of activin B are sparse. Canine <d>IPF</d> C<d>IPF</d> is an incurable <d>interstitial lung disease</d> occurring particularly in West Highland white terriers WHWTs. During the disease course there are acute exacerbations AEs and the condition has a poor prognosis. Microscopically, AEs of C<d>IPF</d> are characterized by <d>diffuse alveolar damage</d>, which is also a key feature of acute respiratory distress syndrome ARDS. The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with C<d>IPF</d> and WHWTs with C<d>IPF</d> and concurrent AE, and dogs of various breeds with ARDS and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid BALF from WHWTs with C<d>IPF</d> and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with C<d>IPF</d> as well as in the lungs of dogs with ARDS. Activin B was detected in the BALF of WHWTs with C<d>IPF</d>, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of C<d>IPF</d> and might act as a marker of alveolar epithelial damage.
25555634|a|Activins, cytokines belonging to the transforming growth factor-b superfamily, have an important role in <d>inflammation</d> and <d>fibrosis</d>. Activin A has been suggested to participate in the pathophysiology of human <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, but studies on the role of activin B are sparse. Canine <d>IPF</d> C<d>IPF</d> is an incurable <d>interstitial lung disease</d> occurring particularly in West Highland white terriers WHWTs. During the disease course there are acute exacerbations AEs and the condition has a poor prognosis. Microscopically, AEs of C<d>IPF</d> are characterized by <d>diffuse alveolar damage</d>, which is also a key feature of <d>acute respiratory distress syndrome</d> ARDS. The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with C<d>IPF</d> and WHWTs with C<d>IPF</d> and concurrent AE, and dogs of various breeds with ARDS and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid BALF from WHWTs with C<d>IPF</d> and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with C<d>IPF</d> as well as in the lungs of dogs with ARDS. Activin B was detected in the BALF of WHWTs with C<d>IPF</d>, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of C<d>IPF</d> and might act as a marker of alveolar epithelial damage.
25555634|a|Activins, cytokines belonging to the transforming growth factor-b superfamily, have an important role in <d>inflammation</d> and <d>fibrosis</d>. Activin A has been suggested to participate in the pathophysiology of human <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, but studies on the role of activin B are sparse. Canine <d>IPF</d> C<d>IPF</d> is an incurable <d>interstitial lung disease</d> occurring particularly in West Highland white terriers WHWTs. During the disease course there are acute exacerbations AEs and the condition has a poor prognosis. Microscopically, AEs of C<d>IPF</d> are characterized by <d>diffuse alveolar damage</d>, which is also a key feature of <d>acute respiratory distress syndrome</d> <d>ARDS</d>. The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with C<d>IPF</d> and WHWTs with C<d>IPF</d> and concurrent AE, and dogs of various breeds with <d>ARDS</d> and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid BALF from WHWTs with C<d>IPF</d> and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with C<d>IPF</d> as well as in the lungs of dogs with <d>ARDS</d>. Activin B was detected in the BALF of WHWTs with C<d>IPF</d>, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of C<d>IPF</d> and might act as a marker of alveolar epithelial damage.
25555634|a|Activins, cytokines belonging to the transforming growth factor-b superfamily, have an important role in <d>inflammation</d> and <d>fibrosis</d>. Activin A has been suggested to participate in the pathophysiology of human <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, but studies on the role of activin B are sparse. Canine <d>IPF</d> C<d>IPF</d> is an incurable <d>interstitial lung disease</d> occurring particularly in West Highland white terriers WHWTs. During the disease course there are acute exacerbations AEs and the condition has a poor prognosis. Microscopically, AEs of C<d>IPF</d> are characterized by <d>diffuse alveolar damage</d>, which is also a key feature of <d>acute respiratory distress syndrome</d> <d>ARDS</d>. The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with C<d>IPF</d> and WHWTs with C<d>IPF</d> and concurrent AE, and dogs of various breeds with <d>ARDS</d> and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid BALF from WHWTs with C<d>IPF</d> and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with C<d>IPF</d> as well as in the lungs of dogs with <d>ARDS</d>. Activin B was detected in the BALF of WHWTs with C<d>IPF</d>, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of C<d>IPF</d> and might act as a marker of <d>alveolar epithelial damage</d>.
25557625|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> IPF is a chronic, progressive, and fatal scarring lung disease of unknown etiology, characterized by changes in microRNA expression. Activation of transforming growth factor TGF-b is a key event in the development of IPF. Recent reports have also identified epigenetic modification as an important player in the pathogenesis of IPF. In this review, we summarize the main results of studies that address the role of microRNAs in IPF and highlight the synergistic actions of these microRNAs in regulating TGF-b, the primary fibrogenic mediator. We outline epigenetic regulation of microRNAs by methylation. Functional studies identify microRNAs that alter proliferative and migratory properties of fibroblasts, and induce phenotypic changes in epithelial cells consistent with epithelial-mesenchymal transition. Though these studies were performed in isolation, we identify multiple co-operative actions after assembling the results into a network. Construction of such networks will help identify disease-propelling hubs that can be targeted for therapeutic purposes.
25557625|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and fatal scarring lung disease of unknown etiology, characterized by changes in microRNA expression. Activation of transforming growth factor TGF-b is a key event in the development of <d>IPF</d>. Recent reports have also identified epigenetic modification as an important player in the pathogenesis of <d>IPF</d>. In this review, we summarize the main results of studies that address the role of microRNAs in <d>IPF</d> and highlight the synergistic actions of these microRNAs in regulating TGF-b, the primary fibrogenic mediator. We outline epigenetic regulation of microRNAs by methylation. Functional studies identify microRNAs that alter proliferative and migratory properties of fibroblasts, and induce phenotypic changes in epithelial cells consistent with epithelial-mesenchymal transition. Though these studies were performed in isolation, we identify multiple co-operative actions after assembling the results into a network. Construction of such networks will help identify disease-propelling hubs that can be targeted for therapeutic purposes.
25557625|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and <d>fatal scarring lung disease</d> of unknown etiology, characterized by changes in microRNA expression. Activation of transforming growth factor TGF-b is a key event in the development of <d>IPF</d>. Recent reports have also identified epigenetic modification as an important player in the pathogenesis of <d>IPF</d>. In this review, we summarize the main results of studies that address the role of microRNAs in <d>IPF</d> and highlight the synergistic actions of these microRNAs in regulating TGF-b, the primary fibrogenic mediator. We outline epigenetic regulation of microRNAs by methylation. Functional studies identify microRNAs that alter proliferative and migratory properties of fibroblasts, and induce phenotypic changes in epithelial cells consistent with epithelial-mesenchymal transition. Though these studies were performed in isolation, we identify multiple co-operative actions after assembling the results into a network. Construction of such networks will help identify disease-propelling hubs that can be targeted for therapeutic purposes.
25575513|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix production, and abnormal lung remodeling. We have recently found that Mmp19-/- mice develop an exaggerated bleomycin-induced lung fibrosis but the mechanisms are unclear. In this study we explored the effect of MMP19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19-/- lung fibroblasts revealed the dysregulation of several profibrotic pathways including extracellular matrix formation, migration, proliferation and autophagy. Functional studies confirmed these findings. Compared with wild type mice, Mmp19-/- lung fibroblasts showed increased alpha 1 I collagen gene and collagen protein production at baseline and after TGF-b treatment, and increased smooth muscle alpha actin expression p< 0.05. Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in growth rate p< 0.01, and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel p< 0.05. These findings suggest that in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation and in migration and proliferation.
25575513|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix production, and abnormal lung remodeling. We have recently found that Mmp19-/- mice develop an exaggerated bleomycin-induced lung fibrosis but the mechanisms are unclear. In this study we explored the effect of MMP19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19-/- lung fibroblasts revealed the dysregulation of several profibrotic pathways including extracellular matrix formation, migration, proliferation and autophagy. Functional studies confirmed these findings. Compared with wild type mice, Mmp19-/- lung fibroblasts showed increased alpha 1 I collagen gene and collagen protein production at baseline and after TGF-b treatment, and increased smooth muscle alpha actin expression p< 0.05. Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in growth rate p< 0.01, and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel p< 0.05. These findings suggest that in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation and in migration and proliferation.
25575513|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and usually lethal <d>interstitial lung disease</d> of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix production, and abnormal lung remodeling. We have recently found that Mmp19-/- mice develop an exaggerated bleomycin-induced lung fibrosis but the mechanisms are unclear. In this study we explored the effect of MMP19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19-/- lung fibroblasts revealed the dysregulation of several profibrotic pathways including extracellular matrix formation, migration, proliferation and autophagy. Functional studies confirmed these findings. Compared with wild type mice, Mmp19-/- lung fibroblasts showed increased alpha 1 I collagen gene and collagen protein production at baseline and after TGF-b treatment, and increased smooth muscle alpha actin expression p< 0.05. Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in growth rate p< 0.01, and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel p< 0.05. These findings suggest that in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation and in migration and proliferation.
25575513|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and usually lethal <d>interstitial lung disease</d> of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix production, and <d>abnormal lung remodeling</d>. We have recently found that Mmp19-/- mice develop an exaggerated bleomycin-induced lung fibrosis but the mechanisms are unclear. In this study we explored the effect of MMP19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19-/- lung fibroblasts revealed the dysregulation of several profibrotic pathways including extracellular matrix formation, migration, proliferation and autophagy. Functional studies confirmed these findings. Compared with wild type mice, Mmp19-/- lung fibroblasts showed increased alpha 1 I collagen gene and collagen protein production at baseline and after TGF-b treatment, and increased smooth muscle alpha actin expression p< 0.05. Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in growth rate p< 0.01, and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel p< 0.05. These findings suggest that in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation and in migration and proliferation.
25575513|a|UNASSIGNED: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive and usually lethal <d>interstitial lung disease</d> of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix production, and <d>abnormal lung remodeling</d>. We have recently found that <g>Mmp19</g>-/- mice develop an exaggerated bleomycin-induced lung <d>fibrosis</d> but the mechanisms are unclear. In this study we explored the effect of MMP19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of <g>Mmp19</g>-/- lung fibroblasts revealed the dysregulation of several profibrotic pathways including extracellular matrix formation, migration, proliferation and autophagy. Functional studies confirmed these findings. Compared with wild type mice, <g>Mmp19</g>-/- lung fibroblasts showed increased alpha 1 I collagen gene and collagen protein production at baseline and after TGF-b treatment, and increased smooth muscle alpha actin expression p< 0.05. Likewise, <g>Mmp19</g>-deficient lung fibroblasts showed a significant increase in growth rate p< 0.01, and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel p< 0.05. These findings suggest that in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation and in migration and proliferation.
25660181|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> IPF is characterized by excessive scarring of the lung parenchyma, resulting in a steady decline of lung function and ultimately respiratory failure. The disease course of IPF is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and loss of lung function. Viral infections have been implicated in IPF and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 TLR9. Activation of TLR9 in  vivo exacerbated IPF in mice and induced differentiation of myofibroblasts in  vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor TGF-b, a pleiotropic cytokine central to IPF pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-b in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated a-smooth muscle actin+/platelet-derived growth factor receptor a+/CD44+/matrix metalloproteinase-14+/matrix metalloproteinase-2+ myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-b and TLR9 responses in myofibroblasts collaborate to drive rapid progression of IPF.
25660181|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by excessive scarring of the lung parenchyma, resulting in a steady decline of lung function and ultimately respiratory failure. The disease course of <d>IPF</d> is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and loss of lung function. Viral infections have been implicated in <d>IPF</d> and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 TLR9. Activation of TLR9 in  vivo exacerbated <d>IPF</d> in mice and induced differentiation of myofibroblasts in  vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor TGF-b, a pleiotropic cytokine central to <d>IPF</d> pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-b in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated a-smooth muscle actin+/platelet-derived growth factor receptor a+/CD44+/matrix metalloproteinase-14+/matrix metalloproteinase-2+ myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-b and TLR9 responses in myofibroblasts collaborate to drive rapid progression of <d>IPF</d>.
25660181|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by excessive scarring of the <d>lung parenchyma</d>, resulting in a steady decline of lung function and ultimately respiratory failure. The disease course of <d>IPF</d> is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and loss of lung function. Viral infections have been implicated in <d>IPF</d> and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 TLR9. Activation of TLR9 in  vivo exacerbated <d>IPF</d> in mice and induced differentiation of myofibroblasts in  vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor TGF-b, a pleiotropic cytokine central to <d>IPF</d> pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-b in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated a-smooth muscle actin+/platelet-derived growth factor receptor a+/CD44+/matrix metalloproteinase-14+/matrix metalloproteinase-2+ myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-b and TLR9 responses in myofibroblasts collaborate to drive rapid progression of <d>IPF</d>.
25660181|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by excessive scarring of the <d>lung parenchyma</d>, resulting in a steady decline of lung function and ultimately <d>respiratory failure</d>. The disease course of <d>IPF</d> is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and loss of lung function. Viral infections have been implicated in <d>IPF</d> and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 TLR9. Activation of TLR9 in  vivo exacerbated <d>IPF</d> in mice and induced differentiation of myofibroblasts in  vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor TGF-b, a pleiotropic cytokine central to <d>IPF</d> pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-b in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated a-smooth muscle actin+/platelet-derived growth factor receptor a+/CD44+/matrix metalloproteinase-14+/matrix metalloproteinase-2+ myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-b and TLR9 responses in myofibroblasts collaborate to drive rapid progression of <d>IPF</d>.
25660181|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by excessive scarring of the <d>lung parenchyma</d>, resulting in a steady decline of lung function and ultimately <d>respiratory failure</d>. The disease course of <d>IPF</d> is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and <d>loss of lung function</d>. Viral infections have been implicated in <d>IPF</d> and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 TLR9. Activation of TLR9 in  vivo exacerbated <d>IPF</d> in mice and induced differentiation of myofibroblasts in  vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor TGF-b, a pleiotropic cytokine central to <d>IPF</d> pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-b in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated a-smooth muscle actin+/platelet-derived growth factor receptor a+/CD44+/matrix metalloproteinase-14+/matrix metalloproteinase-2+ myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-b and TLR9 responses in myofibroblasts collaborate to drive rapid progression of <d>IPF</d>.
25660181|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by excessive scarring of the <d>lung parenchyma</d>, resulting in a steady decline of lung function and ultimately <d>respiratory failure</d>. The disease course of <d>IPF</d> is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and <d>loss of lung function</d>. <d>Viral infections</d> have been implicated in <d>IPF</d> and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 TLR9. Activation of TLR9 in  vivo exacerbated <d>IPF</d> in mice and induced differentiation of myofibroblasts in  vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor TGF-b, a pleiotropic cytokine central to <d>IPF</d> pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-b in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated a-smooth muscle actin+/platelet-derived growth factor receptor a+/CD44+/matrix metalloproteinase-14+/matrix metalloproteinase-2+ myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-b and TLR9 responses in myofibroblasts collaborate to drive rapid progression of <d>IPF</d>.
25660181|a|UNASSIGNED: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is characterized by excessive scarring of the <d>lung parenchyma</d>, resulting in a steady decline of lung function and ultimately <d>respiratory failure</d>. The disease course of <d>IPF</d> is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and <d>loss of lung function</d>. <d>Viral infections</d> have been implicated in <d>IPF</d> and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, <g>Toll-like receptor 9</g> <g>TLR9</g>. Activation of <g>TLR9</g> in  vivo exacerbated <d>IPF</d> in mice and induced differentiation of myofibroblasts in  vitro, but the mechanism of <g>TLR9</g> up-regulation and progression of <d>fibrosis</d> are unknown. Herein, we investigate whether transforming growth factor TGF-b, a pleiotropic cytokine central to <d>IPF</d> pathogenesis, regulates <g>TLR9</g> in lung myofibroblasts. Results showed induction of <g>TLR9</g> expression by TGF-b in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the <g>TLR9</g> agonist, CpG-DNA. Chronic <g>TLR9</g> stimulation resulted in stably differentiated a-smooth muscle actin+/platelet-derived growth factor receptor a+/CD44+/matrix metalloproteinase-14+/matrix metalloproteinase-2+ myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-b and <g>TLR9</g> responses in myofibroblasts collaborate to drive rapid progression of <d>IPF</d>.
25660181|a|UNASSIGNED: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is characterized by excessive scarring of the <d>lung parenchyma</d>, resulting in a steady decline of lung function and ultimately <d>respiratory failure</d>. The disease course of <d>IPF</d> is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and <d>loss of lung function</d>. <d>Viral infections</d> have been implicated in <d>IPF</d> and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, <g>Toll-like receptor 9</g> <g>TLR9</g>. Activation of <g>TLR9</g> in  vivo exacerbated <d>IPF</d> in mice and induced differentiation of myofibroblasts in  vitro, but the mechanism of <g>TLR9</g> up-regulation and progression of <d>fibrosis</d> are unknown. Herein, we investigate whether transforming growth factor <g>TGF-b</g>, a pleiotropic cytokine central to <d>IPF</d> pathogenesis, regulates <g>TLR9</g> in lung myofibroblasts. Results showed induction of <g>TLR9</g> expression by <g>TGF-b</g> in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the <g>TLR9</g> agonist, CpG-DNA. Chronic <g>TLR9</g> stimulation resulted in stably differentiated a-smooth muscle actin+/platelet-derived growth factor receptor a+/CD44+/matrix metalloproteinase-14+/matrix metalloproteinase-2+ myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist <d>hypoxia</d>-induced apoptosis. These results suggest a mechanism by which <g>TGF-b</g> and <g>TLR9</g> responses in myofibroblasts collaborate to drive rapid progression of <d>IPF</d>.
25680454|a|BACKGROUND: Pulmonary fibrosis is characterized by excessive accumulation of collagen and a-smooth muscle actin in the lung. The key molecules that promote these phenotypes are of clinical interest. OBJECTIVES: Thymic stromal lymphopoietin TSLP has been found at high levels in patients with asthma and idiopathic pulmonary fibrosis, and TSLP has been proposed as a primary driver of lung fibrotic disease. We asked whether tumor <d>necrosis</d> factor superfamily protein 14 TNFSF14 aka LIGHT controls TSLP production to initiate fibrosis. METHODS: Expression of TSLP and initiation of pulmonary fibrosis induced by bleomycin were assessed in mice deficient in LIGHT. The ability of recombinant LIGHT, given intratracheally to naive mice, to promote TSLP and fibrosis was also determined. RESULTS: Genetic deletion of LIGHT abolished lung TSLP expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and a-smooth muscle actin. Furthermore, recombinant LIGHT administered in  vivo induced lung expression of TSLP in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a TSLP-dependent manner. Blockade of LIGHT binding to either of its receptors, herpes virus entry mediator and lymphotoxin beta receptor, inhibited clinical symptoms of pulmonary fibrosis, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of TSLP. Moreover, LIGHT induced TSLP directly in human bronchial epithelial cells and synergized with IL-13 and TGF-b in  vivo to promote TSLP in the lungs and drive fibrosis. CONCLUSIONS: These results show that LIGHT is a profibrogenic cytokine that may be a key driver of TSLP production during the initiation and development of lung fibrotic disease.
25680454|a|BACKGROUND: Pulmonary fibrosis is characterized by excessive accumulation of collagen and a-smooth muscle actin in the lung. The key molecules that promote these phenotypes are of clinical interest. OBJECTIVES: Thymic stromal lymphopoietin TSLP has been found at high levels in patients with asthma and idiopathic pulmonary fibrosis, and TSLP has been proposed as a primary driver of lung fibrotic disease. We asked whether tumor <d>necrosis</d> factor superfamily protein 14 TNFSF14 aka <d>LIGHT</d> controls TSLP production to initiate fibrosis. METHODS: Expression of TSLP and initiation of pulmonary fibrosis induced by bleomycin were assessed in mice deficient in <d>LIGHT</d>. The ability of recombinant <d>LIGHT</d>, given intratracheally to naive mice, to promote TSLP and fibrosis was also determined. RESULTS: Genetic deletion of <d>LIGHT</d> abolished lung TSLP expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and a-smooth muscle actin. Furthermore, recombinant <d>LIGHT</d> administered in  vivo induced lung expression of TSLP in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a TSLP-dependent manner. Blockade of <d>LIGHT</d> binding to either of its receptors, herpes virus entry mediator and lymphotoxin beta receptor, inhibited clinical symptoms of pulmonary fibrosis, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of TSLP. Moreover, <d>LIGHT</d> induced TSLP directly in human bronchial epithelial cells and synergized with IL-13 and TGF-b in  vivo to promote TSLP in the lungs and drive fibrosis. CONCLUSIONS: These results show that <d>LIGHT</d> is a profibrogenic cytokine that may be a key driver of TSLP production during the initiation and development of lung fibrotic disease.
25680454|a|BACKGROUND: Pulmonary fibrosis is characterized by excessive accumulation of collagen and a-smooth muscle actin in the lung. The key molecules that promote these phenotypes are of clinical interest. OBJECTIVES: Thymic stromal lymphopoietin TSLP has been found at high levels in patients with asthma and idiopathic <d>pulmonary fibrosis</d>, and TSLP has been proposed as a primary driver of lung fibrotic disease. We asked whether tumor <d>necrosis</d> factor superfamily protein 14 TNFSF14 aka <d>LIGHT</d> controls TSLP production to initiate fibrosis. METHODS: Expression of TSLP and initiation of <d>pulmonary fibrosis</d> induced by bleomycin were assessed in mice deficient in <d>LIGHT</d>. The ability of recombinant <d>LIGHT</d>, given intratracheally to naive mice, to promote TSLP and fibrosis was also determined. RESULTS: Genetic deletion of <d>LIGHT</d> abolished lung TSLP expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and a-smooth muscle actin. Furthermore, recombinant <d>LIGHT</d> administered in  vivo induced lung expression of TSLP in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a TSLP-dependent manner. Blockade of <d>LIGHT</d> binding to either of its receptors, herpes virus entry mediator and lymphotoxin beta receptor, inhibited clinical symptoms of <d>pulmonary fibrosis</d>, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of TSLP. Moreover, <d>LIGHT</d> induced TSLP directly in human bronchial epithelial cells and synergized with IL-13 and TGF-b in  vivo to promote TSLP in the lungs and drive fibrosis. CONCLUSIONS: These results show that <d>LIGHT</d> is a profibrogenic cytokine that may be a key driver of TSLP production during the initiation and development of lung fibrotic disease.
25680454|a|BACKGROUND: <d>Pulmonary fibrosis</d> is characterized by excessive accumulation of collagen and a-smooth muscle actin in the lung. The key molecules that promote these phenotypes are of clinical interest. OBJECTIVES: Thymic stromal lymphopoietin TSLP has been found at high levels in patients with asthma and idiopathic <d>pulmonary fibrosis</d>, and TSLP has been proposed as a primary driver of lung fibrotic disease. We asked whether tumor <d>necrosis</d> factor superfamily protein 14 TNFSF14 aka <d>LIGHT</d> controls TSLP production to initiate fibrosis. METHODS: Expression of TSLP and initiation of <d>pulmonary fibrosis</d> induced by bleomycin were assessed in mice deficient in <d>LIGHT</d>. The ability of recombinant <d>LIGHT</d>, given intratracheally to naive mice, to promote TSLP and fibrosis was also determined. RESULTS: Genetic deletion of <d>LIGHT</d> abolished lung TSLP expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and a-smooth muscle actin. Furthermore, recombinant <d>LIGHT</d> administered in  vivo induced lung expression of TSLP in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a TSLP-dependent manner. Blockade of <d>LIGHT</d> binding to either of its receptors, herpes virus entry mediator and lymphotoxin beta receptor, inhibited clinical symptoms of <d>pulmonary fibrosis</d>, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of TSLP. Moreover, <d>LIGHT</d> induced TSLP directly in human bronchial epithelial cells and synergized with IL-13 and TGF-b in  vivo to promote TSLP in the lungs and drive fibrosis. CONCLUSIONS: These results show that <d>LIGHT</d> is a profibrogenic cytokine that may be a key driver of TSLP production during the initiation and development of lung fibrotic disease.
25680454|a|BACKGROUND: <d>Pulmonary fibrosis</d> is characterized by excessive accumulation of collagen and a-smooth muscle actin in the lung. The key molecules that promote these phenotypes are of clinical interest. OBJECTIVES: <g>Thymic stromal lymphopoietin</g> <g>TSLP</g> has been found at high levels in patients with <d>asthma</d> and idiopathic <d>pulmonary fibrosis</d>, and <g>TSLP</g> has been proposed as a primary driver of lung fibrotic disease. We asked whether tumor <d>necrosis</d> factor superfamily protein 14 TNFSF14 aka <d>LIGHT</d> controls <g>TSLP</g> production to initiate fibrosis. METHODS: Expression of <g>TSLP</g> and initiation of <d>pulmonary fibrosis</d> induced by bleomycin were assessed in mice deficient in <d>LIGHT</d>. The ability of recombinant <d>LIGHT</d>, given intratracheally to naive mice, to promote <g>TSLP</g> and fibrosis was also determined. RESULTS: Genetic deletion of <d>LIGHT</d> abolished lung <g>TSLP</g> expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and a-smooth muscle actin. Furthermore, recombinant <d>LIGHT</d> administered in  vivo induced lung expression of <g>TSLP</g> in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a <g>TSLP</g>-dependent manner. Blockade of <d>LIGHT</d> binding to either of its receptors, herpes virus entry mediator and lymphotoxin beta receptor, inhibited clinical symptoms of <d>pulmonary fibrosis</d>, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of <g>TSLP</g>. Moreover, <d>LIGHT</d> induced <g>TSLP</g> directly in human bronchial epithelial cells and synergized with IL-13 and TGF-b in  vivo to promote <g>TSLP</g> in the lungs and drive fibrosis. CONCLUSIONS: These results show that <d>LIGHT</d> is a profibrogenic cytokine that may be a key driver of <g>TSLP</g> production during the initiation and development of lung fibrotic disease.
25680454|a|BACKGROUND: <d>Pulmonary fibrosis</d> is characterized by excessive accumulation of collagen and a-smooth muscle actin in the lung. The key molecules that promote these phenotypes are of clinical interest. OBJECTIVES: <g>Thymic stromal lymphopoietin</g> <g>TSLP</g> has been found at high levels in patients with <d>asthma</d> and idiopathic <d>pulmonary fibrosis</d>, and <g>TSLP</g> has been proposed as a primary <d>driver of lung fibrotic disease</d>. We asked whether tumor <d>necrosis</d> factor superfamily protein 14 TNFSF14 aka <d>LIGHT</d> controls <g>TSLP</g> production to initiate fibrosis. METHODS: Expression of <g>TSLP</g> and initiation of <d>pulmonary fibrosis</d> induced by bleomycin were assessed in mice deficient in <d>LIGHT</d>. The ability of recombinant <d>LIGHT</d>, given intratracheally to naive mice, to promote <g>TSLP</g> and fibrosis was also determined. RESULTS: Genetic deletion of <d>LIGHT</d> abolished lung <g>TSLP</g> expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and a-smooth muscle actin. Furthermore, recombinant <d>LIGHT</d> administered in  vivo induced lung expression of <g>TSLP</g> in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a <g>TSLP</g>-dependent manner. Blockade of <d>LIGHT</d> binding to either of its receptors, herpes virus entry mediator and lymphotoxin beta receptor, inhibited clinical symptoms of <d>pulmonary fibrosis</d>, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of <g>TSLP</g>. Moreover, <d>LIGHT</d> induced <g>TSLP</g> directly in human bronchial epithelial cells and synergized with IL-13 and TGF-b in  vivo to promote <g>TSLP</g> in the lungs and drive fibrosis. CONCLUSIONS: These results show that <d>LIGHT</d> is a profibrogenic cytokine that may be a key driver of <g>TSLP</g> production during the initiation and development of lung fibrotic disease.
25680454|a|BACKGROUND: <d>Pulmonary <d>fibrosis</d></d> is characterized by excessive accumulation of collagen and a-smooth muscle actin in the lung. The key molecules that promote these phenotypes are of clinical interest. OBJECTIVES: <g>Thymic stromal lymphopoietin</g> <g>TSLP</g> has been found at high levels in patients with <d>asthma</d> and idiopathic <d>pulmonary <d>fibrosis</d></d>, and <g>TSLP</g> has been proposed as a primary <d>driver of lung fibrotic disease</d>. We asked whether tumor <d>necrosis</d> factor superfamily protein 14 <g>TNFSF14</g> aka <d>LIGHT</d> controls <g>TSLP</g> production to initiate <d>fibrosis</d>. METHODS: Expression of <g>TSLP</g> and initiation of <d>pulmonary <d>fibrosis</d></d> induced by bleomycin were assessed in mice deficient in <d>LIGHT</d>. The ability of recombinant <d>LIGHT</d>, given intratracheally to naive mice, to promote <g>TSLP</g> and <d>fibrosis</d> was also determined. RESULTS: Genetic deletion of <d>LIGHT</d> abolished lung <g>TSLP</g> expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and a-smooth muscle actin. Furthermore, recombinant <d>LIGHT</d> administered in  vivo induced lung expression of <g>TSLP</g> in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a <g>TSLP</g>-dependent manner. Blockade of <d>LIGHT</d> binding to either of its receptors, herpes virus entry mediator and lymphotoxin beta receptor, inhibited clinical symptoms of <d>pulmonary <d>fibrosis</d></d>, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of <g>TSLP</g>. Moreover, <d>LIGHT</d> induced <g>TSLP</g> directly in human bronchial epithelial cells and synergized with IL-13 and TGF-b in  vivo to promote <g>TSLP</g> in the lungs and drive <d>fibrosis</d>. CONCLUSIONS: These results show that <d>LIGHT</d> is a profibrogenic cytokine that may be a key driver of <g>TSLP</g> production during the initiation and development of lung fibrotic disease.
25680454|a|BACKGROUND: <d>Pulmonary <d>fibrosis</d></d> is characterized by excessive accumulation of collagen and a-smooth muscle actin in the lung. The key molecules that promote these phenotypes are of clinical interest. OBJECTIVES: <g>Thymic stromal lymphopoietin</g> <g>TSLP</g> has been found at high levels in patients with <d>asthma</d> and idiopathic <d>pulmonary <d>fibrosis</d></d>, and <g>TSLP</g> has been proposed as a primary <d>driver of lung <d>fibrotic disease</d></d>. We asked whether tumor <d>necrosis</d> factor superfamily protein 14 <g>TNFSF14</g> aka <d>LIGHT</d> controls <g>TSLP</g> production to initiate <d>fibrosis</d>. METHODS: Expression of <g>TSLP</g> and initiation of <d>pulmonary <d>fibrosis</d></d> induced by bleomycin were assessed in mice deficient in <d>LIGHT</d>. The ability of recombinant <d>LIGHT</d>, given intratracheally to naive mice, to promote <g>TSLP</g> and <d>fibrosis</d> was also determined. RESULTS: Genetic deletion of <d>LIGHT</d> abolished lung <g>TSLP</g> expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and a-smooth muscle actin. Furthermore, recombinant <d>LIGHT</d> administered in  vivo induced lung expression of <g>TSLP</g> in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a <g>TSLP</g>-dependent manner. Blockade of <d>LIGHT</d> binding to either of its receptors, herpes virus entry mediator and <g>lymphotoxin beta receptor</g>, inhibited clinical symptoms of <d>pulmonary <d>fibrosis</d></d>, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of <g>TSLP</g>. Moreover, <d>LIGHT</d> induced <g>TSLP</g> directly in human bronchial epithelial cells and synergized with <g>IL-13</g> and <g>TGF-b</g> in  vivo to promote <g>TSLP</g> in the lungs and drive <d>fibrosis</d>. CONCLUSIONS: These results show that <d>LIGHT</d> is a profibrogenic cytokine that may be a key driver of <g>TSLP</g> production during the initiation and development of lung <d>fibrotic disease</d>.
25684348|a|UNASSIGNED: IQ motif containing guanosine triphosphatase activating protein  1 <g>IQGAP1</g> is associated with <d>idiopathic pulmonary fibrogenesis</d> IPF; however, characterization of the expression of <g>IQGAP1</g> in lung fibroblasts has remained elusive. The present study therefore evaluated <g>IQGAP1</g> expression in mouse and human lung fibroblasts under fibrotic conditions via western blot analysis. It was revealed that <g>IQGAP1</g> expression levels were significantly decreased in lung fibroblasts isolated from bleomycin  -challenged mice than in those of control mice. Transforming growth factor  -b TGF  -b induced differentiation, as well as decreased expression of <g>IQGAP1</g> in WI  -38  cells human lung fibroblasts. Furthermore, inhibition of nuclear factor NF  -kB activation restored the TGF  -b  -induced inhibition of <g>IQGAP1</g> expression in WI  -38  cells. In lysophosphatidic acid LPA  -challenged WI  -38  cells, the expression of <g>IQGAP1</g> was also decreased, while neutralized anti  -TGF  -b antibody treatment restored the LPA  -induced inhibition of <g>IQGAP1</g> expression. These data indicated that TGF  -b inhibited <g>IQGAP1</g> expression in lung fibroblasts via the NF  -kB signaling pathway, presenting a potential novel therapeutic target for the treatment of IPF.
25684348|a|UNASSIGNED: IQ motif containing guanosine triphosphatase activating protein  1 <g>IQGAP1</g> is associated with <d>idiopathic pulmonary fibrogenesis</d> <d>IPF</d>; however, characterization of the expression of <g>IQGAP1</g> in lung fibroblasts has remained elusive. The present study therefore evaluated <g>IQGAP1</g> expression in mouse and human lung fibroblasts under fibrotic conditions via western blot analysis. It was revealed that <g>IQGAP1</g> expression levels were significantly decreased in lung fibroblasts isolated from bleomycin  -challenged mice than in those of control mice. Transforming growth factor  -b TGF  -b induced differentiation, as well as decreased expression of <g>IQGAP1</g> in WI  -38  cells human lung fibroblasts. Furthermore, inhibition of nuclear factor NF  -kB activation restored the TGF  -b  -induced inhibition of <g>IQGAP1</g> expression in WI  -38  cells. In lysophosphatidic acid LPA  -challenged WI  -38  cells, the expression of <g>IQGAP1</g> was also decreased, while neutralized anti  -TGF  -b antibody treatment restored the LPA  -induced inhibition of <g>IQGAP1</g> expression. These data indicated that TGF  -b inhibited <g>IQGAP1</g> expression in lung fibroblasts via the NF  -kB signaling pathway, presenting a potential novel therapeutic target for the treatment of <d>IPF</d>.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> HGF inhibits lung fibrosis as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed HGF expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   HGF levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with pulmonary sarcoidosis PS, n = 52, idiopathic pulmonary fibrosis IPF, n = 23, nonspecific interstitial pneumonia NSIP, n = 14, extrinsic allergic alveolitis EAA, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular HGF expression in BAL cells was evaluated by flow cytometry. RESULTS:   HGF concentrations were elevated in BAL fluid from nonsmokers with IPF 261   204 pg/ml, P <0.02, smokers with IPF 220   13 pg/ml, P <0.001, and smokers with PS 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. HGF levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular HGF  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic HGF activity. The highest HGF concentrations were observed in BAL fluid from patients with IPF, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the HGF expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with pulmonary sarcoidosis PS, n = 52, idiopathic pulmonary fibrosis IPF, n = 23, nonspecific interstitial pneumonia NSIP, n = 14, extrinsic allergic alveolitis EAA, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with IPF 261   204 pg/ml, P <0.02, smokers with IPF 220   13 pg/ml, P <0.001, and smokers with PS 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with IPF, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> PS, n = 52, idiopathic pulmonary fibrosis IPF, n = 23, nonspecific interstitial pneumonia NSIP, n = 14, extrinsic allergic alveolitis EAA, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with IPF 261   204 pg/ml, P <0.02, smokers with IPF 220   13 pg/ml, P <0.001, and smokers with PS 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with IPF, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, idiopathic pulmonary fibrosis IPF, n = 23, nonspecific interstitial pneumonia NSIP, n = 14, extrinsic allergic alveolitis EAA, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with IPF 261   204 pg/ml, P <0.02, smokers with IPF 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with IPF, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> IPF, n = 23, nonspecific interstitial pneumonia NSIP, n = 14, extrinsic allergic alveolitis EAA, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with IPF 261   204 pg/ml, P <0.02, smokers with IPF 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with IPF, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, n = 23, nonspecific interstitial pneumonia NSIP, n = 14, extrinsic allergic alveolitis EAA, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with <d>IPF</d> 261   204 pg/ml, P <0.02, smokers with <d>IPF</d> 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with <d>IPF</d>, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, n = 23, <d>nonspecific interstitial pneumonia</d> NSIP, n = 14, extrinsic allergic alveolitis EAA, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with <d>IPF</d> 261   204 pg/ml, P <0.02, smokers with <d>IPF</d> 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with <d>IPF</d>, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, n = 23, <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>, n = 14, extrinsic allergic alveolitis EAA, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with <d>IPF</d> 261   204 pg/ml, P <0.02, smokers with <d>IPF</d> 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with <d>IPF</d>, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, n = 23, <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>, n = 14, <d>extrinsic allergic alveolitis</d> EAA, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with <d>IPF</d> 261   204 pg/ml, P <0.02, smokers with <d>IPF</d> 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with <d>IPF</d>, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, n = 23, <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>, n = 14, <d>extrinsic allergic alveolitis</d> <d>EAA</d>, n = 6, bronchiolitis obliterans organizing pneumonia BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with <d>IPF</d> 261   204 pg/ml, P <0.02, smokers with <d>IPF</d> 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with <d>IPF</d>, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, n = 23, <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>, n = 14, <d>extrinsic allergic alveolitis</d> <d>EAA</d>, n = 6, <d>bronchiolitis obliterans organizing pneumonia</d> BOOP, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with <d>IPF</d> 261   204 pg/ml, P <0.02, smokers with <d>IPF</d> 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with <d>IPF</d>, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, n = 23, <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>, n = 14, <d>extrinsic allergic alveolitis</d> <d>EAA</d>, n = 6, <d>bronchiolitis obliterans organizing pneumonia</d> <d>BOOP</d>, n = 8, chronic eosinophilic pneumonia EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with <d>IPF</d> 261   204 pg/ml, P <0.02, smokers with <d>IPF</d> 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with <d>IPF</d>, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits lung fibrosis</d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, n = 23, <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>, n = 14, <d>extrinsic allergic alveolitis</d> <d>EAA</d>, n = 6, <d>bronchiolitis obliterans organizing pneumonia</d> <d>BOOP</d>, n = 8, <d>chronic eosinophilic pneumonia</d> EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with <d>IPF</d> 261   204 pg/ml, P <0.02, smokers with <d>IPF</d> 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with <d>IPF</d>, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent lung fibrosis.
25697336|a|INTRODUCTION:   Previous studies have suggested that <g>hepatocyte growth factor</g> <g>HGF</g> <d>inhibits <d>lung fibrosis</d></d> as an antagonist of transforming growth factor b TGF  -b. OBJECTIVES:   We assessed <g>HGF</g> expression levels in the lower airways of patients with selected <d>interstitial lung diseases</d>. PATIENTS AND METHODS:   <g>HGF</g> levels were examined by an enzyme  -linked immunosorbent assay in bronchoalveolar lavage BAL fluid supernatants from patients with <d>pulmonary sarcoidosis</d> <d>PS</d>, n = 52, <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, n = 23, <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>, n = 14, <d>extrinsic allergic alveolitis</d> <d>EAA</d>, n = 6, <d>bronchiolitis obliterans organizing pneumonia</d> <d>BOOP</d>, n = 8, <d>chronic eosinophilic pneumonia</d> EP, n = 6, and in control subjects n = 13. Intracellular <g>HGF</g> expression in BAL cells was evaluated by flow cytometry. RESULTS:   <g>HGF</g> concentrations were elevated in BAL fluid from nonsmokers with <d>IPF</d> 261   204 pg/ml, P <0.02, smokers with <d>IPF</d> 220   13 pg/ml, P <0.001, and smokers with <d>PS</d> 172   33 pg/ml, P <0.02, as compared with controls 148   17 pg/ml for nonsmokers; 137   9 pg/ml for smokers. <g>HGF</g> levels were positively correlated with TGF  -b concentrations in BAL fluid r = 0.3; P = 0.02 and negatively-with vital capacity r = -0.2; P = 0.02. BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular <g>HGF</g>  -positive cells. CONCLUSIONS:   Our results do not support evidence for strong antifibrotic <g>HGF</g> activity. The highest <g>HGF</g> concentrations were observed in BAL fluid from patients with <d>IPF</d>, and they were also positively correlated with TGF  -b levels. Thus, although the local protective mechanisms such as the <g>HGF</g> expression are upregulated in chronic <d>interstitial lung diseases</d>, they are not enough to prevent <d>lung fibrosis</d>.
25725128|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a chronic fibrosing interstitial lung disease of unknown etiology that is currently untreatable. In this study we aim to characterize the potential of extracellular/circulating microRNAs miRNAs in serum as biomarkers for IPF. METHODS: Total serum RNAs were isolated from serum from healthy control subjects n=12, rapid progressive n=12 and slowly progressive IPF patients n=12. Serum RNA was analyzed by using TaqMan microRNA assays containing probes for 366 human miRNAs, and selected findings were validated with quantitative RT-PCR. Target prediction and pathway analysis on the significant differential miRNAs were performed using DIANA-mirPath. RESULTS: We found 47 significantly differentially expressed serum miRNAs p<0.05 in rapid progressive or slowly progressive IPF patients compared to healthy controls, including 21 up-regulated miRNAs and 26 down-regulated miRNAs. Bioinformatic analysis by DIANA-mirPath demonstrated that 53 KEGG biological processes were significantly enriched p<0.05, FDR corrected among differentially expressed serum miRNAs, including TGF-beta signaling pathway p<0.0001, MAPK signaling pathway p<0.0001, PI3K-Akt signaling pathway p<0.0001, Wnt signaling pathway p<0.0001, HIF-1 signaling pathway p<0.0001, Regulation of actin cytoskeleton p<0.0001, Jak-STAT signaling pathway p<0.0001, Notch signaling pathway p<0.0001, and Cytokine-cytokine receptor interaction p=0.0062. We further validated six miRNAs miR-21, miR-199a-5p, miR-200c, miR-31, let-7a, and let-7d for further validation using an independent cohort of 20 rapid progressive IPF, 24 slowly progressive IPF patients and 20 healthy controls. In agreement with the preliminary data from miRNA assay, miR-21, miR-199a-5p, and miR-200c were significantly increased in serums of IPF patients while miR-31, let-7a, and let-7d were significantly under expressed in serums of IPF patients compared to healthy controls. CONCLUSIONS: These studies demonstrated that extracellular/circulating miRNAs in serum could be potentially served as novel regulators influencing disease progression of IPF.
25725128|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing interstitial lung disease of unknown etiology that is currently untreatable. In this study we aim to characterize the potential of extracellular/circulating microRNAs miRNAs in serum as biomarkers for <d>IPF</d>. METHODS: Total serum RNAs were isolated from serum from healthy control subjects n=12, rapid progressive n=12 and slowly progressive <d>IPF</d> patients n=12. Serum RNA was analyzed by using TaqMan microRNA assays containing probes for 366 human miRNAs, and selected findings were validated with quantitative RT-PCR. Target prediction and pathway analysis on the significant differential miRNAs were performed using DIANA-mirPath. RESULTS: We found 47 significantly differentially expressed serum miRNAs p<0.05 in rapid progressive or slowly progressive <d>IPF</d> patients compared to healthy controls, including 21 up-regulated miRNAs and 26 down-regulated miRNAs. Bioinformatic analysis by DIANA-mirPath demonstrated that 53 KEGG biological processes were significantly enriched p<0.05, FDR corrected among differentially expressed serum miRNAs, including TGF-beta signaling pathway p<0.0001, MAPK signaling pathway p<0.0001, PI3K-Akt signaling pathway p<0.0001, Wnt signaling pathway p<0.0001, HIF-1 signaling pathway p<0.0001, Regulation of actin cytoskeleton p<0.0001, Jak-STAT signaling pathway p<0.0001, Notch signaling pathway p<0.0001, and Cytokine-cytokine receptor interaction p=0.0062. We further validated six miRNAs miR-21, miR-199a-5p, miR-200c, miR-31, let-7a, and let-7d for further validation using an independent cohort of 20 rapid progressive <d>IPF</d>, 24 slowly progressive <d>IPF</d> patients and 20 healthy controls. In agreement with the preliminary data from miRNA assay, miR-21, miR-199a-5p, and miR-200c were significantly increased in serums of <d>IPF</d> patients while miR-31, let-7a, and let-7d were significantly under expressed in serums of <d>IPF</d> patients compared to healthy controls. CONCLUSIONS: These studies demonstrated that extracellular/circulating miRNAs in serum could be potentially served as novel regulators influencing disease progression of <d>IPF</d>.
25725128|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial lung disease</d> of unknown etiology that is currently untreatable. In this study we aim to characterize the potential of extracellular/circulating microRNAs miRNAs in serum as biomarkers for <d>IPF</d>. METHODS: Total serum RNAs were isolated from serum from healthy control subjects n=12, rapid progressive n=12 and slowly progressive <d>IPF</d> patients n=12. Serum RNA was analyzed by using TaqMan microRNA assays containing probes for 366 human miRNAs, and selected findings were validated with quantitative RT-PCR. Target prediction and pathway analysis on the significant differential miRNAs were performed using DIANA-mirPath. RESULTS: We found 47 significantly differentially expressed serum miRNAs p<0.05 in rapid progressive or slowly progressive <d>IPF</d> patients compared to healthy controls, including 21 up-regulated miRNAs and 26 down-regulated miRNAs. Bioinformatic analysis by DIANA-mirPath demonstrated that 53 KEGG biological processes were significantly enriched p<0.05, FDR corrected among differentially expressed serum miRNAs, including TGF-beta signaling pathway p<0.0001, MAPK signaling pathway p<0.0001, PI3K-Akt signaling pathway p<0.0001, Wnt signaling pathway p<0.0001, HIF-1 signaling pathway p<0.0001, Regulation of actin cytoskeleton p<0.0001, Jak-STAT signaling pathway p<0.0001, Notch signaling pathway p<0.0001, and Cytokine-cytokine receptor interaction p=0.0062. We further validated six miRNAs miR-21, miR-199a-5p, miR-200c, miR-31, let-7a, and let-7d for further validation using an independent cohort of 20 rapid progressive <d>IPF</d>, 24 slowly progressive <d>IPF</d> patients and 20 healthy controls. In agreement with the preliminary data from miRNA assay, miR-21, miR-199a-5p, and miR-200c were significantly increased in serums of <d>IPF</d> patients while miR-31, let-7a, and let-7d were significantly under expressed in serums of <d>IPF</d> patients compared to healthy controls. CONCLUSIONS: These studies demonstrated that extracellular/circulating miRNAs in serum could be potentially served as novel regulators influencing disease progression of <d>IPF</d>.
25745043|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix ECM proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor PDGF, fibroblast growth factor FGF and transforming growth factor-b are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials.
25745043|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in <d>IPF</d> have not been fully elucidated, <d>IPF</d> is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix ECM proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor PDGF, fibroblast growth factor FGF and transforming growth factor-b are believed to play important roles in the pathogenesis of <d>IPF</d>. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with <d>IPF</d>, which has recently been demonstrated in phase III clinical trials.
25745043|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and ultimately fatal disease characterised by <d>fibrosis of the lung parenchyma</d> and loss of lung function. Although the pathogenic pathways involved in <d>IPF</d> have not been fully elucidated, <d>IPF</d> is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix ECM proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor PDGF, fibroblast growth factor FGF and transforming growth factor-b are believed to play important roles in the pathogenesis of <d>IPF</d>. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with <d>IPF</d>, which has recently been demonstrated in phase III clinical trials.
25745043|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and ultimately fatal disease characterised by <d>fibrosis of the lung parenchyma</d> and <d>loss of lung function</d>. Although the pathogenic pathways involved in <d>IPF</d> have not been fully elucidated, <d>IPF</d> is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix ECM proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor PDGF, fibroblast growth factor FGF and transforming growth factor-b are believed to play important roles in the pathogenesis of <d>IPF</d>. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with <d>IPF</d>, which has recently been demonstrated in phase III clinical trials.
25745043|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and ultimately fatal disease characterised by <d>fibrosis of the lung parenchyma</d> and <d>loss of lung function</d>. Although the pathogenic pathways involved in <d>IPF</d> have not been fully elucidated, <d>IPF</d> is believed to be caused by repetitive alveolar <d>epithelial cell injury and dysregulated</d> repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix ECM proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor PDGF, fibroblast growth factor FGF and transforming growth factor-b are believed to play important roles in the pathogenesis of <d>IPF</d>. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with <d>IPF</d>, which has recently been demonstrated in phase III clinical trials.
25745043|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive and ultimately fatal disease characterised by <d><d>fibrosis</d> of the lung parenchyma</d> and <d>loss of lung function</d>. Although the pathogenic pathways involved in <d>IPF</d> have not been fully elucidated, <d>IPF</d> is believed to be caused by repetitive alveolar <d>epithelial cell injury and dysregulated</d> repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix ECM proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor PDGF, fibroblast growth factor FGF and transforming growth factor-b are believed to play important roles in the pathogenesis of <d>IPF</d>. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in <d>fibrosis</d> such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung <d>fibrosis</d>. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with <d>IPF</d>, which has recently been demonstrated in phase III clinical trials.
25785991|a|BACKGROUND: Epithelial cell <d>death</d> is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance mitophagy in alveolar epithelial cell <d>death</d> and fibrosis. METHODS: We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 <g>PINK1</g>, in IPF lung tissues by Western blotting, transmission electron microscopy TEM, and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-b1 TGF-b1. Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis. RESULTS: Evaluation of IPF lung tissue demonstrated increased <g>PINK1</g> expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-b1 induced mitochondrial depolarization, mitochondrial ROS, and <g>PINK1</g> expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis. CONCLUSION: TGF-b1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, <g>PINK1</g>. <g>PINK1</g> ameliorates epithelial cell <d>death</d> and may be necessary to limit fibrogenesis.
25785991|a|BACKGROUND: Epithelial cell <d>death</d> is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance mitophagy in alveolar epithelial cell <d>death</d> and <d>fibrosis</d>. METHODS: We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 <g>PINK1</g>, in IPF lung tissues by Western blotting, transmission electron microscopy TEM, and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-b1 TGF-b1. Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung <d>fibrosis</d>. RESULTS: Evaluation of IPF lung tissue demonstrated increased <g>PINK1</g> expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-b1 induced mitochondrial depolarization, mitochondrial ROS, and <g>PINK1</g> expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung <d>fibrosis</d>. CONCLUSION: TGF-b1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, <g>PINK1</g>. <g>PINK1</g> ameliorates epithelial cell <d>death</d> and may be necessary to limit fibrogenesis.
25785991|a|BACKGROUND: Epithelial cell <d>death</d> is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance mitophagy in alveolar epithelial cell <d>death</d> and <d>fibrosis</d>. METHODS: We studied markers of <d>mitochondrial injury</d> and the mitophagy marker, PTEN-induced putative kinase 1 <g>PINK1</g>, in IPF lung tissues by Western blotting, transmission electron microscopy TEM, and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-b1 TGF-b1. Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung <d>fibrosis</d>. RESULTS: Evaluation of IPF lung tissue demonstrated increased <g>PINK1</g> expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-b1 induced mitochondrial depolarization, mitochondrial ROS, and <g>PINK1</g> expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung <d>fibrosis</d>. CONCLUSION: TGF-b1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, <g>PINK1</g>. <g>PINK1</g> ameliorates epithelial cell <d>death</d> and may be necessary to limit fibrogenesis.
25829947|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a common and invariably lethal interstitial lung disease with poorly effective therapy. Blockade of the K+ channel <g>KCa3.1</g> reduces constitutive a-SMA and <g>Smad2/3</g> nuclear translocation in IPF-derived human lung myofibroblasts HLMFs, and inhibits several transforming growth factor beta 1 <g>TGFb1</g>-dependent cell processes. We hypothesized that <g>KCa3.1</g>-dependent cell processes also regulate the <g>TGFb1</g>-dependent <g>Smad2/3</g> signalling pathway in HLMFs. HLMFs obtained from non-fibrotic controls NFC and IPF lungs were grown in vitro and examined for aSMA expression by immunofluorescence, RT-PCR, and flow cytometry. Two specific and distinct <g>KCa3.1</g> blockers TRAM-34 200 nM and ICA-17043 [Senicapoc] 100 nM were used to determine their effects on <g>TGFb1</g>-dependent signalling. Expression of phosphorylated and total <g>Smad2/3</g> following <g>TGFb1</g> stimulation was determined by Western blot and <g>Smad2/3</g> nuclear translocation by immunofluorescence. RESULTS: <g>KCa3.1</g> block attenuated <g>TGFb1</g>-dependent <g>Smad2/3</g> phosphorylation and nuclear translocation, and this was mimicked by lowering the extracellular Ca2+ concentration. <g>KCa3.1</g> block also inhibited <g>Smad2/3</g>-dependent gene transcription aSMA, collagen type I, inhibited <g>KCa3.1</g> mRNA expression, and attenuated <g>TGFb1</g>-dependent aSMA protein expression. CONCLUSIONS: <g>KCa3.1</g> activity regulates <g>TGFb1</g>-dependent effects in NFC- and IPF-derived primary HLMFs through the regulation of the <g>TGFb1</g>/Smad signalling pathway, with promotion of downstream gene transcription and protein expression. <g>KCa3.1</g> blockers may offer a novel approach to treating IPF.
25829947|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a common and invariably lethal interstitial lung disease with poorly effective therapy. Blockade of the K+ channel <g>KCa3.1</g> reduces constitutive a-SMA and <g>Smad2/3</g> nuclear translocation in <d>IPF</d>-derived human lung myofibroblasts HLMFs, and inhibits several transforming growth factor beta 1 <g>TGFb1</g>-dependent cell processes. We hypothesized that <g>KCa3.1</g>-dependent cell processes also regulate the <g>TGFb1</g>-dependent <g>Smad2/3</g> signalling pathway in HLMFs. HLMFs obtained from non-fibrotic controls NFC and <d>IPF</d> lungs were grown in vitro and examined for aSMA expression by immunofluorescence, RT-PCR, and flow cytometry. Two specific and distinct <g>KCa3.1</g> blockers TRAM-34 200 nM and ICA-17043 [Senicapoc] 100 nM were used to determine their effects on <g>TGFb1</g>-dependent signalling. Expression of phosphorylated and total <g>Smad2/3</g> following <g>TGFb1</g> stimulation was determined by Western blot and <g>Smad2/3</g> nuclear translocation by immunofluorescence. RESULTS: <g>KCa3.1</g> block attenuated <g>TGFb1</g>-dependent <g>Smad2/3</g> phosphorylation and nuclear translocation, and this was mimicked by lowering the extracellular Ca2+ concentration. <g>KCa3.1</g> block also inhibited <g>Smad2/3</g>-dependent gene transcription aSMA, collagen type I, inhibited <g>KCa3.1</g> mRNA expression, and attenuated <g>TGFb1</g>-dependent aSMA protein expression. CONCLUSIONS: <g>KCa3.1</g> activity regulates <g>TGFb1</g>-dependent effects in NFC- and <d>IPF</d>-derived primary HLMFs through the regulation of the <g>TGFb1</g>/Smad signalling pathway, with promotion of downstream gene transcription and protein expression. <g>KCa3.1</g> blockers may offer a novel approach to treating <d>IPF</d>.
25829947|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a common and invariably lethal <d>interstitial lung disease</d> with poorly effective therapy. Blockade of the K+ channel <g>KCa3.1</g> reduces constitutive a-SMA and <g>Smad2/3</g> nuclear translocation in <d>IPF</d>-derived human lung myofibroblasts HLMFs, and inhibits several transforming growth factor beta 1 <g>TGFb1</g>-dependent cell processes. We hypothesized that <g>KCa3.1</g>-dependent cell processes also regulate the <g>TGFb1</g>-dependent <g>Smad2/3</g> signalling pathway in HLMFs. HLMFs obtained from non-fibrotic controls NFC and <d>IPF</d> lungs were grown in vitro and examined for aSMA expression by immunofluorescence, RT-PCR, and flow cytometry. Two specific and distinct <g>KCa3.1</g> blockers TRAM-34 200 nM and ICA-17043 [Senicapoc] 100 nM were used to determine their effects on <g>TGFb1</g>-dependent signalling. Expression of phosphorylated and total <g>Smad2/3</g> following <g>TGFb1</g> stimulation was determined by Western blot and <g>Smad2/3</g> nuclear translocation by immunofluorescence. RESULTS: <g>KCa3.1</g> block attenuated <g>TGFb1</g>-dependent <g>Smad2/3</g> phosphorylation and nuclear translocation, and this was mimicked by lowering the extracellular Ca2+ concentration. <g>KCa3.1</g> block also inhibited <g>Smad2/3</g>-dependent gene transcription aSMA, collagen type I, inhibited <g>KCa3.1</g> mRNA expression, and attenuated <g>TGFb1</g>-dependent aSMA protein expression. CONCLUSIONS: <g>KCa3.1</g> activity regulates <g>TGFb1</g>-dependent effects in NFC- and <d>IPF</d>-derived primary HLMFs through the regulation of the <g>TGFb1</g>/Smad signalling pathway, with promotion of downstream gene transcription and protein expression. <g>KCa3.1</g> blockers may offer a novel approach to treating <d>IPF</d>.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> IIP, including idiopathic pulmonary fibrosis IPF, desquamative interstitial pneumonia DIP, cryptogenic organizing pneumonia COP with bronchiolitis obliterans BO, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with IPF, 35 18% with NSIP, 23 12% with DIP, 18 9% with COP + BO. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared IIPs were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including idiopathic pulmonary fibrosis IPF, desquamative interstitial pneumonia DIP, cryptogenic organizing pneumonia COP with bronchiolitis obliterans BO, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with IPF, 35 18% with NSIP, 23 12% with DIP, 18 9% with COP + BO. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> IPF, desquamative interstitial pneumonia DIP, cryptogenic organizing pneumonia COP with bronchiolitis obliterans BO, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with IPF, 35 18% with NSIP, 23 12% with DIP, 18 9% with COP + BO. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, desquamative interstitial pneumonia DIP, cryptogenic organizing pneumonia COP with bronchiolitis obliterans BO, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with NSIP, 23 12% with DIP, 18 9% with COP + BO. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> DIP, cryptogenic organizing pneumonia COP with bronchiolitis obliterans BO, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with NSIP, 23 12% with DIP, 18 9% with COP + BO. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, cryptogenic organizing pneumonia COP with bronchiolitis obliterans BO, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with NSIP, 23 12% with <d>DIP</d>, 18 9% with COP + BO. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, <d>cryptogenic organizing pneumonia</d> COP with bronchiolitis obliterans BO, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with NSIP, 23 12% with <d>DIP</d>, 18 9% with COP + BO. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> with bronchiolitis obliterans BO, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with NSIP, 23 12% with <d>DIP</d>, 18 9% with <d>COP</d> + BO. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> with <d>bronchiolitis obliterans</d> BO, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with NSIP, 23 12% with <d>DIP</d>, 18 9% with <d>COP</d> + BO. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> with <d>bronchiolitis obliterans</d> <d>BO</d>, and nonspecific interstitial pneumonia NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with NSIP, 23 12% with <d>DIP</d>, 18 9% with <d>COP</d> + <d>BO</d>. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> with <d>bronchiolitis obliterans</d> <d>BO</d>, and <d>nonspecific interstitial pneumonia</d> NSIP. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with NSIP, 23 12% with <d>DIP</d>, 18 9% with <d>COP</d> + <d>BO</d>. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> with <d>bronchiolitis obliterans</d> <d>BO</d>, and <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with <d>NSIP</d>, 23 12% with <d>DIP</d>, 18 9% with <d>COP</d> + <d>BO</d>. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas "Novocastra", 1:100, vimentin Vimentin "LabVision" 1:100, SMA "LabVision", 1:100, TGF-b, TNF-a, CD34, Ost-4, and CD117 "Dako", 1:50, CD68, and EMA "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> with <d>bronchiolitis obliterans</d> <d>BO</d>, and <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with <d>NSIP</d>, 23 12% with <d>DIP</d>, 18 9% with <d>COP</d> + <d>BO</d>. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect <g>MMP-1</g>, <g>MMP-2</g>, <g>MMP-7</g>, Apo-Cas "Novocastra", 1:100, <g>vimentin</g> <g>Vimentin</g> "LabVision" 1:100, <g>SMA</g> "LabVision", 1:100, <g>TGF-b</g>, <g>TNF-a</g>, <g>CD34</g>, <g>Ost-4</g>, and <g>CD117</g> "Dako", 1:50, <g>CD68</g>, and <d>EMA</d> "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, <g>Vimentin</g>, <g>SMA</g>, <g>CD117</g>, and <g>CD34</g> expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> with <d>bronchiolitis obliterans</d> <d>BO</d>, and <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with <d>NSIP</d>, 23 12% with <d>DIP</d>, 18 9% with <d>COP</d> + <d>BO</d>. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect <g>MMP-1</g>, <g>MMP-2</g>, <g>MMP-7</g>, Apo-Cas "Novocastra", 1:100, <g>vimentin</g> <g>Vimentin</g> "LabVision" 1:100, <g>SMA</g> "LabVision", 1:100, <g>TGF-b</g>, <g>TNF-a</g>, <g>CD34</g>, <g>Ost-4</g>, and <g>CD117</g> "Dako", 1:50, <g>CD68</g>, and <d>EMA</d> "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the <d>aggressiveness</d> of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, <g>Vimentin</g>, <g>SMA</g>, <g>CD117</g>, and <g>CD34</g> expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25842923|a|The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches SCN in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic <d>idiopathic interstitial pneumonias</d> <d>IIP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, <d>desquamative interstitial pneumonia</d> <d>DIP</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> with <d>bronchiolitis obliterans</d> <d>BO</d>, and <d>nonspecific interstitial pneumonia</d> <d>NSIP</d>. SUBJECTS AND METHODS: The study was performed using open transthoracic n=181 and transbronchial n=71 lung biopsies from 194 patients 118 cases 61% with <d>IPF</d>, 35 18% with <d>NSIP</d>, 23 12% with <d>DIP</d>, 18 9% with <d>COP</d> + <d>BO</d>. The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect <g>MMP-1</g>, <g>MMP-2</g>, <g>MMP-7</g>, Apo-Cas "Novocastra", 1:100, <g>vimentin</g> <g>Vimentin</g> "LabVision" 1:100, <g>SMA</g> "LabVision", 1:100, <g>TGF-b</g>, <g>TNF-a</g>, <g>CD34</g>, <g>Ost-4</g>, and <g>CD117</g> "Dako", 1:50, <g>CD68</g>, and <d>EMA</d> "Dako", 1:100. Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies "Dako" LSAB + KIT, PEROXIDASE were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared <d>IIP</d>s were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the <d>aggressiveness</d> of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by <g>Oct-4</g>, <g>Vimentin</g>, <g>SMA</g>, <g>CD117</g>, and <g>CD34</g> expression by these cells, may be considered to be a marker cell of deep <d>SCN damage</d>. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.
25845491|a|UNASSIGNED: Immunoglobulin IgA is an important immunoglobulin in mucosal immunity and protects the lungs against invading pathogens. The production of IgA is regulated by transforming growth factor TGF-b, a versatile cytokine and key player in the pathogenesis of pulmonary fibrosis. TGF-b is up-regulated in patients with <d>idiopathic pulmonary fibrosis</d> IPF, but difficult to use as a biomarker. The aim of this study was to evaluate the prognostic value of IgA in serum in patients with IPF. We examined IgA levels at time of diagnosis in 86 patients diagnosed with IPF. Mean serum IgA level in IPF is 3  22 g/l and regression analyses showed a significant association with mortality hazard ratio   =   1  445, P = 0  002. A significantly worse survival was found in patients with IgA serum levels   >   2  85 g/l compared to patients with lower IgA serum levels P   =   0  003. These findings were confirmed in a duplication cohort. In conclusion, the level of IgA in blood is a promising prognostic marker in IPF and can be implemented easily in the hospital setting. Future studies are warranted to investigate if repeated measurements of serum IgA can further improve the performance of serum IgA as a prognostic marker.
25845491|a|UNASSIGNED: Immunoglobulin IgA is an important immunoglobulin in mucosal immunity and protects the lungs against invading pathogens. The production of IgA is regulated by transforming growth factor TGF-b, a versatile cytokine and key player in the pathogenesis of <d>pulmonary fibrosis</d>. TGF-b is up-regulated in patients with <d>idiopathic <d>pulmonary fibrosis</d></d> IPF, but difficult to use as a biomarker. The aim of this study was to evaluate the prognostic value of IgA in serum in patients with IPF. We examined IgA levels at time of diagnosis in 86 patients diagnosed with IPF. Mean serum IgA level in IPF is 3  22 g/l and regression analyses showed a significant association with mortality hazard ratio   =   1  445, P = 0  002. A significantly worse survival was found in patients with IgA serum levels   >   2  85 g/l compared to patients with lower IgA serum levels P   =   0  003. These findings were confirmed in a duplication cohort. In conclusion, the level of IgA in blood is a promising prognostic marker in IPF and can be implemented easily in the hospital setting. Future studies are warranted to investigate if repeated measurements of serum IgA can further improve the performance of serum IgA as a prognostic marker.
25845491|a|UNASSIGNED: Immunoglobulin IgA is an important immunoglobulin in mucosal immunity and protects the lungs against invading pathogens. The production of IgA is regulated by transforming growth factor <g>TGF-b</g>, a versatile cytokine and key player in the pathogenesis of <d>pulmonary fibrosis</d>. <g>TGF-b</g> is up-regulated in patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, but difficult to use as a biomarker. The aim of this study was to evaluate the prognostic value of IgA in serum in patients with <d>IPF</d>. We examined IgA levels at time of diagnosis in 86 patients diagnosed with <d>IPF</d>. Mean serum IgA level in <d>IPF</d> is 3  22 g/l and regression analyses showed a significant association with mortality hazard ratio   =   1  445, P = 0  002. A significantly worse survival was found in patients with IgA serum levels   >   2  85 g/l compared to patients with lower IgA serum levels P   =   0  003. These findings were confirmed in a duplication cohort. In conclusion, the level of IgA in blood is a promising prognostic marker in <d>IPF</d> and can be implemented easily in the hospital setting. Future studies are warranted to investigate if repeated measurements of serum IgA can further improve the performance of serum IgA as a prognostic marker.
25848047|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> IPF is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces liver fibrosis. However, altered peroxisome functions in IPF pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and IPF patients, we found that IPF lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism e.g., PEX13p and acyl-CoA oxidase 1. Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta <g>TGF-b</g> receptor II knockout mice indicating a role for <g>TGF-b</g> signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of IPF fibroblasts with the profibrotic factors <g>TGF-b</g>1 or tumor necrosis factor alpha TNF-a was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced fibrosis were further studied. Direct down-regulation of PEX13 by RNAi induced the activation of Smad-dependent <g>TGF-b</g> signaling accompanied by increased ROS production and resulted in the release of cytokines e.g., IL-6, <g>TGF-b</g> and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-a activators, led to peroxisome proliferation and reduced the <g>TGF-b</g>-induced myofibroblast differentiation and collagen protein in IPF cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of IPF and fibrosis progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.
25848047|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces liver fibrosis. However, altered peroxisome functions in <d>IPF</d> pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and <d>IPF</d> patients, we found that <d>IPF</d> lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism e.g., PEX13p and acyl-CoA oxidase 1. Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta <g>TGF-b</g> receptor II knockout mice indicating a role for <g>TGF-b</g> signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of <d>IPF</d> fibroblasts with the profibrotic factors <g>TGF-b</g>1 or tumor necrosis factor alpha TNF-a was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced fibrosis were further studied. Direct down-regulation of PEX13 by RNAi induced the activation of Smad-dependent <g>TGF-b</g> signaling accompanied by increased ROS production and resulted in the release of cytokines e.g., IL-6, <g>TGF-b</g> and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-a activators, led to peroxisome proliferation and reduced the <g>TGF-b</g>-induced myofibroblast differentiation and collagen protein in <d>IPF</d> cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of <d>IPF</d> and fibrosis progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.
25848047|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces <d>liver fibrosis</d>. However, altered peroxisome functions in <d>IPF</d> pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and <d>IPF</d> patients, we found that <d>IPF</d> lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism e.g., PEX13p and acyl-CoA oxidase 1. Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta <g>TGF-b</g> receptor II knockout mice indicating a role for <g>TGF-b</g> signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of <d>IPF</d> fibroblasts with the profibrotic factors <g>TGF-b</g>1 or tumor necrosis factor alpha TNF-a was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced fibrosis were further studied. Direct down-regulation of PEX13 by RNAi induced the activation of Smad-dependent <g>TGF-b</g> signaling accompanied by increased ROS production and resulted in the release of cytokines e.g., IL-6, <g>TGF-b</g> and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-a activators, led to peroxisome proliferation and reduced the <g>TGF-b</g>-induced myofibroblast differentiation and collagen protein in <d>IPF</d> cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of <d>IPF</d> and fibrosis progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.
25848047|a|UNASSIGNED: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces <d>liver <d>fibrosis</d></d>. However, altered peroxisome functions in <d>IPF</d> pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and <d>IPF</d> patients, we found that <d>IPF</d> lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism e.g., <g>PEX13p</g> and <g>acyl-CoA oxidase 1</g>. Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta <g>TGF-b</g> receptor II knockout mice indicating a role for <g>TGF-b</g> signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of <d>IPF</d> fibroblasts with the profibrotic factors <g>TGF-b</g>1 or <g>tumor necrosis factor alpha</g> <g>TNF-a</g> was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced <d>fibrosis</d> were further studied. Direct down-regulation of PEX13 by RNAi induced the activation of Smad-dependent <g>TGF-b</g> signaling accompanied by increased ROS production and resulted in the release of cytokines e.g., IL-6, <g>TGF-b</g> and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-a activators, led to peroxisome proliferation and reduced the <g>TGF-b</g>-induced myofibroblast differentiation and collagen protein in <d>IPF</d> cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of <d>IPF</d> and <d>fibrosis</d> progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.
25848047|a|UNASSIGNED: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces <d>liver <d>fibrosis</d></d>. However, altered peroxisome functions in <d>IPF</d> pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and <d>IPF</d> patients, we found that <d>IPF</d> lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism e.g., <g><g>PEX13</g>p</g> and <g>acyl-CoA oxidase 1</g>. Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta <g>TGF-b</g> receptor II knockout mice indicating a role for <g>TGF-b</g> signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of <d>IPF</d> fibroblasts with the profibrotic factors <g>TGF-b</g>1 or <g>tumor necrosis factor alpha</g> <g>TNF-a</g> was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced <d>fibrosis</d> were further studied. Direct down-regulation of <g>PEX13</g> by RNAi induced the activation of Smad-dependent <g>TGF-b</g> signaling accompanied by <d>increased ROS production</d> and resulted in the release of cytokines e.g., IL-6, <g>TGF-b</g> and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-a activators, led to peroxisome proliferation and reduced the <g>TGF-b</g>-induced myofibroblast differentiation and collagen protein in <d>IPF</d> cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of <d>IPF</d> and <d>fibrosis</d> progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.
25848047|a|UNASSIGNED: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces <d>liver <d>fibrosis</d></d>. However, altered peroxisome functions in <d>IPF</d> pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and <d>IPF</d> patients, we found that <d>IPF</d> lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism e.g., <g><g>PEX13</g>p</g> and <g>acyl-CoA oxidase 1</g>. Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta <g>TGF-b</g> receptor II knockout mice indicating a role for <g>TGF-b</g> signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of <d>IPF</d> fibroblasts with the profibrotic factors <g>TGF-b</g>1 or <g>tumor necrosis factor alpha</g> <g>TNF-a</g> was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced <d>fibrosis</d> were further studied. Direct down-regulation of <g>PEX13</g> by RNAi induced the activation of Smad-dependent <g>TGF-b</g> signaling accompanied by <d>increased ROS production</d> and resulted in the release of cytokines e.g., <g>IL-6</g>, <g>TGF-b</g> and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, <g>PPAR-a</g> activators, led to peroxisome proliferation and reduced the <g>TGF-b</g>-induced myofibroblast differentiation and collagen protein in <d>IPF</d> cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of <d>IPF</d> and <d>fibrosis</d> progression, possibly by exacerbating <d>pulmonary inflammation</d> and intensifying the fibrotic response in the patients.
25906080|a|Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic <d>pulmonary fibrosis</d> suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the <g>ATG4B</g> protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses.
25906080|a|Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic <d>pulmonary fibrosis</d> suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in <d>lung fibrosis</d> is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced <d>lung fibrosis</d> in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the <g>ATG4B</g> protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses.
25906080|a|Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic <d>pulmonary fibrosis</d> suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in <d>lung fibrosis</d> is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced <d>lung fibrosis</d> in vivo using an <g>Atg4b</g>-deficient mouse as a model. <g>Atg4b</g>-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that <g>Atg4b</g> disruption resulted in augmented apoptosis affecting predominantly <d>alveolar</d> and bronchiolar epithelial cells. At 28 d post-bleomycin instillation <g>Atg4b</g>-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the <g>ATG4B</g> protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses.
25906080|a|Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic <d>pulmonary <d>fibrosis</d></d> suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in <d>lung <d>fibrosis</d></d> is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced <d>lung <d>fibrosis</d></d> in vivo using an <g>Atg4b</g>-deficient mouse as a model. <g>Atg4b</g>-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that <g>Atg4b</g> disruption resulted in augmented apoptosis affecting predominantly <d>alveolar</d> and bronchiolar epithelial cells. At 28 d post-bleomycin instillation <g>Atg4b</g>-deficient mice exhibited more extensive and severe <d>fibrosis</d> with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the <g>ATG4B</g> protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses.
25929803|a|UNASSIGNED: Idiopathic pulmonary <d>fibrosis</d> IPF is a chronic disease characterised by a progressive decline in lung function which can be attributed to excessive scarring, inflammation and airway remodelling. Mannose-6-phosphate M6P is a strong inhibitor of <d>fibrosis</d> and its administration has been associated with beneficial effects in tendon repair surgery as well as nerve repair after injury. Given this promising therapeutic approach we developed an improved analogue of M6P, namely PXS64, and explored its anti-fibrotic effects in vitro. Normal human lung fibroblasts NHLF and human lung fibroblast 19 cells HF19 were exposed to active recombinant human TGF-b1 to induce increases in fibrotic markers. rhTGF-b1 increased constitutive protein levels of fibronectin and collagen in the NHLF cells, whereas HF19 cells showed increased levels of fibronectin, collagen as well as aSMA alpha smooth muscle actin. PXS64 demonstrated a robust inhibitory effect on all proteins analysed. IPF patient fibroblasts treated with PXS64 presented an improved phenotype in terms of their morphological appearance, as well as a decrease in fibrotic markers collagen, CTGF, TGF-b3, tenascin C, aSMA and THBS1. To explore the cell signalling pathways involved in the anti-fibrotic effects of PXS64, proteomics analysis with iTRAQ labelling was performed and the data demonstrated a specific antagonistic effect on the TGF-b1 pathway. This study shows that PXS64 effectively inhibits the production of extracellular matrix, as well as myofibroblast differentiation during <d>fibrosis</d>. These results suggest that PXS64 influences tissue remodelling by inhibiting TGF-b1 signalling in NHLF and HF19 cell lines, as well as in IPF patient fibroblasts. Thus PXS64 is a potential candidate for preclinical application in pulmonary <d>fibrosis</d>.
25929803|a|UNASSIGNED: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic disease characterised by a progressive decline in lung function which can be attributed to excessive scarring, inflammation and airway remodelling. Mannose-6-phosphate M6P is a strong inhibitor of <d>fibrosis</d> and its administration has been associated with beneficial effects in tendon repair surgery as well as nerve repair after injury. Given this promising therapeutic approach we developed an improved analogue of M6P, namely PXS64, and explored its anti-fibrotic effects in vitro. Normal human lung fibroblasts NHLF and human lung fibroblast 19 cells HF19 were exposed to active recombinant human <g>TGF-b1</g> to induce increases in fibrotic markers. rh<g>TGF-b1</g> increased constitutive protein levels of fibronectin and collagen in the NHLF cells, whereas HF19 cells showed increased levels of fibronectin, collagen as well as aSMA alpha smooth muscle actin. PXS64 demonstrated a robust inhibitory effect on all proteins analysed. <d>IPF</d> patient fibroblasts treated with PXS64 presented an improved phenotype in terms of their morphological appearance, as well as a decrease in fibrotic markers collagen, CTGF, TGF-b3, tenascin C, aSMA and THBS1. To explore the cell signalling pathways involved in the anti-fibrotic effects of PXS64, proteomics analysis with iTRAQ labelling was performed and the data demonstrated a specific antagonistic effect on the <g>TGF-b1</g> pathway. This study shows that PXS64 effectively inhibits the production of extracellular matrix, as well as myofibroblast differentiation during <d>fibrosis</d>. These results suggest that PXS64 influences tissue remodelling by inhibiting <g>TGF-b1</g> signalling in NHLF and HF19 cell lines, as well as in <d>IPF</d> patient fibroblasts. Thus PXS64 is a potential candidate for preclinical application in pulmonary <d>fibrosis</d>.
25929803|a|UNASSIGNED: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic disease characterised by a progressive decline in lung function which can be attributed to excessive <d>scarring</d>, inflammation and airway remodelling. Mannose-6-phosphate M6P is a strong inhibitor of <d>fibrosis</d> and its administration has been associated with beneficial effects in tendon repair surgery as well as nerve repair after injury. Given this promising therapeutic approach we developed an improved analogue of M6P, namely PXS64, and explored its anti-fibrotic effects in vitro. Normal human lung fibroblasts NHLF and human lung fibroblast 19 cells HF19 were exposed to active recombinant human <g>TGF-b1</g> to induce increases in fibrotic markers. rh<g>TGF-b1</g> increased constitutive protein levels of fibronectin and collagen in the NHLF cells, whereas HF19 cells showed increased levels of fibronectin, collagen as well as aSMA alpha smooth muscle actin. PXS64 demonstrated a robust inhibitory effect on all proteins analysed. <d>IPF</d> patient fibroblasts treated with PXS64 presented an improved phenotype in terms of their morphological appearance, as well as a decrease in fibrotic markers collagen, CTGF, TGF-b3, tenascin C, aSMA and THBS1. To explore the cell signalling pathways involved in the anti-fibrotic effects of PXS64, proteomics analysis with iTRAQ labelling was performed and the data demonstrated a specific antagonistic effect on the <g>TGF-b1</g> pathway. This study shows that PXS64 effectively inhibits the production of extracellular matrix, as well as myofibroblast differentiation during <d>fibrosis</d>. These results suggest that PXS64 influences tissue remodelling by inhibiting <g>TGF-b1</g> signalling in NHLF and HF19 cell lines, as well as in <d>IPF</d> patient fibroblasts. Thus PXS64 is a potential candidate for preclinical application in pulmonary <d>fibrosis</d>.
25929803|a|UNASSIGNED: Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a chronic disease characterised by a progressive decline in lung function which can be attributed to excessive <d>scarring</d>, <d>inflammation</d> and airway remodelling. Mannose-6-phosphate M6P is a strong inhibitor of <d>fibrosis</d> and its administration has been associated with beneficial effects in tendon repair surgery as well as nerve repair after injury. Given this promising therapeutic approach we developed an improved analogue of M6P, namely PXS64, and explored its anti-fibrotic effects in vitro. Normal human lung fibroblasts NHLF and human lung fibroblast 19 cells HF19 were exposed to active recombinant human <g>TGF-b1</g> to induce increases in fibrotic markers. rh<g>TGF-b1</g> increased constitutive protein levels of fibronectin and collagen in the NHLF cells, whereas HF19 cells showed increased levels of fibronectin, collagen as well as aSMA alpha smooth muscle actin. PXS64 demonstrated a robust inhibitory effect on all proteins analysed. <d>IPF</d> patient fibroblasts treated with PXS64 presented an improved phenotype in terms of their morphological appearance, as well as a decrease in fibrotic markers collagen, CTGF, TGF-b3, tenascin C, aSMA and THBS1. To explore the cell signalling pathways involved in the anti-fibrotic effects of PXS64, proteomics analysis with iTRAQ labelling was performed and the data demonstrated a specific antagonistic effect on the <g>TGF-b1</g> pathway. This study shows that PXS64 effectively inhibits the production of extracellular matrix, as well as myofibroblast differentiation during <d>fibrosis</d>. These results suggest that PXS64 influences tissue remodelling by inhibiting <g>TGF-b1</g> signalling in NHLF and HF19 cell lines, as well as in <d>IPF</d> patient fibroblasts. Thus PXS64 is a potential candidate for preclinical application in pulmonary <d>fibrosis</d>.
25959210|a|UNASSIGNED: Bleomycin BLM is a drug used to treat different types of neoplasms. BLM's most severe adverse effect is lung toxicity, which induces remodeling of lung architecture and loss of pulmonary function, rapidly leading to death. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing <d>lung fibrosis</d> in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, epithelial cell injury with reactive hyperplasia, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced <d>lung fibrosis</d> in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced <d>lung fibrosis</d> and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
25959210|a|UNASSIGNED: Bleomycin BLM is a drug used to treat different types of <d>neoplasms</d>. BLM's most severe adverse effect is lung toxicity, which induces remodeling of lung architecture and loss of pulmonary function, rapidly leading to death. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing <d>lung fibrosis</d> in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, epithelial cell injury with reactive hyperplasia, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced <d>lung fibrosis</d> in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced <d>lung fibrosis</d> and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
25959210|a|UNASSIGNED: Bleomycin BLM is a drug used to treat different types of <d>neoplasms</d>. BLM's most severe adverse effect is <d>lung toxicity</d>, which induces remodeling of lung architecture and loss of pulmonary function, rapidly leading to death. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing <d>lung fibrosis</d> in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, epithelial cell injury with reactive hyperplasia, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced <d>lung fibrosis</d> in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced <d>lung fibrosis</d> and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
25959210|a|UNASSIGNED: Bleomycin BLM is a drug used to treat different types of <d>neoplasms</d>. BLM's most severe adverse effect is <d>lung toxicity</d>, which induces remodeling of lung architecture and <d>loss of pulmonary function</d>, rapidly leading to death. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing <d>lung fibrosis</d> in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, epithelial cell injury with reactive hyperplasia, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced <d>lung fibrosis</d> in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced <d>lung fibrosis</d> and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
25959210|a|UNASSIGNED: Bleomycin BLM is a drug used to treat different types of <d>neoplasms</d>. BLM's most severe adverse effect is <d>lung toxicity</d>, which induces remodeling of lung architecture and <d>loss of pulmonary function</d>, rapidly leading to <d>death</d>. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing <d>lung fibrosis</d> in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, epithelial cell injury with reactive hyperplasia, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced <d>lung fibrosis</d> in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced <d>lung fibrosis</d> and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
25959210|a|UNASSIGNED: Bleomycin BLM is a drug used to treat different types of <d>neoplasms</d>. BLM's most severe adverse effect is <d>lung toxicity</d>, which induces remodeling of lung architecture and <d>loss of pulmonary function</d>, rapidly leading to <d>death</d>. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing <d>lung fibrosis</d> in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, <d>epithelial cell injury</d> with reactive hyperplasia, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced <d>lung fibrosis</d> in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced <d>lung fibrosis</d> and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
25959210|a|UNASSIGNED: Bleomycin BLM is a drug used to treat different types of <d>neoplasms</d>. BLM's most severe adverse effect is <d>lung toxicity</d>, which induces remodeling of lung architecture and <d>loss of pulmonary function</d>, rapidly leading to <d>death</d>. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing <d>lung fibrosis</d> in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, <d>epithelial cell injury</d> with <d>reactive hyperplasia</d>, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced <d>lung fibrosis</d> in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced <d>lung fibrosis</d> and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
25959210|a|UNASSIGNED: Bleomycin BLM is a drug used to treat different types of <d>neoplasms</d>. BLM's most severe adverse effect is <d>lung toxicity</d>, which induces remodeling of lung architecture and <d>loss of pulmonary function</d>, rapidly leading to <d>death</d>. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing <d>lung fibrosis</d> in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, <d>epithelial cell injury</d> with <d>reactive hyperplasia</d>, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of <d>pulmonary fibrosis</d> have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced <d>lung fibrosis</d> in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced <d>lung fibrosis</d> and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
25959210|a|UNASSIGNED: Bleomycin BLM is a drug used to treat different types of <d>neoplasms</d>. BLM's most severe adverse effect is <d>lung toxicity</d>, which induces remodeling of lung architecture and <d>loss of pulmonary function</d>, rapidly leading to <d>death</d>. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing <d>lung <d>fibrosis</d></d> in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, <d>epithelial cell injury</d> with <d>reactive hyperplasia</d>, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of <d>pulmonary <d>fibrosis</d></d> have not been fully understood; several studies have analyzed various potential biological molecular factors, such as <g>transforming growth factor beta 1</g>, <g>tumor necrosis factor alpha</g>, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced <d>lung <d>fibrosis</d></d> in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced <d>lung <d>fibrosis</d></d> and of commonly used therapies for counteracting <d>fibrosis</d> provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
26059457|a|Aging constitutes a significant risk factor for fibrosis, and idiopathic <d>pulmonary fibrosis</d> IPF is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to <d>pulmonary fibrosis</d>. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to lung injury in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to lung injury are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy mitophagy. Fibroblast to myofibroblast differentiation FMD is an important feature of <d>pulmonary fibrosis</d> in which the profibrotic cytokine TGFb1 plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, FMD mediated by TGFb1 is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a TGFb1-adenoviral model of lung fibrosis. PINK1 expression is also reduced in the aging murine lung and biopsies from IPF patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to lung injury may contribute to the promotion and/or perpetuation of <d>pulmonary fibrosis</d>. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.
26059457|a|Aging constitutes a significant risk factor for <d>fibrosis</d>, and idiopathic <d>pulmonary <d>fibrosis</d></d> IPF is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to <d>pulmonary <d>fibrosis</d></d>. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to lung injury in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to lung injury are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy mitophagy. Fibroblast to myofibroblast differentiation FMD is an important feature of <d>pulmonary <d>fibrosis</d></d> in which the profibrotic cytokine <g>TGFb1</g> plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, FMD mediated by <g>TGFb1</g> is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a <g>TGFb1</g>-adenoviral model of lung <d>fibrosis</d>. PINK1 expression is also reduced in the aging murine lung and biopsies from IPF patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to lung injury may contribute to the promotion and/or perpetuation of <d>pulmonary <d>fibrosis</d></d>. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.
26059457|a|Aging constitutes a significant risk factor for <d>fibrosis</d>, and idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to <d>pulmonary <d>fibrosis</d></d>. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to lung injury in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to lung injury are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy mitophagy. Fibroblast to myofibroblast differentiation FMD is an important feature of <d>pulmonary <d>fibrosis</d></d> in which the profibrotic cytokine <g>TGFb1</g> plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, FMD mediated by <g>TGFb1</g> is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a <g>TGFb1</g>-adenoviral model of lung <d>fibrosis</d>. PINK1 expression is also reduced in the aging murine lung and biopsies from <d>IPF</d> patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to lung injury may contribute to the promotion and/or perpetuation of <d>pulmonary <d>fibrosis</d></d>. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.
26059457|a|Aging constitutes a significant risk factor for <d>fibrosis</d>, and idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to <d>pulmonary <d>fibrosis</d></d>. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to <d>lung injury</d> in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to <d>lung injury</d> are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy mitophagy. Fibroblast to myofibroblast differentiation FMD is an important feature of <d>pulmonary <d>fibrosis</d></d> in which the profibrotic cytokine <g>TGFb1</g> plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, FMD mediated by <g>TGFb1</g> is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a <g>TGFb1</g>-adenoviral model of lung <d>fibrosis</d>. PINK1 expression is also reduced in the aging murine lung and biopsies from <d>IPF</d> patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to <d>lung injury</d> may contribute to the promotion and/or perpetuation of <d>pulmonary <d>fibrosis</d></d>. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.
26059457|a|Aging constitutes a significant risk factor for <d>fibrosis</d>, and idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to <d>pulmonary <d>fibrosis</d></d>. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to <d>lung injury</d> in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to <d>lung injury</d> are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy mitophagy. <d>Fibroblast to myofibroblast differentiation</d> FMD is an important feature of <d>pulmonary <d>fibrosis</d></d> in which the profibrotic cytokine <g>TGFb1</g> plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, FMD mediated by <g>TGFb1</g> is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a <g>TGFb1</g>-adenoviral model of lung <d>fibrosis</d>. PINK1 expression is also reduced in the aging murine lung and biopsies from <d>IPF</d> patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to <d>lung injury</d> may contribute to the promotion and/or perpetuation of <d>pulmonary <d>fibrosis</d></d>. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.
26059457|a|Aging constitutes a significant risk factor for <d>fibrosis</d>, and idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to <d>pulmonary <d>fibrosis</d></d>. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to <d>lung injury</d> in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to <d>lung injury</d> are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy mitophagy. <d>Fibroblast to myofibroblast differentiation</d> <d>FMD</d> is an important feature of <d>pulmonary <d>fibrosis</d></d> in which the profibrotic cytokine <g>TGFb1</g> plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, <d>FMD</d> mediated by <g>TGFb1</g> is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a <g>TGFb1</g>-adenoviral model of lung <d>fibrosis</d>. PINK1 expression is also reduced in the aging murine lung and biopsies from <d>IPF</d> patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to <d>lung injury</d> may contribute to the promotion and/or perpetuation of <d>pulmonary <d>fibrosis</d></d>. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.
26059457|a|Aging constitutes a significant risk factor for <d>fibrosis</d>, and idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to <d>pulmonary <d>fibrosis</d></d>. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to <d>lung injury</d> in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to <d>lung injury</d> are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy mitophagy. <d>Fibroblast to myofibroblast differentiation</d> <d>FMD</d> is an important feature of <d>pulmonary <d>fibrosis</d></d> in which the profibrotic cytokine <g>TGFb1</g> plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, <d>FMD</d> mediated by <g>TGFb1</g> is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, <g>PINK1</g> expression appeared to be reduced in fibrotic lung tissue from bleomycin and a <g>TGFb1</g>-adenoviral model of lung <d>fibrosis</d>. <g>PINK1</g> expression is also reduced in the aging murine lung and biopsies from <d>IPF</d> patients compared to controls. Furthermore, deficient <g>PINK1</g> promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to <d>lung injury</d> may contribute to the promotion and/or perpetuation of <d>pulmonary <d>fibrosis</d></d>. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related <d>fibrotic diseases</d>.
26072676|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a disease with relentless course and limited therapeutic options. Nintedanib BIBF-1120 is a multiple tyrosine kinase inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of IPF. The precise antifibrotic mechanisms of action of nintedanib, however, is not known. Therefore, we studied the effects of nintedanib on fibroblasts isolated from the lungs of patients with IPF. Protein and gene expression of profibrotic markers were assessed by Western immunoblotting and real-time PCR. Autophagy markers and signaling events were monitored by biochemical assays, Western immunoblotting, microscopy, and immunofluorescence staining. Silencing of autophagy effector proteins was achieved with small interfering RNAs. Nintedanib down-regulated protein and mRNA expression of extracellular matrix ECM proteins, fibronectin, and collagen 1a1 while inhibiting transforming growth factor TGF-b1-induced myofibroblast differentiation. Nintedanib also induced beclin-1-dependent, ATG7-independent autophagy. Nintedanib's ECM-suppressive actions were not mediated by canonical autophagy. Nintedanib inhibited early events in TGF-b signaling, specifically tyrosine phosphorylation of the type II TGF-b receptor, activation of SMAD3, and p38 mitogen-activated protein kinase. Nintedanib down-regulates ECM production and induces noncanonical autophagy in IPF fibroblasts while inhibiting TGF-b signaling. These mechanisms appear to be uncoupled and function independently to mediate its putative antifibrotic effects.
26072676|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a disease with relentless course and limited therapeutic options. Nintedanib BIBF-1120 is a multiple tyrosine kinase inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of <d>IPF</d>. The precise antifibrotic mechanisms of action of nintedanib, however, is not known. Therefore, we studied the effects of nintedanib on fibroblasts isolated from the lungs of patients with <d>IPF</d>. Protein and gene expression of profibrotic markers were assessed by Western immunoblotting and real-time PCR. Autophagy markers and signaling events were monitored by biochemical assays, Western immunoblotting, microscopy, and immunofluorescence staining. Silencing of autophagy effector proteins was achieved with small interfering RNAs. Nintedanib down-regulated protein and mRNA expression of extracellular matrix ECM proteins, fibronectin, and collagen 1a1 while inhibiting transforming growth factor TGF-b1-induced myofibroblast differentiation. Nintedanib also induced beclin-1-dependent, ATG7-independent autophagy. Nintedanib's ECM-suppressive actions were not mediated by canonical autophagy. Nintedanib inhibited early events in TGF-b signaling, specifically tyrosine phosphorylation of the type II TGF-b receptor, activation of SMAD3, and p38 mitogen-activated protein kinase. Nintedanib down-regulates ECM production and induces noncanonical autophagy in <d>IPF</d> fibroblasts while inhibiting TGF-b signaling. These mechanisms appear to be uncoupled and function independently to mediate its putative antifibrotic effects.
26093215|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> IPF is a chronic progressive multifactorial disease with limited therapeutic options. Glycosides based standardized fenugreek seed extract SFSE-G possesses potent anti-inflammatory and anti-oxidant property. AIM: To evaluate the efficacy of SFSE-G against bleomycin BLM induced <d>pulmonary fibrosis</d> by assessing behavioral, biochemical, molecular and ultrastructural changes in the laboratory rats. MATERIALS AND METHODS: IPF was induced in male Sprague-Dawley rats by single intratracheal BLM 6IU/kg injection followed by SFSE-G 5, 10, 20 and 40mg/kg, p.o. or methylprednisolone 10mg/kg, p.o. treatment for 28day. Various parameters were analyzed in lung and bronchoalveolar lavage fluid BALF after 14 and 28days of the drug treatment. RESULTS: SFSE-G 20 and 40mg/kg, p.o. administration significantly prevented the BLM induced alteration in body weight, lung index, lung function test and hematology. The altered total and differential cell count in BALF and blood was significantly prevented by SFSE-G treatment. The decreased peripheral blood oxygen content after BLM instillation was significantly increased by SFSE-G treatment. SFSE-G significantly enhanced the BALF and lung antioxidant status, through modulating the SOD, GSH, T-AOC, MDA, NO level and Nrf2, HO-1 mRNA expression. There was a significant reduction in lung 5-HT level by SFSE-G treatment. The altered mRNA expression of biomarkers of lung inflammation TNF-a, IL-1b, IL-6 and IL-8, fibrosis TGF-b, collagen-1, ET-1, Muc5ac, NF-kB, VEGF, Smad-3 and apoptosis Bax, Bcl-2 and Caspase-3 were significantly prevented by SFSE-G treatment. BLM induced histological inflammatory and fibrotic insult in the lung were reduced by SFSE-G treatment. It also ameliorated BLM induced lung ultrastructural changes as observed by transmission electron microscopic studies. However, administration of SFSE-G 5mg/kg, p.o. failed to show any protective effect against BLM-induced PF whereas SFSE-G 10mg/kg, p.o. showed significant amelioration in BLM-induced PF except lung function test, BALF and lung antioxidant level. CONCLUSION: SFSE-G showed anti-fibrotic efficacy executed through induction of Nrf2, which in turn may modulate anti-inflammatory molecules, inhibit fibrogenic molecules and decreased apoptosis to ameliorate BLM induced <d>pulmonary fibrosis</d>.
26093215|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive multifactorial disease with limited therapeutic options. Glycosides based standardized fenugreek seed extract SFSE-G possesses potent anti-inflammatory and anti-oxidant property. AIM: To evaluate the efficacy of SFSE-G against bleomycin BLM induced <d>pulmonary fibrosis</d> by assessing behavioral, biochemical, molecular and ultrastructural changes in the laboratory rats. MATERIALS AND METHODS: <d>IPF</d> was induced in male Sprague-Dawley rats by single intratracheal BLM 6IU/kg injection followed by SFSE-G 5, 10, 20 and 40mg/kg, p.o. or methylprednisolone 10mg/kg, p.o. treatment for 28day. Various parameters were analyzed in lung and bronchoalveolar lavage fluid BALF after 14 and 28days of the drug treatment. RESULTS: SFSE-G 20 and 40mg/kg, p.o. administration significantly prevented the BLM induced alteration in body weight, lung index, lung function test and hematology. The altered total and differential cell count in BALF and blood was significantly prevented by SFSE-G treatment. The decreased peripheral blood oxygen content after BLM instillation was significantly increased by SFSE-G treatment. SFSE-G significantly enhanced the BALF and lung antioxidant status, through modulating the SOD, GSH, T-AOC, MDA, NO level and <g>Nrf2</g>, HO-1 mRNA expression. There was a significant reduction in lung 5-HT level by SFSE-G treatment. The altered mRNA expression of biomarkers of lung inflammation <g>TNF-a</g>, <g>IL-1b</g>, IL-6 and IL-8, fibrosis TGF-b, collagen-1, ET-1, <g>Muc5ac</g>, <g>NF-kB</g>, VEGF, Smad-3 and apoptosis <g>Bax</g>, Bcl-2 and Caspase-3 were significantly prevented by SFSE-G treatment. BLM induced histological inflammatory and fibrotic insult in the lung were reduced by SFSE-G treatment. It also ameliorated BLM induced lung ultrastructural changes as observed by transmission electron microscopic studies. However, administration of SFSE-G 5mg/kg, p.o. failed to show any protective effect against BLM-induced PF whereas SFSE-G 10mg/kg, p.o. showed significant amelioration in BLM-induced PF except lung function test, BALF and lung antioxidant level. CONCLUSION: SFSE-G showed anti-fibrotic efficacy executed through induction of <g>Nrf2</g>, which in turn may modulate anti-inflammatory molecules, inhibit fibrogenic molecules and decreased apoptosis to ameliorate BLM induced <d>pulmonary fibrosis</d>.
26093215|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive <d>multifactorial disease</d> with limited therapeutic options. Glycosides based standardized fenugreek seed extract SFSE-G possesses potent anti-inflammatory and anti-oxidant property. AIM: To evaluate the efficacy of SFSE-G against bleomycin BLM induced <d>pulmonary fibrosis</d> by assessing behavioral, biochemical, molecular and ultrastructural changes in the laboratory rats. MATERIALS AND METHODS: <d>IPF</d> was induced in male Sprague-Dawley rats by single intratracheal BLM 6IU/kg injection followed by SFSE-G 5, 10, 20 and 40mg/kg, p.o. or methylprednisolone 10mg/kg, p.o. treatment for 28day. Various parameters were analyzed in lung and bronchoalveolar lavage fluid BALF after 14 and 28days of the drug treatment. RESULTS: SFSE-G 20 and 40mg/kg, p.o. administration significantly prevented the BLM induced alteration in body weight, lung index, lung function test and hematology. The altered total and differential cell count in BALF and blood was significantly prevented by SFSE-G treatment. The decreased peripheral blood oxygen content after BLM instillation was significantly increased by SFSE-G treatment. SFSE-G significantly enhanced the BALF and lung antioxidant status, through modulating the SOD, GSH, T-AOC, MDA, NO level and <g>Nrf2</g>, HO-1 mRNA expression. There was a significant reduction in lung 5-HT level by SFSE-G treatment. The altered mRNA expression of biomarkers of lung inflammation <g>TNF-a</g>, <g>IL-1b</g>, IL-6 and IL-8, fibrosis TGF-b, collagen-1, ET-1, <g>Muc5ac</g>, <g>NF-kB</g>, VEGF, Smad-3 and apoptosis <g>Bax</g>, Bcl-2 and Caspase-3 were significantly prevented by SFSE-G treatment. BLM induced histological inflammatory and fibrotic insult in the lung were reduced by SFSE-G treatment. It also ameliorated BLM induced lung ultrastructural changes as observed by transmission electron microscopic studies. However, administration of SFSE-G 5mg/kg, p.o. failed to show any protective effect against BLM-induced PF whereas SFSE-G 10mg/kg, p.o. showed significant amelioration in BLM-induced PF except lung function test, BALF and lung antioxidant level. CONCLUSION: SFSE-G showed anti-fibrotic efficacy executed through induction of <g>Nrf2</g>, which in turn may modulate anti-inflammatory molecules, inhibit fibrogenic molecules and decreased apoptosis to ameliorate BLM induced <d>pulmonary fibrosis</d>.
26093215|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive <d>multifactorial disease</d> with limited therapeutic options. Glycosides based standardized fenugreek seed extract SFSE-G possesses potent anti-inflammatory and anti-oxidant property. AIM: To evaluate the efficacy of SFSE-G against bleomycin BLM induced <d>pulmonary fibrosis</d> by assessing behavioral, biochemical, molecular and ultrastructural changes in the laboratory rats. MATERIALS AND METHODS: <d>IPF</d> was induced in male Sprague-Dawley rats by single intratracheal BLM 6IU/kg injection followed by SFSE-G 5, 10, 20 and 40mg/kg, p.o. or methylprednisolone 10mg/kg, p.o. treatment for 28day. Various parameters were analyzed in lung and bronchoalveolar lavage fluid BALF after 14 and 28days of the drug treatment. RESULTS: SFSE-G 20 and 40mg/kg, p.o. administration significantly prevented the BLM induced alteration in body weight, lung index, lung function test and hematology. The altered total and differential cell count in BALF and blood was significantly prevented by SFSE-G treatment. The decreased peripheral blood oxygen content after BLM instillation was significantly increased by SFSE-G treatment. SFSE-G significantly enhanced the BALF and lung antioxidant status, through modulating the SOD, GSH, T-AOC, MDA, NO level and <g>Nrf2</g>, <g>HO-1</g> mRNA expression. There was a significant reduction in lung 5-HT level by SFSE-G treatment. The altered mRNA expression of biomarkers of <d>lung inflammation</d> <g>TNF-a</g>, <g>IL-1b</g>, IL-6 and IL-8, fibrosis TGF-b, collagen-1, ET-1, <g>Muc5ac</g>, <g>NF-kB</g>, VEGF, Smad-3 and apoptosis <g>Bax</g>, Bcl-2 and Caspase-3 were significantly prevented by SFSE-G treatment. BLM induced histological inflammatory and fibrotic insult in the lung were reduced by SFSE-G treatment. It also ameliorated BLM induced lung ultrastructural changes as observed by transmission electron microscopic studies. However, administration of SFSE-G 5mg/kg, p.o. failed to show any protective effect against BLM-induced PF whereas SFSE-G 10mg/kg, p.o. showed significant amelioration in BLM-induced PF except lung function test, BALF and lung antioxidant level. CONCLUSION: SFSE-G showed anti-fibrotic efficacy executed through induction of <g>Nrf2</g>, which in turn may modulate anti-inflammatory molecules, inhibit fibrogenic molecules and decreased apoptosis to ameliorate BLM induced <d>pulmonary fibrosis</d>.
26093215|a|BACKGROUND: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic progressive <d>multifactorial disease</d> with limited therapeutic options. Glycosides based standardized fenugreek seed extract SFSE-G possesses potent anti-inflammatory and anti-oxidant property. AIM: To evaluate the efficacy of SFSE-G against bleomycin BLM induced <d>pulmonary <d>fibrosis</d></d> by assessing behavioral, biochemical, molecular and ultrastructural changes in the laboratory rats. MATERIALS AND METHODS: <d>IPF</d> was induced in male Sprague-Dawley rats by single intratracheal BLM 6IU/kg injection followed by SFSE-G 5, 10, 20 and 40mg/kg, p.o. or methylprednisolone 10mg/kg, p.o. treatment for 28day. Various parameters were analyzed in lung and bronchoalveolar lavage fluid BALF after 14 and 28days of the drug treatment. RESULTS: SFSE-G 20 and 40mg/kg, p.o. administration significantly prevented the BLM induced alteration in body weight, lung index, lung function test and hematology. The altered total and differential cell count in BALF and blood was significantly prevented by SFSE-G treatment. The decreased peripheral blood oxygen content after BLM instillation was significantly increased by SFSE-G treatment. SFSE-G significantly enhanced the BALF and lung antioxidant status, through modulating the SOD, GSH, T-AOC, MDA, NO level and <g>Nrf2</g>, <g>HO-1</g> mRNA expression. There was a significant reduction in lung 5-HT level by SFSE-G treatment. The altered mRNA expression of biomarkers of <d>lung inflammation</d> <g>TNF-a</g>, <g>IL-1b</g>, <g>IL-6</g> and IL-8, <d>fibrosis</d> TGF-b, collagen-1, ET-1, <g>Muc5ac</g>, <g>NF-kB</g>, VEGF, Smad-3 and apoptosis <g>Bax</g>, Bcl-2 and Caspase-3 were significantly prevented by SFSE-G treatment. BLM induced histological inflammatory and fibrotic insult in the lung were reduced by SFSE-G treatment. It also ameliorated BLM induced lung ultrastructural changes as observed by transmission electron microscopic studies. However, administration of SFSE-G 5mg/kg, p.o. failed to show any protective effect against BLM-induced PF whereas SFSE-G 10mg/kg, p.o. showed significant amelioration in BLM-induced PF except lung function test, BALF and lung antioxidant level. CONCLUSION: SFSE-G showed anti-fibrotic efficacy executed through induction of <g>Nrf2</g>, which in turn may modulate anti-inflammatory molecules, inhibit fibrogenic molecules and decreased apoptosis to ameliorate BLM induced <d>pulmonary <d>fibrosis</d></d>.
26098610|a|UNASSIGNED: Thymosin b4 Tb4 and its amino-terminal fragment comprising N-acetyl-seryl-aspartyl-lysyl-proline Ac-SDKP have been reported to act as anti-inflammatory and anti-fibrotic agents in vitro and in vivo. In recent papers, we have shown that Tb4 exerts a widely protective role in mice treated with bleomycin, and in particular, we have demonstrated its inhibitory effects on both inflammation and early fibrosis. OBJECTIVES: In this study, the putative anti-proliferative and anti-fibrogenic effects of Tb4 and Ac-SDKP were evaluated in vitro. In addition, the effects of Tb4 up to 21 days were evaluated in the bleomycin mouse model of <d>lung fibrosis</d>. METHODS: We utilized both control and <g>TGF-b</g>-stimulated primary human lung fibroblasts isolated from both idiopathic pulmonary fibrosis IPF and control tissues. The in vivo effects of Tb4 were assessed in CD1 mice treated with bleomycin. RESULTS: In the in vitro experiments, we observed significant anti-proliferative effects of Ac-SDKP in IPF fibroblasts. In those cells, Ac-SDKP significantly inhibited <g>TGF-b</g>-induced a-SMA and collagen expression, hallmarks of fibroblast differentiation into myofibroblasts triggered by <g>TGF-b</g>. In vivo, despite its previously described protective role in mice treated with bleomycin at 7 days, Tb4 failed to prevent fibrosis induced by the drug at 14 and 21 days. CONCLUSION: We conclude that, compared to Tb4, Ac-SDKP may have greater potential as an anti-fibrotic agent in the lung. Further in vivo experiments are warranted.
26098610|a|UNASSIGNED: <g>Thymosin b4</g> <g>Tb4</g> and its amino-terminal fragment comprising N-acetyl-seryl-aspartyl-lysyl-proline Ac-SDKP have been reported to act as anti-inflammatory and anti-fibrotic agents in vitro and in vivo. In recent papers, we have shown that <g>Tb4</g> exerts a widely protective role in mice treated with bleomycin, and in particular, we have demonstrated its inhibitory effects on both <d>inflammation</d> and early fibrosis. OBJECTIVES: In this study, the putative anti-proliferative and anti-fibrogenic effects of <g>Tb4</g> and Ac-SDKP were evaluated in vitro. In addition, the effects of <g>Tb4</g> up to 21 days were evaluated in the bleomycin mouse model of <d>lung fibrosis</d>. METHODS: We utilized both control and <g>TGF-b</g>-stimulated primary human lung fibroblasts isolated from both idiopathic pulmonary fibrosis IPF and control tissues. The in vivo effects of <g>Tb4</g> were assessed in CD1 mice treated with bleomycin. RESULTS: In the in vitro experiments, we observed significant anti-proliferative effects of Ac-SDKP in IPF fibroblasts. In those cells, Ac-SDKP significantly inhibited <g>TGF-b</g>-induced a-SMA and collagen expression, hallmarks of fibroblast differentiation into myofibroblasts triggered by <g>TGF-b</g>. In vivo, despite its previously described protective role in mice treated with bleomycin at 7 days, <g>Tb4</g> failed to prevent fibrosis induced by the drug at 14 and 21 days. CONCLUSION: We conclude that, compared to <g>Tb4</g>, Ac-SDKP may have greater potential as an anti-fibrotic agent in the lung. Further in vivo experiments are warranted.
26098610|a|UNASSIGNED: <g>Thymosin b4</g> <g>Tb4</g> and its amino-terminal fragment comprising N-acetyl-seryl-aspartyl-lysyl-proline Ac-SDKP have been reported to act as anti-inflammatory and anti-fibrotic agents in vitro and in vivo. In recent papers, we have shown that <g>Tb4</g> exerts a widely protective role in mice treated with bleomycin, and in particular, we have demonstrated its inhibitory effects on both <d>inflammation</d> and early <d>fibrosis</d>. OBJECTIVES: In this study, the putative anti-proliferative and anti-fibrogenic effects of <g>Tb4</g> and Ac-SDKP were evaluated in vitro. In addition, the effects of <g>Tb4</g> up to 21 days were evaluated in the bleomycin mouse model of <d>lung <d>fibrosis</d></d>. METHODS: We utilized both control and <g>TGF-b</g>-stimulated primary human lung fibroblasts isolated from both idiopathic pulmonary <d>fibrosis</d> IPF and control tissues. The in vivo effects of <g>Tb4</g> were assessed in CD1 mice treated with bleomycin. RESULTS: In the in vitro experiments, we observed significant anti-proliferative effects of Ac-SDKP in IPF fibroblasts. In those cells, Ac-SDKP significantly inhibited <g>TGF-b</g>-induced a-SMA and collagen expression, hallmarks of fibroblast differentiation into myofibroblasts triggered by <g>TGF-b</g>. In vivo, despite its previously described protective role in mice treated with bleomycin at 7 days, <g>Tb4</g> failed to prevent <d>fibrosis</d> induced by the drug at 14 and 21 days. CONCLUSION: We conclude that, compared to <g>Tb4</g>, Ac-SDKP may have greater potential as an anti-fibrotic agent in the lung. Further in vivo experiments are warranted.
26098610|a|UNASSIGNED: <g>Thymosin b4</g> <g>Tb4</g> and its amino-terminal fragment comprising N-acetyl-seryl-aspartyl-lysyl-proline Ac-SDKP have been reported to act as anti-inflammatory and anti-fibrotic agents in vitro and in vivo. In recent papers, we have shown that <g>Tb4</g> exerts a widely protective role in mice treated with bleomycin, and in particular, we have demonstrated its inhibitory effects on both <d>inflammation</d> and early <d>fibrosis</d>. OBJECTIVES: In this study, the putative anti-proliferative and anti-fibrogenic effects of <g>Tb4</g> and Ac-SDKP were evaluated in vitro. In addition, the effects of <g>Tb4</g> up to 21 days were evaluated in the bleomycin mouse model of <d>lung <d>fibrosis</d></d>. METHODS: We utilized both control and <g>TGF-b</g>-stimulated primary human lung fibroblasts isolated from both idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> and control tissues. The in vivo effects of <g>Tb4</g> were assessed in CD1 mice treated with bleomycin. RESULTS: In the in vitro experiments, we observed significant anti-proliferative effects of Ac-SDKP in <d>IPF</d> fibroblasts. In those cells, Ac-SDKP significantly inhibited <g>TGF-b</g>-induced a-SMA and collagen expression, hallmarks of fibroblast differentiation into myofibroblasts triggered by <g>TGF-b</g>. In vivo, despite its previously described protective role in mice treated with bleomycin at 7 days, <g>Tb4</g> failed to prevent <d>fibrosis</d> induced by the drug at 14 and 21 days. CONCLUSION: We conclude that, compared to <g>Tb4</g>, Ac-SDKP may have greater potential as an anti-fibrotic agent in the lung. Further in vivo experiments are warranted.
26138704|a|UNASSIGNED: <g>TGFb</g>-<g>ALK5</g> pro-fibrotic signalling and herpesvirus infections have been implicated in the pathogenesis and exacerbation of <d>pulmonary fibrosis</d>. In this study we addressed the role of <g>TGFb</g>-<g>ALK5</g> signalling during the progression of fibrosis in a two-hit mouse model of murine y-herpesvirus 68 MHV-68 infection on the background of pre-existing bleomycin-induced <d>pulmonary fibrosis</d>. Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography   CT analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated inflammatory response. Moreover,   CT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing fibrosis that were reminiscent of those observed in acute exacerbation of idiopathic <d>pulmonary fibrosis</d> AE-IPF. Virally-infected murine fibrotic lungs further displayed evidence of extensive inflammatory cell infiltration and increased levels of CCL2, TNFa, IL-1b and IL-10. Blockade of <g>TGFb</g>-<g>ALK5</g> signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant viral infection. In contrast, inhibition of <g>TGFb</g>-<g>ALK5</g> signalling in virally-infected fibrotic lungs was associated with reduced inflammatory cell aggregates and increased levels of the antiviral cytokine IFNy. These data reveal newly identified intricacies for the <g>TGFb</g>-<g>ALK5</g> signalling axis in experimental lung fibrosis, with different outcomes in response to <g>ALK5</g> inhibition depending on the presence of viral infection. These findings raise important considerations for the targeting of <g>TGFb</g> signalling responses in the context of <d>pulmonary fibrosis</d>.
26138704|a|UNASSIGNED: <g>TGFb</g>-<g>ALK5</g> pro-fibrotic signalling and <d>herpesvirus infections</d> have been implicated in the pathogenesis and exacerbation of <d>pulmonary fibrosis</d>. In this study we addressed the role of <g>TGFb</g>-<g>ALK5</g> signalling during the progression of fibrosis in a two-hit mouse model of murine y-herpesvirus 68 MHV-68 infection on the background of pre-existing bleomycin-induced <d>pulmonary fibrosis</d>. Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography   CT analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated inflammatory response. Moreover,   CT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing fibrosis that were reminiscent of those observed in acute exacerbation of idiopathic <d>pulmonary fibrosis</d> AE-IPF. Virally-infected murine fibrotic lungs further displayed evidence of extensive inflammatory cell infiltration and increased levels of CCL2, TNFa, IL-1b and IL-10. Blockade of <g>TGFb</g>-<g>ALK5</g> signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant viral infection. In contrast, inhibition of <g>TGFb</g>-<g>ALK5</g> signalling in virally-infected fibrotic lungs was associated with reduced inflammatory cell aggregates and increased levels of the antiviral cytokine IFNy. These data reveal newly identified intricacies for the <g>TGFb</g>-<g>ALK5</g> signalling axis in experimental lung fibrosis, with different outcomes in response to <g>ALK5</g> inhibition depending on the presence of viral infection. These findings raise important considerations for the targeting of <g>TGFb</g> signalling responses in the context of <d>pulmonary fibrosis</d>.
26138704|a|UNASSIGNED: <g>TGFb</g>-<g>ALK5</g> pro-fibrotic signalling and <d>herpesvirus infections</d> have been implicated in the pathogenesis and exacerbation of <d>pulmonary <d>fibrosis</d></d>. In this study we addressed the role of <g>TGFb</g>-<g>ALK5</g> signalling during the progression of <d>fibrosis</d> in a two-hit mouse model of murine y-herpesvirus 68 MHV-68 infection on the background of pre-existing bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography   CT analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated inflammatory response. Moreover,   CT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing <d>fibrosis</d> that were reminiscent of those observed in acute exacerbation of idiopathic <d>pulmonary <d>fibrosis</d></d> AE-IPF. Virally-infected murine fibrotic lungs further displayed evidence of extensive inflammatory cell infiltration and increased levels of CCL2, TNFa, IL-1b and IL-10. Blockade of <g>TGFb</g>-<g>ALK5</g> signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant viral infection. In contrast, inhibition of <g>TGFb</g>-<g>ALK5</g> signalling in virally-infected fibrotic lungs was associated with reduced inflammatory cell aggregates and increased levels of the antiviral cytokine IFNy. These data reveal newly identified intricacies for the <g>TGFb</g>-<g>ALK5</g> signalling axis in experimental lung <d>fibrosis</d>, with different outcomes in response to <g>ALK5</g> inhibition depending on the presence of viral infection. These findings raise important considerations for the targeting of <g>TGFb</g> signalling responses in the context of <d>pulmonary <d>fibrosis</d></d>.
26138704|a|UNASSIGNED: <g>TGFb</g>-<g>ALK5</g> pro-fibrotic signalling and <d>herpesvirus infections</d> have been implicated in the pathogenesis and exacerbation of <d>pulmonary <d>fibrosis</d></d>. In this study we addressed the role of <g>TGFb</g>-<g>ALK5</g> signalling during the progression of <d>fibrosis</d> in a two-hit mouse model of murine y-herpesvirus 68 MHV-68 infection on the background of pre-existing bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography   CT analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated <d>inflammatory</d> response. Moreover,   CT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing <d>fibrosis</d> that were reminiscent of those observed in acute exacerbation of idiopathic <d>pulmonary <d>fibrosis</d></d> AE-IPF. Virally-infected murine fibrotic lungs further displayed evidence of extensive <d>inflammatory</d> cell infiltration and increased levels of CCL2, TNFa, IL-1b and IL-10. Blockade of <g>TGFb</g>-<g>ALK5</g> signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant viral infection. In contrast, inhibition of <g>TGFb</g>-<g>ALK5</g> signalling in virally-infected fibrotic lungs was associated with reduced <d>inflammatory</d> cell aggregates and increased levels of the antiviral cytokine IFNy. These data reveal newly identified intricacies for the <g>TGFb</g>-<g>ALK5</g> signalling axis in experimental lung <d>fibrosis</d>, with different outcomes in response to <g>ALK5</g> inhibition depending on the presence of viral infection. These findings raise important considerations for the targeting of <g>TGFb</g> signalling responses in the context of <d>pulmonary <d>fibrosis</d></d>.
26138704|a|UNASSIGNED: <g>TGFb</g>-<g>ALK5</g> pro-fibrotic signalling and <d>herpesvirus infections</d> have been implicated in the pathogenesis and exacerbation of <d>pulmonary <d>fibrosis</d></d>. In this study we addressed the role of <g>TGFb</g>-<g>ALK5</g> signalling during the progression of <d>fibrosis</d> in a two-hit mouse model of murine y-herpesvirus 68 MHV-68 infection on the background of pre-existing bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography   CT analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated <d>inflammatory</d> response. Moreover,   CT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing <d>fibrosis</d> that were reminiscent of those observed in acute exacerbation of idiopathic <d>pulmonary <d>fibrosis</d></d> AE-IPF. Virally-infected murine fibrotic lungs further displayed evidence of extensive <d>inflammatory</d> cell infiltration and increased levels of <g>CCL2</g>, <g>TNFa</g>, <g>IL-1b</g> and <g>IL-10</g>. Blockade of <g>TGFb</g>-<g>ALK5</g> signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant <d>viral infection</d>. In contrast, inhibition of <g>TGFb</g>-<g>ALK5</g> signalling in virally-infected fibrotic lungs was associated with reduced <d>inflammatory</d> cell aggregates and increased levels of the antiviral cytokine IFNy. These data reveal newly identified intricacies for the <g>TGFb</g>-<g>ALK5</g> signalling axis in experimental lung <d>fibrosis</d>, with different outcomes in response to <g>ALK5</g> inhibition depending on the presence of <d>viral infection</d>. These findings raise important considerations for the targeting of <g>TGFb</g> signalling responses in the context of <d>pulmonary <d>fibrosis</d></d>.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary fibrosis</d> IPF. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of pleural effusions occurs due to an imbalance in the dynamic interaction between junctional proteins, n-cadherin and b-catenin, and phosphorylation of adherens junctions between PMCs, which is caused in part by vascular endothelial growth factor VEGF released by PMCs. PMCs play an important role in defense mechanisms against bacterial and mycobacterial pleural infections, and in pathogenesis of malignant pleural effusion, asbestos related pleural disease and malignant pleural mesothelioma. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of IPF suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of IPF and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of pleural effusions occurs due to an imbalance in the dynamic interaction between junctional proteins, n-cadherin and b-catenin, and phosphorylation of adherens junctions between PMCs, which is caused in part by vascular endothelial growth factor VEGF released by PMCs. PMCs play an important role in defense mechanisms against bacterial and mycobacterial pleural infections, and in pathogenesis of malignant pleural effusion, asbestos related pleural disease and malignant pleural mesothelioma. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, n-cadherin and b-catenin, and phosphorylation of adherens junctions between PMCs, which is caused in part by vascular endothelial growth factor VEGF released by PMCs. PMCs play an important role in defense mechanisms against bacterial and mycobacterial pleural infections, and in pathogenesis of malignant pleural effusion, asbestos related pleural disease and malignant pleural mesothelioma. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, <g>n-cadherin</g> and <g>b-catenin</g>, and phosphorylation of adherens junctions between PMCs, which is caused in part by <g>vascular endothelial growth factor</g> <g>VEGF</g> released by PMCs. PMCs play an important role in defense mechanisms against <d>bacterial and mycobacterial pleural infections</d>, and in pathogenesis of malignant pleural effusion, asbestos related pleural disease and malignant pleural mesothelioma. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, <g>n-cadherin</g> and <g>b-catenin</g>, and phosphorylation of adherens junctions between PMCs, which is caused in part by <g>vascular endothelial growth factor</g> <g>VEGF</g> released by PMCs. PMCs play an important role in defense mechanisms against <d>bacterial and mycobacterial pleural infections</d>, and in pathogenesis of <d>malignant pleural effusion</d>, asbestos related pleural disease and malignant pleural mesothelioma. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, <g>n-cadherin</g> and <g>b-catenin</g>, and phosphorylation of adherens junctions between PMCs, which is caused in part by <g>vascular endothelial growth factor</g> <g>VEGF</g> released by PMCs. PMCs play an important role in defense mechanisms against <d>bacterial and mycobacterial pleural infections</d>, and in pathogenesis of <d>malignant pleural effusion</d>, asbestos related <d>pleural disease</d> and malignant pleural mesothelioma. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, <g>n-cadherin</g> and <g>b-catenin</g>, and phosphorylation of adherens junctions between PMCs, which is caused in part by <g>vascular endothelial growth factor</g> <g>VEGF</g> released by PMCs. PMCs play an important role in defense mechanisms against <d>bacterial and mycobacterial pleural infections</d>, and in pathogenesis of <d>malignant pleural effusion</d>, asbestos related <d>pleural disease</d> and <d>malignant pleural mesothelioma</d>. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, <g>n-cadherin</g> and <g>b-catenin</g>, and phosphorylation of adherens junctions between PMCs, which is caused in part by <g>vascular endothelial growth factor</g> <g>VEGF</g> released by PMCs. PMCs play an important role in defense mechanisms against <d>bacterial and mycobacterial pleural infections</d>, and in pathogenesis of <d>malignant pleural effusion</d>, asbestos related <d>pleural disease</d> and <d>malignant pleural mesothelioma</d>. PMCs also play a key role in the resolution of <d>inflammation</d>, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, <g>n-cadherin</g> and <g>b-catenin</g>, and phosphorylation of adherens junctions between PMCs, which is caused in part by <g>vascular endothelial growth factor</g> <g>VEGF</g> released by PMCs. PMCs play an important role in defense mechanisms against <d>bacterial and mycobacterial pleural infections</d>, and in pathogenesis of <d>malignant pleural effusion</d>, asbestos related <d>pleural disease</d> and <d>malignant pleural mesothelioma</d>. PMCs also play a key role in the resolution of <d>inflammation</d>, which can occur with or without <d>fibrosis</d>. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, <g>n-cadherin</g> and <g>b-catenin</g>, and phosphorylation of adherens junctions between PMCs, which is caused in part by <g>vascular endothelial growth factor</g> <g>VEGF</g> released by PMCs. PMCs play an important role in defense mechanisms against <d>bacterial and mycobacterial pleural infections</d>, and in pathogenesis of <d>malignant pleural effusion</d>, asbestos related <d>pleural disease</d> and <d>malignant pleural mesothelioma</d>. PMCs also play a key role in the resolution of <d>inflammation</d>, which can occur with or without <d>fibrosis</d>. <d>Fibrosis</d> occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, <g>n-cadherin</g> and <g>b-catenin</g>, and phosphorylation of adherens junctions between PMCs, which is caused in part by <g>vascular endothelial growth factor</g> <g>VEGF</g> released by PMCs. PMCs play an important role in defense mechanisms against <d>bacterial and mycobacterial pleural infections</d>, and in pathogenesis of <d>malignant pleural effusion</d>, asbestos related <d>pleural disease</d> and <d>malignant pleural mesothelioma</d>. PMCs also play a key role in the resolution of <d>inflammation</d>, which can occur with or without <d>fibrosis</d>. <d>Fibrosis</d> occurs as a result of <d>disordered fibrin turnover</d> and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other lung diseases need further exploration.
26150910|a|During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells PMCs derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition EMT. An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor TLR recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of <d>pleural effusions</d> occurs due to an imbalance in the dynamic interaction between junctional proteins, <g>n-cadherin</g> and <g>b-catenin</g>, and phosphorylation of adherens junctions between PMCs, which is caused in part by <g>vascular endothelial growth factor</g> <g>VEGF</g> released by PMCs. PMCs play an important role in defense mechanisms against <d>bacterial and mycobacterial pleural infections</d>, and in pathogenesis of <d>malignant pleural effusion</d>, asbestos related <d>pleural disease</d> and <d>malignant pleural mesothelioma</d>. PMCs also play a key role in the resolution of <d>inflammation</d>, which can occur with or without <d>fibrosis</d>. <d>Fibrosis</d> occurs as a result of <d>disordered fibrin turnover</d> and due to the effects of cytokines such as transforming growth factor-b, platelet-derived growth factor PDGF, and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of <d>IPF</d> suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of <d>IPF</d> and other <d>lung diseases</d> need further exploration.
26160872|a|The causes underlying the self-perpetuating nature of idiopathic pulmonary fibrosis IPF, a progressive and usually lethal disease, remain unknown. We hypothesised that <d>alveolar</d> soluble annexin V contributes to lung fibrosis, based on the observation that human IPF broncho<d>alveolar</d> lavage fluid BALF containing high annexin V levels promoted fibroblast involvement in <d>alveolar</d> epithelial wound healing that was reduced when annexin V was depleted from the BALF. Conditioned medium from annexin V-treated <d>alveolar</d> epithelial type 2 cells AEC2, but not annexin V per se, induced proliferation of human fibroblasts and contained pro-fibrotic, IPF-associated proteins, as well as pro-inflammatory cytokines that were found to correlate tightly r>0.95 with annexin V levels in human BALF. ErbB2 receptor tyrosine kinase in AECs was activated by annexin V, and blockade reduced the fibrotic potential of annexin V-treated AEC-conditioned medium. In vivo, aerosol delivery of annexin V to mouse lung induced inflammation, fibrosis and increased hydroxyproline, with activation of Wnt, transforming growth factor-b, mitogen-activated protein kinase and nuclear factor-kB signalling pathways, as seen in IPF. Chronically increased <d>alveolar</d> annexin V levels, as reflected in increased IPF BALF levels, may contribute to the progression of IPF by inducing the release of pro-fibrotic mediators.
26160872|a|The causes underlying the self-perpetuating nature of idiopathic pulmonary <d>fibrosis</d> IPF, a progressive and usually lethal disease, remain unknown. We hypothesised that <d>alveolar</d> soluble <g>annexin V</g> contributes to lung <d>fibrosis</d>, based on the observation that human IPF broncho<d>alveolar</d> lavage fluid BALF containing high <g>annexin V</g> levels promoted fibroblast involvement in <d>alveolar</d> epithelial wound healing that was reduced when <g>annexin V</g> was depleted from the BALF. Conditioned medium from <g>annexin V</g>-treated <d>alveolar</d> epithelial type 2 cells AEC2, but not <g>annexin V</g> per se, induced proliferation of human fibroblasts and contained pro-fibrotic, IPF-associated proteins, as well as pro-inflammatory cytokines that were found to correlate tightly r>0.95 with <g>annexin V</g> levels in human BALF. ErbB2 receptor tyrosine kinase in AECs was activated by <g>annexin V</g>, and blockade reduced the fibrotic potential of <g>annexin V</g>-treated AEC-conditioned medium. In vivo, aerosol delivery of <g>annexin V</g> to mouse lung induced inflammation, <d>fibrosis</d> and increased hydroxyproline, with activation of Wnt, transforming growth factor-b, mitogen-activated protein kinase and nuclear factor-kB signalling pathways, as seen in IPF. Chronically increased <d>alveolar</d> <g>annexin V</g> levels, as reflected in increased IPF BALF levels, may contribute to the progression of IPF by inducing the release of pro-fibrotic mediators.
26160872|a|The causes underlying the self-perpetuating nature of idiopathic pulmonary <d>fibrosis</d> IPF, a progressive and usually lethal disease, remain unknown. We hypothesised that <d>alveolar</d> soluble <g>annexin V</g> contributes to lung <d>fibrosis</d>, based on the observation that human IPF broncho<d>alveolar</d> lavage fluid BALF containing high <g>annexin V</g> levels promoted fibroblast involvement in <d>alveolar</d> epithelial wound healing that was reduced when <g>annexin V</g> was depleted from the BALF. Conditioned medium from <g>annexin V</g>-treated <d>alveolar</d> epithelial type 2 cells AEC2, but not <g>annexin V</g> per se, induced proliferation of human fibroblasts and contained pro-fibrotic, IPF-associated proteins, as well as pro-inflammatory cytokines that were found to correlate tightly r>0.95 with <g>annexin V</g> levels in human BALF. <g>ErbB2</g> receptor tyrosine kinase in AECs was activated by <g>annexin V</g>, and blockade reduced the fibrotic potential of <g>annexin V</g>-treated AEC-conditioned medium. In vivo, aerosol delivery of <g>annexin V</g> to mouse lung induced <d>inflammation</d>, <d>fibrosis</d> and increased hydroxyproline, with activation of Wnt, transforming growth factor-b, mitogen-activated protein kinase and nuclear factor-kB signalling pathways, as seen in IPF. Chronically increased <d>alveolar</d> <g>annexin V</g> levels, as reflected in increased IPF BALF levels, may contribute to the progression of IPF by inducing the release of pro-fibrotic mediators.
26192087|a|Excessive production of <g>connective tissue growth factor</g> <g>CTGF</g>, <g>CCN2</g> and increased motor ability of the activated fibroblast phenotype contribute to the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF. However, molecules and signal pathways regulating <g>CCN2</g> expression and migration of lung fibroblasts are still elusive. We hypothesize that rapamycin, via binding and blocking mammalian target of rapamycin mTOR complex mTORC, affects <g>CCN2</g> expression and migration of lung fibroblasts in vitro. Primary normal and fibrotic human lung fibroblasts were isolated from lung tissues of three patients with primary spontaneous pneumothorax and three with IPF. Cells were incubated with regular medium, or medium containing rapamycin, human recombinant transforming growth factor TGF-b1, or both. <g>CCN2</g> and tissue inhibitor of metalloproteinase TIMP-1 expression in cells or supernatant was detected. Wound healing and migration assay was used to measure the migratory potential. TGF-b type I receptor TbRI/Smad inhibitor, SB431542 and <g>phosphoinositide 3-kinase</g> PI3K inhibitor, LY294002 were used to determine rapamycin's mechanism of action. We demonstrated that rapamycin amplified basal or TGF-b1-induced <g>CCN2</g> mRNA and protein expression in normal or fibrotic fibroblasts by Smad-independent but PI3K-dependent pathway. Additionally, rapamycin also enhanced TIMP-1 expression as indicated by ELISA. However, wound healing and migrating assay showed rapamycin did not affect the mobility of fibroblasts. Collectively, this study implies a significant fibrogenic induction activity of rapamycin by activating AKT and inducing <g>CCN2</g> expression in vitro and provides the possible mechanisms for the in vivo findings which previously showed no antifibrotic effect of rapamycin on lung fibrosis.
26192087|a|Excessive production of <g>connective tissue growth factor</g> <g>CTGF</g>, <g>CCN2</g> and increased motor ability of the activated fibroblast phenotype contribute to the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. However, molecules and signal pathways regulating <g>CCN2</g> expression and migration of lung fibroblasts are still elusive. We hypothesize that rapamycin, via binding and blocking mammalian target of rapamycin mTOR complex mTORC, affects <g>CCN2</g> expression and migration of lung fibroblasts in vitro. Primary normal and fibrotic human lung fibroblasts were isolated from lung tissues of three patients with primary spontaneous pneumothorax and three with <d>IPF</d>. Cells were incubated with regular medium, or medium containing rapamycin, human recombinant transforming growth factor TGF-b1, or both. <g>CCN2</g> and tissue inhibitor of metalloproteinase TIMP-1 expression in cells or supernatant was detected. Wound healing and migration assay was used to measure the migratory potential. TGF-b type I receptor TbRI/Smad inhibitor, SB431542 and <g>phosphoinositide 3-kinase</g> PI3K inhibitor, LY294002 were used to determine rapamycin's mechanism of action. We demonstrated that rapamycin amplified basal or TGF-b1-induced <g>CCN2</g> mRNA and protein expression in normal or fibrotic fibroblasts by Smad-independent but PI3K-dependent pathway. Additionally, rapamycin also enhanced TIMP-1 expression as indicated by ELISA. However, wound healing and migrating assay showed rapamycin did not affect the mobility of fibroblasts. Collectively, this study implies a significant fibrogenic induction activity of rapamycin by activating AKT and inducing <g>CCN2</g> expression in vitro and provides the possible mechanisms for the in vivo findings which previously showed no antifibrotic effect of rapamycin on lung fibrosis.
26192087|a|Excessive production of <g>connective tissue growth factor</g> <g>CTGF</g>, <g>CCN2</g> and increased motor ability of the activated fibroblast phenotype contribute to the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. However, molecules and signal pathways regulating <g>CCN2</g> expression and migration of lung fibroblasts are still elusive. We hypothesize that rapamycin, via binding and blocking mammalian target of rapamycin <g>mTOR</g> complex <g>mTOR</g>C, affects <g>CCN2</g> expression and migration of lung fibroblasts in vitro. Primary normal and fibrotic human lung fibroblasts were isolated from lung tissues of three patients with <d>primary spontaneous pneumothorax</d> and three with <d>IPF</d>. Cells were incubated with regular medium, or medium containing rapamycin, human recombinant transforming growth factor TGF-b1, or both. <g>CCN2</g> and tissue inhibitor of metalloproteinase TIMP-1 expression in cells or supernatant was detected. Wound healing and migration assay was used to measure the migratory potential. TGF-b type I receptor TbRI/Smad inhibitor, SB431542 and <g>phosphoinositide 3-kinase</g> PI3K inhibitor, LY294002 were used to determine rapamycin's mechanism of action. We demonstrated that rapamycin amplified basal or TGF-b1-induced <g>CCN2</g> mRNA and protein expression in normal or fibrotic fibroblasts by Smad-independent but PI3K-dependent pathway. Additionally, rapamycin also enhanced TIMP-1 expression as indicated by ELISA. However, wound healing and migrating assay showed rapamycin did not affect the mobility of fibroblasts. Collectively, this study implies a significant fibrogenic induction activity of rapamycin by activating AKT and inducing <g>CCN2</g> expression in vitro and provides the possible mechanisms for the in vivo findings which previously showed no antifibrotic effect of rapamycin on lung fibrosis.
26192087|a|Excessive production of <g>connective tissue growth factor</g> <g>CTGF</g>, <g>CCN2</g> and increased motor ability of the activated fibroblast phenotype contribute to the pathogenesis of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. However, molecules and signal pathways regulating <g>CCN2</g> expression and migration of lung fibroblasts are still elusive. We hypothesize that rapamycin, via binding and blocking mammalian target of rapamycin <g>mTOR</g> complex <g>mTOR</g>C, affects <g>CCN2</g> expression and migration of lung fibroblasts in vitro. Primary normal and fibrotic human lung fibroblasts were isolated from lung tissues of three patients with <d>primary spontaneous pneumothorax</d> and three with <d>IPF</d>. Cells were incubated with regular medium, or medium containing rapamycin, human recombinant transforming growth factor <g>TGF-b1</g>, or both. <g>CCN2</g> and <g>tissue inhibitor of metalloproteinase <g>TIMP-1</g></g> expression in cells or supernatant was detected. Wound healing and migration assay was used to measure the migratory potential. TGF-b type I receptor TbRI/Smad inhibitor, SB431542 and <g>phosphoinositide 3-kinase</g> <g>PI3K</g> inhibitor, LY294002 were used to determine rapamycin's mechanism of action. We demonstrated that rapamycin amplified basal or <g>TGF-b1</g>-induced <g>CCN2</g> mRNA and protein expression in normal or fibrotic fibroblasts by Smad-independent but <g>PI3K</g>-dependent pathway. Additionally, rapamycin also enhanced <g>TIMP-1</g> expression as indicated by ELISA. However, wound healing and migrating assay showed rapamycin did not affect the mobility of fibroblasts. Collectively, this study implies a significant fibrogenic induction activity of rapamycin by activating AKT and inducing <g>CCN2</g> expression in vitro and provides the possible mechanisms for the in vivo findings which previously showed no antifibrotic effect of rapamycin on lung <d>fibrosis</d>.
26207697|a|RATIONALE: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and temporally controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodeling. Dysregulation of the proteasome has been reported for several chronic <d>diseases of the heart</d>, brain, and lung. We hypothesized that proteasome function is altered upon fibrotic lung remodeling, thereby contributing to the pathogenesis of idiopathic pulmonary fibrosis IPF. OBJECTIVES: To investigate proteasome function during myofibroblast differentiation. METHODS: We treated lung fibroblasts with transforming growth factor TGF-b and examined proteasome composition and activity. For in vivo analysis, we used mouse models of lung fibrosis and fibrotic human lung tissue. MEASUREMENTS AND MAIN RESULTS: We demonstrate that induction of myofibroblast differentiation by TGF-b involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit Rpn6. Silencing of Rpn6 in primary human lung fibroblasts counteracted TGF-b-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of Rpn6 were detected during bleomycin-induced lung remodeling and fibrosis. Importantly, Rpn6 is overexpressed in myofibroblasts and basal cells of the bronchiolar epithelium in lungs of patients with IPF, which is accompanied by enhanced protein polyubiquitination. CONCLUSIONS: We identified Rpn6-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo, and our results suggest it has an important role in IPF pathogenesis.
26207697|a|RATIONALE: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and temporally controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodeling. Dysregulation of the proteasome has been reported for several chronic <d>diseases of the heart</d>, brain, and lung. We hypothesized that proteasome function is altered upon <d>fibrotic lung remodeling</d>, thereby contributing to the pathogenesis of idiopathic pulmonary fibrosis IPF. OBJECTIVES: To investigate proteasome function during myofibroblast differentiation. METHODS: We treated lung fibroblasts with transforming growth factor TGF-b and examined proteasome composition and activity. For in vivo analysis, we used mouse models of lung fibrosis and fibrotic human lung tissue. MEASUREMENTS AND MAIN RESULTS: We demonstrate that induction of myofibroblast differentiation by TGF-b involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit Rpn6. Silencing of Rpn6 in primary human lung fibroblasts counteracted TGF-b-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of Rpn6 were detected during bleomycin-induced lung remodeling and fibrosis. Importantly, Rpn6 is overexpressed in myofibroblasts and basal cells of the bronchiolar epithelium in lungs of patients with IPF, which is accompanied by enhanced protein polyubiquitination. CONCLUSIONS: We identified Rpn6-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo, and our results suggest it has an important role in IPF pathogenesis.
26207697|a|RATIONALE: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and temporally controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodeling. Dysregulation of the proteasome has been reported for several chronic <d>diseases of the heart</d>, brain, and lung. We hypothesized that proteasome function is altered upon <d>fibrotic lung remodeling</d>, thereby contributing to the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF. OBJECTIVES: To investigate proteasome function during myofibroblast differentiation. METHODS: We treated lung fibroblasts with transforming growth factor TGF-b and examined proteasome composition and activity. For in vivo analysis, we used mouse models of lung fibrosis and fibrotic human lung tissue. MEASUREMENTS AND MAIN RESULTS: We demonstrate that induction of myofibroblast differentiation by TGF-b involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit Rpn6. Silencing of Rpn6 in primary human lung fibroblasts counteracted TGF-b-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of Rpn6 were detected during bleomycin-induced lung remodeling and fibrosis. Importantly, Rpn6 is overexpressed in myofibroblasts and basal cells of the bronchiolar epithelium in lungs of patients with IPF, which is accompanied by enhanced protein polyubiquitination. CONCLUSIONS: We identified Rpn6-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo, and our results suggest it has an important role in IPF pathogenesis.
26207697|a|RATIONALE: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and temporally controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodeling. Dysregulation of the proteasome has been reported for several chronic <d>diseases of the heart</d>, brain, and lung. We hypothesized that proteasome function is altered upon <d>fibrotic lung remodeling</d>, thereby contributing to the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. OBJECTIVES: To investigate proteasome function during myofibroblast differentiation. METHODS: We treated lung fibroblasts with transforming growth factor TGF-b and examined proteasome composition and activity. For in vivo analysis, we used mouse models of lung fibrosis and fibrotic human lung tissue. MEASUREMENTS AND MAIN RESULTS: We demonstrate that induction of myofibroblast differentiation by TGF-b involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit Rpn6. Silencing of Rpn6 in primary human lung fibroblasts counteracted TGF-b-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of Rpn6 were detected during bleomycin-induced lung remodeling and fibrosis. Importantly, Rpn6 is overexpressed in myofibroblasts and basal cells of the bronchiolar epithelium in lungs of patients with <d>IPF</d>, which is accompanied by enhanced protein polyubiquitination. CONCLUSIONS: We identified Rpn6-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo, and our results suggest it has an important role in <d>IPF</d> pathogenesis.
26207697|a|RATIONALE: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and temporally controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodeling. Dysregulation of the proteasome has been reported for several chronic <d>diseases of the heart</d>, brain, and lung. We hypothesized that proteasome function is altered upon <d>fibrotic lung remodeling</d>, thereby contributing to the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. OBJECTIVES: To investigate proteasome function during myofibroblast differentiation. METHODS: We treated lung fibroblasts with transforming growth factor TGF-b and examined proteasome composition and activity. For in vivo analysis, we used mouse models of <d>lung fibrosis</d> and fibrotic human lung tissue. MEASUREMENTS AND MAIN RESULTS: We demonstrate that induction of myofibroblast differentiation by TGF-b involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit Rpn6. Silencing of Rpn6 in primary human lung fibroblasts counteracted TGF-b-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of Rpn6 were detected during bleomycin-induced lung remodeling and fibrosis. Importantly, Rpn6 is overexpressed in myofibroblasts and basal cells of the bronchiolar epithelium in lungs of patients with <d>IPF</d>, which is accompanied by enhanced protein polyubiquitination. CONCLUSIONS: We identified Rpn6-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo, and our results suggest it has an important role in <d>IPF</d> pathogenesis.
26207697|a|RATIONALE: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and temporally controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodeling. Dysregulation of the proteasome has been reported for several chronic <d>diseases of the heart</d>, brain, and lung. We hypothesized that proteasome function is altered upon <d>fibrotic <d>lung remodeling</d></d>, thereby contributing to the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. OBJECTIVES: To investigate proteasome function during myofibroblast differentiation. METHODS: We treated lung fibroblasts with transforming growth factor <g>TGF-b</g> and examined proteasome composition and activity. For in vivo analysis, we used mouse models of <d>lung fibrosis</d> and fibrotic human lung tissue. MEASUREMENTS AND MAIN RESULTS: We demonstrate that induction of myofibroblast differentiation by <g>TGF-b</g> involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit <g>Rpn6</g>. Silencing of <g>Rpn6</g> in primary human lung fibroblasts counteracted <g>TGF-b</g>-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of <g>Rpn6</g> were detected during bleomycin-induced <d>lung remodeling</d> and fibrosis. Importantly, <g>Rpn6</g> is overexpressed in myofibroblasts and basal cells of the bronchiolar epithelium in lungs of patients with <d>IPF</d>, which is accompanied by enhanced protein polyubiquitination. CONCLUSIONS: We identified <g>Rpn6</g>-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo, and our results suggest it has an important role in <d>IPF</d> pathogenesis.
26207697|a|RATIONALE: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and temporally controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodeling. Dysregulation of the proteasome has been reported for several chronic <d>diseases of the heart</d>, brain, and lung. We hypothesized that proteasome function is altered upon <d>fibrotic <d>lung remodeling</d></d>, thereby contributing to the pathogenesis of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. OBJECTIVES: To investigate proteasome function during myofibroblast differentiation. METHODS: We treated lung fibroblasts with transforming growth factor <g>TGF-b</g> and examined proteasome composition and activity. For in vivo analysis, we used mouse models of <d>lung <d>fibrosis</d></d> and fibrotic human lung tissue. MEASUREMENTS AND MAIN RESULTS: We demonstrate that induction of myofibroblast differentiation by <g>TGF-b</g> involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit <g>Rpn6</g>. Silencing of <g>Rpn6</g> in primary human lung fibroblasts counteracted <g>TGF-b</g>-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of <g>Rpn6</g> were detected during bleomycin-induced <d>lung remodeling</d> and <d>fibrosis</d>. Importantly, <g>Rpn6</g> is overexpressed in myofibroblasts and basal cells of the bronchiolar epithelium in lungs of patients with <d>IPF</d>, which is accompanied by enhanced protein polyubiquitination. CONCLUSIONS: We identified <g>Rpn6</g>-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo, and our results suggest it has an important role in <d>IPF</d> pathogenesis.
26216407|a|UNASSIGNED: Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive interstitial fibrotic lung disease with an undefined etiology and no effective treatments. By binding to cell surface receptors, transforming growth factor-b TGF-b plays a pivotal role in lung fibrosis. Therefore, the screening of microRNAs miRNAs, especially those interrupting the effects of TGF-b, may provide information not only on the pathomechanism, but also on the treatment of this disease. In the present study, we found that miR-153 expression was dysregulated in the lungs of mice with experimental <d>pulmonary fibrosis</d> and TGF-b1 decreased miR-153 expression in pulmonary fibroblasts. Moreover, increased miR-153 levels attenuated, whereas the knock down of miR-153 promoted the pro-fibrogenic activity of TGF-b1, and miR-153 reduced the contractile and migratory activities of fibroblasts. In addition, TGFBR2, a transmembrane serine/threonine kinase receptor for TGF-b, was identified as a direct target of miR-153. Furthermore, by post-transcriptional regulation of the expression of TGFBR2, phosphorylation of SMAD2/3 was also influenced by miR-153. These data suggest that miR-153 disturbs TGF-b1 signal transduction and its effects on fibroblast activation, acting as an anti-fibrotic element in the development of <d>pulmonary fibrosis</d>.
26216407|a|UNASSIGNED: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive interstitial fibrotic lung disease with an undefined etiology and no effective treatments. By binding to cell surface receptors, transforming growth factor-b TGF-b plays a pivotal role in lung fibrosis. Therefore, the screening of microRNAs miRNAs, especially those interrupting the effects of TGF-b, may provide information not only on the pathomechanism, but also on the treatment of this disease. In the present study, we found that miR-153 expression was dysregulated in the lungs of mice with experimental <d>pulmonary fibrosis</d> and TGF-b1 decreased miR-153 expression in pulmonary fibroblasts. Moreover, increased miR-153 levels attenuated, whereas the knock down of miR-153 promoted the pro-fibrogenic activity of TGF-b1, and miR-153 reduced the contractile and migratory activities of fibroblasts. In addition, TGFBR2, a transmembrane serine/threonine kinase receptor for TGF-b, was identified as a direct target of miR-153. Furthermore, by post-transcriptional regulation of the expression of TGFBR2, phosphorylation of SMAD2/3 was also influenced by miR-153. These data suggest that miR-153 disturbs TGF-b1 signal transduction and its effects on fibroblast activation, acting as an anti-fibrotic element in the development of <d>pulmonary fibrosis</d>.
26216407|a|UNASSIGNED: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>interstitial fibrotic lung disease</d> with an undefined etiology and no effective treatments. By binding to cell surface receptors, transforming growth factor-b TGF-b plays a pivotal role in lung fibrosis. Therefore, the screening of microRNAs miRNAs, especially those interrupting the effects of TGF-b, may provide information not only on the pathomechanism, but also on the treatment of this disease. In the present study, we found that miR-153 expression was dysregulated in the lungs of mice with experimental <d>pulmonary fibrosis</d> and TGF-b1 decreased miR-153 expression in pulmonary fibroblasts. Moreover, increased miR-153 levels attenuated, whereas the knock down of miR-153 promoted the pro-fibrogenic activity of TGF-b1, and miR-153 reduced the contractile and migratory activities of fibroblasts. In addition, TGFBR2, a transmembrane serine/threonine kinase receptor for TGF-b, was identified as a direct target of miR-153. Furthermore, by post-transcriptional regulation of the expression of TGFBR2, phosphorylation of SMAD2/3 was also influenced by miR-153. These data suggest that miR-153 disturbs TGF-b1 signal transduction and its effects on fibroblast activation, acting as an anti-fibrotic element in the development of <d>pulmonary fibrosis</d>.
26216407|a|UNASSIGNED: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive <d>interstitial fibrotic lung disease</d> with an undefined etiology and no effective treatments. By binding to cell surface receptors, <g>transforming growth factor-b</g> <g>TGF-b</g> plays a pivotal role in lung <d>fibrosis</d>. Therefore, the screening of microRNAs miRNAs, especially those interrupting the effects of <g>TGF-b</g>, may provide information not only on the pathomechanism, but also on the treatment of this disease. In the present study, we found that miR-153 expression was dysregulated in the lungs of mice with experimental <d>pulmonary <d>fibrosis</d></d> and <g>TGF-b</g>1 decreased miR-153 expression in pulmonary fibroblasts. Moreover, increased miR-153 levels attenuated, whereas the knock down of miR-153 promoted the pro-fibrogenic activity of <g>TGF-b</g>1, and miR-153 reduced the contractile and migratory activities of fibroblasts. In addition, TGFBR2, a transmembrane serine/threonine kinase receptor for <g>TGF-b</g>, was identified as a direct target of miR-153. Furthermore, by post-transcriptional regulation of the expression of TGFBR2, phosphorylation of SMAD2/3 was also influenced by miR-153. These data suggest that miR-153 disturbs <g>TGF-b</g>1 signal transduction and its effects on fibroblast activation, acting as an anti-fibrotic element in the development of <d>pulmonary <d>fibrosis</d></d>.
26231702|a|BACKGROUND: The beneficial outcome associated with the use of proton pump inhibitors PPIs in idiopathic pulmonary <d>fibrosis</d> IPF has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated. METHODS: Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and <d>fibrosis</d>. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and <d>fibrosis</d>. In addition, we cultured lung fibroblasts from IPF patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease ILD databases to examine the effect of PPIs on transplant-free survival. RESULTS: The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha TNF-a and interleukins IL-1b and IL-6. The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 HO1 and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor b TGFb, fibronectin and matrix metalloproteinases MMPs. Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in IPF patients. Intriguingly, this data demonstrated that IPF patients on PPIs had prolonged survival over controls median survival of 3.4 vs 2  years. CONCLUSIONS: Overall, these data indicate the possibility that PPIs may have protective function in IPF by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.
26231702|a|BACKGROUND: The beneficial outcome associated with the use of proton pump inhibitors PPIs in idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in <d>IPF</d> has not been elucidated. METHODS: Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and <d>fibrosis</d>. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and <d>fibrosis</d>. In addition, we cultured lung fibroblasts from <d>IPF</d> patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease ILD databases to examine the effect of PPIs on transplant-free survival. RESULTS: The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha TNF-a and interleukins IL-1b and IL-6. The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 HO1 and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor b TGFb, fibronectin and matrix metalloproteinases MMPs. Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in <d>IPF</d> patients. Intriguingly, this data demonstrated that <d>IPF</d> patients on PPIs had prolonged survival over controls median survival of 3.4 vs 2  years. CONCLUSIONS: Overall, these data indicate the possibility that PPIs may have protective function in <d>IPF</d> by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.
26231702|a|BACKGROUND: The beneficial outcome associated with the use of proton pump inhibitors PPIs in idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in <d>IPF</d> has not been elucidated. METHODS: Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with <d>inflammation</d> and <d>fibrosis</d>. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce <d>inflammation</d> and <d>fibrosis</d>. In addition, we cultured lung fibroblasts from <d>IPF</d> patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease ILD databases to examine the effect of PPIs on transplant-free survival. RESULTS: The cell culture studies revealed that esomeprazole controls <d>inflammation</d> by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha TNF-a and interleukins IL-1b and IL-6. The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 HO1 and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor b TGFb, fibronectin and matrix metalloproteinases MMPs. Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in <d>IPF</d> patients. Intriguingly, this data demonstrated that <d>IPF</d> patients on PPIs had prolonged survival over controls median survival of 3.4 vs 2  years. CONCLUSIONS: Overall, these data indicate the possibility that PPIs may have protective function in <d>IPF</d> by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.
26231702|a|BACKGROUND: The beneficial outcome associated with the use of proton pump inhibitors PPIs in idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in <d>IPF</d> has not been elucidated. METHODS: Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with <d>inflammation</d> and <d>fibrosis</d>. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce <d>inflammation</d> and <d>fibrosis</d>. In addition, we cultured lung fibroblasts from <d>IPF</d> patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced <d>lung injury</d>. Furthermore, we performed retrospective analysis of interstitial lung disease ILD databases to examine the effect of PPIs on transplant-free survival. RESULTS: The cell culture studies revealed that esomeprazole controls <d>inflammation</d> by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha TNF-a and interleukins IL-1b and IL-6. The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 HO1 and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor b TGFb, fibronectin and matrix metalloproteinases MMPs. Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute <d>lung injury</d>. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in <d>IPF</d> patients. Intriguingly, this data demonstrated that <d>IPF</d> patients on PPIs had prolonged survival over controls median survival of 3.4 vs 2  years. CONCLUSIONS: Overall, these data indicate the possibility that PPIs may have protective function in <d>IPF</d> by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.
26231702|a|BACKGROUND: The beneficial outcome associated with the use of proton pump inhibitors PPIs in idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in <d>IPF</d> has not been elucidated. METHODS: Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with <d>inflammation</d> and <d>fibrosis</d>. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce <d>inflammation</d> and <d>fibrosis</d>. In addition, we cultured lung fibroblasts from <d>IPF</d> patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced <d>lung injury</d>. Furthermore, we performed retrospective analysis of <d>interstitial lung disease</d> ILD databases to examine the effect of PPIs on transplant-free survival. RESULTS: The cell culture studies revealed that esomeprazole controls <d>inflammation</d> by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha TNF-a and interleukins IL-1b and IL-6. The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 HO1 and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor b TGFb, fibronectin and matrix metalloproteinases MMPs. Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute <d>lung injury</d>. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in <d>IPF</d> patients. Intriguingly, this data demonstrated that <d>IPF</d> patients on PPIs had prolonged survival over controls median survival of 3.4 vs 2  years. CONCLUSIONS: Overall, these data indicate the possibility that PPIs may have protective function in <d>IPF</d> by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.
26231702|a|BACKGROUND: The beneficial outcome associated with the use of proton pump inhibitors PPIs in idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in <d>IPF</d> has not been elucidated. METHODS: Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with <d>inflammation</d> and <d>fibrosis</d>. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce <d>inflammation</d> and <d>fibrosis</d>. In addition, we cultured lung fibroblasts from <d>IPF</d> patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced <d>lung injury</d>. Furthermore, we performed retrospective analysis of <d>interstitial lung disease</d> <d>ILD</d> databases to examine the effect of PPIs on transplant-free survival. RESULTS: The cell culture studies revealed that esomeprazole controls <d>inflammation</d> by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha TNF-a and interleukins IL-1b and IL-6. The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 HO1 and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor b TGFb, fibronectin and matrix metalloproteinases MMPs. Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute <d>lung injury</d>. Finally, retrospective analysis of two <d>ILD</d> databases was performed to assess the effect of PPIs on transplant-free survival in <d>IPF</d> patients. Intriguingly, this data demonstrated that <d>IPF</d> patients on PPIs had prolonged survival over controls median survival of 3.4 vs 2  years. CONCLUSIONS: Overall, these data indicate the possibility that PPIs may have protective function in <d>IPF</d> by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.
26248335|a|INTRODUCTION: <d>Idiopathic pulmonary fibrosis</d> IPF is a chronic progressive disease with very few effective treatments. The key effector cells in fibrosis are believed to be fibroblasts, which differentiate to a contractile myofibroblast phenotype with enhanced capacity to proliferate and produce extracellular matrix. The role of the lung epithelium in fibrosis is unclear. While there is evidence that the epithelium is disrupted in IPF, it is not known whether this is a cause or a result of the fibroblast pathology. We hypothesized that healthy epithelial cells are required to maintain normal lung homeostasis and can inhibit the activation and differentiation of lung fibroblasts to the myofibroblast phenotype. To investigate this hypothesis, we employed a novel co-culture model with primary human lung epithelial cells and fibroblasts to investigate whether epithelial cells inhibit myofibroblast differentiation. MEASUREMENTS AND MAIN RESULTS: In the presence of transforming growth factor TGF-b, fibroblasts co-cultured with epithelial cells expressed significantly less a-smooth muscle actin and collagen and showed marked reduction in cell migration, collagen gel contraction, and cell proliferation compared to fibroblasts grown without epithelial cells. Epithelial cells from non-matching tissue origins were capable of inhibiting TGF-b induced myofibroblast differentiation in lung, keloid and Graves' orbital fibroblasts. TGF-b promoted production of prostaglandin PG E2 in lung epithelial cells, and a PGE2 neutralizing antibody blocked the protective effect of epithelial cell co-culture. CONCLUSIONS: We provide the first direct experimental evidence that lung epithelial cells inhibit TGF-b induced myofibroblast differentiation and pro-fibrotic phenotypes in fibroblasts. This effect is not restricted by tissue origin, and is mediated, at least in part, by PGE2. Our data support the hypothesis that the epithelium plays a crucial role in maintaining lung homeostasis, and that damaged and/ or dysfunctional epithelium contributes to the development of fibrosis.
26248335|a|INTRODUCTION: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive disease with very few effective treatments. The key effector cells in fibrosis are believed to be fibroblasts, which differentiate to a contractile myofibroblast phenotype with enhanced capacity to proliferate and produce extracellular matrix. The role of the lung epithelium in fibrosis is unclear. While there is evidence that the epithelium is disrupted in <d>IPF</d>, it is not known whether this is a cause or a result of the fibroblast pathology. We hypothesized that healthy epithelial cells are required to maintain normal lung homeostasis and can inhibit the activation and differentiation of lung fibroblasts to the myofibroblast phenotype. To investigate this hypothesis, we employed a novel co-culture model with primary human lung epithelial cells and fibroblasts to investigate whether epithelial cells inhibit myofibroblast differentiation. MEASUREMENTS AND MAIN RESULTS: In the presence of transforming growth factor TGF-b, fibroblasts co-cultured with epithelial cells expressed significantly less a-smooth muscle actin and collagen and showed marked reduction in cell migration, collagen gel contraction, and cell proliferation compared to fibroblasts grown without epithelial cells. Epithelial cells from non-matching tissue origins were capable of inhibiting TGF-b induced myofibroblast differentiation in lung, keloid and Graves' orbital fibroblasts. TGF-b promoted production of prostaglandin PG E2 in lung epithelial cells, and a PGE2 neutralizing antibody blocked the protective effect of epithelial cell co-culture. CONCLUSIONS: We provide the first direct experimental evidence that lung epithelial cells inhibit TGF-b induced myofibroblast differentiation and pro-fibrotic phenotypes in fibroblasts. This effect is not restricted by tissue origin, and is mediated, at least in part, by PGE2. Our data support the hypothesis that the epithelium plays a crucial role in maintaining lung homeostasis, and that damaged and/ or dysfunctional epithelium contributes to the development of fibrosis.
26248335|a|INTRODUCTION: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic progressive disease with very few effective treatments. The key effector cells in <d>fibrosis</d> are believed to be fibroblasts, which differentiate to a contractile myofibroblast phenotype with enhanced capacity to proliferate and produce extracellular matrix. The role of the lung epithelium in <d>fibrosis</d> is unclear. While there is evidence that the epithelium is disrupted in <d>IPF</d>, it is not known whether this is a cause or a result of the fibroblast pathology. We hypothesized that healthy epithelial cells are required to maintain normal lung homeostasis and can inhibit the activation and differentiation of lung fibroblasts to the myofibroblast phenotype. To investigate this hypothesis, we employed a novel co-culture model with primary human lung epithelial cells and fibroblasts to investigate whether epithelial cells inhibit myofibroblast differentiation. MEASUREMENTS AND MAIN RESULTS: In the presence of transforming growth factor TGF-b, fibroblasts co-cultured with epithelial cells expressed significantly less a-smooth muscle actin and collagen and showed marked reduction in cell migration, collagen gel contraction, and cell proliferation compared to fibroblasts grown without epithelial cells. Epithelial cells from non-matching tissue origins were capable of inhibiting TGF-b induced myofibroblast differentiation in lung, keloid and Graves' orbital fibroblasts. TGF-b promoted production of prostaglandin PG E2 in lung epithelial cells, and a PGE2 neutralizing antibody blocked the protective effect of epithelial cell co-culture. CONCLUSIONS: We provide the first direct experimental evidence that lung epithelial cells inhibit TGF-b induced myofibroblast differentiation and pro-fibrotic phenotypes in fibroblasts. This effect is not restricted by tissue origin, and is mediated, at least in part, by PGE2. Our data support the hypothesis that the epithelium plays a crucial role in maintaining lung homeostasis, and that damaged and/ or dysfunctional epithelium contributes to the development of <d>fibrosis</d>.
26249221|a|PURPOSE: Galectin-9 Gal-9 is a b-galactoside-binding protein that exhibits various biological reactions, such as chemoattraction, cell aggregation, and apoptosis. Recent studies demonstrated that Gal-9 has a role as an immunomodulator in excessive immunological reactions by expanded regulatory T cells Tregs. We examined the role of Gal-9 in the pathogenesis of one of the major idiopathic <d>interstitial pneumonias</d>, cryptogenic organizing pneumonia COP as compared with idiopathic pulmonary fibrosis IPF. METHODS: Gal-9, transforming growth factor-b1, and interleukin IL-10 levels in the bronchoalveolar lavage fluid BALF of patients with COP and IPF were estimated by enzyme-linked immunosorbent assay. Forkhead box protein 3 Foxp3 expressing Tregs were evaluated by flow cytometry. The effect of Gal-9 on interactions between human lung fibroblast cells and hyarulonan was assessed in vitro. RESULTS: Gal-9 and IL-10 levels in the BALF were significantly higher in patients with COP than in patients with IPF. The number of CD4+Foxp3high+cells was significantly higher in the BALF of patients with COP than in those with IPF. Gal-9 levels significantly correlated with the absolute number of CD4+CD25+Foxp3+cells or CD4+Foxp3high+cells, but not with the absolute number of CD4+CD25+Foxp3-cells, in the BALF of patients with COP. Gal-9 suppressed the CD44-dependent interaction of human lung fibroblast cells with hyarulonan in a dose-dependent manner. CONCLUSIONS: Our findings suggest that increased Gal-9 levels in the lung have a protective role against lung inflammation and fibrosis in patients with COP through the induction of Tregs in the lung and CD44-dependent inhibitory effects on lung fibroblast cells.
26249221|a|PURPOSE: Galectin-9 Gal-9 is a b-galactoside-binding protein that exhibits various biological reactions, such as chemoattraction, cell aggregation, and apoptosis. Recent studies demonstrated that Gal-9 has a role as an immunomodulator in excessive immunological reactions by expanded regulatory T cells Tregs. We examined the role of Gal-9 in the pathogenesis of one of the major idiopathic <d>interstitial pneumonias</d>, <d>cryptogenic organizing pneumonia</d> COP as compared with idiopathic pulmonary fibrosis IPF. METHODS: Gal-9, transforming growth factor-b1, and interleukin IL-10 levels in the bronchoalveolar lavage fluid BALF of patients with COP and IPF were estimated by enzyme-linked immunosorbent assay. Forkhead box protein 3 Foxp3 expressing Tregs were evaluated by flow cytometry. The effect of Gal-9 on interactions between human lung fibroblast cells and hyarulonan was assessed in vitro. RESULTS: Gal-9 and IL-10 levels in the BALF were significantly higher in patients with COP than in patients with IPF. The number of CD4+Foxp3high+cells was significantly higher in the BALF of patients with COP than in those with IPF. Gal-9 levels significantly correlated with the absolute number of CD4+CD25+Foxp3+cells or CD4+Foxp3high+cells, but not with the absolute number of CD4+CD25+Foxp3-cells, in the BALF of patients with COP. Gal-9 suppressed the CD44-dependent interaction of human lung fibroblast cells with hyarulonan in a dose-dependent manner. CONCLUSIONS: Our findings suggest that increased Gal-9 levels in the lung have a protective role against lung inflammation and fibrosis in patients with COP through the induction of Tregs in the lung and CD44-dependent inhibitory effects on lung fibroblast cells.
26249221|a|PURPOSE: Galectin-9 Gal-9 is a b-galactoside-binding protein that exhibits various biological reactions, such as chemoattraction, cell aggregation, and apoptosis. Recent studies demonstrated that Gal-9 has a role as an immunomodulator in excessive immunological reactions by expanded regulatory T cells Tregs. We examined the role of Gal-9 in the pathogenesis of one of the major idiopathic <d>interstitial pneumonias</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> as compared with idiopathic pulmonary fibrosis IPF. METHODS: Gal-9, transforming growth factor-b1, and interleukin IL-10 levels in the bronchoalveolar lavage fluid BALF of patients with <d>COP</d> and IPF were estimated by enzyme-linked immunosorbent assay. Forkhead box protein 3 Foxp3 expressing Tregs were evaluated by flow cytometry. The effect of Gal-9 on interactions between human lung fibroblast cells and hyarulonan was assessed in vitro. RESULTS: Gal-9 and IL-10 levels in the BALF were significantly higher in patients with <d>COP</d> than in patients with IPF. The number of CD4+Foxp3high+cells was significantly higher in the BALF of patients with <d>COP</d> than in those with IPF. Gal-9 levels significantly correlated with the absolute number of CD4+CD25+Foxp3+cells or CD4+Foxp3high+cells, but not with the absolute number of CD4+CD25+Foxp3-cells, in the BALF of patients with <d>COP</d>. Gal-9 suppressed the CD44-dependent interaction of human lung fibroblast cells with hyarulonan in a dose-dependent manner. CONCLUSIONS: Our findings suggest that increased Gal-9 levels in the lung have a protective role against lung inflammation and fibrosis in patients with <d>COP</d> through the induction of Tregs in the lung and CD44-dependent inhibitory effects on lung fibroblast cells.
26249221|a|PURPOSE: Galectin-9 Gal-9 is a b-galactoside-binding protein that exhibits various biological reactions, such as chemoattraction, cell aggregation, and apoptosis. Recent studies demonstrated that Gal-9 has a role as an immunomodulator in excessive immunological reactions by expanded regulatory T cells Tregs. We examined the role of Gal-9 in the pathogenesis of one of the major idiopathic <d>interstitial pneumonias</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> as compared with <d>idiopathic pulmonary fibrosis</d> IPF. METHODS: Gal-9, transforming growth factor-b1, and interleukin IL-10 levels in the bronchoalveolar lavage fluid BALF of patients with <d>COP</d> and IPF were estimated by enzyme-linked immunosorbent assay. Forkhead box protein 3 Foxp3 expressing Tregs were evaluated by flow cytometry. The effect of Gal-9 on interactions between human lung fibroblast cells and hyarulonan was assessed in vitro. RESULTS: Gal-9 and IL-10 levels in the BALF were significantly higher in patients with <d>COP</d> than in patients with IPF. The number of CD4+Foxp3high+cells was significantly higher in the BALF of patients with <d>COP</d> than in those with IPF. Gal-9 levels significantly correlated with the absolute number of CD4+CD25+Foxp3+cells or CD4+Foxp3high+cells, but not with the absolute number of CD4+CD25+Foxp3-cells, in the BALF of patients with <d>COP</d>. Gal-9 suppressed the CD44-dependent interaction of human lung fibroblast cells with hyarulonan in a dose-dependent manner. CONCLUSIONS: Our findings suggest that increased Gal-9 levels in the lung have a protective role against lung inflammation and fibrosis in patients with <d>COP</d> through the induction of Tregs in the lung and CD44-dependent inhibitory effects on lung fibroblast cells.
26249221|a|PURPOSE: Galectin-9 Gal-9 is a b-galactoside-binding protein that exhibits various biological reactions, such as chemoattraction, cell aggregation, and apoptosis. Recent studies demonstrated that Gal-9 has a role as an immunomodulator in excessive immunological reactions by expanded regulatory T cells Tregs. We examined the role of Gal-9 in the pathogenesis of one of the major idiopathic <d>interstitial pneumonias</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> as compared with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. METHODS: Gal-9, transforming growth factor-b1, and interleukin IL-10 levels in the bronchoalveolar lavage fluid BALF of patients with <d>COP</d> and <d>IPF</d> were estimated by enzyme-linked immunosorbent assay. Forkhead box protein 3 Foxp3 expressing Tregs were evaluated by flow cytometry. The effect of Gal-9 on interactions between human lung fibroblast cells and hyarulonan was assessed in vitro. RESULTS: Gal-9 and IL-10 levels in the BALF were significantly higher in patients with <d>COP</d> than in patients with <d>IPF</d>. The number of CD4+Foxp3high+cells was significantly higher in the BALF of patients with <d>COP</d> than in those with <d>IPF</d>. Gal-9 levels significantly correlated with the absolute number of CD4+CD25+Foxp3+cells or CD4+Foxp3high+cells, but not with the absolute number of CD4+CD25+Foxp3-cells, in the BALF of patients with <d>COP</d>. Gal-9 suppressed the CD44-dependent interaction of human lung fibroblast cells with hyarulonan in a dose-dependent manner. CONCLUSIONS: Our findings suggest that increased Gal-9 levels in the lung have a protective role against lung inflammation and fibrosis in patients with <d>COP</d> through the induction of Tregs in the lung and CD44-dependent inhibitory effects on lung fibroblast cells.
26249221|a|PURPOSE: Galectin-9 Gal-9 is a b-galactoside-binding protein that exhibits various biological reactions, such as chemoattraction, cell aggregation, and apoptosis. Recent studies demonstrated that Gal-9 has a role as an immunomodulator in excessive immunological reactions by expanded regulatory T cells Tregs. We examined the role of Gal-9 in the pathogenesis of one of the major idiopathic <d>interstitial pneumonias</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> as compared with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. METHODS: Gal-9, transforming growth factor-b1, and interleukin IL-10 levels in the bronchoalveolar lavage fluid BALF of patients with <d>COP</d> and <d>IPF</d> were estimated by enzyme-linked immunosorbent assay. Forkhead box protein 3 Foxp3 expressing Tregs were evaluated by flow cytometry. The effect of Gal-9 on interactions between human lung fibroblast cells and hyarulonan was assessed in vitro. RESULTS: Gal-9 and IL-10 levels in the BALF were significantly higher in patients with <d>COP</d> than in patients with <d>IPF</d>. The number of CD4+Foxp3high+cells was significantly higher in the BALF of patients with <d>COP</d> than in those with <d>IPF</d>. Gal-9 levels significantly correlated with the absolute number of CD4+CD25+Foxp3+cells or CD4+Foxp3high+cells, but not with the absolute number of CD4+CD25+Foxp3-cells, in the BALF of patients with <d>COP</d>. Gal-9 suppressed the CD44-dependent interaction of human lung fibroblast cells with hyarulonan in a dose-dependent manner. CONCLUSIONS: Our findings suggest that increased Gal-9 levels in the lung have a protective role against <d>lung inflammation</d> and fibrosis in patients with <d>COP</d> through the induction of Tregs in the lung and CD44-dependent inhibitory effects on lung fibroblast cells.
26249221|a|PURPOSE: Galectin-9 Gal-9 is a b-galactoside-binding protein that exhibits various biological reactions, such as chemoattraction, cell aggregation, and apoptosis. Recent studies demonstrated that Gal-9 has a role as an immunomodulator in excessive immunological reactions by expanded regulatory T cells Tregs. We examined the role of Gal-9 in the pathogenesis of one of the major idiopathic <d>interstitial pneumonias</d>, <d>cryptogenic organizing pneumonia</d> <d>COP</d> as compared with <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. METHODS: Gal-9, transforming growth factor-b1, and interleukin IL-10 levels in the bronchoalveolar lavage fluid BALF of patients with <d>COP</d> and <d>IPF</d> were estimated by enzyme-linked immunosorbent assay. Forkhead box protein 3 Foxp3 expressing Tregs were evaluated by flow cytometry. The effect of Gal-9 on interactions between human lung fibroblast cells and hyarulonan was assessed in vitro. RESULTS: Gal-9 and IL-10 levels in the BALF were significantly higher in patients with <d>COP</d> than in patients with <d>IPF</d>. The number of CD4+Foxp3high+cells was significantly higher in the BALF of patients with <d>COP</d> than in those with <d>IPF</d>. Gal-9 levels significantly correlated with the absolute number of CD4+CD25+Foxp3+cells or CD4+Foxp3high+cells, but not with the absolute number of CD4+CD25+Foxp3-cells, in the BALF of patients with <d>COP</d>. Gal-9 suppressed the CD44-dependent interaction of human lung fibroblast cells with hyarulonan in a dose-dependent manner. CONCLUSIONS: Our findings suggest that increased Gal-9 levels in the lung have a protective role against <d>lung inflammation</d> and <d>fibrosis</d> in patients with <d>COP</d> through the induction of Tregs in the lung and CD44-dependent inhibitory effects on lung fibroblast cells.
26264443|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and fatal disease and considered as a cancer-like disease. The phosphatase and tensin homologue deleted on chromosome 10 PTEN tumor suppressor has drawn attention in the pathogenesis of IPF. However, the role of PTEN in phenotypic transformation of lung fibroblasts, particularly in the migratory and invasive phenotype, is still elusive. Our data showed that PTEN expression was markedly reduced in both fibroblasts and myofibroblasts from IPF patients. Furthermore, loss of PTEN led to the transformation of normal fibroblasts to myofibroblasts and increased proliferation, apoptosis resistance, and migration/invasion activities. PTEN deficiency upregulated hyaluronan synthase 2 expression and thereby enhanced the invasion ability of fibroblasts. Cross-talk between PTEN and the transforming growth factor b1 TGF-b1 pathway and PTEN reduction by hypoxia were observed. These findings suggest that PTEN is implicated in multiple pathways and plays a crucial role in the pathogenesis of IPF.
26264443|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal disease and considered as a cancer-like disease. The phosphatase and tensin homologue deleted on chromosome 10 PTEN tumor suppressor has drawn attention in the pathogenesis of <d>IPF</d>. However, the role of PTEN in phenotypic transformation of lung fibroblasts, particularly in the migratory and invasive phenotype, is still elusive. Our data showed that PTEN expression was markedly reduced in both fibroblasts and myofibroblasts from <d>IPF</d> patients. Furthermore, loss of PTEN led to the transformation of normal fibroblasts to myofibroblasts and increased proliferation, apoptosis resistance, and migration/invasion activities. PTEN deficiency upregulated hyaluronan synthase 2 expression and thereby enhanced the invasion ability of fibroblasts. Cross-talk between PTEN and the transforming growth factor b1 TGF-b1 pathway and PTEN reduction by hypoxia were observed. These findings suggest that PTEN is implicated in multiple pathways and plays a crucial role in the pathogenesis of <d>IPF</d>.
26264443|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>progressive and fatal disease</d> and considered as a cancer-like disease. The phosphatase and tensin homologue deleted on chromosome 10 PTEN tumor suppressor has drawn attention in the pathogenesis of <d>IPF</d>. However, the role of PTEN in phenotypic transformation of lung fibroblasts, particularly in the migratory and invasive phenotype, is still elusive. Our data showed that PTEN expression was markedly reduced in both fibroblasts and myofibroblasts from <d>IPF</d> patients. Furthermore, loss of PTEN led to the transformation of normal fibroblasts to myofibroblasts and increased proliferation, apoptosis resistance, and migration/invasion activities. PTEN deficiency upregulated hyaluronan synthase 2 expression and thereby enhanced the invasion ability of fibroblasts. Cross-talk between PTEN and the transforming growth factor b1 TGF-b1 pathway and PTEN reduction by hypoxia were observed. These findings suggest that PTEN is implicated in multiple pathways and plays a crucial role in the pathogenesis of <d>IPF</d>.
26264443|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>progressive and fatal disease</d> and considered as a <d>cancer-like disease</d>. The phosphatase and tensin homologue deleted on chromosome 10 PTEN tumor suppressor has drawn attention in the pathogenesis of <d>IPF</d>. However, the role of PTEN in phenotypic transformation of lung fibroblasts, particularly in the migratory and invasive phenotype, is still elusive. Our data showed that PTEN expression was markedly reduced in both fibroblasts and myofibroblasts from <d>IPF</d> patients. Furthermore, loss of PTEN led to the transformation of normal fibroblasts to myofibroblasts and increased proliferation, apoptosis resistance, and migration/invasion activities. PTEN deficiency upregulated hyaluronan synthase 2 expression and thereby enhanced the invasion ability of fibroblasts. Cross-talk between PTEN and the transforming growth factor b1 TGF-b1 pathway and PTEN reduction by hypoxia were observed. These findings suggest that PTEN is implicated in multiple pathways and plays a crucial role in the pathogenesis of <d>IPF</d>.
26264443|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>progressive and fatal disease</d> and considered as a <d>cancer-like disease</d>. The phosphatase and tensin homologue deleted on chromosome 10 <g>PTEN</g> <d>tumor</d> suppressor has drawn attention in the pathogenesis of <d>IPF</d>. However, the role of <g>PTEN</g> in phenotypic transformation of lung fibroblasts, particularly in the migratory and invasive phenotype, is still elusive. Our data showed that <g>PTEN</g> expression was markedly reduced in both fibroblasts and myofibroblasts from <d>IPF</d> patients. Furthermore, loss of <g>PTEN</g> led to the transformation of normal fibroblasts to myofibroblasts and increased proliferation, apoptosis resistance, and migration/invasion activities. <g>PTEN</g> deficiency upregulated hyaluronan synthase 2 expression and thereby enhanced the invasion ability of fibroblasts. Cross-talk between <g>PTEN</g> and the transforming growth factor b1 TGF-b1 pathway and <g>PTEN</g> reduction by hypoxia were observed. These findings suggest that <g>PTEN</g> is implicated in multiple pathways and plays a crucial role in the pathogenesis of <d>IPF</d>.
26264443|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>progressive and fatal disease</d> and considered as a <d>cancer-like disease</d>. The phosphatase and tensin homologue deleted on chromosome 10 <g>PTEN</g> <d>tumor</d> suppressor has drawn attention in the pathogenesis of <d>IPF</d>. However, the role of <g>PTEN</g> in phenotypic transformation of lung fibroblasts, particularly in the migratory and invasive phenotype, is still elusive. Our data showed that <g>PTEN</g> expression was markedly reduced in both fibroblasts and myofibroblasts from <d>IPF</d> patients. Furthermore, loss of <g>PTEN</g> led to the transformation of normal fibroblasts to myofibroblasts and increased proliferation, apoptosis resistance, and migration/invasion activities. <g>PTEN</g> deficiency upregulated <g>hyaluronan synthase 2</g> expression and thereby enhanced the invasion ability of fibroblasts. Cross-talk between <g>PTEN</g> and the <g>transforming growth factor b1</g> <g>TGF-b1</g> pathway and <g>PTEN</g> reduction by <d>hypoxia</d> were observed. These findings suggest that <g>PTEN</g> is implicated in multiple pathways and plays a crucial role in the pathogenesis of <d>IPF</d>.
26268659|a|UNASSIGNED: Epithelial to mesenchymal cell transition <g>EMT</g>, whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF. CXCR3 and its ligands are recognized to play a protective role in pulmonary fibrosis. In this study, we investigated the presence and extent of <g>EMT</g> and CXCR3 expression in human IPF surgical lung biopsies and assessed whether CXCR3 and its ligand <g>CXCL9</g> modulate <g>EMT</g> in alveolar epithelial cells. Coexpression of the epithelial marker thyroid transcription factor-1 and the mesenchymal marker a-smooth muscle actin and CXCR3 expression was examined by immunohistochemical staining of IPF surgical lung biopsies. Epithelial and mesenchymal marker expression was examined by quantitative real-time PCR, Western blotting, and immunofluorescence in human alveolar epithelial A549 cells treated with <g>TGF-b1</g> and <g>CXCL9</g>, with Smad2, Smad3, and Smad7 expression and cellular localization examined by Western blotting. We found that significantly more cells were undergoing <g>EMT</g> in fibrotic versus normal areas of lung in IPF surgical lung biopsy samples. CXCR3 was expressed by type II pneumocytes and fibroblasts in fibrotic areas in close proximity to cells undergoing <g>EMT</g>. In vitro, <g>CXCL9</g> abrogated <g>TGF-b1</g>-induced <g>EMT</g>. A decrease in <g>TGF-b1</g>-induced phosphorylation of Smad2 and Smad3 occurred with <g>CXCL9</g> treatment. This was associated with increased shuttling of Smad7 from the nucleus to the cytoplasm where it inhibits Smad phosphorylation. This suggests a role for <g>EMT</g> in the pathogenesis of IPF and provides a novel mechanism for the inhibitory effects of <g>CXCL9</g> on <g>TGF-b1</g>-induced <g>EMT</g>.
26268659|a|UNASSIGNED: Epithelial to mesenchymal cell transition <g>EMT</g>, whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. CXCR3 and its ligands are recognized to play a protective role in pulmonary fibrosis. In this study, we investigated the presence and extent of <g>EMT</g> and CXCR3 expression in human <d>IPF</d> surgical lung biopsies and assessed whether CXCR3 and its ligand <g>CXCL9</g> modulate <g>EMT</g> in alveolar epithelial cells. Coexpression of the epithelial marker thyroid transcription factor-1 and the mesenchymal marker a-smooth muscle actin and CXCR3 expression was examined by immunohistochemical staining of <d>IPF</d> surgical lung biopsies. Epithelial and mesenchymal marker expression was examined by quantitative real-time PCR, Western blotting, and immunofluorescence in human alveolar epithelial A549 cells treated with <g>TGF-b1</g> and <g>CXCL9</g>, with Smad2, Smad3, and Smad7 expression and cellular localization examined by Western blotting. We found that significantly more cells were undergoing <g>EMT</g> in fibrotic versus normal areas of lung in <d>IPF</d> surgical lung biopsy samples. CXCR3 was expressed by type II pneumocytes and fibroblasts in fibrotic areas in close proximity to cells undergoing <g>EMT</g>. In vitro, <g>CXCL9</g> abrogated <g>TGF-b1</g>-induced <g>EMT</g>. A decrease in <g>TGF-b1</g>-induced phosphorylation of Smad2 and Smad3 occurred with <g>CXCL9</g> treatment. This was associated with increased shuttling of Smad7 from the nucleus to the cytoplasm where it inhibits Smad phosphorylation. This suggests a role for <g>EMT</g> in the pathogenesis of <d>IPF</d> and provides a novel mechanism for the inhibitory effects of <g>CXCL9</g> on <g>TGF-b1</g>-induced <g>EMT</g>.
26268659|a|UNASSIGNED: Epithelial to mesenchymal cell transition <g>EMT</g>, whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. <g>CXCR3</g> and its ligands are recognized to play a protective role in <d>pulmonary fibrosis</d>. In this study, we investigated the presence and extent of <g>EMT</g> and <g>CXCR3</g> expression in human <d>IPF</d> surgical lung biopsies and assessed whether <g>CXCR3</g> and its ligand <g>CXCL9</g> modulate <g>EMT</g> in alveolar epithelial cells. Coexpression of the epithelial marker thyroid transcription factor-1 and the mesenchymal marker a-smooth muscle actin and <g>CXCR3</g> expression was examined by immunohistochemical staining of <d>IPF</d> surgical lung biopsies. Epithelial and mesenchymal marker expression was examined by quantitative real-time PCR, Western blotting, and immunofluorescence in human alveolar epithelial A549 cells treated with <g>TGF-b1</g> and <g>CXCL9</g>, with Smad2, Smad3, and Smad7 expression and cellular localization examined by Western blotting. We found that significantly more cells were undergoing <g>EMT</g> in fibrotic versus normal areas of lung in <d>IPF</d> surgical lung biopsy samples. <g>CXCR3</g> was expressed by type II pneumocytes and fibroblasts in fibrotic areas in close proximity to cells undergoing <g>EMT</g>. In vitro, <g>CXCL9</g> abrogated <g>TGF-b1</g>-induced <g>EMT</g>. A decrease in <g>TGF-b1</g>-induced phosphorylation of Smad2 and Smad3 occurred with <g>CXCL9</g> treatment. This was associated with increased shuttling of Smad7 from the nucleus to the cytoplasm where it inhibits Smad phosphorylation. This suggests a role for <g>EMT</g> in the pathogenesis of <d>IPF</d> and provides a novel mechanism for the inhibitory effects of <g>CXCL9</g> on <g>TGF-b1</g>-induced <g>EMT</g>.
26276873|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a common, progressive, and invariably lethal interstitial lung disease with no effective therapy. The key cell driving the development of fibrosis is the myofibroblast. Lipoxin A4 LXA4 is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts HLMFs have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on <g>TGF-b1</g>-dependent responses in IPF- and nonfibrotic control NFC-derived HLMFs. HLMFs were isolated from IPF and NFC patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, a-smooth muscle actin aSMA expression, and Smad2/3 activation were examined constitutively and following <g>TGF-b1</g> stimulation. The LXA4 receptor ALXR was expressed in both NFC- and IPF-derived HLMFs. LXA4 10-10 and 10-8 mol reduced constitutive aSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and <g>TGF-b1</g>-dependent collagen secretion, aSMA expression, and Smad2/3 nuclear translocation in IPF-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of IPF.
26276873|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a common, progressive, and invariably lethal interstitial lung disease with no effective therapy. The key cell driving the development of fibrosis is the myofibroblast. Lipoxin A4 LXA4 is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts HLMFs have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on <g>TGF-b1</g>-dependent responses in <d>IPF</d>- and nonfibrotic control NFC-derived HLMFs. HLMFs were isolated from <d>IPF</d> and NFC patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, a-smooth muscle actin aSMA expression, and Smad2/3 activation were examined constitutively and following <g>TGF-b1</g> stimulation. The LXA4 receptor ALXR was expressed in both NFC- and <d>IPF</d>-derived HLMFs. LXA4 10-10 and 10-8 mol reduced constitutive aSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and <g>TGF-b1</g>-dependent collagen secretion, aSMA expression, and Smad2/3 nuclear translocation in <d>IPF</d>-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of <d>IPF</d>.
26276873|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a common, progressive, and invariably lethal <d>interstitial lung disease</d> with no effective therapy. The key cell driving the development of fibrosis is the myofibroblast. Lipoxin A4 LXA4 is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts HLMFs have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on <g>TGF-b1</g>-dependent responses in <d>IPF</d>- and nonfibrotic control NFC-derived HLMFs. HLMFs were isolated from <d>IPF</d> and NFC patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, a-smooth muscle actin aSMA expression, and Smad2/3 activation were examined constitutively and following <g>TGF-b1</g> stimulation. The LXA4 receptor ALXR was expressed in both NFC- and <d>IPF</d>-derived HLMFs. LXA4 10-10 and 10-8 mol reduced constitutive aSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and <g>TGF-b1</g>-dependent collagen secretion, aSMA expression, and Smad2/3 nuclear translocation in <d>IPF</d>-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of <d>IPF</d>.
26276873|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a common, progressive, and invariably lethal <d>interstitial lung disease</d> with no effective therapy. The key cell driving the development of <d>fibrosis</d> is the myofibroblast. Lipoxin A4 LXA4 is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts HLMFs have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on <g>TGF-b1</g>-dependent responses in <d>IPF</d>- and nonfibrotic control NFC-derived HLMFs. HLMFs were isolated from <d>IPF</d> and NFC patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, a-smooth muscle actin aSMA expression, and Smad2/3 activation were examined constitutively and following <g>TGF-b1</g> stimulation. The LXA4 receptor ALXR was expressed in both NFC- and <d>IPF</d>-derived HLMFs. LXA4 10-10 and 10-8 mol reduced constitutive aSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and <g>TGF-b1</g>-dependent collagen secretion, aSMA expression, and Smad2/3 nuclear translocation in <d>IPF</d>-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of <d>IPF</d>.
26276873|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a common, progressive, and invariably lethal <d>interstitial lung disease</d> with no effective therapy. The key cell driving the development of <d>fibrosis</d> is the myofibroblast. Lipoxin A4 LXA4 is an anti-inflammatory lipid, important in the resolution of <d>inflammation</d>, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts HLMFs have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on <g>TGF-b1</g>-dependent responses in <d>IPF</d>- and nonfibrotic control NFC-derived HLMFs. HLMFs were isolated from <d>IPF</d> and NFC patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, a-smooth muscle actin aSMA expression, and Smad2/3 activation were examined constitutively and following <g>TGF-b1</g> stimulation. The LXA4 receptor ALXR was expressed in both NFC- and <d>IPF</d>-derived HLMFs. LXA4 10-10 and 10-8 mol reduced constitutive aSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and <g>TGF-b1</g>-dependent collagen secretion, aSMA expression, and Smad2/3 nuclear translocation in <d>IPF</d>-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of <d>IPF</d>.
26276873|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a common, progressive, and invariably lethal <d>interstitial lung disease</d> with no effective therapy. The key cell driving the development of <d>fibrosis</d> is the myofibroblast. Lipoxin A4 LXA4 is an anti-inflammatory lipid, important in the resolution of <d>inflammation</d>, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts HLMFs have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on <g>TGF-b1</g>-dependent responses in <d>IPF</d>- and <d>nonfibrotic control</d> NFC-derived HLMFs. HLMFs were isolated from <d>IPF</d> and NFC patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, a-smooth muscle actin aSMA expression, and Smad2/3 activation were examined constitutively and following <g>TGF-b1</g> stimulation. The LXA4 receptor ALXR was expressed in both NFC- and <d>IPF</d>-derived HLMFs. LXA4 10-10 and 10-8 mol reduced constitutive aSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and <g>TGF-b1</g>-dependent collagen secretion, aSMA expression, and Smad2/3 nuclear translocation in <d>IPF</d>-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of <d>IPF</d>.
26276873|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a common, progressive, and invariably lethal <d>interstitial lung disease</d> with no effective therapy. The key cell driving the development of <d>fibrosis</d> is the myofibroblast. Lipoxin A4 LXA4 is an anti-inflammatory lipid, important in the resolution of <d>inflammation</d>, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts HLMFs have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on <g>TGF-b1</g>-dependent responses in <d>IPF</d>- and <d>nonfibrotic control</d> <d>NFC</d>-derived HLMFs. HLMFs were isolated from <d>IPF</d> and <d>NFC</d> patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, a-smooth muscle actin aSMA expression, and Smad2/3 activation were examined constitutively and following <g>TGF-b1</g> stimulation. The LXA4 receptor ALXR was expressed in both <d>NFC</d>- and <d>IPF</d>-derived HLMFs. LXA4 10-10 and 10-8 mol reduced constitutive aSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and <g>TGF-b1</g>-dependent collagen secretion, aSMA expression, and Smad2/3 nuclear translocation in <d>IPF</d>-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of <d>IPF</d>.
26286721|a|INTRODUCTION: Idiopathic <d>pulmonary fibrosis</d> IPF is characterised by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. Sphingosine-1-phosphate S1P signalling plays a critical role in <d>pulmonary fibrosis</d>. METHODS: S1P lyase S1PL expression in peripheral blood mononuclear cells PBMCs was correlated with pulmonary functions and overall survival; used a murine model to check the role of S1PL on the fibrogenesis and a cell culture system to study the effect of S1PL expression on transforming growth factor TGF-b- and S1P-induced fibroblast differentiation. RESULTS: S1PL expression was upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with IPF and bleomycin-challenged mice. TGF-b increased the expression of S1PL in human lung fibroblasts via activation and binding of Smad3 transcription factor to Sgpl1 promoter. Overexpression of S1PL attenuated TGF-b-induced and S1P-induced differentiation of human lung fibroblasts through regulation of the expression of LC3 and beclin 1. Knockdown of S1PL Sgpl1+/- in mice augmented bleomycin-induced <d>pulmonary fibrosis</d>, and patients with IPF reduced Sgpl1 mRNA expression in PBMCs exhibited higher severity of fibrosis and lower survival rate. CONCLUSION: These studies suggest that S1PL is a novel endogenous suppressor of <d>pulmonary fibrosis</d> in human IPF and animal models.
26286721|a|INTRODUCTION: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is characterised by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. Sphingosine-1-phosphate <g>S1P</g> signalling plays a critical role in <d>pulmonary fibrosis</d>. METHODS: <g>S1P</g> lyase <g>S1P</g>L expression in peripheral blood mononuclear cells PBMCs was correlated with pulmonary functions and overall survival; used a murine model to check the role of <g>S1P</g>L on the fibrogenesis and a cell culture system to study the effect of <g>S1P</g>L expression on transforming growth factor TGF-b- and <g>S1P</g>-induced fibroblast differentiation. RESULTS: <g>S1P</g>L expression was upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with <d>IPF</d> and bleomycin-challenged mice. TGF-b increased the expression of <g>S1P</g>L in human lung fibroblasts via activation and binding of Smad3 transcription factor to Sgpl1 promoter. Overexpression of <g>S1P</g>L attenuated TGF-b-induced and <g>S1P</g>-induced differentiation of human lung fibroblasts through regulation of the expression of LC3 and beclin 1. Knockdown of <g>S1P</g>L Sgpl1+/- in mice augmented bleomycin-induced <d>pulmonary fibrosis</d>, and patients with <d>IPF</d> reduced Sgpl1 mRNA expression in PBMCs exhibited higher severity of fibrosis and lower survival rate. CONCLUSION: These studies suggest that <g>S1P</g>L is a novel endogenous suppressor of <d>pulmonary fibrosis</d> in human <d>IPF</d> and animal models.
26286721|a|INTRODUCTION: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is characterised by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. Sphingosine-1-phosphate <g>S1P</g> signalling plays a critical role in <d>pulmonary <d>fibrosis</d></d>. METHODS: <g>S1P</g> lyase <g>S1P</g>L expression in peripheral blood mononuclear cells PBMCs was correlated with pulmonary functions and overall survival; used a murine model to check the role of <g>S1P</g>L on the fibrogenesis and a cell culture system to study the effect of <g>S1P</g>L expression on transforming growth factor <g>TGF-b</g>- and <g>S1P</g>-induced fibroblast differentiation. RESULTS: <g>S1P</g>L expression was upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with <d>IPF</d> and bleomycin-challenged mice. <g>TGF-b</g> increased the expression of <g>S1P</g>L in human lung fibroblasts via activation and binding of <g>Smad3</g> transcription factor to <g>Sgpl1</g> promoter. Overexpression of <g>S1P</g>L attenuated <g>TGF-b</g>-induced and <g>S1P</g>-induced differentiation of human lung fibroblasts through regulation of the expression of <g>LC3</g> and <g>beclin 1</g>. Knockdown of <g>S1P</g>L <g>Sgpl1</g>+/- in mice augmented bleomycin-induced <d>pulmonary <d>fibrosis</d></d>, and patients with <d>IPF</d> reduced <g>Sgpl1</g> mRNA expression in PBMCs exhibited higher severity of <d>fibrosis</d> and lower survival rate. CONCLUSION: These studies suggest that <g>S1P</g>L is a novel endogenous suppressor of <d>pulmonary <d>fibrosis</d></d> in human <d>IPF</d> and animal models.
26315535|a|UNASSIGNED: Uncontrolled extracellular matrix ECM production by fibroblasts in response to injury contributes to fibrotic diseases, including idiopathic pulmonary <d>fibrosis</d> IPF. Reactive oxygen species ROS generation is involved in the pathogenesis of IPF. Transforming growth factor-b1 TGF-b1 stimulates the production of NADPH oxidase 4 NOX4-dependent ROS, promoting lung <d>fibrosis</d> LF. Dysregulation of microRNAs miRNAs has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for IPF, we performed arrays in human lung fibroblasts exposed to ROS. <g>miR-9-5p</g> was selected as the best candidate and we demonstrate its inhibitory effect on TGF-b receptor type II TGFBR2 and NOX4 expression. Increased expression of <g>miR-9-5p</g> abrogates TGF-b1-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced LF, <g>miR-9-5p</g> dramatically reduces fibrogenesis and inhibition of <g>miR-9-5p</g> and prevents its anti-fibrotic effect both in  vitro and in  vivo. In lung specimens from patients with IPF, high levels of <g>miR-9-5p</g> are found. In omentum-derived mesothelial cells MCs from patients subjected to peritoneal dialysis PD, <g>miR-9-5p</g> also inhibits mesothelial to myofibroblast transformation. We propose that TGF-b1 induces <g>miR-9-5p</g> expression as a self-limiting homeostatic response.
26315535|a|UNASSIGNED: Uncontrolled extracellular matrix ECM production by fibroblasts in response to injury contributes to <d>fibrotic diseases</d>, including idiopathic pulmonary <d>fibrosis</d> IPF. Reactive oxygen species ROS generation is involved in the pathogenesis of IPF. Transforming growth factor-b1 TGF-b1 stimulates the production of NADPH oxidase 4 <g>NOX4</g>-dependent ROS, promoting lung <d>fibrosis</d> LF. Dysregulation of microRNAs miRNAs has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for IPF, we performed arrays in human lung fibroblasts exposed to ROS. <g>miR-9-5p</g> was selected as the best candidate and we demonstrate its inhibitory effect on TGF-b receptor type II <g>TGFBR2</g> and <g>NOX4</g> expression. Increased expression of <g>miR-9-5p</g> abrogates TGF-b1-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced LF, <g>miR-9-5p</g> dramatically reduces fibrogenesis and inhibition of <g>miR-9-5p</g> and prevents its anti-fibrotic effect both in  vitro and in  vivo. In lung specimens from patients with IPF, high levels of <g>miR-9-5p</g> are found. In omentum-derived mesothelial cells MCs from patients subjected to peritoneal dialysis PD, <g>miR-9-5p</g> also inhibits mesothelial to myofibroblast transformation. We propose that TGF-b1 induces <g>miR-9-5p</g> expression as a self-limiting homeostatic response.
26315535|a|UNASSIGNED: Uncontrolled extracellular matrix ECM production by fibroblasts in response to injury contributes to <d>fibrotic diseases</d>, including idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. Reactive oxygen species ROS generation is involved in the pathogenesis of <d>IPF</d>. Transforming growth factor-b1 TGF-b1 stimulates the production of NADPH oxidase 4 <g>NOX4</g>-dependent ROS, promoting lung <d>fibrosis</d> LF. Dysregulation of microRNAs miRNAs has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for <d>IPF</d>, we performed arrays in human lung fibroblasts exposed to ROS. <g>miR-9-5p</g> was selected as the best candidate and we demonstrate its inhibitory effect on TGF-b receptor type II <g>TGFBR2</g> and <g>NOX4</g> expression. Increased expression of <g>miR-9-5p</g> abrogates TGF-b1-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced LF, <g>miR-9-5p</g> dramatically reduces fibrogenesis and inhibition of <g>miR-9-5p</g> and prevents its anti-fibrotic effect both in  vitro and in  vivo. In lung specimens from patients with <d>IPF</d>, high levels of <g>miR-9-5p</g> are found. In omentum-derived mesothelial cells MCs from patients subjected to peritoneal dialysis PD, <g>miR-9-5p</g> also inhibits mesothelial to myofibroblast transformation. We propose that TGF-b1 induces <g>miR-9-5p</g> expression as a self-limiting homeostatic response.
26315535|a|UNASSIGNED: Uncontrolled extracellular matrix ECM production by fibroblasts in response to injury contributes to <d>fibrotic diseases</d>, including idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. Reactive oxygen species ROS generation is involved in the pathogenesis of <d>IPF</d>. <g>Transforming growth factor-b1</g> <g>TGF-b1</g> stimulates the production of <g>NADPH oxidase 4</g> <g>NOX4</g>-dependent ROS, promoting lung <d>fibrosis</d> <d>LF</d>. Dysregulation of microRNAs miRNAs has been shown to contribute to <d>LF</d>. To identify miRNAs involved in redox regulation relevant for <d>IPF</d>, we performed arrays in human lung fibroblasts exposed to ROS. <g>miR-9-5p</g> was selected as the best candidate and we demonstrate its inhibitory effect on TGF-b receptor type II <g>TGFBR2</g> and <g>NOX4</g> expression. Increased expression of <g>miR-9-5p</g> abrogates <g>TGF-b1</g>-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced <d>LF</d>, <g>miR-9-5p</g> dramatically reduces fibrogenesis and inhibition of <g>miR-9-5p</g> and prevents its anti-fibrotic effect both in  vitro and in  vivo. In lung specimens from patients with <d>IPF</d>, high levels of <g>miR-9-5p</g> are found. In omentum-derived mesothelial cells MCs from patients subjected to peritoneal dialysis PD, <g>miR-9-5p</g> also inhibits mesothelial to myofibroblast transformation. We propose that <g>TGF-b1</g> induces <g>miR-9-5p</g> expression as a self-limiting homeostatic response.
26370615|a|To identify microRNAs miRNAs, miRs with potential roles in lung fibrogenesis, we performed genome-wide profiling of miRNA expression in lung tissues from a silica-induced mouse model of <d>pulmonary fibrosis</d> using microarrays. Seventeen miRNAs were selected for validation via qRT-PCR based on the fold changes between the silica and the control group. The dysregulation of five miRNAs, including miR-21, miR-455, miR-151-3p, miR-486-5p and miR-3107, were confirmed by qRT-PCRs in silica-induced mouse model of <d>pulmonary fibrosis</d> and were also confirmed in a bleomycin BLM-induced mouse lung fibrosis. Notably, miR-486-5p levels were decreased in the serum samples of patients with silicosis, as well as in the lung tissues of patients with silicosis and idiopathic <d>pulmonary fibrosis</d> IPF. In addition, as determined by luciferase assays and Western blotting, SMAD2, a crucial mediator of <d>pulmonary fibrosis</d>, was identified to be one of target genes of miR-486-5p. To test the potential therapeutic significance of this miRNA, we overexpressed miR-486-5p in animal models. At day 28, miR-486-5p expression significantly decreased both the distribution and severity of lung lesions compared with the silica group P   <   0.01. In addition, miR-486-5p had a similar effect in the BLM group P   <   0.001. These results indicate that miR-486-5p may inhibit fibrosis.
26370615|a|To identify microRNAs miRNAs, miRs with potential roles in lung fibrogenesis, we performed genome-wide profiling of miRNA expression in lung tissues from a silica-induced mouse model of <d>pulmonary fibrosis</d> using microarrays. Seventeen miRNAs were selected for validation via qRT-PCR based on the fold changes between the silica and the control group. The dysregulation of five miRNAs, including <g>miR-21</g>, <g>miR-455</g>, miR-151-3p, miR-486-5p and <g>miR-3107</g>, were confirmed by qRT-PCRs in silica-induced mouse model of <d>pulmonary fibrosis</d> and were also confirmed in a bleomycin BLM-induced mouse lung fibrosis. Notably, miR-486-5p levels were decreased in the serum samples of patients with <d>silicosis</d>, as well as in the lung tissues of patients with <d>silicosis</d> and idiopathic <d>pulmonary fibrosis</d> IPF. In addition, as determined by luciferase assays and Western blotting, SMAD2, a crucial mediator of <d>pulmonary fibrosis</d>, was identified to be one of target genes of miR-486-5p. To test the potential therapeutic significance of this miRNA, we overexpressed miR-486-5p in animal models. At day 28, miR-486-5p expression significantly decreased both the distribution and severity of lung lesions compared with the silica group P   <   0.01. In addition, miR-486-5p had a similar effect in the BLM group P   <   0.001. These results indicate that miR-486-5p may inhibit fibrosis.
26370615|a|To identify microRNAs miRNAs, miRs with potential roles in lung fibrogenesis, we performed genome-wide profiling of miRNA expression in lung tissues from a silica-induced mouse model of <d>pulmonary fibrosis</d> using microarrays. Seventeen miRNAs were selected for validation via qRT-PCR based on the fold changes between the silica and the control group. The dysregulation of five miRNAs, including <g>miR-21</g>, <g>miR-455</g>, miR-151-3p, miR-486-5p and <g>miR-3107</g>, were confirmed by qRT-PCRs in silica-induced mouse model of <d>pulmonary fibrosis</d> and were also confirmed in a bleomycin BLM-induced mouse lung fibrosis. Notably, miR-486-5p levels were decreased in the serum samples of patients with <d>silicosis</d>, as well as in the lung tissues of patients with <d>silicosis</d> and idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. In addition, as determined by luciferase assays and Western blotting, SMAD2, a crucial mediator of <d>pulmonary fibrosis</d>, was identified to be one of target genes of miR-486-5p. To test the potential therapeutic significance of this miRNA, we overexpressed miR-486-5p in animal models. At day 28, miR-486-5p expression significantly decreased both the distribution and severity of lung lesions compared with the silica group P   <   0.01. In addition, miR-486-5p had a similar effect in the BLM group P   <   0.001. These results indicate that miR-486-5p may inhibit fibrosis.
26370615|a|To identify microRNAs miRNAs, miRs with potential roles in lung fibrogenesis, we performed genome-wide profiling of miRNA expression in lung tissues from a silica-induced mouse model of <d>pulmonary fibrosis</d> using microarrays. Seventeen miRNAs were selected for validation via qRT-PCR based on the fold changes between the silica and the control group. The dysregulation of five miRNAs, including <g>miR-21</g>, <g>miR-455</g>, miR-151-3p, miR-486-5p and <g>miR-3107</g>, were confirmed by qRT-PCRs in silica-induced mouse model of <d>pulmonary fibrosis</d> and were also confirmed in a bleomycin BLM-induced mouse lung fibrosis. Notably, miR-486-5p levels were decreased in the serum samples of patients with <d>silicosis</d>, as well as in the lung tissues of patients with <d>silicosis</d> and idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. In addition, as determined by luciferase assays and Western blotting, <g>SMAD2</g>, a crucial mediator of <d>pulmonary fibrosis</d>, was identified to be one of target genes of miR-486-5p. To test the potential therapeutic significance of this miRNA, we overexpressed miR-486-5p in animal models. At day 28, miR-486-5p expression significantly decreased both the distribution and severity of <d>lung lesions</d> compared with the silica group P   <   0.01. In addition, miR-486-5p had a similar effect in the BLM group P   <   0.001. These results indicate that miR-486-5p may inhibit fibrosis.
26370615|a|To identify microRNAs miRNAs, miRs with potential roles in lung fibrogenesis, we performed genome-wide profiling of miRNA expression in lung tissues from a silica-induced mouse model of <d>pulmonary <d>fibrosis</d></d> using microarrays. Seventeen miRNAs were selected for validation via qRT-PCR based on the fold changes between the silica and the control group. The dysregulation of five miRNAs, including <g>miR-21</g>, <g>miR-455</g>, miR-151-3p, miR-486-5p and <g>miR-3107</g>, were confirmed by qRT-PCRs in silica-induced mouse model of <d>pulmonary <d>fibrosis</d></d> and were also confirmed in a bleomycin BLM-induced mouse lung <d>fibrosis</d>. Notably, miR-486-5p levels were decreased in the serum samples of patients with <d>silicosis</d>, as well as in the lung tissues of patients with <d>silicosis</d> and idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. In addition, as determined by luciferase assays and Western blotting, <g>SMAD2</g>, a crucial mediator of <d>pulmonary <d>fibrosis</d></d>, was identified to be one of target genes of miR-486-5p. To test the potential therapeutic significance of this miRNA, we overexpressed miR-486-5p in animal models. At day 28, miR-486-5p expression significantly decreased both the distribution and severity of <d>lung lesions</d> compared with the silica group P   <   0.01. In addition, miR-486-5p had a similar effect in the BLM group P   <   0.001. These results indicate that miR-486-5p may inhibit <d>fibrosis</d>.
26386411|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> IPF is a chronic lethal interstitial lung disease of unknown etiology. We previously reported that high plasma levels of vascular cell adhesion molecule 1 <g>VCAM-1</g> predict mortality in IPF subjects. Here we investigated the cellular origin and potential role of <g>VCAM-1</g> in regulating primary lung fibroblast behavior. <g>VCAM-1</g> mRNA was significantly increased in lungs of subjects with IPF compared to lungs from control subjects p=0.001, and it negatively correlated with two markers of lung function, forced vital capacity FVC and pulmonary diffusion capacity for carbon monoxide DLCO. <g>VCAM-1</g> protein levels were highly expressed in IPF subjects where it was detected in fibrotic foci and blood vessels of IPF lung. Treatment of human lung fibroblasts with <g>TGF-b1</g> significantly increased steady-state VCAM1 mRNA and protein levels without affecting VCAM1 mRNA stability. Further, cellular depletion of <g>VCAM-1</g> inhibited fibroblast cell proliferation and reduced G2/M and S phases of the cell cycle suggestive of cell cycle arrest. These effects on cell cycle progression triggered by VCAM1 depletion were associated with reductions in levels of phosphorylated extracellular regulated kinase 1/2 and cyclin D1. Thus, these observations suggest that <g>VCAM-1</g> is a <g>TGF-b1</g> responsive mediator that partakes in fibroblast proliferation in subjects with IPF.
26386411|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic lethal interstitial lung disease of unknown etiology. We previously reported that high plasma levels of vascular cell adhesion molecule 1 <g>VCAM-1</g> predict mortality in <d>IPF</d> subjects. Here we investigated the cellular origin and potential role of <g>VCAM-1</g> in regulating primary lung fibroblast behavior. <g>VCAM-1</g> mRNA was significantly increased in lungs of subjects with <d>IPF</d> compared to lungs from control subjects p=0.001, and it negatively correlated with two markers of lung function, forced vital capacity FVC and pulmonary diffusion capacity for carbon monoxide DLCO. <g>VCAM-1</g> protein levels were highly expressed in <d>IPF</d> subjects where it was detected in fibrotic foci and blood vessels of <d>IPF</d> lung. Treatment of human lung fibroblasts with <g>TGF-b1</g> significantly increased steady-state VCAM1 mRNA and protein levels without affecting VCAM1 mRNA stability. Further, cellular depletion of <g>VCAM-1</g> inhibited fibroblast cell proliferation and reduced G2/M and S phases of the cell cycle suggestive of cell cycle arrest. These effects on cell cycle progression triggered by VCAM1 depletion were associated with reductions in levels of phosphorylated extracellular regulated kinase 1/2 and cyclin D1. Thus, these observations suggest that <g>VCAM-1</g> is a <g>TGF-b1</g> responsive mediator that partakes in fibroblast proliferation in subjects with <d>IPF</d>.
26386411|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic lethal <d>interstitial lung disease</d> of unknown etiology. We previously reported that high plasma levels of vascular cell adhesion molecule 1 <g>VCAM-1</g> predict mortality in <d>IPF</d> subjects. Here we investigated the cellular origin and potential role of <g>VCAM-1</g> in regulating primary lung fibroblast behavior. <g>VCAM-1</g> mRNA was significantly increased in lungs of subjects with <d>IPF</d> compared to lungs from control subjects p=0.001, and it negatively correlated with two markers of lung function, forced vital capacity FVC and pulmonary diffusion capacity for carbon monoxide DLCO. <g>VCAM-1</g> protein levels were highly expressed in <d>IPF</d> subjects where it was detected in fibrotic foci and blood vessels of <d>IPF</d> lung. Treatment of human lung fibroblasts with <g>TGF-b1</g> significantly increased steady-state VCAM1 mRNA and protein levels without affecting VCAM1 mRNA stability. Further, cellular depletion of <g>VCAM-1</g> inhibited fibroblast cell proliferation and reduced G2/M and S phases of the cell cycle suggestive of cell cycle arrest. These effects on cell cycle progression triggered by VCAM1 depletion were associated with reductions in levels of phosphorylated extracellular regulated kinase 1/2 and cyclin D1. Thus, these observations suggest that <g>VCAM-1</g> is a <g>TGF-b1</g> responsive mediator that partakes in fibroblast proliferation in subjects with <d>IPF</d>.
26415510|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> IPF is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that <g>BARD1</g> expression is upregulated in response to hypoxia and associated with <g>TGF-b</g> signaling, both recognized factors driving lung fibrosis. Differentially spliced <g>BARD1</g> isoforms, in particular <g>BARD1</g>b, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that <g>BARD1</g> and/or its isoforms might play a role in lung fibrosis. METHODS: We investigated <g>BARD1</g> expression as a function of <g>TGF-b</g> in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from <d>pulmonary fibrosis</d> patients. RESULTS: FL <g>BARD1</g> and <g>BARD1</g>b were upregulated in response to <g>TGF-b</g> in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length FL <g>BARD1</g> and <g>BARD1</g>b in fibrotic tissues. CONCLUSION: Our data suggest that FL <g>BARD1</g> and <g>BARD1</g>b might be mediators of pleiotropic effects of <g>TGF-b</g>. In particular <g>BARD1</g>b might be a driver of proliferation and of <d>pulmonary fibrosis</d> pathogenesis and progression and represent a target for treatment.
26415510|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of <d>IPF</d> is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that <g>BARD1</g> expression is upregulated in response to hypoxia and associated with <g>TGF-b</g> signaling, both recognized factors driving lung fibrosis. Differentially spliced <g>BARD1</g> isoforms, in particular <g>BARD1</g>b, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that <g>BARD1</g> and/or its isoforms might play a role in lung fibrosis. METHODS: We investigated <g>BARD1</g> expression as a function of <g>TGF-b</g> in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from <d>pulmonary fibrosis</d> patients. RESULTS: FL <g>BARD1</g> and <g>BARD1</g>b were upregulated in response to <g>TGF-b</g> in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length FL <g>BARD1</g> and <g>BARD1</g>b in fibrotic tissues. CONCLUSION: Our data suggest that FL <g>BARD1</g> and <g>BARD1</g>b might be mediators of pleiotropic effects of <g>TGF-b</g>. In particular <g>BARD1</g>b might be a driver of proliferation and of <d>pulmonary fibrosis</d> pathogenesis and progression and represent a target for treatment.
26415510|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a rapid progressive <d>fibro-proliferative disorder</d> with poor prognosis similar to lung cancer. The pathogenesis of <d>IPF</d> is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that <g>BARD1</g> expression is upregulated in response to hypoxia and associated with <g>TGF-b</g> signaling, both recognized factors driving lung fibrosis. Differentially spliced <g>BARD1</g> isoforms, in particular <g>BARD1</g>b, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that <g>BARD1</g> and/or its isoforms might play a role in lung fibrosis. METHODS: We investigated <g>BARD1</g> expression as a function of <g>TGF-b</g> in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from <d>pulmonary fibrosis</d> patients. RESULTS: FL <g>BARD1</g> and <g>BARD1</g>b were upregulated in response to <g>TGF-b</g> in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length FL <g>BARD1</g> and <g>BARD1</g>b in fibrotic tissues. CONCLUSION: Our data suggest that FL <g>BARD1</g> and <g>BARD1</g>b might be mediators of pleiotropic effects of <g>TGF-b</g>. In particular <g>BARD1</g>b might be a driver of proliferation and of <d>pulmonary fibrosis</d> pathogenesis and progression and represent a target for treatment.
26415510|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a rapid progressive <d>fibro-proliferative disorder</d> with poor prognosis similar to <d>lung cancer</d>. The pathogenesis of <d>IPF</d> is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that <g>BARD1</g> expression is upregulated in response to hypoxia and associated with <g>TGF-b</g> signaling, both recognized factors driving lung fibrosis. Differentially spliced <g>BARD1</g> isoforms, in particular <g>BARD1</g>b, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that <g>BARD1</g> and/or its isoforms might play a role in lung fibrosis. METHODS: We investigated <g>BARD1</g> expression as a function of <g>TGF-b</g> in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from <d>pulmonary fibrosis</d> patients. RESULTS: FL <g>BARD1</g> and <g>BARD1</g>b were upregulated in response to <g>TGF-b</g> in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length FL <g>BARD1</g> and <g>BARD1</g>b in fibrotic tissues. CONCLUSION: Our data suggest that FL <g>BARD1</g> and <g>BARD1</g>b might be mediators of pleiotropic effects of <g>TGF-b</g>. In particular <g>BARD1</g>b might be a driver of proliferation and of <d>pulmonary fibrosis</d> pathogenesis and progression and represent a target for treatment.
26415510|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a rapid progressive <d>fibro-proliferative disorder</d> with poor prognosis similar to <d>lung cancer</d>. The pathogenesis of <d>IPF</d> is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that <g>BARD1</g> expression is upregulated in response to <d>hypoxia</d> and associated with <g>TGF-b</g> signaling, both recognized factors driving lung fibrosis. Differentially spliced <g>BARD1</g> isoforms, in particular <g>BARD1</g>b, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that <g>BARD1</g> and/or its isoforms might play a role in lung fibrosis. METHODS: We investigated <g>BARD1</g> expression as a function of <g>TGF-b</g> in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from <d>pulmonary fibrosis</d> patients. RESULTS: FL <g>BARD1</g> and <g>BARD1</g>b were upregulated in response to <g>TGF-b</g> in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length FL <g>BARD1</g> and <g>BARD1</g>b in fibrotic tissues. CONCLUSION: Our data suggest that FL <g>BARD1</g> and <g>BARD1</g>b might be mediators of pleiotropic effects of <g>TGF-b</g>. In particular <g>BARD1</g>b might be a driver of proliferation and of <d>pulmonary fibrosis</d> pathogenesis and progression and represent a target for treatment.
26415510|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a rapid progressive <d>fibro-proliferative disorder</d> with poor prognosis similar to <d>lung cancer</d>. The pathogenesis of <d>IPF</d> is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that <g>BARD1</g> expression is upregulated in response to <d>hypoxia</d> and associated with <g>TGF-b</g> signaling, both recognized factors driving <d>lung fibrosis</d>. Differentially spliced <g>BARD1</g> isoforms, in particular <g>BARD1</g>b, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that <g>BARD1</g> and/or its isoforms might play a role in <d>lung fibrosis</d>. METHODS: We investigated <g>BARD1</g> expression as a function of <g>TGF-b</g> in cultured cells, in mice with experimentally induced <d>lung fibrosis</d>, and in lung biopsies from <d>pulmonary fibrosis</d> patients. RESULTS: FL <g>BARD1</g> and <g>BARD1</g>b were upregulated in response to <g>TGF-b</g> in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length FL <g>BARD1</g> and <g>BARD1</g>b in fibrotic tissues. CONCLUSION: Our data suggest that FL <g>BARD1</g> and <g>BARD1</g>b might be mediators of pleiotropic effects of <g>TGF-b</g>. In particular <g>BARD1</g>b might be a driver of proliferation and of <d>pulmonary fibrosis</d> pathogenesis and progression and represent a target for treatment.
26415510|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a rapid progressive <d>fibro-proliferative disorder</d> with poor prognosis similar to <d>lung cancer</d>. The pathogenesis of <d>IPF</d> is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that <g>BARD1</g> expression is upregulated in response to <d>hypoxia</d> and associated with <g>TGF-b</g> signaling, both recognized factors driving <d>lung fibrosis</d>. Differentially spliced <g>BARD1</g> isoforms, in particular <g>BARD1</g>b, are oncogenic drivers of proliferation in <d>cancers</d> of various origins. We therefore hypothesized that <g>BARD1</g> and/or its isoforms might play a role in <d>lung fibrosis</d>. METHODS: We investigated <g>BARD1</g> expression as a function of <g>TGF-b</g> in cultured cells, in mice with experimentally induced <d>lung fibrosis</d>, and in lung biopsies from <d>pulmonary fibrosis</d> patients. RESULTS: FL <g>BARD1</g> and <g>BARD1</g>b were upregulated in response to <g>TGF-b</g> in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length FL <g>BARD1</g> and <g>BARD1</g>b in fibrotic tissues. CONCLUSION: Our data suggest that FL <g>BARD1</g> and <g>BARD1</g>b might be mediators of pleiotropic effects of <g>TGF-b</g>. In particular <g>BARD1</g>b might be a driver of proliferation and of <d>pulmonary fibrosis</d> pathogenesis and progression and represent a target for treatment.
26442443|a|Idiopathic pulmonary <d>fibrosis</d> IPF is a progressive lung disease. Although the pathogenesis is poorly understood, evidence suggests that genetic and epigenetic alterations, such as DNA methylation, may play a key role. Bone morphogenetic proteins BMPs are members of the transforming growth factor-b TGF-b superfamily and are important regulators in IPF. Here we identified BMP endothelial cell precursor-derived regulator <g>BMPER</g> as a key regulator of fibroblast activation. <g>BMPER</g> is a secreted glycoprotein that binds directly to BMPs and may regulate TGF-b/BMP signaling, but its role in lung <d>fibrosis</d> is not clear. <g>BMPER</g> is highly expressed in human IPF lung fibroblasts compared to normal lung fibroblasts. Demethylation agent 5'-azacytidine decreased <g>BMPER</g> expression in fibroblasts, and attenuated the invasion and migration of IPF lung fibroblasts. Furthermore, siRNA-mediated reduction of <g>BMPER</g> in the human lung fibroblasts impaired cell migration and invasion. 5'-azacytidine treatment additionally regulated <g>BMPER</g> expression and reduced lung <d>fibrosis</d> in mice in vivo. These findings demonstrate that methylation of specific genes in fibroblasts may offer a new therapeutic strategy for IPF by modulating fibroblast activation.
26442443|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive lung disease. Although the pathogenesis is poorly understood, evidence suggests that genetic and epigenetic alterations, such as DNA methylation, may play a key role. Bone morphogenetic proteins BMPs are members of the transforming growth factor-b TGF-b superfamily and are important regulators in <d>IPF</d>. Here we identified BMP endothelial cell precursor-derived regulator <g>BMPER</g> as a key regulator of fibroblast activation. <g>BMPER</g> is a secreted glycoprotein that binds directly to BMPs and may regulate TGF-b/BMP signaling, but its role in lung <d>fibrosis</d> is not clear. <g>BMPER</g> is highly expressed in human <d>IPF</d> lung fibroblasts compared to normal lung fibroblasts. Demethylation agent 5'-azacytidine decreased <g>BMPER</g> expression in fibroblasts, and attenuated the invasion and migration of <d>IPF</d> lung fibroblasts. Furthermore, siRNA-mediated reduction of <g>BMPER</g> in the human lung fibroblasts impaired cell migration and invasion. 5'-azacytidine treatment additionally regulated <g>BMPER</g> expression and reduced lung <d>fibrosis</d> in mice in vivo. These findings demonstrate that methylation of specific genes in fibroblasts may offer a new therapeutic strategy for <d>IPF</d> by modulating fibroblast activation.
26442443|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> is a progressive <d>lung disease</d>. Although the pathogenesis is poorly understood, evidence suggests that genetic and epigenetic alterations, such as DNA methylation, may play a key role. Bone morphogenetic proteins BMPs are members of the transforming growth factor-b TGF-b superfamily and are important regulators in <d>IPF</d>. Here we identified BMP endothelial cell precursor-derived regulator <g>BMPER</g> as a key regulator of fibroblast activation. <g>BMPER</g> is a secreted glycoprotein that binds directly to BMPs and may regulate TGF-b/BMP signaling, but its role in lung <d>fibrosis</d> is not clear. <g>BMPER</g> is highly expressed in human <d>IPF</d> lung fibroblasts compared to normal lung fibroblasts. Demethylation agent 5'-azacytidine decreased <g>BMPER</g> expression in fibroblasts, and attenuated the invasion and migration of <d>IPF</d> lung fibroblasts. Furthermore, siRNA-mediated reduction of <g>BMPER</g> in the human lung fibroblasts impaired cell migration and invasion. 5'-azacytidine treatment additionally regulated <g>BMPER</g> expression and reduced lung <d>fibrosis</d> in mice in vivo. These findings demonstrate that methylation of specific genes in fibroblasts may offer a new therapeutic strategy for <d>IPF</d> by modulating fibroblast activation.
26474459|a|Idiopathic pulmonary fibrosis IPF is a destructive disease in part resulting from premature or mature cellular aging. Protease-activated receptor-1 PAR-1 recently emerged as a critical component in the context of fibrotic lung diseases. Therefore, we aimed to study the role of macrophages in PAR-1-mediated <d>idiopathic pulmonary fibrosis</d>. The number of macrophages were significantly reduced in lungs of PAR-1 antagonist P1pal-12 treated animals upon bleomycin instillation. In line with these data, PAR-1 stimulation increased monocyte / macrophage recruitment in response to epithelium injury in in vitro trans-well assays. Moreover, macrophages induced fibroblasts migration, differentiation and secretion of collagen, which were inhibited in the presence of TGF-b receptor inhibitors. Interestingly, these profibrotic effects were partially inhibited by treatment with the PAR-1 inhibitor P1pal-12. Using shRNA mediated PAR-1 knock down in fibroblasts, we demonstrate that fibroblast PAR-1 contributes to TGF-b activation and production. Finally, we show that the macrophage-dependent induction of PAR-1 driven TGF-b activation was mediated by FXa. Our data identify novel mechanisms by which PAR-1 stimulation on different cell types can contribute to IPF and identify macrophages as key players in PAR-1 dependent development of this devastating disease. IPF may result from cellular senescence mediated by macrophages in the lung.
26474459|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a destructive disease in part resulting from premature or mature cellular aging. Protease-activated receptor-1 PAR-1 recently emerged as a critical component in the context of fibrotic lung diseases. Therefore, we aimed to study the role of macrophages in PAR-1-mediated <d>idiopathic pulmonary fibrosis</d>. The number of macrophages were significantly reduced in lungs of PAR-1 antagonist P1pal-12 treated animals upon bleomycin instillation. In line with these data, PAR-1 stimulation increased monocyte / macrophage recruitment in response to epithelium injury in in vitro trans-well assays. Moreover, macrophages induced fibroblasts migration, differentiation and secretion of collagen, which were inhibited in the presence of TGF-b receptor inhibitors. Interestingly, these profibrotic effects were partially inhibited by treatment with the PAR-1 inhibitor P1pal-12. Using shRNA mediated PAR-1 knock down in fibroblasts, we demonstrate that fibroblast PAR-1 contributes to TGF-b activation and production. Finally, we show that the macrophage-dependent induction of PAR-1 driven TGF-b activation was mediated by FXa. Our data identify novel mechanisms by which PAR-1 stimulation on different cell types can contribute to IPF and identify macrophages as key players in PAR-1 dependent development of this devastating disease. IPF may result from cellular senescence mediated by macrophages in the lung.
26474459|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a destructive disease in part resulting from premature or mature cellular aging. Protease-activated receptor-1 PAR-1 recently emerged as a critical component in the context of fibrotic lung diseases. Therefore, we aimed to study the role of macrophages in PAR-1-mediated <d>idiopathic pulmonary fibrosis</d>. The number of macrophages were significantly reduced in lungs of PAR-1 antagonist P1pal-12 treated animals upon bleomycin instillation. In line with these data, PAR-1 stimulation increased monocyte / macrophage recruitment in response to epithelium injury in in vitro trans-well assays. Moreover, macrophages induced fibroblasts migration, differentiation and secretion of collagen, which were inhibited in the presence of TGF-b receptor inhibitors. Interestingly, these profibrotic effects were partially inhibited by treatment with the PAR-1 inhibitor P1pal-12. Using shRNA mediated PAR-1 knock down in fibroblasts, we demonstrate that fibroblast PAR-1 contributes to TGF-b activation and production. Finally, we show that the macrophage-dependent induction of PAR-1 driven TGF-b activation was mediated by FXa. Our data identify novel mechanisms by which PAR-1 stimulation on different cell types can contribute to <d>IPF</d> and identify macrophages as key players in PAR-1 dependent development of this devastating disease. <d>IPF</d> may result from cellular senescence mediated by macrophages in the lung.
26474459|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a destructive disease in part resulting from premature or mature cellular aging. <g>Protease-activated receptor-1</g> <g>PAR-1</g> recently emerged as a critical component in the context of <d>fibrotic lung diseases</d>. Therefore, we aimed to study the role of macrophages in <g>PAR-1</g>-mediated <d>idiopathic pulmonary fibrosis</d>. The number of macrophages were significantly reduced in lungs of <g>PAR-1</g> antagonist P1pal-12 treated animals upon bleomycin instillation. In line with these data, <g>PAR-1</g> stimulation increased monocyte / macrophage recruitment in response to epithelium injury in in vitro trans-well assays. Moreover, macrophages induced fibroblasts migration, differentiation and secretion of collagen, which were inhibited in the presence of TGF-b receptor inhibitors. Interestingly, these profibrotic effects were partially inhibited by treatment with the <g>PAR-1</g> inhibitor P1pal-12. Using shRNA mediated <g>PAR-1</g> knock down in fibroblasts, we demonstrate that fibroblast <g>PAR-1</g> contributes to TGF-b activation and production. Finally, we show that the macrophage-dependent induction of <g>PAR-1</g> driven TGF-b activation was mediated by FXa. Our data identify novel mechanisms by which <g>PAR-1</g> stimulation on different cell types can contribute to <d>IPF</d> and identify macrophages as key players in <g>PAR-1</g> dependent development of this devastating disease. <d>IPF</d> may result from cellular senescence mediated by macrophages in the lung.
26523510|a|UNASSIGNED: Various methods have been used to evaluate anti-fibrotic activity of drugs. However, most of them are complicated, labor-intensive and lack of efficiency. This study was intended to develop a rapid method for anti-fibrotic drugs screening based on biophysical properties. A549 cells in  vitro were stimulated with <g>transforming growth factor-b1</g> <g>TGF-b1</g>, and fibrogenesis was confirmed by conventional immunological assays. Meanwhile, the alterations of cyto-biophysical properties including morphology, roughness and <d>stiffness</d> were measured utilizing atomic force microscopy AFM. It was found that fibrogenesis was accompanied with changes of cellular biophysical properties. <g>TGF-b1</g>-stimulated A549 cells became remarkably longer, rougher and stiffer than the control. Then, the effect of N-acetyl-l-cysteine NAC as a positive drug on ameliorating fibrogenesis in <g>TGF-b1</g>-stimulated A549 cells was verified respectively by immunological and biophysical markers. The result of Principal Component Analysis showed that <d>stiffness</d> was a leading index among all biophysical markers during fibrogenesis. Salvianolic acid B SalB, a natural anti-oxidant, was detected by AFM to protect <g>TGF-b1</g>-stimulated A549 cells against stiffening. Then, SalB treatment was provided in preventive mode on a rat model of bleomycin BLM -induced pulmonary fibrosis. The results showed that SalB treatment significantly ameliorated BLM-induced histological alterations, blocked collagen accumulations and reduced a-SMA expression in lung tissues. All these results revealed the anti-pulmonary fibrotic activity of SalB. Detection of cyto-biophysical properties were therefore recommended as a rapid method for anti-pulmonary fibrotic drugs screening.
26523510|a|UNASSIGNED: Various methods have been used to evaluate anti-fibrotic activity of drugs. However, most of them are complicated, labor-intensive and lack of efficiency. This study was intended to develop a rapid method for anti-fibrotic drugs screening based on biophysical properties. A549 cells in  vitro were stimulated with <g>transforming growth factor-b1</g> <g>TGF-b1</g>, and fibrogenesis was confirmed by conventional immunological assays. Meanwhile, the alterations of cyto-biophysical properties including morphology, roughness and <d>stiffness</d> were measured utilizing atomic force microscopy AFM. It was found that fibrogenesis was accompanied with changes of cellular biophysical properties. <g>TGF-b1</g>-stimulated A549 cells became remarkably longer, rougher and stiffer than the control. Then, the effect of N-acetyl-l-cysteine NAC as a positive drug on ameliorating fibrogenesis in <g>TGF-b1</g>-stimulated A549 cells was verified respectively by immunological and biophysical markers. The result of Principal Component Analysis showed that <d>stiffness</d> was a leading index among all biophysical markers during fibrogenesis. Salvianolic acid B SalB, a natural anti-oxidant, was detected by AFM to protect <g>TGF-b1</g>-stimulated A549 cells against stiffening. Then, SalB treatment was provided in preventive mode on a rat model of bleomycin BLM -induced <d>pulmonary fibrosis</d>. The results showed that SalB treatment significantly ameliorated BLM-induced histological alterations, blocked collagen accumulations and reduced a-SMA expression in lung tissues. All these results revealed the anti-pulmonary fibrotic activity of SalB. Detection of cyto-biophysical properties were therefore recommended as a rapid method for anti-pulmonary fibrotic drugs screening.
26538547|a|The wingless Wnt family of signaling ligands contributes significantly to lung development and is highly expressed in patients with <d>usual interstitial pneumonia</d> UIP. We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis IPF and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with <g>TGF-b</g>1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without <g>TGF-b</g>1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and <g>TGF-b</g>1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF.
26538547|a|The wingless Wnt family of signaling ligands contributes significantly to lung development and is highly expressed in patients with <d>usual interstitial pneumonia</d> <d>UIP</d>. We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis IPF and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or <d>UIP</d> were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with <g>TGF-b</g>1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without <g>TGF-b</g>1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and <g>TGF-b</g>1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF.
26538547|a|The wingless Wnt family of signaling ligands contributes significantly to lung development and is highly expressed in patients with <d>usual interstitial pneumonia</d> <d>UIP</d>. We sought to define the cellular distribution of <g>Wnt5A</g> in the lung tissue of patients with <d>idiopathic pulmonary fibrosis</d> IPF and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or <d>UIP</d> were probed for the immunolocalization of <g>Wnt5A</g>. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with <g>TGF-b</g>1 or its inhibitor, were analyzed for <g>Wnt5A</g> protein expression. <g>Wnt5A</g> was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without <g>TGF-b</g>1 treatment significantly increased <g>Wnt5A</g> protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where <g>Wnt5A</g> was already highly expressed. The results demonstrate a wide distribution of <g>Wnt5A</g> expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and <g>TGF-b</g>1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF.
26538547|a|The wingless Wnt family of signaling ligands contributes significantly to lung development and is highly expressed in patients with <d>usual interstitial pneumonia</d> <d>UIP</d>. We sought to define the cellular distribution of <g>Wnt5A</g> in the lung tissue of patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and the signaling ligands that control its expression in human lung fibroblasts and <d>IPF</d> myofibroblasts. Tissue sections from 40 patients diagnosed with <d>IPF</d> or <d>UIP</d> were probed for the immunolocalization of <g>Wnt5A</g>. Further, isolated lung fibroblasts from normal or <d>IPF</d> human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with <g>TGF-b</g>1 or its inhibitor, were analyzed for <g>Wnt5A</g> protein expression. <g>Wnt5A</g> was expressed in <d>IPF</d> lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without <g>TGF-b</g>1 treatment significantly increased <g>Wnt5A</g> protein expression in normal human smooth muscle cells and fibroblasts but not in <d>IPF</d> myofibroblasts where <g>Wnt5A</g> was already highly expressed. The results demonstrate a wide distribution of <g>Wnt5A</g> expression in cells of the <d>IPF</d> lung and reveal that it is significantly increased by Wnt7B and <g>TGF-b</g>1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of <d>IPF</d>.
26542979|a|UNASSIGNED: Irreversible respiratory obstruction resulting from progressive airway damage, inflammation and <d>fibrosis</d> is a feature of several chronic respiratory diseases, including cystic <d>fibrosis</d>, idiopathic pulmonary <d>fibrosis</d> and chronic obstructive pulmonary disease. The cytokine transforming growth factor beta TGF-b has a pivotal role in promoting lung <d>fibrosis</d> and is implicated in respiratory disease severity. Here we show that a previously uncharacterized microRNA, miR-1343, reduces the expression of both TGF-b receptor 1 and 2 by directly targeting their 3' UTRs. After TGF-b exposure, elevated intracellular miR-1343 significantly decreases levels of activated TGF-b effector molecules, pSMAD2 and pSMAD3, when compared to a non-targeting control miRNA. As a result, the abundance of fibrotic markers is reduced, cell migration into a scratch wound impaired, and epithelial-to-mesenchymal transition repressed. Mature miR-1343 is readily detected in human neutrophils and HL-60 cells and is activated in response to stress in A549 lung epithelial cells. miR-1343 may have direct therapeutic applications in fibrotic lung disease.
26542979|a|UNASSIGNED: Irreversible <d>respiratory obstruction</d> resulting from progressive airway damage, inflammation and <d>fibrosis</d> is a feature of several chronic respiratory diseases, including cystic <d>fibrosis</d>, idiopathic pulmonary <d>fibrosis</d> and chronic obstructive pulmonary disease. The cytokine transforming growth factor beta <g>TGF-b</g> has a pivotal role in promoting lung <d>fibrosis</d> and is implicated in respiratory disease severity. Here we show that a previously uncharacterized microRNA, miR-1343, reduces the expression of both <g>TGF-b</g> receptor 1 and 2 by directly targeting their 3' UTRs. After <g>TGF-b</g> exposure, elevated intracellular miR-1343 significantly decreases levels of activated <g>TGF-b</g> effector molecules, pSMAD2 and pSMAD3, when compared to a non-targeting control miRNA. As a result, the abundance of fibrotic markers is reduced, cell migration into a scratch wound impaired, and epithelial-to-mesenchymal transition repressed. Mature miR-1343 is readily detected in human neutrophils and HL-60 cells and is activated in response to stress in A549 lung epithelial cells. miR-1343 may have direct therapeutic applications in fibrotic lung disease.
26542979|a|UNASSIGNED: Irreversible <d>respiratory obstruction</d> resulting from progressive airway damage, <d>inflammation</d> and <d>fibrosis</d> is a feature of several chronic respiratory diseases, including cystic <d>fibrosis</d>, idiopathic pulmonary <d>fibrosis</d> and chronic obstructive pulmonary disease. The cytokine transforming growth factor beta <g>TGF-b</g> has a pivotal role in promoting lung <d>fibrosis</d> and is implicated in respiratory disease severity. Here we show that a previously uncharacterized microRNA, miR-1343, reduces the expression of both <g>TGF-b</g> receptor 1 and 2 by directly targeting their 3' UTRs. After <g>TGF-b</g> exposure, elevated intracellular miR-1343 significantly decreases levels of activated <g>TGF-b</g> effector molecules, pSMAD2 and pSMAD3, when compared to a non-targeting control miRNA. As a result, the abundance of fibrotic markers is reduced, cell migration into a scratch wound impaired, and epithelial-to-mesenchymal transition repressed. Mature miR-1343 is readily detected in human neutrophils and HL-60 cells and is activated in response to stress in A549 lung epithelial cells. miR-1343 may have direct therapeutic applications in fibrotic lung disease.
26542979|a|UNASSIGNED: Irreversible <d>respiratory obstruction</d> resulting from progressive airway damage, <d>inflammation</d> and <d>fibrosis</d> is a feature of several chronic <d>respiratory diseases</d>, including cystic <d>fibrosis</d>, idiopathic pulmonary <d>fibrosis</d> and chronic obstructive pulmonary disease. The cytokine transforming growth factor beta <g>TGF-b</g> has a pivotal role in promoting lung <d>fibrosis</d> and is implicated in respiratory disease severity. Here we show that a previously uncharacterized microRNA, miR-1343, reduces the expression of both <g>TGF-b</g> receptor 1 and 2 by directly targeting their 3' UTRs. After <g>TGF-b</g> exposure, elevated intracellular miR-1343 significantly decreases levels of activated <g>TGF-b</g> effector molecules, pSMAD2 and pSMAD3, when compared to a non-targeting control miRNA. As a result, the abundance of fibrotic markers is reduced, cell migration into a scratch wound impaired, and epithelial-to-mesenchymal transition repressed. Mature miR-1343 is readily detected in human neutrophils and HL-60 cells and is activated in response to stress in A549 lung epithelial cells. miR-1343 may have direct therapeutic applications in fibrotic lung disease.
26542979|a|UNASSIGNED: Irreversible <d>respiratory obstruction</d> resulting from progressive airway damage, <d>inflammation</d> and <d>fibrosis</d> is a feature of several chronic <d>respiratory diseases</d>, including cystic <d>fibrosis</d>, idiopathic pulmonary <d>fibrosis</d> and <d>chronic obstructive pulmonary disease</d>. The cytokine transforming growth factor beta <g>TGF-b</g> has a pivotal role in promoting lung <d>fibrosis</d> and is implicated in respiratory disease severity. Here we show that a previously uncharacterized microRNA, miR-1343, reduces the expression of both <g>TGF-b</g> receptor 1 and 2 by directly targeting their 3' UTRs. After <g>TGF-b</g> exposure, elevated intracellular miR-1343 significantly decreases levels of activated <g>TGF-b</g> effector molecules, pSMAD2 and pSMAD3, when compared to a non-targeting control miRNA. As a result, the abundance of fibrotic markers is reduced, cell migration into a scratch wound impaired, and epithelial-to-mesenchymal transition repressed. Mature miR-1343 is readily detected in human neutrophils and HL-60 cells and is activated in response to stress in A549 lung epithelial cells. miR-1343 may have direct therapeutic applications in fibrotic lung disease.
26542979|a|UNASSIGNED: Irreversible <d>respiratory obstruction</d> resulting from progressive airway damage, <d>inflammation</d> and <d>fibrosis</d> is a feature of several chronic <d><d>respiratory disease</d>s</d>, including cystic <d>fibrosis</d>, idiopathic pulmonary <d>fibrosis</d> and <d>chronic obstructive pulmonary disease</d>. The cytokine <g>transforming growth factor beta</g> <g>TGF-b</g> has a pivotal role in promoting lung <d>fibrosis</d> and is implicated in <d>respiratory disease</d> severity. Here we show that a previously uncharacterized microRNA, miR-1343, reduces the expression of both <g>TGF-b</g> receptor 1 and 2 by directly targeting their 3' UTRs. After <g>TGF-b</g> exposure, elevated intracellular miR-1343 significantly decreases levels of activated <g>TGF-b</g> effector molecules, pSMAD2 and pSMAD3, when compared to a non-targeting control miRNA. As a result, the abundance of fibrotic markers is reduced, cell migration into a scratch wound impaired, and epithelial-to-mesenchymal transition repressed. Mature miR-1343 is readily detected in human neutrophils and HL-60 cells and is activated in response to stress in A549 lung epithelial cells. miR-1343 may have direct therapeutic applications in fibrotic lung disease.
26542979|a|UNASSIGNED: Irreversible <d>respiratory obstruction</d> resulting from progressive airway damage, <d>inflammation</d> and <d>fibrosis</d> is a feature of several chronic <d><d>respiratory disease</d>s</d>, including cystic <d>fibrosis</d>, idiopathic pulmonary <d>fibrosis</d> and <d>chronic obstructive pulmonary disease</d>. The cytokine <g>transforming growth factor beta</g> <g>TGF-b</g> has a pivotal role in promoting lung <d>fibrosis</d> and is implicated in <d>respiratory disease</d> severity. Here we show that a previously uncharacterized microRNA, <g>miR-1343</g>, reduces the expression of both <g>TGF-b</g> receptor 1 and 2 by directly targeting their 3' UTRs. After <g>TGF-b</g> exposure, elevated intracellular <g>miR-1343</g> significantly decreases levels of activated <g>TGF-b</g> effector molecules, pSMAD2 and pSMAD3, when compared to a non-targeting control miRNA. As a result, the abundance of fibrotic markers is reduced, cell migration into a scratch wound impaired, and epithelial-to-mesenchymal transition repressed. Mature <g>miR-1343</g> is readily detected in human neutrophils and HL-60 cells and is activated in response to stress in A549 lung epithelial cells. <g>miR-1343</g> may have direct therapeutic applications in <d>fibrotic lung disease</d>.
26545872|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive chronic interstitial lung disease with poor survival. Previous reports suggested the contributory effect of receptor for advanced glycation end products RAGE to the pathogenesis of IPF. But the findings are controversial. The present in  vivo study with RAGE null mice, we further confirmed the evidence that lack of RAGE evolves worse bleomycin-induced pulmonary fibrosis compared with control mice. Moreover, RAGE null mice spontaneously developed similar pathogenesis of lung fibrosis via immunohistochemical staining. In addition, we investigated the negative roles of RAGE on epithelial-mesenchymal transition EMT indicated by elevated a-smooth muscle actin a-SMA and collagen-I Col-I deposition in A549  cell treated with transforming growth factor-b TGF-b, all of which were blocked by sRAGE, a decoy receptor. Furthermore, interacting with the specific ligand as AGE, RAGE blocked TGF-b-induced activation of Smad2, ERK and JNK signals in A549  cells, which were also challenged by sRAGE administration. This present study confirmed an important role of RAGE in  vivo and vitro models of pulmonary fibrosis and suggested the therapeutic possibility for pulmonary fibrosis via RAGE regulation.
26545872|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive chronic interstitial lung disease with poor survival. Previous reports suggested the contributory effect of receptor for advanced glycation end products RAGE to the pathogenesis of <d>IPF</d>. But the findings are controversial. The present in  vivo study with RAGE null mice, we further confirmed the evidence that lack of RAGE evolves worse bleomycin-induced pulmonary fibrosis compared with control mice. Moreover, RAGE null mice spontaneously developed similar pathogenesis of lung fibrosis via immunohistochemical staining. In addition, we investigated the negative roles of RAGE on epithelial-mesenchymal transition EMT indicated by elevated a-smooth muscle actin a-SMA and collagen-I Col-I deposition in A549  cell treated with transforming growth factor-b TGF-b, all of which were blocked by sRAGE, a decoy receptor. Furthermore, interacting with the specific ligand as AGE, RAGE blocked TGF-b-induced activation of Smad2, ERK and JNK signals in A549  cells, which were also challenged by sRAGE administration. This present study confirmed an important role of RAGE in  vivo and vitro models of pulmonary fibrosis and suggested the therapeutic possibility for pulmonary fibrosis via RAGE regulation.
26545872|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>chronic interstitial lung disease</d> with poor survival. Previous reports suggested the contributory effect of receptor for advanced glycation end products RAGE to the pathogenesis of <d>IPF</d>. But the findings are controversial. The present in  vivo study with RAGE null mice, we further confirmed the evidence that lack of RAGE evolves worse bleomycin-induced pulmonary fibrosis compared with control mice. Moreover, RAGE null mice spontaneously developed similar pathogenesis of lung fibrosis via immunohistochemical staining. In addition, we investigated the negative roles of RAGE on epithelial-mesenchymal transition EMT indicated by elevated a-smooth muscle actin a-SMA and collagen-I Col-I deposition in A549  cell treated with transforming growth factor-b TGF-b, all of which were blocked by sRAGE, a decoy receptor. Furthermore, interacting with the specific ligand as AGE, RAGE blocked TGF-b-induced activation of Smad2, ERK and JNK signals in A549  cells, which were also challenged by sRAGE administration. This present study confirmed an important role of RAGE in  vivo and vitro models of pulmonary fibrosis and suggested the therapeutic possibility for pulmonary fibrosis via RAGE regulation.
26545872|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive <d>chronic interstitial lung disease</d> with poor survival. Previous reports suggested the contributory effect of receptor for advanced glycation end products <g>RAGE</g> to the pathogenesis of <d>IPF</d>. But the findings are controversial. The present in  vivo study with <g>RAGE</g> null mice, we further confirmed the evidence that lack of <g>RAGE</g> evolves worse bleomycin-induced <d>pulmonary fibrosis</d> compared with control mice. Moreover, <g>RAGE</g> null mice spontaneously developed similar pathogenesis of lung fibrosis via immunohistochemical staining. In addition, we investigated the negative roles of <g>RAGE</g> on epithelial-mesenchymal transition EMT indicated by elevated a-smooth muscle actin a-SMA and collagen-I Col-I deposition in A549  cell treated with transforming growth factor-b TGF-b, all of which were blocked by s<g>RAGE</g>, a decoy receptor. Furthermore, interacting with the specific ligand as AGE, <g>RAGE</g> blocked TGF-b-induced activation of Smad2, ERK and JNK signals in A549  cells, which were also challenged by s<g>RAGE</g> administration. This present study confirmed an important role of <g>RAGE</g> in  vivo and vitro models of <d>pulmonary fibrosis</d> and suggested the therapeutic possibility for <d>pulmonary fibrosis</d> via <g>RAGE</g> regulation.
26545872|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive <d>chronic interstitial lung disease</d> with poor survival. Previous reports suggested the contributory effect of receptor for advanced glycation end products <g>RAGE</g> to the pathogenesis of <d>IPF</d>. But the findings are controversial. The present in  vivo study with <g>RAGE</g> null mice, we further confirmed the evidence that lack of <g>RAGE</g> evolves worse bleomycin-induced <d>pulmonary fibrosis</d> compared with control mice. Moreover, <g>RAGE</g> null mice spontaneously developed similar pathogenesis of <d>lung fibrosis</d> via immunohistochemical staining. In addition, we investigated the negative roles of <g>RAGE</g> on epithelial-mesenchymal transition EMT indicated by elevated a-smooth muscle actin a-SMA and collagen-I Col-I deposition in A549  cell treated with transforming growth factor-b TGF-b, all of which were blocked by s<g>RAGE</g>, a decoy receptor. Furthermore, interacting with the specific ligand as AGE, <g>RAGE</g> blocked TGF-b-induced activation of Smad2, ERK and JNK signals in A549  cells, which were also challenged by s<g>RAGE</g> administration. This present study confirmed an important role of <g>RAGE</g> in  vivo and vitro models of <d>pulmonary fibrosis</d> and suggested the therapeutic possibility for <d>pulmonary fibrosis</d> via <g>RAGE</g> regulation.
26599507|a|RATIONALE: <d>Idiopathic pulmonary fibrosis</d> IPF is a devastating disease that remains refractory to current therapies. OBJECTIVES: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. METHODS: <g>Matriptase</g> expression was assessed in tissue specimens from patients with IPF versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. <g>Matriptase</g>-induced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate CM, or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. MEASUREMENTS AND MAIN RESULTS: <g>Matriptase</g> expression and activity were up-regulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-b. Furthermore, matriptase elicited signaling via protease-activated receptor-2 PAR-2, and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic down-regulation, diminished lung injury, collagen production, and transforming growth factor-b expression and signaling. CONCLUSIONS: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for IPF.
26599507|a|RATIONALE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating disease that remains refractory to current therapies. OBJECTIVES: To characterize the expression and activity of the membrane-anchored serine protease matriptase in <d>IPF</d> in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. METHODS: <g>Matriptase</g> expression was assessed in tissue specimens from patients with <d>IPF</d> versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. <g>Matriptase</g>-induced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate CM, or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. MEASUREMENTS AND MAIN RESULTS: <g>Matriptase</g> expression and activity were up-regulated in <d>IPF</d> and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-b. Furthermore, matriptase elicited signaling via protease-activated receptor-2 PAR-2, and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic down-regulation, diminished lung injury, collagen production, and transforming growth factor-b expression and signaling. CONCLUSIONS: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human <d>IPF</d> and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for <d>IPF</d>.
26599507|a|RATIONALE: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a devastating disease that remains refractory to current therapies. OBJECTIVES: To characterize the expression and activity of the membrane-anchored <g>serine protease</g> <g>matriptase</g> in <d>IPF</d> in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. METHODS: <g>Matriptase</g> expression was assessed in tissue specimens from patients with <d>IPF</d> versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while <g>matriptase</g> activity was monitored by fluorogenic substrate cleavage. <g>Matriptase</g>-induced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced <d>pulmonary fibrosis</d>, the consequences of <g>matriptase</g> depletion, either by using the pharmacological inhibitor camostat mesilate CM, or by genetic down-regulation using <g>matriptase</g> hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. MEASUREMENTS AND MAIN RESULTS: <g>Matriptase</g> expression and activity were up-regulated in <d>IPF</d> and bleomycin-induced <d>pulmonary fibrosis</d>. In cultured human pulmonary fibroblasts, <g>matriptase</g> expression was significantly induced by transforming growth factor-b. Furthermore, <g>matriptase</g> elicited signaling via protease-activated receptor-2 PAR-2, and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, <g>matriptase</g> depletion, by the pharmacological inhibitor CM or by genetic down-regulation, diminished lung injury, collagen production, and transforming growth factor-b expression and signaling. CONCLUSIONS: These results implicate increased <g>matriptase</g> expression and activity in the pathogenesis of <d>pulmonary fibrosis</d> in human <d>IPF</d> and in an experimental mouse model. Overall, targeting <g>matriptase</g>, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for <d>IPF</d>.
26599507|a|RATIONALE: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a devastating disease that remains refractory to current therapies. OBJECTIVES: To characterize the expression and activity of the membrane-anchored <g>serine protease</g> <g>matriptase</g> in <d>IPF</d> in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. METHODS: <g>Matriptase</g> expression was assessed in tissue specimens from patients with <d>IPF</d> versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while <g>matriptase</g> activity was monitored by fluorogenic substrate cleavage. <g>Matriptase</g>-induced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced <d>pulmonary fibrosis</d>, the consequences of <g>matriptase</g> depletion, either by using the pharmacological inhibitor camostat mesilate CM, or by genetic down-regulation using <g>matriptase</g> hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. MEASUREMENTS AND MAIN RESULTS: <g>Matriptase</g> expression and activity were up-regulated in <d>IPF</d> and bleomycin-induced <d>pulmonary fibrosis</d>. In cultured human pulmonary fibroblasts, <g>matriptase</g> expression was significantly induced by transforming growth factor-b. Furthermore, <g>matriptase</g> elicited signaling via <g>protease-activated receptor-2</g> <g>PAR-2</g>, and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, <g>matriptase</g> depletion, by the pharmacological inhibitor CM or by genetic down-regulation, diminished <d>lung injury</d>, collagen production, and transforming growth factor-b expression and signaling. CONCLUSIONS: These results implicate increased <g>matriptase</g> expression and activity in the pathogenesis of <d>pulmonary fibrosis</d> in human <d>IPF</d> and in an experimental mouse model. Overall, targeting <g>matriptase</g>, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for <d>IPF</d>.
26600305|a|Pathologic accumulation of fibroblasts in <d>pulmonary fibrosis</d> appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic <d>pulmonary fibrosis</d> IPF have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic e.g., bleomycin-induced rather than nonfibrogenic e.g., LPS-induced lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-b, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in <d>pulmonary fibrosis</d>. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for <d>pulmonary fibrosis</d>. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.
26600305|a|Pathologic accumulation of fibroblasts in <d>pulmonary fibrosis</d> appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with <d>IPF</d> contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic e.g., bleomycin-induced rather than nonfibrogenic e.g., LPS-induced lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-b, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in <d>pulmonary fibrosis</d>. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for <d>pulmonary fibrosis</d>. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of <d>IPF</d> and other fibrotic lung diseases.
26600305|a|Pathologic accumulation of fibroblasts in <d>pulmonary fibrosis</d> appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by <d>lung injury</d>. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with <d>IPF</d> contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after <d>lung injury</d> and are preferentially produced by fibrogenic e.g., bleomycin-induced rather than nonfibrogenic e.g., LPS-induced <d>lung injury</d>. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-b, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in <d>pulmonary fibrosis</d>. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for <d>pulmonary fibrosis</d>. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of <d>IPF</d> and other fibrotic lung diseases.
26600305|a|Pathologic accumulation of fibroblasts in <d>pulmonary fibrosis</d> appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by <d>lung injury</d>. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with <d>IPF</d> contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after <d>lung injury</d> and are preferentially produced by fibrogenic e.g., bleomycin-induced rather than nonfibrogenic e.g., LPS-induced <d>lung injury</d>. Comparison of invasion and <d>migration</d> induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-b, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in <d>pulmonary fibrosis</d>. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for <d>pulmonary fibrosis</d>. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of <d>IPF</d> and other fibrotic lung diseases.
26600305|a|Pathologic accumulation of fibroblasts in <d>pulmonary fibrosis</d> appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by <d>lung injury</d>. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with <d>IPF</d> contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after <d>lung injury</d> and are preferentially produced by fibrogenic e.g., bleomycin-induced rather than nonfibrogenic e.g., LPS-induced <d>lung injury</d>. Comparison of invasion and <d>migration</d> induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-b, lysophosphatidic acid 1, <g>epidermal growth factor receptor</g>, and <g>fibroblast growth factor receptor 2</g>, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in <d>pulmonary fibrosis</d>. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for <d>pulmonary fibrosis</d>. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of <d>IPF</d> and other <d>fibrotic lung diseases</d>.
26610737|a|BACKGROUND AND OBJECTIVE: <d>IPF</d> is a form of interstitial pneumonia of unknown origin that has a poor prognosis for which current treatments are limited. Recent studies have shown that EMT plays a role in <d>IPF</d> and tumour metastasis. L1-CAM has also been linked to EMT during tumour development and tumour metastasis. Our aim was to determine prospectively the level of L1-CAM in <d>IPF</d> patients. METHODS: Forty consecutive Chinese patients with <d>IPF</d>, 16; LC, 12; and CC, 12, but no apparent lung or other organ's diseases were enrolled. Soluble L1-CAM <g>sL1</g>-CAM, TGF-b1, PDGF, y-INF levels in BALF and serum <g>sL1</g>-CAM were measured using ELISA. RESULTS: BALF <g>sL1</g>-CAM levels of <d>IPF</d>, LC and CC patients were 10.87        0.88   ng/mL, 6.34        0.67   ng/mL and 5.43        0.65   ng/mL, respectively. BALF <g>sL1</g>-CAM concentration of <d>IPF</d> patients was significantly higher than that in LC and in CC patients. Besides, serum <g>sL1</g>-CAM levels in patients with <d>IPF</d>, LC and CC were 9.60        1.41   ng/mL, 9.82        0.72   ng/mL and 5.41        1.07   ng/mL, respectively. The serum <g>sL1</g>-CAM levels in patients with <d>IPF</d> and LC were significantly higher than those in patients with CC P   <   0.001, respectively. CONCLUSIONS: The concentrations of <g>sL1</g>-CAM both in BALF and in serum of patients with <d>IPF</d> are markedly increased compared with controls. This indicates that L1-CAM might be involved in the pathogenesis of <d>IPF</d> as well as that of LC.
26610737|a|BACKGROUND AND OBJECTIVE: <d>IPF</d> is a form of <d>interstitial pneumonia</d> of unknown origin that has a poor prognosis for which current treatments are limited. Recent studies have shown that EMT plays a role in <d>IPF</d> and tumour metastasis. L1-CAM has also been linked to EMT during tumour development and tumour metastasis. Our aim was to determine prospectively the level of L1-CAM in <d>IPF</d> patients. METHODS: Forty consecutive Chinese patients with <d>IPF</d>, 16; LC, 12; and CC, 12, but no apparent lung or other organ's diseases were enrolled. Soluble L1-CAM <g>sL1</g>-CAM, TGF-b1, PDGF, y-INF levels in BALF and serum <g>sL1</g>-CAM were measured using ELISA. RESULTS: BALF <g>sL1</g>-CAM levels of <d>IPF</d>, LC and CC patients were 10.87        0.88   ng/mL, 6.34        0.67   ng/mL and 5.43        0.65   ng/mL, respectively. BALF <g>sL1</g>-CAM concentration of <d>IPF</d> patients was significantly higher than that in LC and in CC patients. Besides, serum <g>sL1</g>-CAM levels in patients with <d>IPF</d>, LC and CC were 9.60        1.41   ng/mL, 9.82        0.72   ng/mL and 5.41        1.07   ng/mL, respectively. The serum <g>sL1</g>-CAM levels in patients with <d>IPF</d> and LC were significantly higher than those in patients with CC P   <   0.001, respectively. CONCLUSIONS: The concentrations of <g>sL1</g>-CAM both in BALF and in serum of patients with <d>IPF</d> are markedly increased compared with controls. This indicates that L1-CAM might be involved in the pathogenesis of <d>IPF</d> as well as that of LC.
26610737|a|BACKGROUND AND OBJECTIVE: <d>IPF</d> is a form of <d>interstitial pneumonia</d> of unknown origin that has a poor prognosis for which current treatments are limited. Recent studies have shown that EMT plays a role in <d>IPF</d> and <d>tumour</d> metastasis. L1-CAM has also been linked to EMT during <d>tumour</d> development and <d>tumour</d> metastasis. Our aim was to determine prospectively the level of L1-CAM in <d>IPF</d> patients. METHODS: Forty consecutive Chinese patients with <d>IPF</d>, 16; LC, 12; and CC, 12, but no apparent lung or other organ's diseases were enrolled. Soluble L1-CAM <g>sL1</g>-CAM, TGF-b1, PDGF, y-INF levels in BALF and serum <g>sL1</g>-CAM were measured using ELISA. RESULTS: BALF <g>sL1</g>-CAM levels of <d>IPF</d>, LC and CC patients were 10.87        0.88   ng/mL, 6.34        0.67   ng/mL and 5.43        0.65   ng/mL, respectively. BALF <g>sL1</g>-CAM concentration of <d>IPF</d> patients was significantly higher than that in LC and in CC patients. Besides, serum <g>sL1</g>-CAM levels in patients with <d>IPF</d>, LC and CC were 9.60        1.41   ng/mL, 9.82        0.72   ng/mL and 5.41        1.07   ng/mL, respectively. The serum <g>sL1</g>-CAM levels in patients with <d>IPF</d> and LC were significantly higher than those in patients with CC P   <   0.001, respectively. CONCLUSIONS: The concentrations of <g>sL1</g>-CAM both in BALF and in serum of patients with <d>IPF</d> are markedly increased compared with controls. This indicates that L1-CAM might be involved in the pathogenesis of <d>IPF</d> as well as that of LC.
26675886|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive, fatal lung disease for which, thus far, there are no effective treatments. The pericarp of Citrus reticulata, as a traditional herbal drug, has been used for the clinical treatment of lung-related diseases in China for many years. In the present study, the amines from the pericarp of Citrus reticulata were isolated, and their hydrochlorides were prepared. The results of screening using cultured human embryonic lung fibroblasts hELFs revealed that, of the amines, 4-methoxyphenethylamine hydrochloride designated as amine hydrochloride 1 possessed the most potent inhibitory effect. Further in vivo experiments using a rat model of bleomycin-induced <d>pulmonary fibrosis</d> demonstrated that the oral administration of amine hydrochloride 1 significantly lowered the hydroxyproline content in both serum and lung tissue, and alleviated pulmonary alveolitis and fibrosis. Immunohistochemical analysis revealed that amine hydrochloride 1 exerted its inhibitory effect against IPF through the downregulation of lung transforming growth factor TGF-b1 protein expression. Our results demonstrated that amine hydrochloride 1 prevented the development of bleomycin  -induced lung fibrosis in rats. Thus, our data suggest that the amines from the pericarp of Citrus reticulata have therapeutic potential for use in the treatment of IPF.
26675886|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, fatal lung disease for which, thus far, there are no effective treatments. The pericarp of Citrus reticulata, as a traditional herbal drug, has been used for the clinical treatment of lung-related diseases in China for many years. In the present study, the amines from the pericarp of Citrus reticulata were isolated, and their hydrochlorides were prepared. The results of screening using cultured human embryonic lung fibroblasts hELFs revealed that, of the amines, 4-methoxyphenethylamine hydrochloride designated as amine hydrochloride 1 possessed the most potent inhibitory effect. Further in vivo experiments using a rat model of bleomycin-induced <d>pulmonary fibrosis</d> demonstrated that the oral administration of amine hydrochloride 1 significantly lowered the hydroxyproline content in both serum and lung tissue, and alleviated pulmonary alveolitis and fibrosis. Immunohistochemical analysis revealed that amine hydrochloride 1 exerted its inhibitory effect against <d>IPF</d> through the downregulation of lung transforming growth factor TGF-b1 protein expression. Our results demonstrated that amine hydrochloride 1 prevented the development of bleomycin  -induced lung fibrosis in rats. Thus, our data suggest that the amines from the pericarp of Citrus reticulata have therapeutic potential for use in the treatment of <d>IPF</d>.
26675886|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, fatal <d>lung disease</d> for which, thus far, there are no effective treatments. The pericarp of Citrus reticulata, as a traditional herbal drug, has been used for the clinical treatment of lung-related diseases in China for many years. In the present study, the amines from the pericarp of Citrus reticulata were isolated, and their hydrochlorides were prepared. The results of screening using cultured human embryonic lung fibroblasts hELFs revealed that, of the amines, 4-methoxyphenethylamine hydrochloride designated as amine hydrochloride 1 possessed the most potent inhibitory effect. Further in vivo experiments using a rat model of bleomycin-induced <d>pulmonary fibrosis</d> demonstrated that the oral administration of amine hydrochloride 1 significantly lowered the hydroxyproline content in both serum and lung tissue, and alleviated pulmonary alveolitis and fibrosis. Immunohistochemical analysis revealed that amine hydrochloride 1 exerted its inhibitory effect against <d>IPF</d> through the downregulation of lung transforming growth factor TGF-b1 protein expression. Our results demonstrated that amine hydrochloride 1 prevented the development of bleomycin  -induced lung fibrosis in rats. Thus, our data suggest that the amines from the pericarp of Citrus reticulata have therapeutic potential for use in the treatment of <d>IPF</d>.
26675886|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive, fatal <d>lung disease</d> for which, thus far, there are no effective treatments. The pericarp of Citrus reticulata, as a traditional herbal drug, has been used for the clinical treatment of lung-related diseases in China for many years. In the present study, the amines from the pericarp of Citrus reticulata were isolated, and their hydrochlorides were prepared. The results of screening using cultured human embryonic lung fibroblasts hELFs revealed that, of the amines, 4-methoxyphenethylamine hydrochloride designated as amine hydrochloride 1 possessed the most potent inhibitory effect. Further in vivo experiments using a rat model of bleomycin-induced <d>pulmonary fibrosis</d> demonstrated that the oral administration of amine hydrochloride 1 significantly lowered the hydroxyproline content in both serum and lung tissue, and alleviated <d>pulmonary alveolitis</d> and fibrosis. Immunohistochemical analysis revealed that amine hydrochloride 1 exerted its inhibitory effect against <d>IPF</d> through the downregulation of lung transforming growth factor TGF-b1 protein expression. Our results demonstrated that amine hydrochloride 1 prevented the development of bleomycin  -induced lung fibrosis in rats. Thus, our data suggest that the amines from the pericarp of Citrus reticulata have therapeutic potential for use in the treatment of <d>IPF</d>.
26675886|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive, fatal <d>lung disease</d> for which, thus far, there are no effective treatments. The pericarp of Citrus reticulata, as a traditional herbal drug, has been used for the clinical treatment of lung-related diseases in China for many years. In the present study, the amines from the pericarp of Citrus reticulata were isolated, and their hydrochlorides were prepared. The results of screening using cultured human embryonic lung fibroblasts hELFs revealed that, of the amines, 4-methoxyphenethylamine hydrochloride designated as amine hydrochloride 1 possessed the most potent inhibitory effect. Further in vivo experiments using a rat model of bleomycin-induced <d>pulmonary <d>fibrosis</d></d> demonstrated that the oral administration of amine hydrochloride 1 significantly lowered the hydroxyproline content in both serum and lung tissue, and alleviated <d>pulmonary alveolitis</d> and <d>fibrosis</d>. Immunohistochemical analysis revealed that amine hydrochloride 1 exerted its inhibitory effect against <d>IPF</d> through the downregulation of lung transforming growth factor TGF-b1 protein expression. Our results demonstrated that amine hydrochloride 1 prevented the development of bleomycin  -induced lung <d>fibrosis</d> in rats. Thus, our data suggest that the amines from the pericarp of Citrus reticulata have therapeutic potential for use in the treatment of <d>IPF</d>.
26709222|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a rare, progressive, and lethal interstitial lung disease with unknown etiology. Divergent observations have suggested that genetic factors contribute to IPF susceptibility. This study investigated the relationship between human leukocyte antigen HLA, cytokine gene polymorphisms, and IPF in a Chinese Han population. The gene polymorphisms of HLA-A, -B, -DRB1, tumor necrosis factor alpha [TNF-a -308 A/G], transforming growth factor beta [TGF-b1 +869 T/C], interleukin 10 [IL-10 -592 C/A, -819 T/C, and -1082 G/A], and interferon gamma [IFN-y +874 T/A] were detected in 102 individuals with IPF and 266 unrelated normal controls using PCR with sequence-specific primers and a high-resolution melt HRM approach. The data showed that there was no difference in HLA allele frequencies between the IPF and control groups. However, the data showed the frequency of HLA-A*02-DRB1*04 haplotype in the IPF group was significantly higher than that in the control group [odds ratio OR  =  4.69, 95% confidence interval CI  =  1.82-12.08, p  <  0.001]. In addition, no differences in the allele and genotype distributions of the cytokines were found between the IPF and control groups p  >  0.01. Our findings suggest that there is an association between specific HLA haplotype and IPF genetic susceptibility and that the genetic variability of some cytokines may not be involved in the pathogenesis of IPF.
26709222|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a rare, progressive, and lethal interstitial lung disease with unknown etiology. Divergent observations have suggested that genetic factors contribute to <d>IPF</d> susceptibility. This study investigated the relationship between human leukocyte antigen HLA, cytokine gene polymorphisms, and <d>IPF</d> in a Chinese Han population. The gene polymorphisms of HLA-A, -B, -DRB1, tumor necrosis factor alpha [TNF-a -308 A/G], transforming growth factor beta [TGF-b1 +869 T/C], interleukin 10 [IL-10 -592 C/A, -819 T/C, and -1082 G/A], and interferon gamma [IFN-y +874 T/A] were detected in 102 individuals with <d>IPF</d> and 266 unrelated normal controls using PCR with sequence-specific primers and a high-resolution melt HRM approach. The data showed that there was no difference in HLA allele frequencies between the <d>IPF</d> and control groups. However, the data showed the frequency of HLA-A*02-DRB1*04 haplotype in the <d>IPF</d> group was significantly higher than that in the control group [odds ratio OR  =  4.69, 95% confidence interval CI  =  1.82-12.08, p  <  0.001]. In addition, no differences in the allele and genotype distributions of the cytokines were found between the <d>IPF</d> and control groups p  >  0.01. Our findings suggest that there is an association between specific HLA haplotype and <d>IPF</d> genetic susceptibility and that the genetic variability of some cytokines may not be involved in the pathogenesis of <d>IPF</d>.
26709222|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a rare, progressive, and lethal <d>interstitial lung disease</d> with unknown etiology. Divergent observations have suggested that genetic factors contribute to <d>IPF</d> susceptibility. This study investigated the relationship between human leukocyte antigen HLA, cytokine gene polymorphisms, and <d>IPF</d> in a Chinese Han population. The gene polymorphisms of HLA-A, -B, -DRB1, tumor necrosis factor alpha [TNF-a -308 A/G], transforming growth factor beta [TGF-b1 +869 T/C], interleukin 10 [IL-10 -592 C/A, -819 T/C, and -1082 G/A], and interferon gamma [IFN-y +874 T/A] were detected in 102 individuals with <d>IPF</d> and 266 unrelated normal controls using PCR with sequence-specific primers and a high-resolution melt HRM approach. The data showed that there was no difference in HLA allele frequencies between the <d>IPF</d> and control groups. However, the data showed the frequency of HLA-A*02-DRB1*04 haplotype in the <d>IPF</d> group was significantly higher than that in the control group [odds ratio OR  =  4.69, 95% confidence interval CI  =  1.82-12.08, p  <  0.001]. In addition, no differences in the allele and genotype distributions of the cytokines were found between the <d>IPF</d> and control groups p  >  0.01. Our findings suggest that there is an association between specific HLA haplotype and <d>IPF</d> genetic susceptibility and that the genetic variability of some cytokines may not be involved in the pathogenesis of <d>IPF</d>.
26787543|a|Idiopathic pulmonary fibrosis <d>IPF</d> is a chronic, progressive, and highly lethal fibrotic lung disease with unknown cause or cure. Although some microRNAs miRNAs, such as <g>miR-26a</g> and <g>let-7d</g>, have been confirmed, the contribution to the pathophysiological processes of <d>IPF</d>, the roles of miRNAs and intrinsic links between them in fibrotic lung diseases are not yet well understood. In this study, we found that <g>Lin28B</g> could induce the process of epithelial-mesenchymal transition EMT by inhibiting <g>let-7d</g>, whereas inhibition of <g>Lin28B</g> mitigated TGF-b1-induced fibrogenesis and attenuated EMT in both cultured A549 cells and MLE-12 cells. More importantly, over-expression of <g>miR-26a</g> could simultaneously enhance the expression of <g>let-7d</g> in A549 cells, and further study confirmed that <g>Lin28B</g> was one of the direct targets of <g>miR-26a</g>, which mediates, at least in part, the regulatory effects of <g>miR-26a</g> on the biogenesis of <g>let-7d</g>. Finally, we constructed a regulatory network among miRNAs involved in the progression of <d>IPF</d>. Taken together, our study deciphered the essential role of <g>Lin28B</g> in the pathogenesis of EMT, and unraveled a novel mechanism that <g>miR-26a</g> is a modulator of <g>let-7d</g>. This study also defines the miRNAs network involved in <d>IPF</d>, which may have implications for developing new strategies for pulmonary fibrosis. KEY MESSAGE: Upregulation of <g>Lin28B</g> contributes to idiopathic pulmonary fibrosis. <g>Lin28B</g> causes epithelial-mesenchymal transition EMT by inhibition of <g>let-7d</g>. <g>Lin28B</g> is one of the targets of microRNA-26a. <g>miR-26a</g> enhances the expression of <g>let-7d</g> via targeting regulation of <g>Lin28B</g>. A regulatory network among miRNAs involved in the progression of <d>IPF</d>.
26787543|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and highly lethal fibrotic lung disease with unknown cause or cure. Although some microRNAs miRNAs, such as <g>miR-26a</g> and <g>let-7d</g>, have been confirmed, the contribution to the pathophysiological processes of <d>IPF</d>, the roles of miRNAs and intrinsic links between them in fibrotic lung diseases are not yet well understood. In this study, we found that <g>Lin28B</g> could induce the process of epithelial-mesenchymal transition EMT by inhibiting <g>let-7d</g>, whereas inhibition of <g>Lin28B</g> mitigated TGF-b1-induced fibrogenesis and attenuated EMT in both cultured A549 cells and MLE-12 cells. More importantly, over-expression of <g>miR-26a</g> could simultaneously enhance the expression of <g>let-7d</g> in A549 cells, and further study confirmed that <g>Lin28B</g> was one of the direct targets of <g>miR-26a</g>, which mediates, at least in part, the regulatory effects of <g>miR-26a</g> on the biogenesis of <g>let-7d</g>. Finally, we constructed a regulatory network among miRNAs involved in the progression of <d>IPF</d>. Taken together, our study deciphered the essential role of <g>Lin28B</g> in the pathogenesis of EMT, and unraveled a novel mechanism that <g>miR-26a</g> is a modulator of <g>let-7d</g>. This study also defines the miRNAs network involved in <d>IPF</d>, which may have implications for developing new strategies for pulmonary fibrosis. KEY MESSAGE: Upregulation of <g>Lin28B</g> contributes to idiopathic pulmonary fibrosis. <g>Lin28B</g> causes epithelial-mesenchymal transition EMT by inhibition of <g>let-7d</g>. <g>Lin28B</g> is one of the targets of microRNA-26a. <g>miR-26a</g> enhances the expression of <g>let-7d</g> via targeting regulation of <g>Lin28B</g>. A regulatory network among miRNAs involved in the progression of <d>IPF</d>.
26787543|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive, and highly lethal <d>fibrotic lung disease</d> with unknown cause or cure. Although some microRNAs miRNAs, such as <g>miR-26a</g> and <g>let-7d</g>, have been confirmed, the contribution to the pathophysiological processes of <d>IPF</d>, the roles of miRNAs and intrinsic links between them in <d>fibrotic lung disease</d>s are not yet well understood. In this study, we found that <g>Lin28B</g> could induce the process of epithelial-mesenchymal transition EMT by inhibiting <g>let-7d</g>, whereas inhibition of <g>Lin28B</g> mitigated TGF-b1-induced fibrogenesis and attenuated EMT in both cultured A549 cells and MLE-12 cells. More importantly, over-expression of <g>miR-26a</g> could simultaneously enhance the expression of <g>let-7d</g> in A549 cells, and further study confirmed that <g>Lin28B</g> was one of the direct targets of <g>miR-26a</g>, which mediates, at least in part, the regulatory effects of <g>miR-26a</g> on the biogenesis of <g>let-7d</g>. Finally, we constructed a regulatory network among miRNAs involved in the progression of <d>IPF</d>. Taken together, our study deciphered the essential role of <g>Lin28B</g> in the pathogenesis of EMT, and unraveled a novel mechanism that <g>miR-26a</g> is a modulator of <g>let-7d</g>. This study also defines the miRNAs network involved in <d>IPF</d>, which may have implications for developing new strategies for pulmonary fibrosis. KEY MESSAGE: Upregulation of <g>Lin28B</g> contributes to idiopathic pulmonary fibrosis. <g>Lin28B</g> causes epithelial-mesenchymal transition EMT by inhibition of <g>let-7d</g>. <g>Lin28B</g> is one of the targets of microRNA-26a. <g>miR-26a</g> enhances the expression of <g>let-7d</g> via targeting regulation of <g>Lin28B</g>. A regulatory network among miRNAs involved in the progression of <d>IPF</d>.
26787543|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a chronic, progressive, and highly lethal <d>fibrotic lung disease</d> with unknown cause or cure. Although some microRNAs miRNAs, such as <g>miR-26a</g> and <g>let-7d</g>, have been confirmed, the contribution to the pathophysiological processes of <d>IPF</d>, the roles of miRNAs and intrinsic links between them in <d>fibrotic lung disease</d>s are not yet well understood. In this study, we found that <g>Lin28B</g> could induce the process of epithelial-mesenchymal transition EMT by inhibiting <g>let-7d</g>, whereas inhibition of <g>Lin28B</g> mitigated <g>TGF-b1</g>-induced fibrogenesis and attenuated EMT in both cultured A549 cells and MLE-12 cells. More importantly, over-expression of <g>miR-26a</g> could simultaneously enhance the expression of <g>let-7d</g> in A549 cells, and further study confirmed that <g>Lin28B</g> was one of the direct targets of <g>miR-26a</g>, which mediates, at least in part, the regulatory effects of <g>miR-26a</g> on the biogenesis of <g>let-7d</g>. Finally, we constructed a regulatory network among miRNAs involved in the progression of <d>IPF</d>. Taken together, our study deciphered the essential role of <g>Lin28B</g> in the pathogenesis of EMT, and unraveled a novel mechanism that <g>miR-26a</g> is a modulator of <g>let-7d</g>. This study also defines the miRNAs network involved in <d>IPF</d>, which may have implications for developing new strategies for <d>pulmonary fibrosis</d>. KEY MESSAGE: Upregulation of <g>Lin28B</g> contributes to idiopathic <d>pulmonary fibrosis</d>. <g>Lin28B</g> causes epithelial-mesenchymal transition EMT by inhibition of <g>let-7d</g>. <g>Lin28B</g> is one of the targets of microRNA-26a. <g>miR-26a</g> enhances the expression of <g>let-7d</g> via targeting regulation of <g>Lin28B</g>. A regulatory network among miRNAs involved in the progression of <d>IPF</d>.
26846484|a|Idiopathic pulmonary fibrosis IPF is characterized by progressive interstitial fibrosis, and is associated with a fatal outcome. The critical pathological mechanisms underlying IPF are largely unknown; however, accumulating evidence has indicated similarities between IPF and cancer. Therefore, the present study examined the expression levels of the <d>tumor</d> suppressor phosphatase and tensin homolog deleted on chromosome 10 PTEN in Chinese patients with IPF, using an enzyme  -linked immunosorbent assay. To determine the effects of PTEN on the development of pulmonary fibrosis, PTEN was overexpressed in transforming growth factor TGF  -b1  -treated human embryonic lung fibroblasts HFL  -I cells. The serum levels of PTEN were significantly lower in 42 patients with IPF, as compared with in the healthy controls. In addition, PTEN overexpression enhanced apoptosis, and suppressed basal levels of proliferation and migration in fibroblasts. Notably, PTEN was able to specifically inhibit TGF  -b1  -induced proliferation and migration of the cells. Overexpression of PTEN also suppressed phosphorylation of Akt and Smad3, and decreased the expression levels of numerous proteins with critical roles in TGF  -b1  -induced fibrosis, including a  -smooth muscle actin, matrix metalloproteinase MMP  -2 and MMP  -9. These results indicated that PTEN may inhibit TGF  -b1  -mediated myofibroblast differentiation of fibroblasts by attenuating signaling via the phosphatidylinositol 3  -kinase/Akt and TGF  -b/Smad3 pathways.
26846484|a|<d>Idiopathic pulmonary fibrosis</d> IPF is characterized by progressive interstitial fibrosis, and is associated with a fatal outcome. The critical pathological mechanisms underlying IPF are largely unknown; however, accumulating evidence has indicated similarities between IPF and cancer. Therefore, the present study examined the expression levels of the <d>tumor</d> suppressor phosphatase and tensin homolog deleted on chromosome 10 <g>PTEN</g> in Chinese patients with IPF, using an enzyme  -linked immunosorbent assay. To determine the effects of <g>PTEN</g> on the development of pulmonary fibrosis, <g>PTEN</g> was overexpressed in transforming growth factor TGF  -b1  -treated human embryonic lung fibroblasts HFL  -I cells. The serum levels of <g>PTEN</g> were significantly lower in 42 patients with IPF, as compared with in the healthy controls. In addition, <g>PTEN</g> overexpression enhanced apoptosis, and suppressed basal levels of proliferation and migration in fibroblasts. Notably, <g>PTEN</g> was able to specifically inhibit TGF  -b1  -induced proliferation and migration of the cells. Overexpression of <g>PTEN</g> also suppressed phosphorylation of Akt and Smad3, and decreased the expression levels of numerous proteins with critical roles in TGF  -b1  -induced fibrosis, including a  -smooth muscle actin, matrix metalloproteinase MMP  -2 and MMP  -9. These results indicated that <g>PTEN</g> may inhibit TGF  -b1  -mediated myofibroblast differentiation of fibroblasts by attenuating signaling via the phosphatidylinositol 3  -kinase/Akt and TGF  -b/Smad3 pathways.
26846484|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by progressive interstitial fibrosis, and is associated with a fatal outcome. The critical pathological mechanisms underlying <d>IPF</d> are largely unknown; however, accumulating evidence has indicated similarities between <d>IPF</d> and cancer. Therefore, the present study examined the expression levels of the <d>tumor</d> suppressor phosphatase and tensin homolog deleted on chromosome 10 <g>PTEN</g> in Chinese patients with <d>IPF</d>, using an enzyme  -linked immunosorbent assay. To determine the effects of <g>PTEN</g> on the development of pulmonary fibrosis, <g>PTEN</g> was overexpressed in transforming growth factor TGF  -b1  -treated human embryonic lung fibroblasts HFL  -I cells. The serum levels of <g>PTEN</g> were significantly lower in 42 patients with <d>IPF</d>, as compared with in the healthy controls. In addition, <g>PTEN</g> overexpression enhanced apoptosis, and suppressed basal levels of proliferation and migration in fibroblasts. Notably, <g>PTEN</g> was able to specifically inhibit TGF  -b1  -induced proliferation and migration of the cells. Overexpression of <g>PTEN</g> also suppressed phosphorylation of Akt and Smad3, and decreased the expression levels of numerous proteins with critical roles in TGF  -b1  -induced fibrosis, including a  -smooth muscle actin, matrix metalloproteinase MMP  -2 and MMP  -9. These results indicated that <g>PTEN</g> may inhibit TGF  -b1  -mediated myofibroblast differentiation of fibroblasts by attenuating signaling via the phosphatidylinositol 3  -kinase/Akt and TGF  -b/Smad3 pathways.
26846484|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by progressive <d>interstitial fibrosis</d>, and is associated with a fatal outcome. The critical pathological mechanisms underlying <d>IPF</d> are largely unknown; however, accumulating evidence has indicated similarities between <d>IPF</d> and cancer. Therefore, the present study examined the expression levels of the <d>tumor</d> suppressor phosphatase and tensin homolog deleted on chromosome 10 <g>PTEN</g> in Chinese patients with <d>IPF</d>, using an enzyme  -linked immunosorbent assay. To determine the effects of <g>PTEN</g> on the development of pulmonary fibrosis, <g>PTEN</g> was overexpressed in transforming growth factor TGF  -b1  -treated human embryonic lung fibroblasts HFL  -I cells. The serum levels of <g>PTEN</g> were significantly lower in 42 patients with <d>IPF</d>, as compared with in the healthy controls. In addition, <g>PTEN</g> overexpression enhanced apoptosis, and suppressed basal levels of proliferation and migration in fibroblasts. Notably, <g>PTEN</g> was able to specifically inhibit TGF  -b1  -induced proliferation and migration of the cells. Overexpression of <g>PTEN</g> also suppressed phosphorylation of Akt and Smad3, and decreased the expression levels of numerous proteins with critical roles in TGF  -b1  -induced fibrosis, including a  -smooth muscle actin, matrix metalloproteinase MMP  -2 and MMP  -9. These results indicated that <g>PTEN</g> may inhibit TGF  -b1  -mediated myofibroblast differentiation of fibroblasts by attenuating signaling via the phosphatidylinositol 3  -kinase/Akt and TGF  -b/Smad3 pathways.
26846484|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by progressive <d>interstitial fibrosis</d>, and is associated with a fatal outcome. The critical pathological mechanisms underlying <d>IPF</d> are largely unknown; however, accumulating evidence has indicated similarities between <d>IPF</d> and <d>cancer</d>. Therefore, the present study examined the expression levels of the <d>tumor</d> suppressor phosphatase and tensin homolog deleted on chromosome 10 <g>PTEN</g> in Chinese patients with <d>IPF</d>, using an enzyme  -linked immunosorbent assay. To determine the effects of <g>PTEN</g> on the development of pulmonary fibrosis, <g>PTEN</g> was overexpressed in transforming growth factor TGF  -b1  -treated human embryonic lung fibroblasts HFL  -I cells. The serum levels of <g>PTEN</g> were significantly lower in 42 patients with <d>IPF</d>, as compared with in the healthy controls. In addition, <g>PTEN</g> overexpression enhanced apoptosis, and suppressed basal levels of proliferation and migration in fibroblasts. Notably, <g>PTEN</g> was able to specifically inhibit TGF  -b1  -induced proliferation and migration of the cells. Overexpression of <g>PTEN</g> also suppressed phosphorylation of Akt and Smad3, and decreased the expression levels of numerous proteins with critical roles in TGF  -b1  -induced fibrosis, including a  -smooth muscle actin, matrix metalloproteinase MMP  -2 and MMP  -9. These results indicated that <g>PTEN</g> may inhibit TGF  -b1  -mediated myofibroblast differentiation of fibroblasts by attenuating signaling via the phosphatidylinositol 3  -kinase/Akt and TGF  -b/Smad3 pathways.
26846484|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is characterized by progressive <d>interstitial fibrosis</d>, and is associated with a fatal outcome. The critical pathological mechanisms underlying <d>IPF</d> are largely unknown; however, accumulating evidence has indicated similarities between <d>IPF</d> and <d>cancer</d>. Therefore, the present study examined the expression levels of the <d>tumor</d> suppressor phosphatase and tensin homolog deleted on chromosome 10 <g>PTEN</g> in Chinese patients with <d>IPF</d>, using an enzyme  -linked immunosorbent assay. To determine the effects of <g>PTEN</g> on the development of <d>pulmonary fibrosis</d>, <g>PTEN</g> was overexpressed in transforming growth factor TGF  -b1  -treated human embryonic lung fibroblasts HFL  -I cells. The serum levels of <g>PTEN</g> were significantly lower in 42 patients with <d>IPF</d>, as compared with in the healthy controls. In addition, <g>PTEN</g> overexpression enhanced apoptosis, and suppressed basal levels of proliferation and migration in fibroblasts. Notably, <g>PTEN</g> was able to specifically inhibit TGF  -b1  -induced proliferation and migration of the cells. Overexpression of <g>PTEN</g> also suppressed phosphorylation of Akt and Smad3, and decreased the expression levels of numerous proteins with critical roles in TGF  -b1  -induced fibrosis, including a  -smooth muscle actin, matrix metalloproteinase MMP  -2 and MMP  -9. These results indicated that <g>PTEN</g> may inhibit TGF  -b1  -mediated myofibroblast differentiation of fibroblasts by attenuating signaling via the phosphatidylinositol 3  -kinase/Akt and TGF  -b/Smad3 pathways.
26846484|a|<d>Idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d> is characterized by progressive <d>interstitial <d>fibrosis</d></d>, and is associated with a fatal outcome. The critical pathological mechanisms underlying <d>IPF</d> are largely unknown; however, accumulating evidence has indicated similarities between <d>IPF</d> and <d>cancer</d>. Therefore, the present study examined the expression levels of the <d>tumor</d> suppressor phosphatase and tensin homolog deleted on chromosome 10 <g>PTEN</g> in Chinese patients with <d>IPF</d>, using an enzyme  -linked immunosorbent assay. To determine the effects of <g>PTEN</g> on the development of <d>pulmonary <d>fibrosis</d></d>, <g>PTEN</g> was overexpressed in transforming growth factor <g>TGF  -b1</g>  -treated human embryonic lung fibroblasts HFL  -I cells. The serum levels of <g>PTEN</g> were significantly lower in 42 patients with <d>IPF</d>, as compared with in the healthy controls. In addition, <g>PTEN</g> overexpression enhanced apoptosis, and suppressed basal levels of proliferation and migration in fibroblasts. Notably, <g>PTEN</g> was able to specifically inhibit <g>TGF  -b1</g>  -induced proliferation and migration of the cells. Overexpression of <g>PTEN</g> also suppressed phosphorylation of <g>Akt</g> and <g>Smad3</g>, and decreased the expression levels of numerous proteins with critical roles in <g>TGF  -b1</g>  -induced <d>fibrosis</d>, including a  -smooth muscle actin, matrix metalloproteinase MMP  -2 and MMP  -9. These results indicated that <g>PTEN</g> may inhibit <g>TGF  -b1</g>  -mediated myofibroblast differentiation of fibroblasts by attenuating signaling via the phosphatidylinositol 3  -kinase/<g>Akt</g> and TGF  -b/<g>Smad3</g> pathways.
26861876|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive fibrotic lung disease with high mortality. Active TGFb1 is considered central to the pathogenesis of IPF. A major mechanism of TGFb1 activation in the lung involves the epithelially restricted avb6 integrin. Expression of the avb6 integrin is dramatically increased in IPF. How avb6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the b6 subunit gene ITGB6 promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein Elk1 Elk1 and the glucocorticoid receptor GR. Both Elk1 and GR can regulate avb6 integrin expression in vitro We demonstrate Elk1 binding to the ITGB6 promoter basally and that manipulation of Elk1 or Elk1 binding alters ITGB6 promoter activity, gene transcription, and avb6 integrin expression. Crucially, we find that loss of Elk1 causes enhanced Itgb6 expression and exaggerated lung fibrosis in an in vivo model of fibrosis, whereas the GR agonist dexamethasone inhibits Itgb6 expression. Moreover, Elk1 dysregulation is present in epithelium from patients with IPF. These data reveal a novel role for Elk1 regulating ITGB6 expression and highlight how dysregulation of Elk1 can contribute to human disease.
26861876|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive fibrotic lung disease with high mortality. Active TGFb1 is considered central to the pathogenesis of <d>IPF</d>. A major mechanism of TGFb1 activation in the lung involves the epithelially restricted avb6 integrin. Expression of the avb6 integrin is dramatically increased in <d>IPF</d>. How avb6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the b6 subunit gene ITGB6 promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein Elk1 Elk1 and the glucocorticoid receptor GR. Both Elk1 and GR can regulate avb6 integrin expression in vitro We demonstrate Elk1 binding to the ITGB6 promoter basally and that manipulation of Elk1 or Elk1 binding alters ITGB6 promoter activity, gene transcription, and avb6 integrin expression. Crucially, we find that loss of Elk1 causes enhanced Itgb6 expression and exaggerated lung fibrosis in an in vivo model of fibrosis, whereas the GR agonist dexamethasone inhibits Itgb6 expression. Moreover, Elk1 dysregulation is present in epithelium from patients with <d>IPF</d>. These data reveal a novel role for Elk1 regulating ITGB6 expression and highlight how dysregulation of Elk1 can contribute to human disease.
26861876|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> with high mortality. Active TGFb1 is considered central to the pathogenesis of <d>IPF</d>. A major mechanism of TGFb1 activation in the lung involves the epithelially restricted avb6 integrin. Expression of the avb6 integrin is dramatically increased in <d>IPF</d>. How avb6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the b6 subunit gene ITGB6 promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein Elk1 Elk1 and the glucocorticoid receptor GR. Both Elk1 and GR can regulate avb6 integrin expression in vitro We demonstrate Elk1 binding to the ITGB6 promoter basally and that manipulation of Elk1 or Elk1 binding alters ITGB6 promoter activity, gene transcription, and avb6 integrin expression. Crucially, we find that loss of Elk1 causes enhanced Itgb6 expression and exaggerated lung fibrosis in an in vivo model of fibrosis, whereas the GR agonist dexamethasone inhibits Itgb6 expression. Moreover, Elk1 dysregulation is present in epithelium from patients with <d>IPF</d>. These data reveal a novel role for Elk1 regulating ITGB6 expression and highlight how dysregulation of Elk1 can contribute to human disease.
26861876|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> with high mortality. Active <g>TGFb1</g> is considered central to the pathogenesis of <d>IPF</d>. A major mechanism of <g>TGFb1</g> activation in the lung involves the epithelially restricted avb6 integrin. Expression of the avb6 integrin is dramatically increased in <d>IPF</d>. How avb6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the b6 subunit gene <g>ITGB6</g> promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein <g>Elk1</g> <g>Elk1</g> and the <g>glucocorticoid receptor</g> <g>GR</g>. Both <g>Elk1</g> and <g>GR</g> can regulate avb6 integrin expression in vitro We demonstrate <g>Elk1</g> binding to the <g>ITGB6</g> promoter basally and that manipulation of <g>Elk1</g> or <g>Elk1</g> binding alters <g>ITGB6</g> promoter activity, gene transcription, and avb6 integrin expression. Crucially, we find that loss of <g>Elk1</g> causes enhanced <g>Itgb6</g> expression and exaggerated <d>lung fibrosis</d> in an in vivo model of fibrosis, whereas the <g>GR</g> agonist dexamethasone inhibits <g>Itgb6</g> expression. Moreover, <g>Elk1</g> dysregulation is present in epithelium from patients with <d>IPF</d>. These data reveal a novel role for <g>Elk1</g> regulating <g>ITGB6</g> expression and highlight how dysregulation of <g>Elk1</g> can contribute to human disease.
26861876|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive <d>fibrotic lung disease</d> with high mortality. Active <g>TGFb1</g> is considered central to the pathogenesis of <d>IPF</d>. A major mechanism of <g>TGFb1</g> activation in the lung involves the epithelially restricted avb6 integrin. Expression of the avb6 integrin is dramatically increased in <d>IPF</d>. How avb6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the b6 subunit gene <g>ITGB6</g> promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein <g>Elk1</g> <g>Elk1</g> and the <g>glucocorticoid receptor</g> <g>GR</g>. Both <g>Elk1</g> and <g>GR</g> can regulate avb6 integrin expression in vitro We demonstrate <g>Elk1</g> binding to the <g>ITGB6</g> promoter basally and that manipulation of <g>Elk1</g> or <g>Elk1</g> binding alters <g>ITGB6</g> promoter activity, gene transcription, and avb6 integrin expression. Crucially, we find that loss of <g>Elk1</g> causes enhanced <g>Itgb6</g> expression and exaggerated <d>lung <d>fibrosis</d></d> in an in vivo model of <d>fibrosis</d>, whereas the <g>GR</g> agonist dexamethasone inhibits <g>Itgb6</g> expression. Moreover, <g>Elk1</g> dysregulation is present in epithelium from patients with <d>IPF</d>. These data reveal a novel role for <g>Elk1</g> regulating <g>ITGB6</g> expression and highlight how dysregulation of <g>Elk1</g> can contribute to human disease.
26867691|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and fatal interstitial lung disease. IPF is characterized by epithelial cell injury and reprogramming, increases in myofibroblasts, and altered deposition of extracellular matrix. The Wnt1-inducible signaling protein 1 <g>WISP1</g> is involved in impaired epithelial-mesenchymal crosstalk in pulmonary fibrosis. Here, we aimed to further investigate <g>WISP1</g> regulation and function in primary human lung fibroblasts phLFs. We demonstrate that <g>WISP1</g> is directly upregulated by Transforming growth factor b1 TGFb1 and Tumor necrosis factor a TNFa in phLFs, using a luciferase-based reporter system. <g>WISP1</g> mRNA and protein secretion increased in a time- and concentration-dependent manner by TGFb1 and TNFa in phLFs, as analysed by qPCR and ELISA, respectively. Notably, <g>WISP1</g> is required for TGFb1- and TNFa-dependent induction of interleukin 6 <g>IL-6</g>, a mechanism that is conserved in IPF phLFs. The siRNA-mediated <g>WISP1</g> knockdown led to a significant <g>IL-6</g> reduction after TGFb1 or TNFa stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of <g>WISP1</g> reduced phLFs proliferation, a process that was in part rescued by <g>IL-6</g>. Taken together, these results strongly indicate that <g>WISP1</g>-induced <g>IL-6</g> expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFb1 and TNFa.
26867691|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal interstitial lung disease. <d>IPF</d> is characterized by epithelial cell injury and reprogramming, increases in myofibroblasts, and altered deposition of extracellular matrix. The Wnt1-inducible signaling protein 1 <g>WISP1</g> is involved in impaired epithelial-mesenchymal crosstalk in pulmonary fibrosis. Here, we aimed to further investigate <g>WISP1</g> regulation and function in primary human lung fibroblasts phLFs. We demonstrate that <g>WISP1</g> is directly upregulated by Transforming growth factor b1 TGFb1 and Tumor necrosis factor a TNFa in phLFs, using a luciferase-based reporter system. <g>WISP1</g> mRNA and protein secretion increased in a time- and concentration-dependent manner by TGFb1 and TNFa in phLFs, as analysed by qPCR and ELISA, respectively. Notably, <g>WISP1</g> is required for TGFb1- and TNFa-dependent induction of interleukin 6 <g>IL-6</g>, a mechanism that is conserved in <d>IPF</d> phLFs. The siRNA-mediated <g>WISP1</g> knockdown led to a significant <g>IL-6</g> reduction after TGFb1 or TNFa stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of <g>WISP1</g> reduced phLFs proliferation, a process that was in part rescued by <g>IL-6</g>. Taken together, these results strongly indicate that <g>WISP1</g>-induced <g>IL-6</g> expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFb1 and TNFa.
26867691|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal <d>interstitial lung disease</d>. <d>IPF</d> is characterized by epithelial cell injury and reprogramming, increases in myofibroblasts, and altered deposition of extracellular matrix. The Wnt1-inducible signaling protein 1 <g>WISP1</g> is involved in impaired epithelial-mesenchymal crosstalk in pulmonary fibrosis. Here, we aimed to further investigate <g>WISP1</g> regulation and function in primary human lung fibroblasts phLFs. We demonstrate that <g>WISP1</g> is directly upregulated by Transforming growth factor b1 TGFb1 and Tumor necrosis factor a TNFa in phLFs, using a luciferase-based reporter system. <g>WISP1</g> mRNA and protein secretion increased in a time- and concentration-dependent manner by TGFb1 and TNFa in phLFs, as analysed by qPCR and ELISA, respectively. Notably, <g>WISP1</g> is required for TGFb1- and TNFa-dependent induction of interleukin 6 <g>IL-6</g>, a mechanism that is conserved in <d>IPF</d> phLFs. The siRNA-mediated <g>WISP1</g> knockdown led to a significant <g>IL-6</g> reduction after TGFb1 or TNFa stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of <g>WISP1</g> reduced phLFs proliferation, a process that was in part rescued by <g>IL-6</g>. Taken together, these results strongly indicate that <g>WISP1</g>-induced <g>IL-6</g> expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFb1 and TNFa.
26867691|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and fatal <d>interstitial lung disease</d>. <d>IPF</d> is characterized by epithelial cell injury and reprogramming, increases in myofibroblasts, and altered deposition of extracellular matrix. The <g>Wnt1-inducible signaling protein 1</g> <g>WISP1</g> is involved in <d>impaired epithelial-mesenchymal crosstalk</d> in pulmonary fibrosis. Here, we aimed to further investigate <g>WISP1</g> regulation and function in primary human lung fibroblasts phLFs. We demonstrate that <g>WISP1</g> is directly upregulated by Transforming growth factor b1 TGFb1 and Tumor necrosis factor a TNFa in phLFs, using a luciferase-based reporter system. <g>WISP1</g> mRNA and protein secretion increased in a time- and concentration-dependent manner by TGFb1 and TNFa in phLFs, as analysed by qPCR and ELISA, respectively. Notably, <g>WISP1</g> is required for TGFb1- and TNFa-dependent induction of interleukin 6 <g>IL-6</g>, a mechanism that is conserved in <d>IPF</d> phLFs. The siRNA-mediated <g>WISP1</g> knockdown led to a significant <g>IL-6</g> reduction after TGFb1 or TNFa stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of <g>WISP1</g> reduced phLFs proliferation, a process that was in part rescued by <g>IL-6</g>. Taken together, these results strongly indicate that <g>WISP1</g>-induced <g>IL-6</g> expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFb1 and TNFa.
26867691|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive and fatal <d>interstitial lung disease</d>. <d>IPF</d> is characterized by epithelial cell injury and reprogramming, increases in myofibroblasts, and altered deposition of extracellular matrix. The <g>Wnt1-inducible signaling protein 1</g> <g>WISP1</g> is involved in <d>impaired epithelial-mesenchymal crosstalk</d> in <d>pulmonary fibrosis</d>. Here, we aimed to further investigate <g>WISP1</g> regulation and function in primary human lung fibroblasts phLFs. We demonstrate that <g>WISP1</g> is directly upregulated by Transforming growth factor b1 TGFb1 and Tumor necrosis factor a TNFa in phLFs, using a luciferase-based reporter system. <g>WISP1</g> mRNA and protein secretion increased in a time- and concentration-dependent manner by TGFb1 and TNFa in phLFs, as analysed by qPCR and ELISA, respectively. Notably, <g>WISP1</g> is required for TGFb1- and TNFa-dependent induction of interleukin 6 <g>IL-6</g>, a mechanism that is conserved in <d>IPF</d> phLFs. The siRNA-mediated <g>WISP1</g> knockdown led to a significant <g>IL-6</g> reduction after TGFb1 or TNFa stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of <g>WISP1</g> reduced phLFs proliferation, a process that was in part rescued by <g>IL-6</g>. Taken together, these results strongly indicate that <g>WISP1</g>-induced <g>IL-6</g> expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFb1 and TNFa.
26883801|a|<g>C/EBP homologous protein</g> <g>Chop</g> has been shown to have altered expression in patients with <d>idiopathic pulmonary fibrosis</d> IPF, but its exact role in IPF pathoaetiology has not been fully addressed. Studies conducted in patients with IPF and <g>Chop</g>-/- mice have dissected the role of <g>Chop</g> and endoplasmic reticulum ER stress in pulmonary fibrosis pathogenesis. The effect of <g>Chop</g> deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with IPF and mice with bleomycin BLM-induced pulmonary fibrosis were affected by the altered <g>Chop</g> expression and ER stress. In particular, <g>Chop</g> deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of <g>Chop</g> significantly attenuated transforming growth factor b TGF-b production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that <g>Chop</g> deficiency repressed the M2 program in macrophages, which then attenuated TGF-b secretion. Specifically, loss of <g>Chop</g> promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which <g>Chop</g> deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that <g>Chop</g> and ER stress are implicated in IPF pathoaetiology, involving at least the induction and differentiation of M2 macrophages.
26883801|a|<g>C/EBP homologous protein</g> <g>Chop</g> has been shown to have altered expression in patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, but its exact role in <d>IPF</d> pathoaetiology has not been fully addressed. Studies conducted in patients with <d>IPF</d> and <g>Chop</g>-/- mice have dissected the role of <g>Chop</g> and endoplasmic reticulum ER stress in pulmonary fibrosis pathogenesis. The effect of <g>Chop</g> deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with <d>IPF</d> and mice with bleomycin BLM-induced pulmonary fibrosis were affected by the altered <g>Chop</g> expression and ER stress. In particular, <g>Chop</g> deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of <g>Chop</g> significantly attenuated transforming growth factor b TGF-b production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that <g>Chop</g> deficiency repressed the M2 program in macrophages, which then attenuated TGF-b secretion. Specifically, loss of <g>Chop</g> promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which <g>Chop</g> deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that <g>Chop</g> and ER stress are implicated in <d>IPF</d> pathoaetiology, involving at least the induction and differentiation of M2 macrophages.
26883801|a|<g>C/EBP homologous protein</g> <g>Chop</g> has been shown to have altered expression in patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, but its exact role in <d>IPF</d> pathoaetiology has not been fully addressed. Studies conducted in patients with <d>IPF</d> and <g>Chop</g>-/- mice have dissected the role of <g>Chop</g> and endoplasmic reticulum ER stress in <d>pulmonary fibrosis</d> pathogenesis. The effect of <g>Chop</g> deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with <d>IPF</d> and mice with bleomycin BLM-induced <d>pulmonary fibrosis</d> were affected by the altered <g>Chop</g> expression and ER stress. In particular, <g>Chop</g> deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of <g>Chop</g> significantly attenuated transforming growth factor b TGF-b production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that <g>Chop</g> deficiency repressed the M2 program in macrophages, which then attenuated TGF-b secretion. Specifically, loss of <g>Chop</g> promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which <g>Chop</g> deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that <g>Chop</g> and ER stress are implicated in <d>IPF</d> pathoaetiology, involving at least the induction and differentiation of M2 macrophages.
26883801|a|<g>C/EBP homologous protein</g> <g>Chop</g> has been shown to have altered expression in patients with <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>, but its exact role in <d>IPF</d> pathoaetiology has not been fully addressed. Studies conducted in patients with <d>IPF</d> and <g>Chop</g>-/- mice have dissected the role of <g>Chop</g> and endoplasmic reticulum ER stress in <d>pulmonary fibrosis</d> pathogenesis. The effect of <g>Chop</g> deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with <d>IPF</d> and mice with bleomycin BLM-induced <d>pulmonary fibrosis</d> were affected by the altered <g>Chop</g> expression and ER stress. In particular, <g>Chop</g> deficiency protected mice against BLM-induced <d>lung injury</d> and fibrosis. Loss of <g>Chop</g> significantly attenuated transforming growth factor b TGF-b production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that <g>Chop</g> deficiency repressed the M2 program in macrophages, which then attenuated TGF-b secretion. Specifically, loss of <g>Chop</g> promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which <g>Chop</g> deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that <g>Chop</g> and ER stress are implicated in <d>IPF</d> pathoaetiology, involving at least the induction and differentiation of M2 macrophages.
26883801|a|<g>C/EBP homologous protein</g> <g>Chop</g> has been shown to have altered expression in patients with <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d>, but its exact role in <d>IPF</d> pathoaetiology has not been fully addressed. Studies conducted in patients with <d>IPF</d> and <g>Chop</g>-/- mice have dissected the role of <g>Chop</g> and endoplasmic reticulum ER stress in <d>pulmonary <d>fibrosis</d></d> pathogenesis. The effect of <g>Chop</g> deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with <d>IPF</d> and mice with bleomycin BLM-induced <d>pulmonary <d>fibrosis</d></d> were affected by the altered <g>Chop</g> expression and ER stress. In particular, <g>Chop</g> deficiency protected mice against BLM-induced <d>lung injury</d> and <d>fibrosis</d>. Loss of <g>Chop</g> significantly attenuated transforming growth factor b TGF-b production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that <g>Chop</g> deficiency repressed the M2 program in macrophages, which then attenuated TGF-b secretion. Specifically, loss of <g>Chop</g> promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which <g>Chop</g> deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that <g>Chop</g> and ER stress are implicated in <d>IPF</d> pathoaetiology, involving at least the induction and differentiation of M2 macrophages.
26884454|a|Matricellular proteins mediate pleiotropic effects during tissue injury and repair. <g>CCN1</g> is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified <g>CCN1</g> as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis IPF. Elevated levels of <g>CCN1</g> mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and <g>CCN1</g> protein was predominantly localized to fibroblastic foci. <g>CCN1</g> expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen Col1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference RNAi-mediated knockdown of <g>CCN1</g> down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. <g>TGF-b1</g>, a known mediator of tissue fibrogenesis, induces gene and protein expression of <g>CCN1</g> via a mothers against decapentaplegic homolog 3 <g>SMAD3</g>-dependent mechanism. Importantly, endogenous <g>CCN1</g> potentiates <g>TGF-b1</g>-induced <g>SMAD3</g> activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of <g>CCN1</g> attenuates fibrogenic responses to bleomycin-induced <d>lung injury</d>. These studies support previously unrecognized, cooperative interaction between the <g>CCN1</g> matricellular protein and canonical <g>TGF-b1</g>/<g>SMAD3</g> signaling that promotes lung fibrosis.-Kurundkar, A. R., Kurundkar, D., Rangarajan, S., Locy, M. L., Zhou, Y., Liu, R.-M., Zmijewski, J., Thannickal, V. J. The matricellular protein <g>CCN1</g> enhances <g>TGF-b1</g>/<g>SMAD3</g>-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to <d>lung injury</d>.
26884454|a|Matricellular proteins mediate pleiotropic effects during tissue injury and repair. <g>CCN1</g> is a matricellular protein that has been implicated in angiogenesis, <d>inflammation</d>, and wound repair. In this study, we identified <g>CCN1</g> as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis IPF. Elevated levels of <g>CCN1</g> mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and <g>CCN1</g> protein was predominantly localized to fibroblastic foci. <g>CCN1</g> expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen Col1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference RNAi-mediated knockdown of <g>CCN1</g> down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. <g>TGF-b1</g>, a known mediator of tissue fibrogenesis, induces gene and protein expression of <g>CCN1</g> via a mothers against decapentaplegic homolog 3 <g>SMAD3</g>-dependent mechanism. Importantly, endogenous <g>CCN1</g> potentiates <g>TGF-b1</g>-induced <g>SMAD3</g> activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of <g>CCN1</g> attenuates fibrogenic responses to bleomycin-induced <d>lung injury</d>. These studies support previously unrecognized, cooperative interaction between the <g>CCN1</g> matricellular protein and canonical <g>TGF-b1</g>/<g>SMAD3</g> signaling that promotes lung fibrosis.-Kurundkar, A. R., Kurundkar, D., Rangarajan, S., Locy, M. L., Zhou, Y., Liu, R.-M., Zmijewski, J., Thannickal, V. J. The matricellular protein <g>CCN1</g> enhances <g>TGF-b1</g>/<g>SMAD3</g>-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to <d>lung injury</d>.
26884454|a|Matricellular proteins mediate pleiotropic effects during tissue injury and repair. <g>CCN1</g> is a matricellular protein that has been implicated in angiogenesis, <d>inflammation</d>, and wound repair. In this study, we identified <g>CCN1</g> as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive <d>idiopathic pulmonary fibrosis</d> IPF. Elevated levels of <g>CCN1</g> mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and <g>CCN1</g> protein was predominantly localized to fibroblastic foci. <g>CCN1</g> expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen Col1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference RNAi-mediated knockdown of <g>CCN1</g> down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. <g>TGF-b1</g>, a known mediator of tissue fibrogenesis, induces gene and protein expression of <g>CCN1</g> via a mothers against decapentaplegic homolog 3 <g>SMAD3</g>-dependent mechanism. Importantly, endogenous <g>CCN1</g> potentiates <g>TGF-b1</g>-induced <g>SMAD3</g> activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of <g>CCN1</g> attenuates fibrogenic responses to bleomycin-induced <d>lung injury</d>. These studies support previously unrecognized, cooperative interaction between the <g>CCN1</g> matricellular protein and canonical <g>TGF-b1</g>/<g>SMAD3</g> signaling that promotes lung fibrosis.-Kurundkar, A. R., Kurundkar, D., Rangarajan, S., Locy, M. L., Zhou, Y., Liu, R.-M., Zmijewski, J., Thannickal, V. J. The matricellular protein <g>CCN1</g> enhances <g>TGF-b1</g>/<g>SMAD3</g>-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to <d>lung injury</d>.
26884454|a|Matricellular proteins mediate pleiotropic effects during tissue injury and repair. <g>CCN1</g> is a matricellular protein that has been implicated in angiogenesis, <d>inflammation</d>, and wound repair. In this study, we identified <g>CCN1</g> as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Elevated levels of <g>CCN1</g> mRNA were confirmed in lung tissues of <d>IPF</d> subjects undergoing lung transplantation, and <g>CCN1</g> protein was predominantly localized to fibroblastic foci. <g>CCN1</g> expression in ex vivo <d>IPF</d> lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen Col1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference RNAi-mediated knockdown of <g>CCN1</g> down-regulated the constitutive expression of these profibrotic genes in <d>IPF</d> fibroblasts. <g>TGF-b1</g>, a known mediator of tissue fibrogenesis, induces gene and protein expression of <g>CCN1</g> via a mothers against decapentaplegic homolog 3 <g>SMAD3</g>-dependent mechanism. Importantly, endogenous <g>CCN1</g> potentiates <g>TGF-b1</g>-induced <g>SMAD3</g> activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of <g>CCN1</g> attenuates fibrogenic responses to bleomycin-induced <d>lung injury</d>. These studies support previously unrecognized, cooperative interaction between the <g>CCN1</g> matricellular protein and canonical <g>TGF-b1</g>/<g>SMAD3</g> signaling that promotes lung fibrosis.-Kurundkar, A. R., Kurundkar, D., Rangarajan, S., Locy, M. L., Zhou, Y., Liu, R.-M., Zmijewski, J., Thannickal, V. J. The matricellular protein <g>CCN1</g> enhances <g>TGF-b1</g>/<g>SMAD3</g>-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to <d>lung injury</d>.
26884454|a|Matricellular proteins mediate pleiotropic effects during tissue injury and repair. <g>CCN1</g> is a matricellular protein that has been implicated in angiogenesis, <d>inflammation</d>, and wound repair. In this study, we identified <g>CCN1</g> as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Elevated levels of <g>CCN1</g> mRNA were confirmed in lung tissues of <d>IPF</d> subjects undergoing lung transplantation, and <g>CCN1</g> protein was predominantly localized to fibroblastic foci. <g>CCN1</g> expression in ex vivo <d>IPF</d> lung fibroblasts correlated with gene expression of the extracellular matrix proteins, <g>collagen Col1a1</g>, <g>Col1a2</g>, and <g>fibronectin</g> as well as the myofibroblast marker, a-smooth muscle actin. RNA interference RNAi-mediated knockdown of <g>CCN1</g> down-regulated the constitutive expression of these profibrotic genes in <d>IPF</d> fibroblasts. <g>TGF-b1</g>, a known mediator of tissue fibrogenesis, induces gene and protein expression of <g>CCN1</g> via a <g>mothers against decapentaplegic homolog 3</g> <g>SMAD3</g>-dependent mechanism. Importantly, endogenous <g>CCN1</g> potentiates <g>TGF-b1</g>-induced <g>SMAD3</g> activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of <g>CCN1</g> attenuates fibrogenic responses to bleomycin-induced <d>lung injury</d>. These studies support previously unrecognized, cooperative interaction between the <g>CCN1</g> matricellular protein and canonical <g>TGF-b1</g>/<g>SMAD3</g> signaling that promotes <d>lung fibrosis</d>.-Kurundkar, A. R., Kurundkar, D., Rangarajan, S., Locy, M. L., Zhou, Y., Liu, R.-M., Zmijewski, J., Thannickal, V. J. The matricellular protein <g>CCN1</g> enhances <g>TGF-b1</g>/<g>SMAD3</g>-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to <d>lung injury</d>.
26887531|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a chronic progressively fatal disease. <g>Extracellular Matrix Metalloproteinase Inducer</g> <g>EMMPRIN</g> is a glycosylated transmembrane protein that induces the expression of some matrix metalloproteinase MMP in neighboring stromal cells through direct epithelial-stromal interactions. <g>EMMPRIN</g> is highly expressed in type II alveolar epithelial cells at the edges of the fibrotic areas in IPF lung sections. However, the exact role of <g>EMMPRIN</g> in IPF is unknown. METHODS: To determine if <g>EMMPRIN</g> contributes to lung fibroblast proliferation, resistance to apoptosis, and differentiation to myofibroblasts, normal Human lung fibroblasts NHLF transiently transfected with either <g>EMMPRIN</g>/GFP or GFP were treated with TGF- b1 from 0 to 10 ng/ml for 48 h and examined for cell proliferation thymidine incorporation, apoptosis FACS analysis and Cell Death Detection ELISA assay, cell migration Modified Boyden chamber and differentiation to myofibroblasts using Western blot for a-smooth actin of cell lysates. The effect of <g>EMMPRIN</g> inhibition on NHLF proliferation, apoptosis, migration and differentiation to myofibroblasts after TGF- b1 treatment was examined using <g>EMMPRIN</g> blocking antibody. We examined the mechanism by which <g>EMMPRIN</g> induces its effects on fibroblasts by studying the b-catenin/canonical Wnt signaling pathway using Wnt luciferase reporter assays and Western blot for total and phosphorylated b-catenin. RESULTS: Human lung fibroblasts overexpressing <g>EMMPRIN</g> had a significant increase in cell proliferation and migration compared to control fibroblasts. Furthermore, <g>EMMPRIN</g> promoted lung fibroblasts resistance to apoptosis. Lung fibroblasts overexpressing <g>EMMPRIN</g> showed a significantly increased expression of a- smooth muscle actin, a marker of differentiation to myofibroblasts compared to control cells. TGF-b1 increased the expression of <g>EMMPRIN</g> in lung fibroblasts in a dose-dependent manner. Attenuation of <g>EMMPRIN</g> expression with the use of an <g>EMMPRIN</g> blocking antibody markedly inhibited TGF-b1 induced proliferation, migration, and differentiation of fibroblasts to myofibroblasts. <g>EMMPRIN</g> overexpression in lung fibroblasts was found to induce an increase in TOPFLASH luciferase reporter activity when compared with control fibroblasts. CONCLUSION: These findings indicate that TGF-b1 induces the release of <g>EMMPRIN</g> that activates b-catenin/canonical Wnt signaling pathway. <g>EMMPRIN</g> overexpression induces an anti-apoptotic and pro-fibrotic phenotype in lung fibroblasts that may contribute to the persistent fibro-proliferative state seen in IPF.
26887531|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressively fatal disease. <g>Extracellular Matrix Metalloproteinase Inducer</g> <g>EMMPRIN</g> is a glycosylated transmembrane protein that induces the expression of some matrix metalloproteinase MMP in neighboring stromal cells through direct epithelial-stromal interactions. <g>EMMPRIN</g> is highly expressed in type II alveolar epithelial cells at the edges of the fibrotic areas in <d>IPF</d> lung sections. However, the exact role of <g>EMMPRIN</g> in <d>IPF</d> is unknown. METHODS: To determine if <g>EMMPRIN</g> contributes to lung fibroblast proliferation, resistance to apoptosis, and differentiation to myofibroblasts, normal Human lung fibroblasts NHLF transiently transfected with either <g>EMMPRIN</g>/GFP or GFP were treated with TGF- b1 from 0 to 10 ng/ml for 48 h and examined for cell proliferation thymidine incorporation, apoptosis FACS analysis and Cell Death Detection ELISA assay, cell migration Modified Boyden chamber and differentiation to myofibroblasts using Western blot for a-smooth actin of cell lysates. The effect of <g>EMMPRIN</g> inhibition on NHLF proliferation, apoptosis, migration and differentiation to myofibroblasts after TGF- b1 treatment was examined using <g>EMMPRIN</g> blocking antibody. We examined the mechanism by which <g>EMMPRIN</g> induces its effects on fibroblasts by studying the b-catenin/canonical Wnt signaling pathway using Wnt luciferase reporter assays and Western blot for total and phosphorylated b-catenin. RESULTS: Human lung fibroblasts overexpressing <g>EMMPRIN</g> had a significant increase in cell proliferation and migration compared to control fibroblasts. Furthermore, <g>EMMPRIN</g> promoted lung fibroblasts resistance to apoptosis. Lung fibroblasts overexpressing <g>EMMPRIN</g> showed a significantly increased expression of a- smooth muscle actin, a marker of differentiation to myofibroblasts compared to control cells. TGF-b1 increased the expression of <g>EMMPRIN</g> in lung fibroblasts in a dose-dependent manner. Attenuation of <g>EMMPRIN</g> expression with the use of an <g>EMMPRIN</g> blocking antibody markedly inhibited TGF-b1 induced proliferation, migration, and differentiation of fibroblasts to myofibroblasts. <g>EMMPRIN</g> overexpression in lung fibroblasts was found to induce an increase in TOPFLASH luciferase reporter activity when compared with control fibroblasts. CONCLUSION: These findings indicate that TGF-b1 induces the release of <g>EMMPRIN</g> that activates b-catenin/canonical Wnt signaling pathway. <g>EMMPRIN</g> overexpression induces an anti-apoptotic and pro-fibrotic phenotype in lung fibroblasts that may contribute to the persistent fibro-proliferative state seen in <d>IPF</d>.
26895395|a|PURPOSE: Idiopathic pulmonary fibrosis IPF is a chronic fibrosing interstitial pneumonia, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic aerobic training AT have been demonstrated in the context of lung injury, this study investigated whether AT attenuates bleomycin-induced lung fibrosis partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d>Fibrosis</d> Fi, and <d>Fibrosis</d> + Exercise Fi + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill AT began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, interleukin IL-1b, IL-6, CXCL1/KC, IL-10, tumor necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: AT reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, IL-6 P < 0.05, CXCL1/KC P < 0.001, tumor necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine IL-10 P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: AT accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced lung fibrosis partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> IPF is a chronic fibrosing interstitial pneumonia, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic aerobic training AT have been demonstrated in the context of lung injury, this study investigated whether AT attenuates bleomycin-induced lung fibrosis partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d>Fibrosis</d> Fi, and <d>Fibrosis</d> + Exercise Fi + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill AT began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, interleukin IL-1b, IL-6, CXCL1/KC, IL-10, tumor necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: AT reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, IL-6 P < 0.05, CXCL1/KC P < 0.001, tumor necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine IL-10 P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: AT accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced lung fibrosis partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing interstitial pneumonia, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic aerobic training AT have been demonstrated in the context of lung injury, this study investigated whether AT attenuates bleomycin-induced lung fibrosis partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d>Fibrosis</d> Fi, and <d>Fibrosis</d> + Exercise Fi + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill AT began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, interleukin IL-1b, IL-6, CXCL1/KC, IL-10, tumor necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: AT reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, IL-6 P < 0.05, CXCL1/KC P < 0.001, tumor necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine IL-10 P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: AT accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced lung fibrosis partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic aerobic training AT have been demonstrated in the context of lung injury, this study investigated whether AT attenuates bleomycin-induced lung fibrosis partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d>Fibrosis</d> Fi, and <d>Fibrosis</d> + Exercise Fi + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill AT began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, interleukin IL-1b, IL-6, CXCL1/KC, IL-10, tumor necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: AT reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, IL-6 P < 0.05, CXCL1/KC P < 0.001, tumor necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine IL-10 P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: AT accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced lung fibrosis partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic <d>aerobic training</d> AT have been demonstrated in the context of lung injury, this study investigated whether AT attenuates bleomycin-induced lung fibrosis partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d>Fibrosis</d> Fi, and <d>Fibrosis</d> + Exercise Fi + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill AT began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, interleukin IL-1b, IL-6, CXCL1/KC, IL-10, tumor necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: AT reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, IL-6 P < 0.05, CXCL1/KC P < 0.001, tumor necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine IL-10 P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: AT accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced lung fibrosis partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic <d>aerobic training</d> <d>AT</d> have been demonstrated in the context of lung injury, this study investigated whether <d>AT</d> attenuates bleomycin-induced lung fibrosis partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d>Fibrosis</d> Fi, and <d>Fibrosis</d> + Exercise Fi + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill <d>AT</d> began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, interleukin IL-1b, IL-6, CXCL1/KC, IL-10, tumor necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: <d>AT</d> reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, IL-6 P < 0.05, CXCL1/KC P < 0.001, tumor necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine IL-10 P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: <d>AT</d> accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced lung fibrosis partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic <d>aerobic training</d> <d>AT</d> have been demonstrated in the context of <d>lung injury</d>, this study investigated whether <d>AT</d> attenuates bleomycin-induced lung fibrosis partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d>Fibrosis</d> Fi, and <d>Fibrosis</d> + Exercise Fi + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill <d>AT</d> began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, interleukin IL-1b, IL-6, CXCL1/KC, IL-10, tumor necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: <d>AT</d> reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, IL-6 P < 0.05, CXCL1/KC P < 0.001, tumor necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine IL-10 P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: <d>AT</d> accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced lung fibrosis partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic <d>aerobic training</d> <d>AT</d> have been demonstrated in the context of <d>lung injury</d>, this study investigated whether <d>AT</d> attenuates bleomycin-induced <d>lung fibrosis</d> partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d>Fibrosis</d> Fi, and <d>Fibrosis</d> + Exercise Fi + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill <d>AT</d> began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, interleukin IL-1b, IL-6, CXCL1/KC, IL-10, tumor necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: <d>AT</d> reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, IL-6 P < 0.05, CXCL1/KC P < 0.001, tumor necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine IL-10 P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: <d>AT</d> accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced <d>lung fibrosis</d> partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic <d>aerobic training</d> <d>AT</d> have been demonstrated in the context of <d>lung injury</d>, this study investigated whether <d>AT</d> attenuates bleomycin-induced <d>lung fibrosis</d> partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d><d>Fi</d>brosis</d> <d>Fi</d>, and <d><d>Fi</d>brosis</d> + Exercise <d>Fi</d> + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill <d>AT</d> began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, interleukin IL-1b, IL-6, CXCL1/KC, IL-10, tumor necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: <d>AT</d> reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, IL-6 P < 0.05, CXCL1/KC P < 0.001, tumor necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine IL-10 P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: <d>AT</d> accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced <d>lung fibrosis</d> partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic <d>aerobic training</d> <d>AT</d> have been demonstrated in the context of <d>lung injury</d>, this study investigated whether <d>AT</d> attenuates bleomycin-induced <d>lung fibrosis</d> partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d><d>Fi</d>brosis</d> <d>Fi</d>, and <d><d>Fi</d>brosis</d> + Exercise <d>Fi</d> + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill <d>AT</d> began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, <g>interleukin IL-1b</g>, <g>IL-6</g>, <g>CXCL1</g>/KC, <g>IL-10</g>, <d>tumor</d> necrosis factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: <d>AT</d> reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, <g>IL-6</g> P < 0.05, <g>CXCL1</g>/KC P < 0.001, <d>tumor</d> necrosis factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine <g>IL-10</g> P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: <d>AT</d> accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced <d>lung fibrosis</d> partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic <d>aerobic training</d> <d>AT</d> have been demonstrated in the context of <d>lung injury</d>, this study investigated whether <d>AT</d> attenuates bleomycin-induced <d>lung fibrosis</d> partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d><d>Fi</d>brosis</d> <d>Fi</d>, and <d><d>Fi</d>brosis</d> + Exercise <d>Fi</d> + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill <d>AT</d> began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, <g>interleukin IL-1b</g>, <g>IL-6</g>, <g>CXCL1</g>/KC, <g>IL-10</g>, <d>tumor</d> <d>necrosis</d> factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: <d>AT</d> reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of IL-1b P < 0.01, <g>IL-6</g> P < 0.05, <g>CXCL1</g>/KC P < 0.001, <d>tumor</d> <d>necrosis</d> factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine <g>IL-10</g> P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: <d>AT</d> accelerates the resolution of lung inflammation and fibrosis in a model of bleomycin-induced <d>lung fibrosis</d> partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic <d>aerobic training</d> <d>AT</d> have been demonstrated in the context of <d>lung injury</d>, this study investigated whether <d>AT</d> attenuates bleomycin-induced <d>lung fibrosis</d> partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d><d>Fi</d>brosis</d> <d>Fi</d>, and <d><d>Fi</d>brosis</d> + Exercise <d>Fi</d> + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill <d>AT</d> began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, <g>interleukin <g>IL-1b</g></g>, <g>IL-6</g>, <g>CXCL1</g>/KC, <g>IL-10</g>, <d>tumor</d> <d>necrosis</d> factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: <d>AT</d> reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of <g>IL-1b</g> P < 0.01, <g>IL-6</g> P < 0.05, <g>CXCL1</g>/KC P < 0.001, <d>tumor</d> <d>necrosis</d> factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine <g>IL-10</g> P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: <d>AT</d> accelerates the resolution of <d>lung inflammation</d> and fibrosis in a model of bleomycin-induced <d>lung fibrosis</d> partly via attenuation of 5-HT/Akt signaling.
26895395|a|PURPOSE: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic fibrosing <d>interstitial pneumonia</d>, which involves aberrant serotonin 5-hydroxytryptamine [5-HT] and Akt signaling. As protective effects of chronic <d>aerobic training</d> <d>AT</d> have been demonstrated in the context of <d>lung injury</d>, this study investigated whether <d>AT</d> attenuates bleomycin-induced <d>lung <d>fibrosis</d></d> partly via a reduction of 5-HT and AKT signaling. METHODS: Seventy-two C57BL/6 male mice were distributed in Control Co, Exercise Ex, <d><d>Fi</d>brosis</d> <d>Fi</d>, and <d><d>Fi</d>brosis</d> + Exercise <d>Fi</d> + Ex groups. Bleomycin 1.5 UI  kg was administered on day 1 and treadmill <d>AT</d> began on day 15 and continued for 60 min  d, 5 d  wk for 4 wk. We evaluated total and differential cell counts in bronchoalveolar lavage BAL, <g>interleukin <g>IL-1b</g></g>, <g>IL-6</g>, <g>CXCL1</g>/KC, <g>IL-10</g>, <d>tumor</d> <d>necrosis</d> factor a, and transforming growth factor b levels in BAL, collagen content in lung parenchyma, 5-HT levels in BAL fluid and in serum, the expression of 5-HT2B receptor, and Akt phosphorylation in lung tissue. RESULTS: <d>AT</d> reduced bleomycin-increased number of total cells P < 0.001, neutrophils P < 0.01, macrophages P < 0.01, and lymphocytes P < 0.05 in BAL. It also reduced the levels of <g>IL-1b</g> P < 0.01, <g>IL-6</g> P < 0.05, <g>CXCL1</g>/KC P < 0.001, <d>tumor</d> <d>necrosis</d> factor a P < 0.001, and transforming growth factor b P < 0.001. It increased expression of ant-inflammatory cytokine <g>IL-10</g> P < 0.001. It reduced bleomycin-increased 5-HT levels in BAL P < 0.001 and in serum P < 0.05. Reductions in collagen fiber deposition P < 0.01, 5-HT2B receptor expression P < 0.01, and Akt phosphorylation in lung tissue were observed. CONCLUSIONS: <d>AT</d> accelerates the resolution of <d>lung inflammation</d> and <d>fibrosis</d> in a model of bleomycin-induced <d>lung <d>fibrosis</d></d> partly via attenuation of 5-HT/Akt signaling.
26934369|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and lethal disease of unknown etiology. A growing body of evidence indicates that it may result from an aberrant activation of alveolar epithelium, which induces the expansion of the fibroblast population, their differentiation to myofibroblasts and the excessive accumulation of extracellular matrix. The mechanisms that activate the alveolar epithelium are unknown, but several studies indicate that smoking is the main environmental risk factor for the development of IPF. In this study we explored the effect of cigarette smoke on the gene expression profile and signaling pathways in alveolar epithelial cells. Lung epithelial cell line from human A549, was exposed to cigarette smoke extract CSE for 1, 3, and 5 weeks at 1, 5 and 10% and gene expression was evaluated by complete transcriptome microarrays. Signaling networks were analyzed with the Ingenuity Pathway Analysis software. At 5 weeks of exposure, alveolar epithelial cells acquired a fibroblast-like phenotype. At this time, gene expression profile revealed a significant increase of more than 1000 genes and deregulation of canonical signaling pathways such as TGF-b and Wnt. Several profibrotic genes involved in EMT were over-expressed, and incomplete EMT was observed in these cells, and corroborated in mouse MLE-12 and rat RLE-6TN epithelial cells. The secretion of activated TGF-b1 increased in cells exposed to cigarette smoke, which decreased when the integrin alpha v gene was silenced. These findings suggest that the exposure of alveolar epithelial cells to CSE induces the expression and release of a variety of profibrotic genes, and the activation of TGF-b1, which may explain at least partially, the increased risk of developing IPF in smokers.
26934369|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and lethal disease of unknown etiology. A growing body of evidence indicates that it may result from an aberrant activation of alveolar epithelium, which induces the expansion of the fibroblast population, their differentiation to myofibroblasts and the excessive accumulation of extracellular matrix. The mechanisms that activate the alveolar epithelium are unknown, but several studies indicate that smoking is the main environmental risk factor for the development of <d>IPF</d>. In this study we explored the effect of cigarette smoke on the gene expression profile and signaling pathways in alveolar epithelial cells. Lung epithelial cell line from human A549, was exposed to cigarette smoke extract CSE for 1, 3, and 5 weeks at 1, 5 and 10% and gene expression was evaluated by complete transcriptome microarrays. Signaling networks were analyzed with the Ingenuity Pathway Analysis software. At 5 weeks of exposure, alveolar epithelial cells acquired a fibroblast-like phenotype. At this time, gene expression profile revealed a significant increase of more than 1000 genes and deregulation of canonical signaling pathways such as TGF-b and Wnt. Several profibrotic genes involved in EMT were over-expressed, and incomplete EMT was observed in these cells, and corroborated in mouse MLE-12 and rat RLE-6TN epithelial cells. The secretion of activated TGF-b1 increased in cells exposed to cigarette smoke, which decreased when the integrin alpha v gene was silenced. These findings suggest that the exposure of alveolar epithelial cells to CSE induces the expression and release of a variety of profibrotic genes, and the activation of TGF-b1, which may explain at least partially, the increased risk of developing <d>IPF</d> in smokers.
26956419|a|Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic <d>pulmonary fibrosis</d> IPF. Whereas we have previously reported elevated anaphylatoxins-complement component 3a C3a and complement component 5a C5a-in IPF, which interact with TGF-b and augment epithelial injury in vitro, their role in IPF pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of C3a/C5a to their respective receptors <g>C3aR</g> and <g>C5aR</g> in the progression of lung fibrosis. In normal primary human fetal lung fibroblasts, C3a and C5a induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of <g>C3aR</g> and <g>C5aR</g> in lung fibrosis by using bleomycin-injured mice with fibrotic lungs, elevated local C3a and C5a, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition Masson's trichrome, hydroxyproline, collagen type I a 1 chain, and collagen type I a 2 chain. Pharmacologic or RNA interference-specific interventions suppressed complement activation C3a and C5a and soluble terminal complement complex formation C5b-9 locally and active TGF-b1 systemically. <g>C3aR</g>/<g>C5aR</g> antagonists suppressed local mRNA expressions of tgfb2, tgfbr1/2, ltbp1/2, serpine1, tsp1, bmp1/4, pdgfbb, igf1, but restored the proteoglycan, dcn Clinically, compared with pathologically normal human subjects, patients with IPF presented local induction of <g>C5aR</g>, local and systemic induction of soluble C5b-9, and amplified expression of <g>C3aR</g>/<g>C5aR</g> in lesions. The blockade of <g>C3aR</g> and <g>C5aR</g> arrested the progression of fibrosis by attenuating local complement activation and TGF-b/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with IPF.-Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Peters-Golden, M., Twigg, H. L., III, Woodruff, T. M., Wilkes, D. S., Vittal, R. Contribution of the anaphylatoxin receptors, <g>C3aR</g> and <g>C5aR</g>, to the pathogenesis of <d>pulmonary fibrosis</d>.
26956419|a|Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. Whereas we have previously reported elevated anaphylatoxins-complement component 3a C3a and complement component 5a C5a-in <d>IPF</d>, which interact with TGF-b and augment epithelial injury in vitro, their role in <d>IPF</d> pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of C3a/C5a to their respective receptors <g>C3aR</g> and <g>C5aR</g> in the progression of lung fibrosis. In normal primary human fetal lung fibroblasts, C3a and C5a induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of <g>C3aR</g> and <g>C5aR</g> in lung fibrosis by using bleomycin-injured mice with fibrotic lungs, elevated local C3a and C5a, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition Masson's trichrome, hydroxyproline, collagen type I a 1 chain, and collagen type I a 2 chain. Pharmacologic or RNA interference-specific interventions suppressed complement activation C3a and C5a and soluble terminal complement complex formation C5b-9 locally and active TGF-b1 systemically. <g>C3aR</g>/<g>C5aR</g> antagonists suppressed local mRNA expressions of tgfb2, tgfbr1/2, ltbp1/2, serpine1, tsp1, bmp1/4, pdgfbb, igf1, but restored the proteoglycan, dcn Clinically, compared with pathologically normal human subjects, patients with <d>IPF</d> presented local induction of <g>C5aR</g>, local and systemic induction of soluble C5b-9, and amplified expression of <g>C3aR</g>/<g>C5aR</g> in lesions. The blockade of <g>C3aR</g> and <g>C5aR</g> arrested the progression of fibrosis by attenuating local complement activation and TGF-b/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with <d>IPF</d>.-Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Peters-Golden, M., Twigg, H. L., III, Woodruff, T. M., Wilkes, D. S., Vittal, R. Contribution of the anaphylatoxin receptors, <g>C3aR</g> and <g>C5aR</g>, to the pathogenesis of <d>pulmonary fibrosis</d>.
26956419|a|Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. Whereas we have previously reported elevated anaphylatoxins-complement component 3a <g>C3a</g> and complement component 5a <g>C5a</g>-in <d>IPF</d>, which interact with <g>TGF-b</g> and augment epithelial injury in vitro, their role in <d>IPF</d> pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of <g>C3a</g>/<g>C5a</g> to their respective receptors <g><g>C3a</g>R</g> and <g><g>C5a</g>R</g> in the progression of <d>lung fibrosis</d>. In normal primary human fetal lung fibroblasts, <g>C3a</g> and <g>C5a</g> induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of <g><g>C3a</g>R</g> and <g><g>C5a</g>R</g> in <d>lung fibrosis</d> by using bleomycin-injured mice with fibrotic lungs, elevated local <g>C3a</g> and <g>C5a</g>, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition Masson's trichrome, hydroxyproline, collagen type I a 1 chain, and collagen type I a 2 chain. Pharmacologic or RNA interference-specific interventions suppressed complement activation <g>C3a</g> and <g>C5a</g> and soluble terminal complement complex formation C5b-9 locally and active <g>TGF-b</g>1 systemically. <g><g>C3a</g>R</g>/<g><g>C5a</g>R</g> antagonists suppressed local mRNA expressions of tgfb2, tgfbr1/2, ltbp1/2, serpine1, tsp1, bmp1/4, pdgfbb, igf1, but restored the proteoglycan, dcn Clinically, compared with pathologically normal human subjects, patients with <d>IPF</d> presented local induction of <g><g>C5a</g>R</g>, local and systemic induction of soluble C5b-9, and amplified expression of <g><g>C3a</g>R</g>/<g><g>C5a</g>R</g> in lesions. The blockade of <g><g>C3a</g>R</g> and <g><g>C5a</g>R</g> arrested the progression of fibrosis by attenuating local complement activation and <g>TGF-b</g>/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with <d>IPF</d>.-Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Peters-Golden, M., Twigg, H. L., III, Woodruff, T. M., Wilkes, D. S., Vittal, R. Contribution of the anaphylatoxin receptors, <g><g>C3a</g>R</g> and <g><g>C5a</g>R</g>, to the pathogenesis of <d>pulmonary fibrosis</d>.
26956419|a|Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>. Whereas we have previously reported elevated anaphylatoxins-complement component 3a <g>C3a</g> and complement component 5a <g>C5a</g>-in <d>IPF</d>, which interact with <g>TGF-b</g> and augment epithelial injury in vitro, their role in <d>IPF</d> pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of <g>C3a</g>/<g>C5a</g> to their respective receptors <g><g>C3a</g>R</g> and <g><g>C5a</g>R</g> in the progression of <d>lung <d>fibrosis</d></d>. In normal primary human fetal lung fibroblasts, <g>C3a</g> and <g>C5a</g> induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of <g><g>C3a</g>R</g> and <g><g>C5a</g>R</g> in <d>lung <d>fibrosis</d></d> by using bleomycin-injured mice with fibrotic lungs, elevated local <g>C3a</g> and <g>C5a</g>, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition Masson's trichrome, hydroxyproline, collagen type I a 1 chain, and collagen type I a 2 chain. Pharmacologic or RNA interference-specific interventions suppressed complement activation <g>C3a</g> and <g>C5a</g> and soluble terminal complement complex formation C5b-9 locally and active <g>TGF-b</g>1 systemically. <g><g>C3a</g>R</g>/<g><g>C5a</g>R</g> antagonists suppressed local mRNA expressions of <g>tgfb2</g>, <g>tgfbr1/2</g>, <g>ltbp1/2</g>, <g>serpine1</g>, <g>tsp1</g>, <g>bmp1</g>/4, pdgfbb, <g>igf1</g>, but restored the proteoglycan, dcn Clinically, compared with pathologically normal human subjects, patients with <d>IPF</d> presented local induction of <g><g>C5a</g>R</g>, local and systemic induction of soluble C5b-9, and amplified expression of <g><g>C3a</g>R</g>/<g><g>C5a</g>R</g> in lesions. The blockade of <g><g>C3a</g>R</g> and <g><g>C5a</g>R</g> arrested the progression of <d>fibrosis</d> by attenuating local complement activation and <g>TGF-b</g>/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with <d>IPF</d>.-Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Peters-Golden, M., Twigg, H. L., III, Woodruff, T. M., Wilkes, D. S., Vittal, R. Contribution of the anaphylatoxin receptors, <g><g>C3a</g>R</g> and <g><g>C5a</g>R</g>, to the pathogenesis of <d>pulmonary <d>fibrosis</d></d>.
26971883|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the <g>PI3K</g>/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained <g>PI3K</g> activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates IPF, in a murine model of bleomycin-induced pulmonary fibrosis BIPF. We found that myeloid PTEN deficient mice PTENMyKO, after induction of BIPF, exhibit increased TGF-b1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTENMyKO mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-a in PTENMyKO mice during BIPF. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.
26971883|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the <g>PI3K</g>/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained <g>PI3K</g> activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates <d>IPF</d>, in a murine model of bleomycin-induced pulmonary fibrosis B<d>IPF</d>. We found that myeloid PTEN deficient mice PTENMyKO, after induction of B<d>IPF</d>, exhibit increased TGF-b1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTENMyKO mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-a in PTENMyKO mice during B<d>IPF</d>. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.
26971883|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the <g>PI3K</g>/<g>PTEN</g> pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained <g>PI3K</g> activity induced by cell-type specific <d>genetic deficiency</d> of its antagonist <g>PTEN</g> modulates <d>IPF</d>, in a murine model of bleomycin-induced pulmonary fibrosis B<d>IPF</d>. We found that myeloid <g>PTEN</g> deficient mice <g>PTEN</g>MyKO, after induction of B<d>IPF</d>, exhibit increased TGF-b1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that <g>PTEN</g>MyKO mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-a in <g>PTEN</g>MyKO mice during B<d>IPF</d>. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.
26971883|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the <g>PI3K</g>/<g>PTEN</g> pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained <g>PI3K</g> activity induced by cell-type specific <d>genetic deficiency</d> of its antagonist <g>PTEN</g> modulates <d>IPF</d>, in a murine model of bleomycin-induced <d>pulmonary fibrosis</d> B<d>IPF</d>. We found that myeloid <g>PTEN</g> deficient mice <g>PTEN</g>MyKO, after induction of B<d>IPF</d>, exhibit increased TGF-b1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that <g>PTEN</g>MyKO mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-a in <g>PTEN</g>MyKO mice during B<d>IPF</d>. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.
26971883|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the <g>PI3K</g>/<g>PTEN</g> pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained <g>PI3K</g> activity induced by cell-type specific <d>genetic deficiency</d> of its antagonist <g>PTEN</g> modulates <d>IPF</d>, in a murine model of bleomycin-induced <d>pulmonary fibrosis</d> B<d>IPF</d>. We found that myeloid <g>PTEN</g> deficient mice <g>PTEN</g>MyKO, after induction of B<d>IPF</d>, exhibit increased <g>TGF-b1</g> activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that <g>PTEN</g>MyKO mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an <d>impaired recruitment function</d>. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-a in <g>PTEN</g>MyKO mice during B<d>IPF</d>. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.
26971883|a|<d>Idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d> is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the <g>PI3K</g>/<g>PTEN</g> pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained <g>PI3K</g> activity induced by cell-type specific <d>genetic deficiency</d> of its antagonist <g>PTEN</g> modulates <d>IPF</d>, in a murine model of bleomycin-induced <d>pulmonary <d>fibrosis</d></d> B<d>IPF</d>. We found that myeloid <g>PTEN</g> deficient mice <g>PTEN</g>MyKO, after induction of B<d>IPF</d>, exhibit increased <g>TGF-b1</g> activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that <g>PTEN</g>MyKO mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an <d>impaired recruitment function</d>. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and <g>TNF-a</g> in <g>PTEN</g>MyKO mice during B<d>IPF</d>. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive <d>fibrosis</d>.
26993524|a|Idiopathic pulmonary <d>fibrosis</d> IPF poses challenges to understanding its underlying cellular and molecular mechanisms and the development of better therapies. Previous studies suggest a pathophysiological role for neuraminidase 1 <g>NEU1</g>, an enzyme that removes terminal sialic acid from glycoproteins. We observed increased <g>NEU1</g> expression in epithelial and endothelial cells, as well as fibroblasts, in the lungs of patients with IPF compared with healthy control lungs. Recombinant adenovirus-mediated gene delivery of <g>NEU1</g> to cultured primary human cells elicited profound changes in cellular phenotypes. Small airway epithelial cell migration was impaired in wounding assays, whereas, in pulmonary microvascular endothelial cells, <g>NEU1</g> overexpression strongly impacted global gene expression, increased T cell adhesion to endothelial monolayers, and disrupted endothelial capillary-like tube formation. <g>NEU1</g> overexpression in fibroblasts provoked increased levels of collagen types I and III, substantial changes in global gene expression, and accelerated degradation of matrix metalloproteinase-14. Intratracheal instillation of <g>NEU1</g> encoding, but not control adenovirus, induced lymphocyte accumulation in bronchoalveolar lavage samples and lung tissues and elevations of pulmonary transforming growth factor-b and collagen. The lymphocytes were predominantly T cells, with CD8+ cells exceeding CD4+ cells by nearly twofold. These combined data indicate that elevated <g>NEU1</g> expression alters functional activities of distinct lung cell types in vitro and recapitulates lymphocytic infiltration and collagen accumulation in vivo, consistent with mechanisms implicated in lung <d>fibrosis</d>.
26993524|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> poses challenges to understanding its underlying cellular and molecular mechanisms and the development of better therapies. Previous studies suggest a pathophysiological role for neuraminidase 1 <g>NEU1</g>, an enzyme that removes terminal sialic acid from glycoproteins. We observed increased <g>NEU1</g> expression in epithelial and endothelial cells, as well as fibroblasts, in the lungs of patients with <d>IPF</d> compared with healthy control lungs. Recombinant adenovirus-mediated gene delivery of <g>NEU1</g> to cultured primary human cells elicited profound changes in cellular phenotypes. Small airway epithelial cell migration was impaired in wounding assays, whereas, in pulmonary microvascular endothelial cells, <g>NEU1</g> overexpression strongly impacted global gene expression, increased T cell adhesion to endothelial monolayers, and disrupted endothelial capillary-like tube formation. <g>NEU1</g> overexpression in fibroblasts provoked increased levels of collagen types I and III, substantial changes in global gene expression, and accelerated degradation of matrix metalloproteinase-14. Intratracheal instillation of <g>NEU1</g> encoding, but not control adenovirus, induced lymphocyte accumulation in bronchoalveolar lavage samples and lung tissues and elevations of pulmonary transforming growth factor-b and collagen. The lymphocytes were predominantly T cells, with CD8+ cells exceeding CD4+ cells by nearly twofold. These combined data indicate that elevated <g>NEU1</g> expression alters functional activities of distinct lung cell types in vitro and recapitulates lymphocytic infiltration and collagen accumulation in vivo, consistent with mechanisms implicated in lung <d>fibrosis</d>.
27002405|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive disorder with poor prognosis. The treatment options for IPF are very limited. Gambogic acid GA has anticancer effect and anti-proliferative activity which is extracted from a dried yellow resin of the Garcinia hanburyi Hook.f. [Clusiaceae Guttiferae] in Southeast Asia. However, the anti-fibrotic activities of GA have not been previously investigated. METHODS: In this study, the effects of GA on TGF-b1-mediated epithelial-mesenchymal transition EMT in A549 cells and endothelial-mesenchymal transition EndoMT in human pulmonary microvascular endothelial cells HPMECs, on the proliferation of human lung fibroblasts HLF-1 were investigated in vitro, and on bleomycin BLM-induced <d>pulmonary fibrosis</d> was investigated in vivo. RESULTS: In TGF-b1 stimulated A549 cells, treatment with GA resulted in a reduction of EMT with a decrease in vimentin and p-Smad3 and an increase in E-cadherin instead. In TGF-b1 stimulated HPMECs, treatment with GA resulted in a reduction of EndoMT with a decrease in vimentin, and an increase in VE-cadherin instead. In the hypoxic HPMECs, treatment with GA reduced Vasohibin-2 VASH-2, whereas increased VASH-1. In TGF-b1 stimulated HLF-1, treatment with GA reduced HLF-1 proliferation with a decrease in platelet-derived growth factor PDGF and fibroblast growth factor FGF-2 expressions. In vivo, treatment with GA for 2 weeks resulted in an amelioration of the BLM-induced <d>pulmonary fibrosis</d> in rats with a lower VASH-2. Instead, it was observed a higher VASH-1 expression at early stage of fibrosis at 1 mg/kg, with reductions of the pathological score, collagen deposition, a-SMA, PDGF and FGF-2 expressions at fibrotic stage at 0.5 mg/kg and 1 mg/kg. CONCLUSION: In summary, GA reversed EMT and EndoMT, as well as HLF-1 proliferation in vitro and prevented <d>pulmonary fibrosis</d> in vivo by modulating VASH-2/VASH-1 and suppressing the TGF-b1/Smad3 pathway.
27002405|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive disorder with poor prognosis. The treatment options for <d>IPF</d> are very limited. Gambogic acid GA has anticancer effect and anti-proliferative activity which is extracted from a dried yellow resin of the Garcinia hanburyi Hook.f. [Clusiaceae Guttiferae] in Southeast Asia. However, the anti-fibrotic activities of GA have not been previously investigated. METHODS: In this study, the effects of GA on TGF-b1-mediated epithelial-mesenchymal transition EMT in A549 cells and endothelial-mesenchymal transition EndoMT in human pulmonary microvascular endothelial cells HPMECs, on the proliferation of human lung fibroblasts HLF-1 were investigated in vitro, and on bleomycin BLM-induced <d>pulmonary fibrosis</d> was investigated in vivo. RESULTS: In TGF-b1 stimulated A549 cells, treatment with GA resulted in a reduction of EMT with a decrease in vimentin and p-Smad3 and an increase in E-cadherin instead. In TGF-b1 stimulated HPMECs, treatment with GA resulted in a reduction of EndoMT with a decrease in vimentin, and an increase in VE-cadherin instead. In the hypoxic HPMECs, treatment with GA reduced Vasohibin-2 VASH-2, whereas increased VASH-1. In TGF-b1 stimulated HLF-1, treatment with GA reduced HLF-1 proliferation with a decrease in platelet-derived growth factor PDGF and fibroblast growth factor FGF-2 expressions. In vivo, treatment with GA for 2 weeks resulted in an amelioration of the BLM-induced <d>pulmonary fibrosis</d> in rats with a lower VASH-2. Instead, it was observed a higher VASH-1 expression at early stage of fibrosis at 1 mg/kg, with reductions of the pathological score, collagen deposition, a-SMA, PDGF and FGF-2 expressions at fibrotic stage at 0.5 mg/kg and 1 mg/kg. CONCLUSION: In summary, GA reversed EMT and EndoMT, as well as HLF-1 proliferation in vitro and prevented <d>pulmonary fibrosis</d> in vivo by modulating VASH-2/VASH-1 and suppressing the TGF-b1/Smad3 pathway.
27002405|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive disorder with poor prognosis. The treatment options for <d>IPF</d> are very limited. Gambogic acid GA has anticancer effect and anti-proliferative activity which is extracted from a dried yellow resin of the Garcinia hanburyi Hook.f. [Clusiaceae Guttiferae] in Southeast Asia. However, the anti-fibrotic activities of GA have not been previously investigated. METHODS: In this study, the effects of GA on <g>TGF-b1</g>-mediated epithelial-mesenchymal transition EMT in A549 cells and endothelial-mesenchymal transition EndoMT in human pulmonary microvascular endothelial cells HPMECs, on the proliferation of human lung fibroblasts HLF-1 were investigated in vitro, and on bleomycin BLM-induced <d>pulmonary fibrosis</d> was investigated in vivo. RESULTS: In <g>TGF-b1</g> stimulated A549 cells, treatment with GA resulted in a reduction of EMT with a decrease in vimentin and p-<g>Smad3</g> and an increase in <g>E-cadherin</g> instead. In <g>TGF-b1</g> stimulated HPMECs, treatment with GA resulted in a reduction of EndoMT with a decrease in vimentin, and an increase in V<g>E-cadherin</g> instead. In the <d>hypoxic</d> HPMECs, treatment with GA reduced Vasohibin-2 VASH-2, whereas increased VASH-1. In <g>TGF-b1</g> stimulated HLF-1, treatment with GA reduced HLF-1 proliferation with a decrease in platelet-derived growth factor PDGF and fibroblast growth factor FGF-2 expressions. In vivo, treatment with GA for 2 weeks resulted in an amelioration of the BLM-induced <d>pulmonary fibrosis</d> in rats with a lower VASH-2. Instead, it was observed a higher VASH-1 expression at early stage of fibrosis at 1 mg/kg, with reductions of the pathological score, collagen deposition, a-SMA, PDGF and FGF-2 expressions at fibrotic stage at 0.5 mg/kg and 1 mg/kg. CONCLUSION: In summary, GA reversed EMT and EndoMT, as well as HLF-1 proliferation in vitro and prevented <d>pulmonary fibrosis</d> in vivo by modulating VASH-2/VASH-1 and suppressing the <g>TGF-b1</g>/<g>Smad3</g> pathway.
27002405|a|BACKGROUND: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive disorder with poor prognosis. The treatment options for <d>IPF</d> are very limited. Gambogic acid GA has anticancer effect and anti-proliferative activity which is extracted from a dried yellow resin of the Garcinia hanburyi Hook.f. [Clusiaceae Guttiferae] in Southeast Asia. However, the anti-fibrotic activities of GA have not been previously investigated. METHODS: In this study, the effects of GA on <g>TGF-b1</g>-mediated epithelial-mesenchymal transition EMT in A549 cells and endothelial-mesenchymal transition EndoMT in human pulmonary microvascular endothelial cells HPMECs, on the proliferation of human lung fibroblasts HLF-1 were investigated in vitro, and on bleomycin BLM-induced <d>pulmonary <d>fibrosis</d></d> was investigated in vivo. RESULTS: In <g>TGF-b1</g> stimulated A549 cells, treatment with GA resulted in a reduction of EMT with a decrease in vimentin and p-<g>Smad3</g> and an increase in <g>E-cadherin</g> instead. In <g>TGF-b1</g> stimulated HPMECs, treatment with GA resulted in a reduction of EndoMT with a decrease in vimentin, and an increase in V<g>E-cadherin</g> instead. In the <d>hypoxic</d> HPMECs, treatment with GA reduced <g>Vasohibin-2</g> <g>VASH-2</g>, whereas increased <g>VASH-1</g>. In <g>TGF-b1</g> stimulated HLF-1, treatment with GA reduced HLF-1 proliferation with a decrease in platelet-derived growth factor PDGF and fibroblast growth factor <g>FGF-2</g> expressions. In vivo, treatment with GA for 2 weeks resulted in an amelioration of the BLM-induced <d>pulmonary <d>fibrosis</d></d> in rats with a lower <g>VASH-2</g>. Instead, it was observed a higher <g>VASH-1</g> expression at early stage of <d>fibrosis</d> at 1 mg/kg, with reductions of the pathological score, collagen deposition, a-SMA, PDGF and <g>FGF-2</g> expressions at fibrotic stage at 0.5 mg/kg and 1 mg/kg. CONCLUSION: In summary, GA reversed EMT and EndoMT, as well as HLF-1 proliferation in vitro and prevented <d>pulmonary <d>fibrosis</d></d> in vivo by modulating <g>VASH-2</g>/<g>VASH-1</g> and suppressing the <g>TGF-b1</g>/<g>Smad3</g> pathway.
27013092|a|AIM OF THE STUDY: Idiopathic pulmonary fibrosis <d>IPF</d>, one of the clinical common diseases, shares similar pathogenesis with ancient disease "Feibi" in Chinese medicine, Renshen pingfei decoction RPFS, a classical prescription, was commonly used in treating Feibi. In the current study, the protective role of RPFS in rats model of <d>IPF</d> and the mechanism via regulation of TGF-b1/Smad3, were evaluated and explored. METHODS: The chemicals of RPFS were analyzed by UPLC-QTOF-MS. Under the optimized chromatographic and MS condition, the major components in RPFS were well separated and detected. An <d>IPF</d> model was established in rats which were induced with Bleomycin BLM. After treated with corresponding medicine for 7 days, 14 days, 21 days and 28 days respectively, lung function of rats were measured; peripheral blood and bronchoalveolar lavage fluid BALF were assessed; histopathological changes and homogenate of lung tissue were detected; TGF-b1 and Smad3 mRNA and protein expressions in lung tissue were examined as well. RESULTS: 43 signal peaks of chemical components in RPFS were identified by UPLC-QTOF-MS method. Compared with model group, RPFS group exerted significant effects on <d>IPF</d> model rats in improving lung function and decreasing HYP content of lung tissue P<0.01, reducing the level of TGF-b1 and NFkB in BALF P<0.05, decreasing SOD and MDA level in serum P<0.01, as well as down-regulating TGF-b1 and Smad3 mRNA and protein expressions of lung tissue P<0.01. CONCLUSION: RPFS could reduce the lung injury and fibrosis degree and improve lung function of <d>IPF</d> model rats. The protective role might mediated by down-regulating TGF-b1/Smad3 signaling pathway.
27013092|a|AIM OF THE STUDY: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d>, one of the clinical common diseases, shares similar pathogenesis with ancient disease "Feibi" in Chinese medicine, Renshen pingfei decoction RPFS, a classical prescription, was commonly used in treating Feibi. In the current study, the protective role of RPFS in rats model of <d>IPF</d> and the mechanism via regulation of <g>TGF-b1</g>/<g>Smad3</g>, were evaluated and explored. METHODS: The chemicals of RPFS were analyzed by UPLC-QTOF-MS. Under the optimized chromatographic and MS condition, the major components in RPFS were well separated and detected. An <d>IPF</d> model was established in rats which were induced with Bleomycin BLM. After treated with corresponding medicine for 7 days, 14 days, 21 days and 28 days respectively, lung function of rats were measured; peripheral blood and bronchoalveolar lavage fluid BALF were assessed; histopathological changes and homogenate of lung tissue were detected; <g>TGF-b1</g> and <g>Smad3</g> mRNA and protein expressions in lung tissue were examined as well. RESULTS: 43 signal peaks of chemical components in RPFS were identified by UPLC-QTOF-MS method. Compared with model group, RPFS group exerted significant effects on <d>IPF</d> model rats in improving lung function and decreasing HYP content of lung tissue P<0.01, reducing the level of <g>TGF-b1</g> and NFkB in BALF P<0.05, decreasing SOD and MDA level in serum P<0.01, as well as down-regulating <g>TGF-b1</g> and <g>Smad3</g> mRNA and protein expressions of lung tissue P<0.01. CONCLUSION: RPFS could reduce the lung injury and fibrosis degree and improve lung function of <d>IPF</d> model rats. The protective role might mediated by down-regulating <g>TGF-b1</g>/<g>Smad3</g> signaling pathway.
27013092|a|AIM OF THE STUDY: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d>, one of the clinical common diseases, shares similar pathogenesis with <d>ancient disease</d> "Feibi" in Chinese medicine, Renshen pingfei decoction RPFS, a classical prescription, was commonly used in treating Feibi. In the current study, the protective role of RPFS in rats model of <d>IPF</d> and the mechanism via regulation of <g>TGF-b1</g>/<g>Smad3</g>, were evaluated and explored. METHODS: The chemicals of RPFS were analyzed by UPLC-QTOF-MS. Under the optimized chromatographic and MS condition, the major components in RPFS were well separated and detected. An <d>IPF</d> model was established in rats which were induced with Bleomycin BLM. After treated with corresponding medicine for 7 days, 14 days, 21 days and 28 days respectively, lung function of rats were measured; peripheral blood and bronchoalveolar lavage fluid BALF were assessed; histopathological changes and homogenate of lung tissue were detected; <g>TGF-b1</g> and <g>Smad3</g> mRNA and protein expressions in lung tissue were examined as well. RESULTS: 43 signal peaks of chemical components in RPFS were identified by UPLC-QTOF-MS method. Compared with model group, RPFS group exerted significant effects on <d>IPF</d> model rats in improving lung function and decreasing HYP content of lung tissue P<0.01, reducing the level of <g>TGF-b1</g> and NFkB in BALF P<0.05, decreasing SOD and MDA level in serum P<0.01, as well as down-regulating <g>TGF-b1</g> and <g>Smad3</g> mRNA and protein expressions of lung tissue P<0.01. CONCLUSION: RPFS could reduce the lung injury and fibrosis degree and improve lung function of <d>IPF</d> model rats. The protective role might mediated by down-regulating <g>TGF-b1</g>/<g>Smad3</g> signaling pathway.
27013092|a|AIM OF THE STUDY: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d>, one of the clinical common diseases, shares similar pathogenesis with <d>ancient disease</d> "Feibi" in Chinese medicine, Renshen pingfei decoction RPFS, a classical prescription, was commonly used in treating Feibi. In the current study, the protective role of RPFS in rats model of <d>IPF</d> and the mechanism via regulation of <g>TGF-b1</g>/<g>Smad3</g>, were evaluated and explored. METHODS: The chemicals of RPFS were analyzed by UPLC-QTOF-MS. Under the optimized chromatographic and MS condition, the major components in RPFS were well separated and detected. An <d>IPF</d> model was established in rats which were induced with Bleomycin BLM. After treated with corresponding medicine for 7 days, 14 days, 21 days and 28 days respectively, lung function of rats were measured; peripheral blood and bronchoalveolar lavage fluid BALF were assessed; histopathological changes and homogenate of lung tissue were detected; <g>TGF-b1</g> and <g>Smad3</g> mRNA and protein expressions in lung tissue were examined as well. RESULTS: 43 signal peaks of chemical components in RPFS were identified by UPLC-QTOF-MS method. Compared with model group, RPFS group exerted significant effects on <d>IPF</d> model rats in improving lung function and decreasing HYP content of lung tissue P<0.01, reducing the level of <g>TGF-b1</g> and <g>NFkB</g> in BALF P<0.05, decreasing SOD and MDA level in serum P<0.01, as well as down-regulating <g>TGF-b1</g> and <g>Smad3</g> mRNA and protein expressions of lung tissue P<0.01. CONCLUSION: RPFS could reduce the <d>lung injury</d> and fibrosis degree and improve lung function of <d>IPF</d> model rats. The protective role might mediated by down-regulating <g>TGF-b1</g>/<g>Smad3</g> signaling pathway.
27013092|a|AIM OF THE STUDY: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, one of the clinical common diseases, shares similar pathogenesis with <d>ancient disease</d> "Feibi" in Chinese medicine, Renshen pingfei decoction RPFS, a classical prescription, was commonly used in treating Feibi. In the current study, the protective role of RPFS in rats model of <d>IPF</d> and the mechanism via regulation of <g>TGF-b1</g>/<g>Smad3</g>, were evaluated and explored. METHODS: The chemicals of RPFS were analyzed by UPLC-QTOF-MS. Under the optimized chromatographic and MS condition, the major components in RPFS were well separated and detected. An <d>IPF</d> model was established in rats which were induced with Bleomycin BLM. After treated with corresponding medicine for 7 days, 14 days, 21 days and 28 days respectively, lung function of rats were measured; peripheral blood and bronchoalveolar lavage fluid BALF were assessed; histopathological changes and homogenate of lung tissue were detected; <g>TGF-b1</g> and <g>Smad3</g> mRNA and protein expressions in lung tissue were examined as well. RESULTS: 43 signal peaks of chemical components in RPFS were identified by UPLC-QTOF-MS method. Compared with model group, RPFS group exerted significant effects on <d>IPF</d> model rats in improving lung function and decreasing HYP content of lung tissue P<0.01, reducing the level of <g>TGF-b1</g> and <g>NFkB</g> in BALF P<0.05, decreasing SOD and MDA level in serum P<0.01, as well as down-regulating <g>TGF-b1</g> and <g>Smad3</g> mRNA and protein expressions of lung tissue P<0.01. CONCLUSION: RPFS could reduce the <d>lung injury</d> and <d>fibrosis</d> degree and improve lung function of <d>IPF</d> model rats. The protective role might mediated by down-regulating <g>TGF-b1</g>/<g>Smad3</g> signaling pathway.
27070485|a|PURPOSE: To explore and establish an animal model of AE-IPF. METHODS: An animal model of <d>idiopathic pulmonary fibrosis</d> IPF was established using bleomycin BLM. Then, BLM was administered a second time on day 21 to induce AE-IPF which mimics human AE-IPF. Evaluation of the success of animal model was based on the survival of mice, as well as assessment of pathological changes in lung tissue. Preliminary investigation into the immunological mechanism of AE-IPF was also explored via the detection and identification of the inflammatory cells in mouse bronchoalveolar lavage fluid BALF and the concentrations of six cytokines IL-4, IL-6, IL-10, IL-17A, MIG, and TGF-b1 in BALF supernatants, which were closely associated with IPF and AE-IPF. The intervention role of IL-17A antibody to AE was explored. RESULTS: By week 4 after the second BLM administration, the mortality in the AE-IPF group was significantly greater 45%, 9/20 than that in stable-IPF group 0/18 P = .0017. The average body weight in AE-IPF group was significantly lower than that in stable group P < .0001. In AE-IPF group, inflammation and fibrosis were severer by histopathology analysis. In BALF, IL-17A, MIG CXCL-9, IL-6, and TGF-b1 levels in AE group were significantly higher. The percentages of neutrophils and Th17 cells in BALF were significantly higher in AE group P < .01; P = .0281. IL-17A antibody could attenuated the lung inflammation induced by twice BLM challenges. CONCLUSION: A mouse model of AE-IPF can be established using two administrations of BLM; Th17 cells may play a key role during the pathological process of AE-IPF.
27070485|a|PURPOSE: To explore and establish an animal model of <d>AE-IPF</d>. METHODS: An animal model of <d>idiopathic pulmonary fibrosis</d> IPF was established using bleomycin BLM. Then, BLM was administered a second time on day 21 to induce <d>AE-IPF</d> which mimics human <d>AE-IPF</d>. Evaluation of the success of animal model was based on the survival of mice, as well as assessment of pathological changes in lung tissue. Preliminary investigation into the immunological mechanism of <d>AE-IPF</d> was also explored via the detection and identification of the inflammatory cells in mouse bronchoalveolar lavage fluid BALF and the concentrations of six cytokines IL-4, IL-6, IL-10, IL-17A, MIG, and TGF-b1 in BALF supernatants, which were closely associated with IPF and <d>AE-IPF</d>. The intervention role of IL-17A antibody to AE was explored. RESULTS: By week 4 after the second BLM administration, the mortality in the <d>AE-IPF</d> group was significantly greater 45%, 9/20 than that in stable-IPF group 0/18 P = .0017. The average body weight in <d>AE-IPF</d> group was significantly lower than that in stable group P < .0001. In <d>AE-IPF</d> group, inflammation and fibrosis were severer by histopathology analysis. In BALF, IL-17A, MIG CXCL-9, IL-6, and TGF-b1 levels in AE group were significantly higher. The percentages of neutrophils and Th17 cells in BALF were significantly higher in AE group P < .01; P = .0281. IL-17A antibody could attenuated the lung inflammation induced by twice BLM challenges. CONCLUSION: A mouse model of <d>AE-IPF</d> can be established using two administrations of BLM; Th17 cells may play a key role during the pathological process of <d>AE-IPF</d>.
27070485|a|PURPOSE: To explore and establish an animal model of <d>AE-<d>IPF</d></d>. METHODS: An animal model of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> was established using bleomycin BLM. Then, BLM was administered a second time on day 21 to induce <d>AE-<d>IPF</d></d> which mimics human <d>AE-<d>IPF</d></d>. Evaluation of the success of animal model was based on the survival of mice, as well as assessment of pathological changes in lung tissue. Preliminary investigation into the immunological mechanism of <d>AE-<d>IPF</d></d> was also explored via the detection and identification of the inflammatory cells in mouse bronchoalveolar lavage fluid BALF and the concentrations of six cytokines IL-4, IL-6, IL-10, IL-17A, MIG, and TGF-b1 in BALF supernatants, which were closely associated with <d>IPF</d> and <d>AE-<d>IPF</d></d>. The intervention role of IL-17A antibody to AE was explored. RESULTS: By week 4 after the second BLM administration, the mortality in the <d>AE-<d>IPF</d></d> group was significantly greater 45%, 9/20 than that in stable-<d>IPF</d> group 0/18 P = .0017. The average body weight in <d>AE-<d>IPF</d></d> group was significantly lower than that in stable group P < .0001. In <d>AE-<d>IPF</d></d> group, inflammation and fibrosis were severer by histopathology analysis. In BALF, IL-17A, MIG CXCL-9, IL-6, and TGF-b1 levels in AE group were significantly higher. The percentages of neutrophils and Th17 cells in BALF were significantly higher in AE group P < .01; P = .0281. IL-17A antibody could attenuated the lung inflammation induced by twice BLM challenges. CONCLUSION: A mouse model of <d>AE-<d>IPF</d></d> can be established using two administrations of BLM; Th17 cells may play a key role during the pathological process of <d>AE-<d>IPF</d></d>.
27070485|a|PURPOSE: To explore and establish an animal model of <d>AE-<d>IPF</d></d>. METHODS: An animal model of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> was established using bleomycin BLM. Then, BLM was administered a second time on day 21 to induce <d>AE-<d>IPF</d></d> which mimics human <d>AE-<d>IPF</d></d>. Evaluation of the success of animal model was based on the survival of mice, as well as assessment of pathological changes in lung tissue. Preliminary investigation into the immunological mechanism of <d>AE-<d>IPF</d></d> was also explored via the detection and identification of the inflammatory cells in mouse bronchoalveolar lavage fluid BALF and the concentrations of six cytokines <g>IL-4</g>, <g>IL-6</g>, <g>IL-10</g>, <g>IL-17A</g>, <g>MIG</g>, and <g>TGF-b1</g> in BALF supernatants, which were closely associated with <d>IPF</d> and <d>AE-<d>IPF</d></d>. The intervention role of <g>IL-17A</g> antibody to AE was explored. RESULTS: By week 4 after the second BLM administration, the mortality in the <d>AE-<d>IPF</d></d> group was significantly greater 45%, 9/20 than that in stable-<d>IPF</d> group 0/18 P = .0017. The average body weight in <d>AE-<d>IPF</d></d> group was significantly lower than that in stable group P < .0001. In <d>AE-<d>IPF</d></d> group, <d>inflammation</d> and fibrosis were severer by histopathology analysis. In BALF, <g>IL-17A</g>, <g>MIG</g> CXCL-9, <g>IL-6</g>, and <g>TGF-b1</g> levels in AE group were significantly higher. The percentages of neutrophils and Th17 cells in BALF were significantly higher in AE group P < .01; P = .0281. <g>IL-17A</g> antibody could attenuated the lung <d>inflammation</d> induced by twice BLM challenges. CONCLUSION: A mouse model of <d>AE-<d>IPF</d></d> can be established using two administrations of BLM; Th17 cells may play a key role during the pathological process of <d>AE-<d>IPF</d></d>.
27070485|a|PURPOSE: To explore and establish an animal model of <d>AE-<d>IPF</d></d>. METHODS: An animal model of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> was established using bleomycin BLM. Then, BLM was administered a second time on day 21 to induce <d>AE-<d>IPF</d></d> which mimics human <d>AE-<d>IPF</d></d>. Evaluation of the success of animal model was based on the survival of mice, as well as assessment of pathological changes in lung tissue. Preliminary investigation into the immunological mechanism of <d>AE-<d>IPF</d></d> was also explored via the detection and identification of the inflammatory cells in mouse bronchoalveolar lavage fluid BALF and the concentrations of six cytokines <g>IL-4</g>, <g>IL-6</g>, <g>IL-10</g>, <g>IL-17A</g>, <g>MIG</g>, and <g>TGF-b1</g> in BALF supernatants, which were closely associated with <d>IPF</d> and <d>AE-<d>IPF</d></d>. The intervention role of <g>IL-17A</g> antibody to AE was explored. RESULTS: By week 4 after the second BLM administration, the mortality in the <d>AE-<d>IPF</d></d> group was significantly greater 45%, 9/20 than that in stable-<d>IPF</d> group 0/18 P = .0017. The average body weight in <d>AE-<d>IPF</d></d> group was significantly lower than that in stable group P < .0001. In <d>AE-<d>IPF</d></d> group, <d>inflammation</d> and <d>fibrosis</d> were severer by histopathology analysis. In BALF, <g>IL-17A</g>, <g>MIG</g> CXCL-9, <g>IL-6</g>, and <g>TGF-b1</g> levels in AE group were significantly higher. The percentages of neutrophils and Th17 cells in BALF were significantly higher in AE group P < .01; P = .0281. <g>IL-17A</g> antibody could attenuated the lung <d>inflammation</d> induced by twice BLM challenges. CONCLUSION: A mouse model of <d>AE-<d>IPF</d></d> can be established using two administrations of BLM; Th17 cells may play a key role during the pathological process of <d>AE-<d>IPF</d></d>.
27071460|a|BACKGROUND: WNT/b-catenin signaling plays an important role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF; however, the role of <g>WNT10A</g> via transforming growth factor <g>TGF-b</g> signaling remains unclear. METHODS: We evaluated the expression of <g>WNT10A</g> and <g>TGF-b</g> in bleomycin BLM-treated mice and the interactions between <g>TGF-b</g> or BLM and <g>WNT10A</g> in vitro. Additionally, we investigated IPF patients who underwent video-assisted thoracoscopic surgery to determine whether the <g>WNT10A</g> expression is related to the survival. RESULTS: Increased <g>WNT10A</g> and <g>TGF-b</g> expressions were noted in the BLM-treated mice. Real-time PCR and luciferase reporter assays demonstrated the levels of <g>WNT10A</g> and collagen in the fibroblasts cells to increase after <g>TGF-b</g> administration. Conversely, <g>WNT10A</g> siRNA treatment inhibited the synthesis of collagen in the transfected fibroblasts cells. A Kaplan-Meier survival analysis demonstrated a tendency toward a poor survival among the IPF patients with a <g>WNT10A</g>-positive expression compared to those with a negative expression Hazard ratio 5.351, 95 % CI 1.703-16.82; p   =   0.0041. An overexpression of <g>WNT10A</g> was found to be significantly predictive of an acute exacerbation of IPF AE-IPF Odds ratio 13.69, 95 % CI 1.728-108.5; p   =   0.013. CONCLUSIONS: <g>WNT10A</g> plays an important role in the pathogenesis of IPF via <g>TGF-b</g> activation and it may also be a sensitive predictor for the onset of an AE-IPF.
27071460|a|BACKGROUND: WNT/b-catenin signaling plays an important role in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>; however, the role of <g>WNT10A</g> via transforming growth factor <g>TGF-b</g> signaling remains unclear. METHODS: We evaluated the expression of <g>WNT10A</g> and <g>TGF-b</g> in bleomycin BLM-treated mice and the interactions between <g>TGF-b</g> or BLM and <g>WNT10A</g> in vitro. Additionally, we investigated <d>IPF</d> patients who underwent video-assisted thoracoscopic surgery to determine whether the <g>WNT10A</g> expression is related to the survival. RESULTS: Increased <g>WNT10A</g> and <g>TGF-b</g> expressions were noted in the BLM-treated mice. Real-time PCR and luciferase reporter assays demonstrated the levels of <g>WNT10A</g> and collagen in the fibroblasts cells to increase after <g>TGF-b</g> administration. Conversely, <g>WNT10A</g> siRNA treatment inhibited the synthesis of collagen in the transfected fibroblasts cells. A Kaplan-Meier survival analysis demonstrated a tendency toward a poor survival among the <d>IPF</d> patients with a <g>WNT10A</g>-positive expression compared to those with a negative expression Hazard ratio 5.351, 95 % CI 1.703-16.82; p   =   0.0041. An overexpression of <g>WNT10A</g> was found to be significantly predictive of an acute exacerbation of <d>IPF</d> AE-<d>IPF</d> Odds ratio 13.69, 95 % CI 1.728-108.5; p   =   0.013. CONCLUSIONS: <g>WNT10A</g> plays an important role in the pathogenesis of <d>IPF</d> via <g>TGF-b</g> activation and it may also be a sensitive predictor for the onset of an AE-<d>IPF</d>.
27080864|a|BACKGROUND: <g>CD248</g> or <g>Endosialin</g> is a transmembrane molecule expressed in stromal cells binding to extracellular matrix ECM components. It has been previously implicated in kidney <d>fibrosis</d>, rheumatoid arthritis as well as in tumour-stromal interactions. This study investigates the role of <g>CD248</g> in the pathogenesis of fibrotic diseases in Idiopathic Pulmonary Fibrosis IPF. METHODS: <g>CD248</g> quantitative immunohistochemistry IHC was performed on lung samples from 22 IPF patients and its expression was assayed in cultured pulmonary fibroblasts and epithelial cells. Effects of <g>CD248</g> silencing was evaluated on fibroblast proliferation and myofibroblast differentiation. RESULTS: IHC revealed strong <g>CD248</g> expression in mesenchymal cells of normal lung structures such as pleura and adventitia but not in epithelium. Fibrotic areas showed markedly stronger staining than unaffected lung tissue. The extent of <g>CD248</g> staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO r2   >   0        35, p   <   0        01. <g>CD248</g> protein levels were significantly greater in IPF-derived lung fibroblasts vs normal lung fibroblasts p   <   0        01 and <g>CD248</g> silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation. CONCLUSION: We conclude that <g>CD248</g> overexpression is possibly involved in the pathogenesis of IPF and it has potential as a disease severity marker. Given that <g>CD248</g> ligands are collagen type I, IV and fibronectin, we hypothesise that <g>CD248</g> signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in IPF.
27080864|a|BACKGROUND: <g>CD248</g> or <g>Endosialin</g> is a transmembrane molecule expressed in stromal cells binding to extracellular matrix ECM components. It has been previously implicated in kidney <d>fibrosis</d>, <d>rheumatoid arthritis</d> as well as in tumour-stromal interactions. This study investigates the role of <g>CD248</g> in the pathogenesis of fibrotic diseases in Idiopathic Pulmonary Fibrosis IPF. METHODS: <g>CD248</g> quantitative immunohistochemistry IHC was performed on lung samples from 22 IPF patients and its expression was assayed in cultured pulmonary fibroblasts and epithelial cells. Effects of <g>CD248</g> silencing was evaluated on fibroblast proliferation and myofibroblast differentiation. RESULTS: IHC revealed strong <g>CD248</g> expression in mesenchymal cells of normal lung structures such as pleura and adventitia but not in epithelium. Fibrotic areas showed markedly stronger staining than unaffected lung tissue. The extent of <g>CD248</g> staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO r2   >   0        35, p   <   0        01. <g>CD248</g> protein levels were significantly greater in IPF-derived lung fibroblasts vs normal lung fibroblasts p   <   0        01 and <g>CD248</g> silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation. CONCLUSION: We conclude that <g>CD248</g> overexpression is possibly involved in the pathogenesis of IPF and it has potential as a disease severity marker. Given that <g>CD248</g> ligands are collagen type I, IV and fibronectin, we hypothesise that <g>CD248</g> signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in IPF.
27080864|a|BACKGROUND: <g>CD248</g> or <g>Endosialin</g> is a transmembrane molecule expressed in stromal cells binding to extracellular matrix ECM components. It has been previously implicated in kidney <d>fibrosis</d>, <d>rheumatoid arthritis</d> as well as in <d>tumour</d>-stromal interactions. This study investigates the role of <g>CD248</g> in the pathogenesis of fibrotic diseases in Idiopathic Pulmonary Fibrosis IPF. METHODS: <g>CD248</g> quantitative immunohistochemistry IHC was performed on lung samples from 22 IPF patients and its expression was assayed in cultured pulmonary fibroblasts and epithelial cells. Effects of <g>CD248</g> silencing was evaluated on fibroblast proliferation and myofibroblast differentiation. RESULTS: IHC revealed strong <g>CD248</g> expression in mesenchymal cells of normal lung structures such as pleura and adventitia but not in epithelium. Fibrotic areas showed markedly stronger staining than unaffected lung tissue. The extent of <g>CD248</g> staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO r2   >   0        35, p   <   0        01. <g>CD248</g> protein levels were significantly greater in IPF-derived lung fibroblasts vs normal lung fibroblasts p   <   0        01 and <g>CD248</g> silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation. CONCLUSION: We conclude that <g>CD248</g> overexpression is possibly involved in the pathogenesis of IPF and it has potential as a disease severity marker. Given that <g>CD248</g> ligands are collagen type I, IV and fibronectin, we hypothesise that <g>CD248</g> signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in IPF.
27080864|a|BACKGROUND: <g>CD248</g> or <g>Endosialin</g> is a transmembrane molecule expressed in stromal cells binding to extracellular matrix ECM components. It has been previously implicated in kidney <d>fibrosis</d>, <d>rheumatoid arthritis</d> as well as in <d>tumour</d>-stromal interactions. This study investigates the role of <g>CD248</g> in the pathogenesis of <d>fibrotic diseases</d> in Idiopathic Pulmonary Fibrosis IPF. METHODS: <g>CD248</g> quantitative immunohistochemistry IHC was performed on lung samples from 22 IPF patients and its expression was assayed in cultured pulmonary fibroblasts and epithelial cells. Effects of <g>CD248</g> silencing was evaluated on fibroblast proliferation and myofibroblast differentiation. RESULTS: IHC revealed strong <g>CD248</g> expression in mesenchymal cells of normal lung structures such as pleura and adventitia but not in epithelium. Fibrotic areas showed markedly stronger staining than unaffected lung tissue. The extent of <g>CD248</g> staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO r2   >   0        35, p   <   0        01. <g>CD248</g> protein levels were significantly greater in IPF-derived lung fibroblasts vs normal lung fibroblasts p   <   0        01 and <g>CD248</g> silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation. CONCLUSION: We conclude that <g>CD248</g> overexpression is possibly involved in the pathogenesis of IPF and it has potential as a disease severity marker. Given that <g>CD248</g> ligands are collagen type I, IV and fibronectin, we hypothesise that <g>CD248</g> signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in IPF.
27080864|a|BACKGROUND: <g>CD248</g> or <g>Endosialin</g> is a transmembrane molecule expressed in stromal cells binding to extracellular matrix ECM components. It has been previously implicated in kidney <d>fibrosis</d>, <d>rheumatoid arthritis</d> as well as in <d>tumour</d>-stromal interactions. This study investigates the role of <g>CD248</g> in the pathogenesis of <d>fibrotic diseases</d> in <d>Idiopathic Pulmonary Fibrosis</d> IPF. METHODS: <g>CD248</g> quantitative immunohistochemistry IHC was performed on lung samples from 22 IPF patients and its expression was assayed in cultured pulmonary fibroblasts and epithelial cells. Effects of <g>CD248</g> silencing was evaluated on fibroblast proliferation and myofibroblast differentiation. RESULTS: IHC revealed strong <g>CD248</g> expression in mesenchymal cells of normal lung structures such as pleura and adventitia but not in epithelium. Fibrotic areas showed markedly stronger staining than unaffected lung tissue. The extent of <g>CD248</g> staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO r2   >   0        35, p   <   0        01. <g>CD248</g> protein levels were significantly greater in IPF-derived lung fibroblasts vs normal lung fibroblasts p   <   0        01 and <g>CD248</g> silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation. CONCLUSION: We conclude that <g>CD248</g> overexpression is possibly involved in the pathogenesis of IPF and it has potential as a disease severity marker. Given that <g>CD248</g> ligands are collagen type I, IV and fibronectin, we hypothesise that <g>CD248</g> signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in IPF.
27080864|a|BACKGROUND: <g>CD248</g> or <g>Endosialin</g> is a transmembrane molecule expressed in stromal cells binding to extracellular matrix ECM components. It has been previously implicated in kidney <d>fibrosis</d>, <d>rheumatoid arthritis</d> as well as in <d>tumour</d>-stromal interactions. This study investigates the role of <g>CD248</g> in the pathogenesis of <d>fibrotic diseases</d> in <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d>. METHODS: <g>CD248</g> quantitative immunohistochemistry IHC was performed on lung samples from 22 <d>IPF</d> patients and its expression was assayed in cultured pulmonary fibroblasts and epithelial cells. Effects of <g>CD248</g> silencing was evaluated on fibroblast proliferation and myofibroblast differentiation. RESULTS: IHC revealed strong <g>CD248</g> expression in mesenchymal cells of normal lung structures such as pleura and adventitia but not in epithelium. Fibrotic areas showed markedly stronger staining than unaffected lung tissue. The extent of <g>CD248</g> staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO r2   >   0        35, p   <   0        01. <g>CD248</g> protein levels were significantly greater in <d>IPF</d>-derived lung fibroblasts vs normal lung fibroblasts p   <   0        01 and <g>CD248</g> silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation. CONCLUSION: We conclude that <g>CD248</g> overexpression is possibly involved in the pathogenesis of <d>IPF</d> and it has potential as a disease severity marker. Given that <g>CD248</g> ligands are collagen type I, IV and fibronectin, we hypothesise that <g>CD248</g> signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in <d>IPF</d>.
27107963|a|BACKGROUND: <d>Interstitial pneumonia</d> in connective tissue diseases CTD-IP featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells MSCs may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts HLFs from patients pathologically diagnosed with usual interstitial pneumonia UIP and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals HBMSCs on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell Treg level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of a-smooth muscle actin a-SMA. The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis IPF. HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked a-SMA activation in CTD-UIP HLFs through a TGF-b1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-b1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice. CONCLUSIONS: Impairment of TGF-b signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-b1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.
27107963|a|BACKGROUND: <d>Interstitial pneumonia</d> in <d>connective tissue diseases</d> CTD-IP featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells MSCs may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts HLFs from patients pathologically diagnosed with usual interstitial pneumonia UIP and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals HBMSCs on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell Treg level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of a-smooth muscle actin a-SMA. The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis IPF. HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked a-SMA activation in CTD-UIP HLFs through a TGF-b1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-b1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice. CONCLUSIONS: Impairment of TGF-b signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-b1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.
27107963|a|BACKGROUND: <d>Interstitial pneumonia</d> in <d>connective tissue diseases</d> CTD-<d>IP</d> featuring inflammation and fibrosis is a leading cause of death in CTD-<d>IP</d> patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells MSCs may represent a promising therapeutic agent in CTD-<d>IP</d>. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-<d>IP</d> patients, and human primary lung fibroblasts HLFs from patients pathologically diagnosed with usual interstitial pneumonia U<d>IP</d> and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-<d>IP</d> were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals HBMSCs on cytotoxic T cells and CTD-U<d>IP</d> HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-<d>IP</d> patients, accompanied with a reduced regulatory T cell Treg level. CTD-U<d>IP</d> HLFs secreted proinflammatory cytokines in combination with upregulation of a-smooth muscle actin a-SMA. The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis <d>IP</d>F. HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked a-SMA activation in CTD-U<d>IP</d> HLFs through a TGF-b1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to <d>IP</d>-10 expression. MSCs secreting a higher level of TGF-b1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice. CONCLUSIONS: Impairment of TGF-b signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-<d>IP</d> and to myofibroblast differentiation in CTD-U<d>IP</d> HLFs. HBMSCs can sensitize TGF-b1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic <d>IP</d>-10 production. This may in turn block progression of lung fibrosis in autoimmunity.
27107963|a|BACKGROUND: <d>Interstitial pneumonia</d> in <d>connective tissue diseases</d> CTD-<d>IP</d> featuring <d>inflammation</d> and fibrosis is a leading cause of death in CTD-<d>IP</d> patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells MSCs may represent a promising therapeutic agent in CTD-<d>IP</d>. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-<d>IP</d> patients, and human primary lung fibroblasts HLFs from patients pathologically diagnosed with usual interstitial pneumonia U<d>IP</d> and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-<d>IP</d> were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals HBMSCs on cytotoxic T cells and CTD-U<d>IP</d> HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-<d>IP</d> patients, accompanied with a reduced regulatory T cell Treg level. CTD-U<d>IP</d> HLFs secreted proinflammatory cytokines in combination with upregulation of a-smooth muscle actin a-SMA. The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis <d>IP</d>F. HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked a-SMA activation in CTD-U<d>IP</d> HLFs through a TGF-b1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to <d>IP</d>-10 expression. MSCs secreting a higher level of TGF-b1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice. CONCLUSIONS: Impairment of TGF-b signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-<d>IP</d> and to myofibroblast differentiation in CTD-U<d>IP</d> HLFs. HBMSCs can sensitize TGF-b1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic <d>IP</d>-10 production. This may in turn block progression of lung fibrosis in autoimmunity.
27107963|a|BACKGROUND: <d>Interstitial pneumonia</d> in <d>connective tissue diseases</d> CTD-<d>IP</d> featuring <d>inflammation</d> and <d>fibrosis</d> is a leading cause of death in CTD-<d>IP</d> patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells MSCs may represent a promising therapeutic agent in CTD-<d>IP</d>. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-<d>IP</d> patients, and human primary lung fibroblasts HLFs from patients pathologically diagnosed with usual interstitial pneumonia U<d>IP</d> and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-<d>IP</d> were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals HBMSCs on cytotoxic T cells and CTD-U<d>IP</d> HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-<d>IP</d> patients, accompanied with a reduced regulatory T cell Treg level. CTD-U<d>IP</d> HLFs secreted proinflammatory cytokines in combination with upregulation of a-smooth muscle actin a-SMA. The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary <d>fibrosis</d> <d>IP</d>F. HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked a-SMA activation in CTD-U<d>IP</d> HLFs through a TGF-b1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to <d>IP</d>-10 expression. MSCs secreting a higher level of TGF-b1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary <d>fibrosis</d> in mice. CONCLUSIONS: Impairment of TGF-b signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-<d>IP</d> and to myofibroblast differentiation in CTD-U<d>IP</d> HLFs. HBMSCs can sensitize TGF-b1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic <d>IP</d>-10 production. This may in turn block progression of lung <d>fibrosis</d> in autoimmunity.
27107963|a|BACKGROUND: <d>Interstitial pneumonia</d> in <d>connective tissue diseases</d> CTD-<d>IP</d> featuring <d>inflammation</d> and <d>fibrosis</d> is a leading cause of <d>death</d> in CTD-<d>IP</d> patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells MSCs may represent a promising therapeutic agent in CTD-<d>IP</d>. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-<d>IP</d> patients, and human primary lung fibroblasts HLFs from patients pathologically diagnosed with usual interstitial pneumonia U<d>IP</d> and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-<d>IP</d> were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals HBMSCs on cytotoxic T cells and CTD-U<d>IP</d> HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-<d>IP</d> patients, accompanied with a reduced regulatory T cell Treg level. CTD-U<d>IP</d> HLFs secreted proinflammatory cytokines in combination with upregulation of a-smooth muscle actin a-SMA. The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary <d>fibrosis</d> <d>IP</d>F. HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked a-SMA activation in CTD-U<d>IP</d> HLFs through a TGF-b1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to <d>IP</d>-10 expression. MSCs secreting a higher level of TGF-b1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary <d>fibrosis</d> in mice. CONCLUSIONS: Impairment of TGF-b signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-<d>IP</d> and to myofibroblast differentiation in CTD-U<d>IP</d> HLFs. HBMSCs can sensitize TGF-b1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic <d>IP</d>-10 production. This may in turn block progression of lung <d>fibrosis</d> in autoimmunity.
27107963|a|BACKGROUND: <d>Interstitial pneumonia</d> in <d>connective tissue diseases</d> CTD-<d>IP</d> featuring <d>inflammation</d> and <d>fibrosis</d> is a leading cause of <d>death</d> in CTD-<d>IP</d> patients. The related <d>autoimmune lung injury</d> and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells MSCs may represent a promising therapeutic agent in CTD-<d>IP</d>. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-<d>IP</d> patients, and human primary lung fibroblasts HLFs from patients pathologically diagnosed with usual interstitial pneumonia U<d>IP</d> and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-<d>IP</d> were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals HBMSCs on cytotoxic T cells and CTD-U<d>IP</d> HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-<d>IP</d> patients, accompanied with a reduced regulatory T cell Treg level. CTD-U<d>IP</d> HLFs secreted proinflammatory cytokines in combination with upregulation of a-smooth muscle actin a-SMA. The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary <d>fibrosis</d> <d>IP</d>F. HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked a-SMA activation in CTD-U<d>IP</d> HLFs through a TGF-b1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to <d>IP</d>-10 expression. MSCs secreting a higher level of TGF-b1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary <d>fibrosis</d> in mice. CONCLUSIONS: Impairment of TGF-b signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-<d>IP</d> and to myofibroblast differentiation in CTD-U<d>IP</d> HLFs. HBMSCs can sensitize TGF-b1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic <d>IP</d>-10 production. This may in turn block progression of lung <d>fibrosis</d> in autoimmunity.
27107963|a|BACKGROUND: <d>Interstitial pneumonia</d> in <d>connective tissue diseases</d> CTD-<d>IP</d> featuring <d>inflammation</d> and <d>fibrosis</d> is a leading cause of <d>death</d> in CTD-<d>IP</d> patients. The related <d>autoimmune lung injury</d> and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells MSCs may represent a promising therapeutic agent in CTD-<d>IP</d>. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during <d>autoimmunity</d> and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-<d>IP</d> patients, and human primary lung fibroblasts HLFs from patients pathologically diagnosed with usual interstitial pneumonia U<d>IP</d> and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-<d>IP</d> were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals HBMSCs on cytotoxic T cells and CTD-U<d>IP</d> HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-<d>IP</d> patients, accompanied with a reduced regulatory T cell Treg level. CTD-U<d>IP</d> HLFs secreted proinflammatory cytokines in combination with upregulation of a-smooth muscle actin a-SMA. The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary <d>fibrosis</d> <d>IP</d>F. HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked a-SMA activation in CTD-U<d>IP</d> HLFs through a TGF-b1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to <d>IP</d>-10 expression. MSCs secreting a higher level of TGF-b1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary <d>fibrosis</d> in mice. CONCLUSIONS: Impairment of TGF-b signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-<d>IP</d> and to myofibroblast differentiation in CTD-U<d>IP</d> HLFs. HBMSCs can sensitize TGF-b1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic <d>IP</d>-10 production. This may in turn block progression of lung <d>fibrosis</d> in <d>autoimmunity</d>.
27107963|a|BACKGROUND: <d>Interstitial pneumonia</d> in <d>connective tissue diseases</d> CTD-<d>IP</d> featuring <d>inflammation</d> and <d>fibrosis</d> is a leading cause of <d>death</d> in CTD-<d>IP</d> patients. The related <d>autoimmune lung injury</d> and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells MSCs may represent a promising therapeutic agent in CTD-<d>IP</d>. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during <d>autoimmunity</d> and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-<d>IP</d> patients, and human primary lung fibroblasts HLFs from patients pathologically diagnosed with <d>usual interstitial pneumonia</d> U<d>IP</d> and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-<d>IP</d> were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals HBMSCs on cytotoxic T cells and CTD-U<d>IP</d> HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-<d>IP</d> patients, accompanied with a reduced regulatory T cell Treg level. CTD-U<d>IP</d> HLFs secreted proinflammatory cytokines in combination with upregulation of a-smooth muscle actin a-SMA. The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary <d>fibrosis</d> <d>IP</d>F. HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked a-SMA activation in CTD-U<d>IP</d> HLFs through a TGF-b1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to <d>IP</d>-10 expression. MSCs secreting a higher level of TGF-b1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary <d>fibrosis</d> in mice. CONCLUSIONS: Impairment of TGF-b signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-<d>IP</d> and to myofibroblast differentiation in CTD-U<d>IP</d> HLFs. HBMSCs can sensitize TGF-b1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic <d>IP</d>-10 production. This may in turn block progression of lung <d>fibrosis</d> in <d>autoimmunity</d>.
27144281|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> IPF is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine <g>TGF-b</g> has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, <g>MAP3K19</g>, upregulated in IPF tissue, in <g>TGF-b</g>-induced signal transduction and in bleomycin-induced pulmonary fibrosis. <g>MAP3K19</g> has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. <g>MAP3K19</g> was also found to be overexpressed in bronchoalveolar lavage macrophages from IPF patients compared to normal patients. Treatment of A549 or THP-1 cells with either <g>MAP3K19</g> siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 _ 3 nuclear translocation following <g>TGF-b</g> stimulation. <g>TGF-b</g>-induced gene transcription was also strongly inhibited by both the <g>MAP3K19</g> inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the <g>MAP3K19</g> inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of IPF, inhibition of <g>MAP3K19</g> strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of <g>MAP3K19</g> may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease.
27144281|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine <g>TGF-b</g> has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, <g>MAP3K19</g>, upregulated in <d>IPF</d> tissue, in <g>TGF-b</g>-induced signal transduction and in bleomycin-induced pulmonary fibrosis. <g>MAP3K19</g> has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. <g>MAP3K19</g> was also found to be overexpressed in bronchoalveolar lavage macrophages from <d>IPF</d> patients compared to normal patients. Treatment of A549 or THP-1 cells with either <g>MAP3K19</g> siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 _ 3 nuclear translocation following <g>TGF-b</g> stimulation. <g>TGF-b</g>-induced gene transcription was also strongly inhibited by both the <g>MAP3K19</g> inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the <g>MAP3K19</g> inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of <d>IPF</d>, inhibition of <g>MAP3K19</g> strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of <g>MAP3K19</g> may have a beneficial therapeutic effect in the treatment of <d>IPF</d> and represents a novel strategy to target this disease.
27144281|a|UNASSIGNED: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine <g>TGF-b</g> has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, <g>MAP3K19</g>, upregulated in <d>IPF</d> tissue, in <g>TGF-b</g>-induced signal transduction and in bleomycin-induced <d>pulmonary fibrosis</d>. <g>MAP3K19</g> has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. <g>MAP3K19</g> was also found to be overexpressed in bronchoalveolar lavage macrophages from <d>IPF</d> patients compared to normal patients. Treatment of A549 or THP-1 cells with either <g>MAP3K19</g> siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 _ 3 nuclear translocation following <g>TGF-b</g> stimulation. <g>TGF-b</g>-induced gene transcription was also strongly inhibited by both the <g>MAP3K19</g> inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the <g>MAP3K19</g> inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of <d>IPF</d>, inhibition of <g>MAP3K19</g> strongly attenuated bleomycin-induced <d>pulmonary fibrosis</d> when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of <g>MAP3K19</g> may have a beneficial therapeutic effect in the treatment of <d>IPF</d> and represents a novel strategy to target this disease.
27144281|a|UNASSIGNED: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine <g>TGF-b</g> has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, <g>MAP3K19</g>, upregulated in <d>IPF</d> tissue, in <g>TGF-b</g>-induced signal transduction and in bleomycin-induced <d>pulmonary fibrosis</d>. <g>MAP3K19</g> has a very limited tissue expression, restricted primarily to the lungs and <d>trachea</d>. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. <g>MAP3K19</g> was also found to be overexpressed in bronchoalveolar lavage macrophages from <d>IPF</d> patients compared to normal patients. Treatment of A549 or THP-1 cells with either <g>MAP3K19</g> siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 _ 3 nuclear translocation following <g>TGF-b</g> stimulation. <g>TGF-b</g>-induced gene transcription was also strongly inhibited by both the <g>MAP3K19</g> inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the <g>MAP3K19</g> inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of <d>IPF</d>, inhibition of <g>MAP3K19</g> strongly attenuated bleomycin-induced <d>pulmonary fibrosis</d> when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of <g>MAP3K19</g> may have a beneficial therapeutic effect in the treatment of <d>IPF</d> and represents a novel strategy to target this disease.
27215343|a|BACKGROUND: Idiopathic pulmonary fibrosis IPF is a chronic lung disorder of unknown origin, which ultimately leads to death. Several growth factors such as IGFs insulin-like-growth factor and IGFBPs insulin like growth factor binding proteins seem to take part to the pathogenesis. We evaluated IGFs and IGFBPs in serum from patients with IPF and healthy subjects including 24 untreated IPF and 26 IPF receiving anti-fibrotic therapy and to compare them with healthy subjects. METHODS: Serum of 50 <d>idiopathic pulmonary fibrosis</d> and 55 healthy subjects HS were analysed by ELISA for IGFs and IGFBPs, TGF-b and KL-6, the latter being tested as positive control in IPF. RESULTS: Serum levels of <g>IGFBP-1</g> and <g>IGFBP-2</g> and KL-6 were significantly higher in the IPF group than in the healthy subjects p   <   0.05, p   <   0.001 and p   <   0.0001 respectively while the picture was inversed regarding IGFs. By contrast there was no significant difference between the groups with respect to TGF-b. <g>IGFBP-2</g> was significantly reduced in the patients with specific anti-fibrotic therapy pirfenidone and nintedanib compared to untreated patients p   <   0.05 but still significantly elevated in comparison to HS p   <   0.001. CONCLUSION: Serum <g>IGFBP-1</g> and -2 are increased in <d>idiopathic pulmonary fibrosis</d> and <g>IGFBP-2</g> may be reduced by anti-fibrosing therapy. IGFBPs may be promising biomarkers in IPF.
27215343|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is a chronic lung disorder of unknown origin, which ultimately leads to death. Several growth factors such as IGFs insulin-like-growth factor and IGFBPs insulin like growth factor binding proteins seem to take part to the pathogenesis. We evaluated IGFs and IGFBPs in serum from patients with IPF and healthy subjects including 24 untreated IPF and 26 IPF receiving anti-fibrotic therapy and to compare them with healthy subjects. METHODS: Serum of 50 <d>idiopathic pulmonary fibrosis</d> and 55 healthy subjects HS were analysed by ELISA for IGFs and IGFBPs, TGF-b and KL-6, the latter being tested as positive control in IPF. RESULTS: Serum levels of <g>IGFBP-1</g> and <g>IGFBP-2</g> and KL-6 were significantly higher in the IPF group than in the healthy subjects p   <   0.05, p   <   0.001 and p   <   0.0001 respectively while the picture was inversed regarding IGFs. By contrast there was no significant difference between the groups with respect to TGF-b. <g>IGFBP-2</g> was significantly reduced in the patients with specific anti-fibrotic therapy pirfenidone and nintedanib compared to untreated patients p   <   0.05 but still significantly elevated in comparison to HS p   <   0.001. CONCLUSION: Serum <g>IGFBP-1</g> and -2 are increased in <d>idiopathic pulmonary fibrosis</d> and <g>IGFBP-2</g> may be reduced by anti-fibrosing therapy. IGFBPs may be promising biomarkers in IPF.
27215343|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic lung disorder of unknown origin, which ultimately leads to death. Several growth factors such as IGFs insulin-like-growth factor and IGFBPs insulin like growth factor binding proteins seem to take part to the pathogenesis. We evaluated IGFs and IGFBPs in serum from patients with <d>IPF</d> and healthy subjects including 24 untreated <d>IPF</d> and 26 <d>IPF</d> receiving anti-fibrotic therapy and to compare them with healthy subjects. METHODS: Serum of 50 <d>idiopathic pulmonary fibrosis</d> and 55 healthy subjects HS were analysed by ELISA for IGFs and IGFBPs, TGF-b and KL-6, the latter being tested as positive control in <d>IPF</d>. RESULTS: Serum levels of <g>IGFBP-1</g> and <g>IGFBP-2</g> and KL-6 were significantly higher in the <d>IPF</d> group than in the healthy subjects p   <   0.05, p   <   0.001 and p   <   0.0001 respectively while the picture was inversed regarding IGFs. By contrast there was no significant difference between the groups with respect to TGF-b. <g>IGFBP-2</g> was significantly reduced in the patients with specific anti-fibrotic therapy pirfenidone and nintedanib compared to untreated patients p   <   0.05 but still significantly elevated in comparison to HS p   <   0.001. CONCLUSION: Serum <g>IGFBP-1</g> and -2 are increased in <d>idiopathic pulmonary fibrosis</d> and <g>IGFBP-2</g> may be reduced by anti-fibrosing therapy. IGFBPs may be promising biomarkers in <d>IPF</d>.
27215343|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic lung disorder</d> of unknown origin, which ultimately leads to death. Several growth factors such as IGFs insulin-like-growth factor and IGFBPs insulin like growth factor binding proteins seem to take part to the pathogenesis. We evaluated IGFs and IGFBPs in serum from patients with <d>IPF</d> and healthy subjects including 24 untreated <d>IPF</d> and 26 <d>IPF</d> receiving anti-fibrotic therapy and to compare them with healthy subjects. METHODS: Serum of 50 <d>idiopathic pulmonary fibrosis</d> and 55 healthy subjects HS were analysed by ELISA for IGFs and IGFBPs, TGF-b and KL-6, the latter being tested as positive control in <d>IPF</d>. RESULTS: Serum levels of <g>IGFBP-1</g> and <g>IGFBP-2</g> and KL-6 were significantly higher in the <d>IPF</d> group than in the healthy subjects p   <   0.05, p   <   0.001 and p   <   0.0001 respectively while the picture was inversed regarding IGFs. By contrast there was no significant difference between the groups with respect to TGF-b. <g>IGFBP-2</g> was significantly reduced in the patients with specific anti-fibrotic therapy pirfenidone and nintedanib compared to untreated patients p   <   0.05 but still significantly elevated in comparison to HS p   <   0.001. CONCLUSION: Serum <g>IGFBP-1</g> and -2 are increased in <d>idiopathic pulmonary fibrosis</d> and <g>IGFBP-2</g> may be reduced by anti-fibrosing therapy. IGFBPs may be promising biomarkers in <d>IPF</d>.
27215343|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic lung disorder</d> of unknown origin, which ultimately leads to <d>death</d>. Several growth factors such as IGFs insulin-like-growth factor and IGFBPs insulin like growth factor binding proteins seem to take part to the pathogenesis. We evaluated IGFs and IGFBPs in serum from patients with <d>IPF</d> and healthy subjects including 24 untreated <d>IPF</d> and 26 <d>IPF</d> receiving anti-fibrotic therapy and to compare them with healthy subjects. METHODS: Serum of 50 <d>idiopathic pulmonary fibrosis</d> and 55 healthy subjects HS were analysed by ELISA for IGFs and IGFBPs, TGF-b and KL-6, the latter being tested as positive control in <d>IPF</d>. RESULTS: Serum levels of <g>IGFBP-1</g> and <g>IGFBP-2</g> and KL-6 were significantly higher in the <d>IPF</d> group than in the healthy subjects p   <   0.05, p   <   0.001 and p   <   0.0001 respectively while the picture was inversed regarding IGFs. By contrast there was no significant difference between the groups with respect to TGF-b. <g>IGFBP-2</g> was significantly reduced in the patients with specific anti-fibrotic therapy pirfenidone and nintedanib compared to untreated patients p   <   0.05 but still significantly elevated in comparison to HS p   <   0.001. CONCLUSION: Serum <g>IGFBP-1</g> and -2 are increased in <d>idiopathic pulmonary fibrosis</d> and <g>IGFBP-2</g> may be reduced by anti-fibrosing therapy. IGFBPs may be promising biomarkers in <d>IPF</d>.
27279470|a|The aim of the present study was to investigate the hypotheses that cytomegalovirus CMV may trigger idiopathic <d>pulmonary fibrosis</d> IPF in a susceptible host and/or that the presence of CMV may alter IPF in response to a well-defined trigger of <d>pulmonary fibrosis</d>. A mouse model of murine CMV MCMV infection was established, and the mice were divided into a control group, bleomycin group and an MCMV+bleomycin group. Changes in the weights of the mice were determined in the three groups. Pulmonary fibrosis was detected using a histopathological method. The activity of transforming growth factor TGF  -b1 was measured, and the levels of E  -cadherin, Vimentin and phosphorylated phospho  -small mothers against decapentaplegic SMAD2 were determined using western blot analysis. MCMV was found to invade the lungs, however, it did not cause <d>pulmonary fibrosis</d>. The progression of fibrosis in the mice treated with MCMV+bleomycin was more rapid, compared with that in the control mice. The protein levels of Vimentin and phospho-SMAD2 were upregulated, whereas the level of E  -cadherin was downregulated in the MCMV+bleomycin group,. The results suggested that latent MCMV infection aggravated <d>pulmonary fibrosis</d> in the mouse model, possibly through the activation of TGF-b1.
27279470|a|The aim of the present study was to investigate the hypotheses that cytomegalovirus CMV may trigger idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> in a susceptible host and/or that the presence of CMV may alter <d>IPF</d> in response to a well-defined trigger of <d>pulmonary fibrosis</d>. A mouse model of murine CMV MCMV infection was established, and the mice were divided into a control group, bleomycin group and an MCMV+bleomycin group. Changes in the weights of the mice were determined in the three groups. Pulmonary fibrosis was detected using a histopathological method. The activity of transforming growth factor TGF  -b1 was measured, and the levels of E  -cadherin, Vimentin and phosphorylated phospho  -small mothers against decapentaplegic SMAD2 were determined using western blot analysis. MCMV was found to invade the lungs, however, it did not cause <d>pulmonary fibrosis</d>. The progression of fibrosis in the mice treated with MCMV+bleomycin was more rapid, compared with that in the control mice. The protein levels of Vimentin and phospho-SMAD2 were upregulated, whereas the level of E  -cadherin was downregulated in the MCMV+bleomycin group,. The results suggested that latent MCMV infection aggravated <d>pulmonary fibrosis</d> in the mouse model, possibly through the activation of <g>TGF-b1</g>.
27279470|a|The aim of the present study was to investigate the hypotheses that cytomegalovirus CMV may trigger idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> in a susceptible host and/or that the presence of CMV may alter <d>IPF</d> in response to a well-defined trigger of <d>pulmonary fibrosis</d>. <d>A mouse model of murine CMV MCMV infection</d> was established, and the mice were divided into a control group, bleomycin group and an MCMV+bleomycin group. Changes in the weights of the mice were determined in the three groups. Pulmonary fibrosis was detected using a histopathological method. The activity of transforming growth factor TGF  -b1 was measured, and the levels of E  -cadherin, Vimentin and phosphorylated phospho  -small mothers against decapentaplegic SMAD2 were determined using western blot analysis. MCMV was found to invade the lungs, however, it did not cause <d>pulmonary fibrosis</d>. The progression of fibrosis in the mice treated with MCMV+bleomycin was more rapid, compared with that in the control mice. The protein levels of Vimentin and phospho-SMAD2 were upregulated, whereas the level of E  -cadherin was downregulated in the MCMV+bleomycin group,. The results suggested that latent MCMV infection aggravated <d>pulmonary fibrosis</d> in the mouse model, possibly through the activation of <g>TGF-b1</g>.
27279470|a|The aim of the present study was to investigate the hypotheses that cytomegalovirus CMV may trigger idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> in a susceptible host and/or that the presence of CMV may alter <d>IPF</d> in response to a well-defined trigger of <d>pulmonary fibrosis</d>. <d>A mouse model of murine CMV MCMV infection</d> was established, and the mice were divided into a control group, bleomycin group and an MCMV+bleomycin group. Changes in the weights of the mice were determined in the three groups. <d>Pulmonary fibrosis</d> was detected using a histopathological method. The activity of transforming growth factor TGF  -b1 was measured, and the levels of E  -cadherin, Vimentin and phosphorylated phospho  -small mothers against decapentaplegic SMAD2 were determined using western blot analysis. MCMV was found to invade the lungs, however, it did not cause <d>pulmonary fibrosis</d>. The progression of fibrosis in the mice treated with MCMV+bleomycin was more rapid, compared with that in the control mice. The protein levels of Vimentin and phospho-SMAD2 were upregulated, whereas the level of E  -cadherin was downregulated in the MCMV+bleomycin group,. The results suggested that latent MCMV infection aggravated <d>pulmonary fibrosis</d> in the mouse model, possibly through the activation of <g>TGF-b1</g>.
27279470|a|The aim of the present study was to investigate the hypotheses that cytomegalovirus CMV may trigger idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> in a susceptible host and/or that the presence of CMV may alter <d>IPF</d> in response to a well-defined trigger of <d>pulmonary <d>fibrosis</d></d>. <d>A mouse model of murine CMV MCMV infection</d> was established, and the mice were divided into a control group, bleomycin group and an MCMV+bleomycin group. Changes in the weights of the mice were determined in the three groups. <d>Pulmonary <d>fibrosis</d></d> was detected using a histopathological method. The activity of transforming growth factor TGF  -b1 was measured, and the levels of <g>E  -cadherin</g>, <g>Vimentin</g> and phosphorylated phospho  -small mothers against decapentaplegic <g>SMAD2</g> were determined using western blot analysis. MCMV was found to invade the lungs, however, it did not cause <d>pulmonary <d>fibrosis</d></d>. The progression of <d>fibrosis</d> in the mice treated with MCMV+bleomycin was more rapid, compared with that in the control mice. The protein levels of <g>Vimentin</g> and phospho-<g>SMAD2</g> were upregulated, whereas the level of <g>E  -cadherin</g> was downregulated in the MCMV+bleomycin group,. The results suggested that latent MCMV infection aggravated <d>pulmonary <d>fibrosis</d></d> in the mouse model, possibly through the activation of <g>TGF-b1</g>.
27317687|a|UNASSIGNED: <d>Idiopathic Pulmonary Fibrosis</d> IPF is a lethal lung disease of unknown etiology. The development of pulmonary hypertension PH is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced <g>BMPR2</g> expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3 demonstrating reduced <g>BMPR2</g> signaling and elevated TGF-b activity in IPF. In the bleomycin BLM model of lung fibrosis and PH, we also report decreased <g>BMPR2</g> expression compared to control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of <g>BMPR2</g> and reduced levels of a collection of microRNAs miRs that are able to degrade <g>BMPR2</g>. We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced <g>BMPR2</g> levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with IHC showing reduced <g>BMPR2</g> in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of <g>BMPR2</g> mediated by a collection of miRs induced by IL-6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF.
27317687|a|UNASSIGNED: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a lethal lung disease of unknown etiology. The development of pulmonary hypertension PH is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in <d>IPF</d> are not fully understood. Using human lung explant samples from patients with <d>IPF</d> with or without a diagnosis of PH as well as normal control tissue, we report reduced <g>BMPR2</g> expression in patients with <d>IPF</d> or <d>IPF</d>+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3 demonstrating reduced <g>BMPR2</g> signaling and elevated TGF-b activity in <d>IPF</d>. In the bleomycin BLM model of lung fibrosis and PH, we also report decreased <g>BMPR2</g> expression compared to control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of <g>BMPR2</g> and reduced levels of a collection of microRNAs miRs that are able to degrade <g>BMPR2</g>. We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced <g>BMPR2</g> levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with IHC showing reduced <g>BMPR2</g> in CD206 expressing macrophages from lung sections from <d>IPF</d> and <d>IPF</d>+PH patients. In conclusion, our data suggest that depletion of <g>BMPR2</g> mediated by a collection of miRs induced by IL-6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in <d>IPF</d>.
27317687|a|UNASSIGNED: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a lethal lung disease of unknown etiology. The development of <d>pulmonary hypertension</d> PH is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in <d>IPF</d> are not fully understood. Using human lung explant samples from patients with <d>IPF</d> with or without a diagnosis of PH as well as normal control tissue, we report reduced <g>BMPR2</g> expression in patients with <d>IPF</d> or <d>IPF</d>+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3 demonstrating reduced <g>BMPR2</g> signaling and elevated TGF-b activity in <d>IPF</d>. In the bleomycin BLM model of lung fibrosis and PH, we also report decreased <g>BMPR2</g> expression compared to control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of <g>BMPR2</g> and reduced levels of a collection of microRNAs miRs that are able to degrade <g>BMPR2</g>. We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced <g>BMPR2</g> levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with IHC showing reduced <g>BMPR2</g> in CD206 expressing macrophages from lung sections from <d>IPF</d> and <d>IPF</d>+PH patients. In conclusion, our data suggest that depletion of <g>BMPR2</g> mediated by a collection of miRs induced by IL-6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in <d>IPF</d>.
27317687|a|UNASSIGNED: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a lethal lung disease of unknown etiology. The development of <d>pulmonary hypertension</d> <d>PH</d> is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in <d>IPF</d> are not fully understood. Using human lung explant samples from patients with <d>IPF</d> with or without a diagnosis of <d>PH</d> as well as normal control tissue, we report reduced <g>BMPR2</g> expression in patients with <d>IPF</d> or <d>IPF</d>+<d>PH</d>. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3 demonstrating reduced <g>BMPR2</g> signaling and elevated TGF-b activity in <d>IPF</d>. In the bleomycin BLM model of lung fibrosis and <d>PH</d>, we also report decreased <g>BMPR2</g> expression compared to control animals that correlated with vascular remodeling and <d>PH</d>. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and <d>PH</d> consistent with elevated levels of <g>BMPR2</g> and reduced levels of a collection of microRNAs miRs that are able to degrade <g>BMPR2</g>. We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced <g>BMPR2</g> levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with IHC showing reduced <g>BMPR2</g> in CD206 expressing macrophages from lung sections from <d>IPF</d> and <d>IPF</d>+<d>PH</d> patients. In conclusion, our data suggest that depletion of <g>BMPR2</g> mediated by a collection of miRs induced by IL-6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in <d>IPF</d>.
27317687|a|UNASSIGNED: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a lethal lung disease of unknown etiology. The development of <d>pulmonary hypertension</d> <d>PH</d> is considered the single most significant predictor of mortality in patients with chronic <d>lung diseases</d>. The processes that govern the progression and development of fibroproliferative and vascular lesions in <d>IPF</d> are not fully understood. Using human lung explant samples from patients with <d>IPF</d> with or without a diagnosis of <d>PH</d> as well as normal control tissue, we report reduced <g>BMPR2</g> expression in patients with <d>IPF</d> or <d>IPF</d>+<d>PH</d>. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3 demonstrating reduced <g>BMPR2</g> signaling and elevated TGF-b activity in <d>IPF</d>. In the bleomycin BLM model of lung fibrosis and <d>PH</d>, we also report decreased <g>BMPR2</g> expression compared to control animals that correlated with vascular remodeling and <d>PH</d>. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and <d>PH</d> consistent with elevated levels of <g>BMPR2</g> and reduced levels of a collection of microRNAs miRs that are able to degrade <g>BMPR2</g>. We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced <g>BMPR2</g> levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with IHC showing reduced <g>BMPR2</g> in CD206 expressing macrophages from lung sections from <d>IPF</d> and <d>IPF</d>+<d>PH</d> patients. In conclusion, our data suggest that depletion of <g>BMPR2</g> mediated by a collection of miRs induced by IL-6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in <d>IPF</d>.
27317687|a|UNASSIGNED: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a lethal lung disease of unknown etiology. The development of <d>pulmonary hypertension</d> <d>PH</d> is considered the single most significant predictor of mortality in patients with chronic <d>lung diseases</d>. The processes that govern the progression and development of fibroproliferative and <d>vascular lesions</d> in <d>IPF</d> are not fully understood. Using human lung explant samples from patients with <d>IPF</d> with or without a diagnosis of <d>PH</d> as well as normal control tissue, we report reduced <g>BMPR2</g> expression in patients with <d>IPF</d> or <d>IPF</d>+<d>PH</d>. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3 demonstrating reduced <g>BMPR2</g> signaling and elevated TGF-b activity in <d>IPF</d>. In the bleomycin BLM model of lung fibrosis and <d>PH</d>, we also report decreased <g>BMPR2</g> expression compared to control animals that correlated with vascular remodeling and <d>PH</d>. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and <d>PH</d> consistent with elevated levels of <g>BMPR2</g> and reduced levels of a collection of microRNAs miRs that are able to degrade <g>BMPR2</g>. We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced <g>BMPR2</g> levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with IHC showing reduced <g>BMPR2</g> in CD206 expressing macrophages from lung sections from <d>IPF</d> and <d>IPF</d>+<d>PH</d> patients. In conclusion, our data suggest that depletion of <g>BMPR2</g> mediated by a collection of miRs induced by IL-6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in <d>IPF</d>.
27317687|a|UNASSIGNED: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a lethal lung disease of unknown etiology. The development of <d>pulmonary hypertension</d> <d>PH</d> is considered the single most significant predictor of mortality in patients with chronic <d>lung diseases</d>. The processes that govern the progression and development of fibroproliferative and <d>vascular lesions</d> in <d>IPF</d> are not fully understood. Using human lung explant samples from patients with <d>IPF</d> with or without a diagnosis of <d>PH</d> as well as normal control tissue, we report reduced <g>BMPR2</g> expression in patients with <d>IPF</d> or <d>IPF</d>+<d>PH</d>. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3 demonstrating reduced <g>BMPR2</g> signaling and elevated <g>TGF-b</g> activity in <d>IPF</d>. In the bleomycin BLM model of <d>lung fibrosis</d> and <d>PH</d>, we also report decreased <g>BMPR2</g> expression compared to control animals that correlated with vascular remodeling and <d>PH</d>. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and <d>PH</d> consistent with elevated levels of <g>BMPR2</g> and reduced levels of a collection of microRNAs miRs that are able to degrade <g>BMPR2</g>. We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced <g>BMPR2</g> levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with IHC showing reduced <g>BMPR2</g> in CD206 expressing macrophages from lung sections from <d>IPF</d> and <d>IPF</d>+<d>PH</d> patients. In conclusion, our data suggest that depletion of <g>BMPR2</g> mediated by a collection of miRs induced by IL-6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in <d>IPF</d>.
27317687|a|UNASSIGNED: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a lethal lung disease of unknown etiology. The development of <d>pulmonary hypertension</d> <d>PH</d> is considered the single most significant predictor of mortality in patients with chronic <d>lung diseases</d>. The processes that govern the progression and development of fibroproliferative and <d>vascular lesions</d> in <d>IPF</d> are not fully understood. Using human lung explant samples from patients with <d>IPF</d> with or without a diagnosis of <d>PH</d> as well as normal control tissue, we report reduced <g>BMPR2</g> expression in patients with <d>IPF</d> or <d>IPF</d>+<d>PH</d>. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3 demonstrating reduced <g>BMPR2</g> signaling and elevated <g>TGF-b</g> activity in <d>IPF</d>. In the bleomycin BLM model of <d>lung <d>fibrosis</d></d> and <d>PH</d>, we also report decreased <g>BMPR2</g> expression compared to control animals that correlated with vascular remodeling and <d>PH</d>. We show that genetic abrogation or pharmacological inhibition of <g>interleukin-6</g> leads to diminished markers of <d>fibrosis</d> and <d>PH</d> consistent with elevated levels of <g>BMPR2</g> and reduced levels of a collection of microRNAs miRs that are able to degrade <g>BMPR2</g>. We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced <g>BMPR2</g> levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with IHC showing reduced <g>BMPR2</g> in CD206 expressing macrophages from lung sections from <d>IPF</d> and <d>IPF</d>+<d>PH</d> patients. In conclusion, our data suggest that depletion of <g>BMPR2</g> mediated by a collection of miRs induced by IL-6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in <d>IPF</d>.
27317687|a|UNASSIGNED: <d>Idiopathic Pulmonary Fibrosis</d> <d>IPF</d> is a lethal lung disease of unknown etiology. The development of <d>pulmonary hypertension</d> <d>PH</d> is considered the single most significant predictor of mortality in patients with chronic <d>lung diseases</d>. The processes that govern the progression and development of fibroproliferative and <d>vascular lesions</d> in <d>IPF</d> are not fully understood. Using human lung explant samples from patients with <d>IPF</d> with or without a diagnosis of <d>PH</d> as well as normal control tissue, we report reduced <g>BMPR2</g> expression in patients with <d>IPF</d> or <d>IPF</d>+<d>PH</d>. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3 demonstrating reduced <g>BMPR2</g> signaling and elevated <g>TGF-b</g> activity in <d>IPF</d>. In the bleomycin BLM model of <d>lung <d>fibrosis</d></d> and <d>PH</d>, we also report decreased <g>BMPR2</g> expression compared to control animals that correlated with vascular remodeling and <d>PH</d>. We show that genetic abrogation or pharmacological inhibition of <g>interleukin-6</g> leads to diminished markers of <d>fibrosis</d> and <d>PH</d> consistent with elevated levels of <g>BMPR2</g> and reduced levels of a collection of microRNAs miRs that are able to degrade <g>BMPR2</g>. We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced <g>BMPR2</g> levels upon exposure with <g>IL6</g> or the <g>IL6</g>+<g>IL6</g>R complex that are consistent with IHC showing reduced <g>BMPR2</g> in <g>CD206</g> expressing macrophages from lung sections from <d>IPF</d> and <d>IPF</d>+<d>PH</d> patients. In conclusion, our data suggest that depletion of <g>BMPR2</g> mediated by a collection of miRs induced by <g>IL-6</g> and subsequent <g>STAT3</g> phosphorylation as a novel mechanism participating to fibroproliferative and <d>vascular injuries</d> in <d>IPF</d>.
27350126|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a lethal human disease with short survival time and few treatment options. Herein, we demonstrated that discoidin domain receptor 2 <g>DDR2</g>, a receptor tyrosine kinase that predominantly transduces signals from fibrillar collagens, plays a critical role in the induction of fibrosis and angiogenesis in the lung. In vitro cell studies showed that <g>DDR2</g> can synergize the actions of both transforming growth factor TGF-b and fibrillar collagen to stimulate lung fibroblasts to undergo myofibroblastic changes and vascular endothelial growth factor VEGF expression. In addition, we confirmed that late treatment of the injured mice with specific siRNA against <g>DDR2</g> or its kinase inhibitor exhibited therapeutic efficacy against lung fibrosis. Thus, this study not only elucidated novel mechanisms by which <g>DDR2</g> controls the development of pulmonary fibrosis, but also provided candidate target for the intervention of this stubborn disease.
27350126|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal human disease with short survival time and few treatment options. Herein, we demonstrated that discoidin domain receptor 2 <g>DDR2</g>, a receptor tyrosine kinase that predominantly transduces signals from fibrillar collagens, plays a critical role in the induction of fibrosis and angiogenesis in the lung. In vitro cell studies showed that <g>DDR2</g> can synergize the actions of both transforming growth factor TGF-b and fibrillar collagen to stimulate lung fibroblasts to undergo myofibroblastic changes and vascular endothelial growth factor VEGF expression. In addition, we confirmed that late treatment of the injured mice with specific siRNA against <g>DDR2</g> or its kinase inhibitor exhibited therapeutic efficacy against lung fibrosis. Thus, this study not only elucidated novel mechanisms by which <g>DDR2</g> controls the development of pulmonary fibrosis, but also provided candidate target for the intervention of this stubborn disease.
27350126|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a lethal human disease with short survival time and few treatment options. Herein, we demonstrated that <g>discoidin domain receptor 2</g> <g>DDR2</g>, a receptor tyrosine kinase that predominantly transduces signals from fibrillar collagens, plays a critical role in the induction of <d>fibrosis</d> and angiogenesis in the lung. In vitro cell studies showed that <g>DDR2</g> can synergize the actions of both transforming growth factor TGF-b and fibrillar collagen to stimulate lung fibroblasts to undergo myofibroblastic changes and vascular endothelial growth factor VEGF expression. In addition, we confirmed that late treatment of the injured mice with specific siRNA against <g>DDR2</g> or its kinase inhibitor exhibited therapeutic efficacy against lung <d>fibrosis</d>. Thus, this study not only elucidated novel mechanisms by which <g>DDR2</g> controls the development of pulmonary <d>fibrosis</d>, but also provided candidate target for the intervention of this stubborn disease.
27350126|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a lethal human disease with short survival time and few treatment options. Herein, we demonstrated that <g>discoidin domain receptor 2</g> <g>DDR2</g>, a receptor tyrosine kinase that predominantly transduces signals from fibrillar collagens, plays a critical role in the induction of <d>fibrosis</d> and angiogenesis in the lung. In vitro cell studies showed that <g>DDR2</g> can synergize the actions of both transforming growth factor TGF-b and fibrillar collagen to stimulate lung fibroblasts to undergo myofibroblastic changes and <g>vascular endothelial growth factor</g> <g>VEGF</g> expression. In addition, we confirmed that late treatment of the injured mice with specific siRNA against <g>DDR2</g> or its kinase inhibitor exhibited therapeutic efficacy against lung <d>fibrosis</d>. Thus, this study not only elucidated novel mechanisms by which <g>DDR2</g> controls the development of pulmonary <d>fibrosis</d>, but also provided candidate target for the intervention of this <d>stubborn disease</d>.
27367854|a|BACKGROUND: Resveratrol, a phytoalexin found in berries, peanuts, grapes, and red wine, inhibits oxidation, <d>inflammation</d>, and cell proliferation and collagen synthesis in multiple cell types and or animal models. It represses collagen deposition in the vasculature, heart, lung, kidney, liver, and esophagus in animal models and may have some utility as an anti-fibrotic. Recent studies have shown that increased collagen deposition and tissue stiffness in the peri-urethral area of the prostate are associated with lower urinary tract dysfunction LUTD and urinary obstructive symptoms. The aim of this study was to determine whether Resveratrol might be useful to inhibit or revert TGFb- and/or CXCL12-mediated myofibroblast phenoconversion of prostate fibroblasts in vitro, and therefore whether the use of anti-fibrotic therapeutics might be efficacious for the treatment of LUTD. METHODS: Primary prostate and lung tissues were explanted and fibroblast monolayers expanded in vitro. Primary and N1 immortalized prostate stromal fibroblasts, as well as primary fibroblasts cultured from a normal lung and one affected by idiopathic pulmonary fibrosis IPF for comparison, were grown in serum-free defined media supplemented with vehicle, TGFb or CXCL12, pre- or post-treatment with Resveratrol, and were evaluated using immunofluorescence for alpha smooth muscle actin aSMA and collagen I COL1 protein expression and assessed for cell proliferation, apoptosis, and COL1 and EGR1 transcript expression. RESULTS: This study showed that low concentrations of Resveratrol <= 50  M had no effect on N1 or primary prostate fibroblast cell proliferation, apoptosis, or COL1 or EGR1 gene transcription but repressed and reversed myofibroblast phenoconversion. As expected, these same effects were observed for IPF lung fibroblasts though higher levels of Resveratrol >= 100uM were required. Taken together, these data suggest that, like lung fibroblasts, prostate fibroblast to myofibroblast phenoconversion can be both repressed and reversed by Resveratrol treatment. Thus, anti-fibrotic therapeutics might be efficacious for the treatment of LUTD.
27367854|a|BACKGROUND: Resveratrol, a phytoalexin found in berries, peanuts, grapes, and red wine, inhibits oxidation, <d>inflammation</d>, and cell proliferation and collagen synthesis in multiple cell types and or animal models. It represses collagen deposition in the vasculature, heart, lung, kidney, liver, and esophagus in animal models and may have some utility as an anti-fibrotic. Recent studies have shown that increased collagen deposition and tissue stiffness in the peri-urethral area of the prostate are associated with lower urinary tract dysfunction LUTD and <d>urinary obstructive symptoms</d>. The aim of this study was to determine whether Resveratrol might be useful to inhibit or revert TGFb- and/or CXCL12-mediated myofibroblast phenoconversion of prostate fibroblasts in vitro, and therefore whether the use of anti-fibrotic therapeutics might be efficacious for the treatment of LUTD. METHODS: Primary prostate and lung tissues were explanted and fibroblast monolayers expanded in vitro. Primary and N1 immortalized prostate stromal fibroblasts, as well as primary fibroblasts cultured from a normal lung and one affected by idiopathic pulmonary fibrosis IPF for comparison, were grown in serum-free defined media supplemented with vehicle, TGFb or CXCL12, pre- or post-treatment with Resveratrol, and were evaluated using immunofluorescence for alpha smooth muscle actin aSMA and collagen I COL1 protein expression and assessed for cell proliferation, apoptosis, and COL1 and EGR1 transcript expression. RESULTS: This study showed that low concentrations of Resveratrol <= 50  M had no effect on N1 or primary prostate fibroblast cell proliferation, apoptosis, or COL1 or EGR1 gene transcription but repressed and reversed myofibroblast phenoconversion. As expected, these same effects were observed for IPF lung fibroblasts though higher levels of Resveratrol >= 100uM were required. Taken together, these data suggest that, like lung fibroblasts, prostate fibroblast to myofibroblast phenoconversion can be both repressed and reversed by Resveratrol treatment. Thus, anti-fibrotic therapeutics might be efficacious for the treatment of LUTD.
27367854|a|BACKGROUND: Resveratrol, a phytoalexin found in berries, peanuts, grapes, and red wine, inhibits oxidation, <d>inflammation</d>, and cell proliferation and collagen synthesis in multiple cell types and or animal models. It represses collagen deposition in the vasculature, heart, lung, kidney, liver, and esophagus in animal models and may have some utility as an anti-fibrotic. Recent studies have shown that increased collagen deposition and tissue stiffness in the peri-urethral area of the prostate are associated with lower urinary tract dysfunction LUTD and <d>urinary obstructive symptoms</d>. The aim of this study was to determine whether Resveratrol might be useful to inhibit or revert <g>TGFb</g>- and/or <g>CXCL12</g>-mediated myofibroblast phenoconversion of prostate fibroblasts in vitro, and therefore whether the use of anti-fibrotic therapeutics might be efficacious for the treatment of LUTD. METHODS: Primary prostate and lung tissues were explanted and fibroblast monolayers expanded in vitro. Primary and N1 immortalized prostate stromal fibroblasts, as well as primary fibroblasts cultured from a normal lung and one affected by <d>idiopathic pulmonary fibrosis</d> IPF for comparison, were grown in serum-free defined media supplemented with vehicle, <g>TGFb</g> or <g>CXCL12</g>, pre- or post-treatment with Resveratrol, and were evaluated using immunofluorescence for alpha smooth muscle actin aSMA and collagen I COL1 protein expression and assessed for cell proliferation, apoptosis, and COL1 and EGR1 transcript expression. RESULTS: This study showed that low concentrations of Resveratrol <= 50  M had no effect on N1 or primary prostate fibroblast cell proliferation, apoptosis, or COL1 or EGR1 gene transcription but repressed and reversed myofibroblast phenoconversion. As expected, these same effects were observed for IPF lung fibroblasts though higher levels of Resveratrol >= 100uM were required. Taken together, these data suggest that, like lung fibroblasts, prostate fibroblast to myofibroblast phenoconversion can be both repressed and reversed by Resveratrol treatment. Thus, anti-fibrotic therapeutics might be efficacious for the treatment of LUTD.
27367854|a|BACKGROUND: Resveratrol, a phytoalexin found in berries, peanuts, grapes, and red wine, inhibits oxidation, <d>inflammation</d>, and cell proliferation and collagen synthesis in multiple cell types and or animal models. It represses collagen deposition in the vasculature, heart, lung, kidney, liver, and esophagus in animal models and may have some utility as an anti-fibrotic. Recent studies have shown that increased collagen deposition and tissue stiffness in the peri-urethral area of the prostate are associated with lower urinary tract dysfunction LUTD and <d>urinary obstructive symptoms</d>. The aim of this study was to determine whether Resveratrol might be useful to inhibit or revert <g>TGFb</g>- and/or <g>CXCL12</g>-mediated myofibroblast phenoconversion of prostate fibroblasts in vitro, and therefore whether the use of anti-fibrotic therapeutics might be efficacious for the treatment of LUTD. METHODS: Primary prostate and lung tissues were explanted and fibroblast monolayers expanded in vitro. Primary and N1 immortalized prostate stromal fibroblasts, as well as primary fibroblasts cultured from a normal lung and one affected by <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> for comparison, were grown in serum-free defined media supplemented with vehicle, <g>TGFb</g> or <g>CXCL12</g>, pre- or post-treatment with Resveratrol, and were evaluated using immunofluorescence for alpha smooth muscle actin aSMA and collagen I COL1 protein expression and assessed for cell proliferation, apoptosis, and COL1 and EGR1 transcript expression. RESULTS: This study showed that low concentrations of Resveratrol <= 50  M had no effect on N1 or primary prostate fibroblast cell proliferation, apoptosis, or COL1 or EGR1 gene transcription but repressed and reversed myofibroblast phenoconversion. As expected, these same effects were observed for <d>IPF</d> lung fibroblasts though higher levels of Resveratrol >= 100uM were required. Taken together, these data suggest that, like lung fibroblasts, prostate fibroblast to myofibroblast phenoconversion can be both repressed and reversed by Resveratrol treatment. Thus, anti-fibrotic therapeutics might be efficacious for the treatment of LUTD.
27390284|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> IPF is a progressive and usually lethal disease of unknown aetiology. A growing body of evidence supports that IPF represents an epithelial-driven process characterised by aberrant epithelial cell behaviour, fibroblast/myofibroblast activation and excessive accumulation of extracellular matrix with the subsequent destruction of the lung architecture. The mechanisms involved in the abnormal hyper-activation of the epithelium are unclear, but we propose that recapitulation of pathways and processes critical to embryological development associated with a tissue specific age-related stochastic epigenetic drift may be implicated. These pathways may also contribute to the distinctive behaviour of IPF fibroblasts. Genomic and epigenomic studies have revealed that wingless/Int, sonic hedgehog and other developmental signalling pathways are reactivated and deregulated in IPF. Moreover, some of these pathways cross-talk with transforming growth factor-b activating a profibrotic feedback loop. The expression pattern of microRNAs is also dysregulated in IPF and exhibits a similar expression profile to embryonic lungs. In addition, senescence, a process usually associated with ageing, which occurs early in alveolar epithelial cells of IPF lungs, likely represents a conserved programmed developmental mechanism. Here, we review the major developmental pathways that get twisted in IPF, and discuss the connection with ageing and potential therapeutic approaches.
27390284|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive and usually lethal disease of unknown aetiology. A growing body of evidence supports that <d>IPF</d> represents an epithelial-driven process characterised by aberrant epithelial cell behaviour, fibroblast/myofibroblast activation and excessive accumulation of extracellular matrix with the subsequent destruction of the lung architecture. The mechanisms involved in the abnormal hyper-activation of the epithelium are unclear, but we propose that recapitulation of pathways and processes critical to embryological development associated with a tissue specific age-related stochastic epigenetic drift may be implicated. These pathways may also contribute to the distinctive behaviour of <d>IPF</d> fibroblasts. Genomic and epigenomic studies have revealed that wingless/Int, sonic hedgehog and other developmental signalling pathways are reactivated and deregulated in <d>IPF</d>. Moreover, some of these pathways cross-talk with transforming growth factor-b activating a profibrotic feedback loop. The expression pattern of microRNAs is also dysregulated in <d>IPF</d> and exhibits a similar expression profile to embryonic lungs. In addition, senescence, a process usually associated with ageing, which occurs early in alveolar epithelial cells of <d>IPF</d> lungs, likely represents a conserved programmed developmental mechanism. Here, we review the major developmental pathways that get twisted in <d>IPF</d>, and discuss the connection with ageing and potential therapeutic approaches.
27439438|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of alveolar architecture. IPF is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition EMT. However, there is still a lack of strategies to target EMT for the treatment of IPF. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis. Here, we explored the therapeutic potential of sunitinib using a mouse model of pulmonary fibrosis. Mice received intratracheal instillation of bleomycin BLM. Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the pulmonary fibrosis and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells HBEs and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-b, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-b in HBEs. As EMT and accumulation of fibroblasts are critical for the development of pulmonary fibrosis, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat pulmonary fibrosis.
27439438|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of alveolar architecture. <d>IPF</d> is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition EMT. However, there is still a lack of strategies to target EMT for the treatment of <d>IPF</d>. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis. Here, we explored the therapeutic potential of sunitinib using a mouse model of pulmonary fibrosis. Mice received intratracheal instillation of bleomycin BLM. Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the pulmonary fibrosis and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells HBEs and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-b, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-b in HBEs. As EMT and accumulation of fibroblasts are critical for the development of pulmonary fibrosis, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat pulmonary fibrosis.
27439438|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of <d>alveolar architecture</d>. <d>IPF</d> is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition EMT. However, there is still a lack of strategies to target EMT for the treatment of <d>IPF</d>. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis. Here, we explored the therapeutic potential of sunitinib using a mouse model of pulmonary fibrosis. Mice received intratracheal instillation of bleomycin BLM. Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the pulmonary fibrosis and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells HBEs and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-b, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-b in HBEs. As EMT and accumulation of fibroblasts are critical for the development of pulmonary fibrosis, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat pulmonary fibrosis.
27439438|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of <d>alveolar architecture</d>. <d>IPF</d> is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition EMT. However, there is still a lack of strategies to target EMT for the treatment of <d>IPF</d>. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing <d>pulmonary fibrosis</d>. Here, we explored the therapeutic potential of sunitinib using a mouse model of <d>pulmonary fibrosis</d>. Mice received intratracheal instillation of bleomycin BLM. Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the <d>pulmonary fibrosis</d> and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells HBEs and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-b, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-b in HBEs. As EMT and accumulation of fibroblasts are critical for the development of <d>pulmonary fibrosis</d>, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat <d>pulmonary fibrosis</d>.
27439438|a|<d>Idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d> is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of <d>alveolar architecture</d>. <d>IPF</d> is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition EMT. However, there is still a lack of strategies to target EMT for the treatment of <d>IPF</d>. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing <d>pulmonary <d>fibrosis</d></d>. Here, we explored the therapeutic potential of sunitinib using a mouse model of <d>pulmonary <d>fibrosis</d></d>. Mice received intratracheal instillation of bleomycin BLM. Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the <d>pulmonary <d>fibrosis</d></d> and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells HBEs and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by <g>TGF-b</g>, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on <g>Smad2/3</g> that was induced by <g>TGF-b</g> in HBEs. As EMT and accumulation of fibroblasts are critical for the development of <d>pulmonary <d>fibrosis</d></d>, targeting multiple pro-<d>fibrosis</d> signaling pathways with sunitinib may be a novel strategy to treat <d>pulmonary <d>fibrosis</d></d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and <d>pulmonary fibrosis</d>. Transforming growth factor b <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary fibrosis</d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary fibrosis</d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of SPP1 Osteopontin expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung fibrosis IPF, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of lung cancer.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung cancer</d>, but the effective dose is often limited by the development of radiation-induced pneumonitis and <d>pulmonary fibrosis</d>. Transforming growth factor b <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary fibrosis</d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary fibrosis</d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of SPP1 Osteopontin expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung fibrosis IPF, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of <d>lung cancer</d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung cancer</d>, but the effective dose is often limited by the development of radiation-induced <d>pneumonitis</d> and <d>pulmonary fibrosis</d>. Transforming growth factor b <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary fibrosis</d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary fibrosis</d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of SPP1 Osteopontin expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung fibrosis IPF, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of <d>lung cancer</d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung cancer</d>, but the effective dose is often limited by the development of radiation-induced <d>pneumonitis</d> and <d>pulmonary <d>fibrosis</d></d>. <g>Transforming growth factor b</g> <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary <d>fibrosis</d></d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary <d>fibrosis</d></d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal <d>fibrosis</d> were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and <d>fibrosis</d> and decreased radiological and histological signs of lung damage. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and <d>fibrosis</d> in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of SPP1 Osteopontin expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung <d>fibrosis</d> IPF, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of <d>lung cancer</d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung cancer</d>, but the effective dose is often limited by the development of radiation-induced <d>pneumonitis</d> and <d>pulmonary <d>fibrosis</d></d>. <g>Transforming growth factor b</g> <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary <d>fibrosis</d></d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary <d>fibrosis</d></d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal <d>fibrosis</d> were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and <g>Osteopontin</g> levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> and decreased radiological and histological signs of lung damage. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of SPP1 <g>Osteopontin</g> expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung <d>fibrosis</d> IPF, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of <d>lung cancer</d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung cancer</d>, but the effective dose is often limited by the development of radiation-induced <d>pneumonitis</d> and <d>pulmonary <d>fibrosis</d></d>. <g>Transforming growth factor b</g> <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary <d>fibrosis</d></d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary <d>fibrosis</d></d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal <d>fibrosis</d> were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and <g>Osteopontin</g> levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> and decreased radiological and histological signs of <d>lung damage</d>. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced <d>lung damage</d> and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced <d>lung damage</d> compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of SPP1 <g>Osteopontin</g> expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung <d>fibrosis</d> IPF, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of <d>lung cancer</d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung cancer</d>, but the effective dose is often limited by the development of radiation-induced <d>pneumonitis</d> and <d>pulmonary <d>fibrosis</d></d>. <g>Transforming growth factor b</g> <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary <d>fibrosis</d></d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary <d>fibrosis</d></d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal <d>fibrosis</d> were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and <g>Osteopontin</g> levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> and decreased radiological and histological signs of <d>lung damage</d>. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced <d>lung damage</d> and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> in mice and may offer a novel approach for treatment of <d>fibrotic lung diseases</d> in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced <d>lung damage</d> compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of SPP1 <g>Osteopontin</g> expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung <d>fibrosis</d> IPF, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of <d>lung cancer</d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung <d>cancer</d></d>, but the effective dose is often limited by the development of radiation-induced <d>pneumonitis</d> and <d>pulmonary <d>fibrosis</d></d>. <g>Transforming growth factor b</g> <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary <d>fibrosis</d></d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary <d>fibrosis</d></d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal <d>fibrosis</d> were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and <g>Osteopontin</g> levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> and decreased radiological and histological signs of <d>lung damage</d>. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced <d>lung damage</d> and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> in mice and may offer a novel approach for treatment of <d>fibrotic lung diseases</d> in humans. Translational statement : RT is an effective treatment modality for <d>cancer</d> with limitations due to acute and chronic toxicities, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced <d>lung damage</d> compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anti<d>cancer</d> compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of SPP1 <g>Osteopontin</g> expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as <d>cancer</d> therapeutics or already approved for certain <d>cancer</d>s or idiopathic lung <d>fibrosis</d> IPF, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of <d>lung <d>cancer</d></d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung <d>cancer</d></d>, but the effective dose is often limited by the development of radiation-induced <d>pneumonitis</d> and <d>pulmonary <d>fibrosis</d></d>. <g>Transforming growth factor b</g> <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary <d>fibrosis</d></d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary <d>fibrosis</d></d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal <d>fibrosis</d> were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and <g>Osteopontin</g> levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> and decreased radiological and histological signs of <d>lung damage</d>. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced <d>lung damage</d> and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> in mice and may offer a novel approach for treatment of <d>fibrotic lung diseases</d> in humans. Translational statement : RT is an effective treatment modality for <d>cancer</d> with limitations due to acute and chronic <d>toxicities</d>, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced <d>lung damage</d> compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anti<d>cancer</d> compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of SPP1 <g>Osteopontin</g> expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as <d>cancer</d> therapeutics or already approved for certain <d>cancer</d>s or idiopathic lung <d>fibrosis</d> IPF, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of <d>lung <d>cancer</d></d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung <d>cancer</d></d>, but the effective dose is often limited by the development of radiation-induced <d>pneumonitis</d> and <d>pulmonary <d>fibrosis</d></d>. <g>Transforming growth factor b</g> <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary <d>fibrosis</d></d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary <d>fibrosis</d></d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal <d>fibrosis</d> were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and <g>Osteopontin</g> levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> and decreased radiological and histological signs of <d>lung damage</d>. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced <d>lung damage</d> and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> in mice and may offer a novel approach for treatment of <d>fibrotic lung diseases</d> in humans. Translational statement : RT is an effective treatment modality for <d>cancer</d> with limitations due to acute and chronic <d>toxicities</d>, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced <d>lung damage</d> compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anti<d>cancer</d> compound in preclinical models and the <g>PDGFR</g> inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of <g>SPP1</g> <g>Osteopontin</g> expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as <d>cancer</d> therapeutics or already approved for certain <d>cancer</d>s or idiopathic lung <d>fibrosis</d> <d>IPF</d>, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of <d>lung <d>cancer</d></d>.
27467922|a|UNASSIGNED: Background : Radiotherapy RT is a mainstay for the treatment of <d>lung <d>cancer</d></d>, but the effective dose is often limited by the development of radiation-induced <d>pneumonitis</d> and <d>pulmonary <d>fibrosis</d></d>. <g>Transforming growth factor b</g> <g>TGFb</g> and platelet-derived growth factor PDGF play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on <d>pulmonary <d>fibrosis</d></d> development remain unclear. Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce <d>pulmonary <d>fibrosis</d></d>. PDGF receptor inhibitors SU9518 and SU14816 imatinib and <g>TGFb</g> receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal <d>fibrosis</d> were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and <g>Osteopontin</g> levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> and decreased radiological and histological signs of <d>lung damage</d>. Combining PDGF and <g>TGFb</g> inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced <d>lung damage</d> and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and <g>TGFb</g>-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and <g>TGFb</g> pathways. Conclusion : Combined small-molecule inhibition of PDGF and <g>TGFb</g> signaling is a safe and effective treatment for radiation-induced <d>pulmonary inflammation</d> and <d>fibrosis</d> in mice and may offer a novel approach for treatment of <d>fibrotic lung diseases</d> in humans. Translational statement : RT is an effective treatment modality for <d>cancer</d> with limitations due to acute and chronic <d>toxicities</d>, where <g>TGFb</g> and PDGF play a key role. Here, we show that a combined inhibition of <g>TGFb</g> and PDGF signaling is more effective in attenuating radiation-induced <d>lung damage</d> compared to blocking either pathway alone. We used the <g>TGFb</g>-receptor I inhibitor galunisertib, an effective anti<d>cancer</d> compound in preclinical models and the <g>PDGFR</g> inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of <g>TGFb</g> and PDGF signaling and the attenuation of <g>SPP1</g> <g>Osteopontin</g> expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as <d>cancer</d> therapeutics or already approved for certain <d>cancer</d>s or idiopathic lung <d>fibrosis</d> <d>IPF</d>, our study suggests that the combined application of small molecule inhibitors of <g>TGFb</g> and PDGF signaling may offer a promising approach to treat radiation-associated <d>toxicity</d> in RT of <d>lung <d>cancer</d></d>.
27494713|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a devastating, progressive disease with poor survival rates and limited treatment options. Upregulation of avb6 integrins within the alveolar epithelial cells is a characteristic feature of IPF and correlates with poor patient survival. The pro-fibrotic cytokine <g>TGFb</g>1 can upregulate avb6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous <g>TGFb</g>1 increases expression of the integrin b6 subunit gene <g>ITGB6</g> and avb6 integrin cell surface expression in a time- and concentration-dependent manner. <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via transcriptional activation of the <g>ITGB6</g> gene, but does not result from effects on <g>ITGB6</g> mRNA stability. Basal expression of <g>ITGB6</g> in, and avb6 integrins on, lung epithelial cells occurs via homeostatic avb6-mediated <g>TGFb</g>1 activation in the absence of exogenous stimulation, and can be amplified by <g>TGFb</g>1 activation. Fundamentally, we show for the first time that <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via canonical Smad signalling since dominant negative constructs directed against Smad3 and 4 inhibit <g>ITGB6</g> transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the <g>ITGB6</g> promoter abolishes <g>TGFb</g>1-induced <g>ITGB6</g> transcriptional activity. Using chromatin immunoprecipitation we demonstrate that <g>TGFb</g>1 stimulation of lung epithelial cells results in direct binding of Smad3, and Smad4, to the <g>ITGB6</g> gene promoter within this region. Finally, using an adenoviral <g>TGFb</g>1 over-expression model of pulmonary fibrosis we demonstrate that Smad3 is crucial for <g>TGFb</g>1-induced avb6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of avb6 integrin activated <g>TGFb</g>1-induced <g>ITGB6</g> gene expression regulates epithelial basal avb6 integrin expression, and demonstrates that this occurs via Smad-dependent transcriptional regulation at a single Smad binding site in the promoter of the b6 subunit gene. Active <g>TGFb</g>1 amplifies this pathway both in vitro and in vivo, which may promote fibrosis.
27494713|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating, progressive disease with poor survival rates and limited treatment options. Upregulation of avb6 integrins within the alveolar epithelial cells is a characteristic feature of <d>IPF</d> and correlates with poor patient survival. The pro-fibrotic cytokine <g>TGFb</g>1 can upregulate avb6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous <g>TGFb</g>1 increases expression of the integrin b6 subunit gene <g>ITGB6</g> and avb6 integrin cell surface expression in a time- and concentration-dependent manner. <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via transcriptional activation of the <g>ITGB6</g> gene, but does not result from effects on <g>ITGB6</g> mRNA stability. Basal expression of <g>ITGB6</g> in, and avb6 integrins on, lung epithelial cells occurs via homeostatic avb6-mediated <g>TGFb</g>1 activation in the absence of exogenous stimulation, and can be amplified by <g>TGFb</g>1 activation. Fundamentally, we show for the first time that <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via canonical Smad signalling since dominant negative constructs directed against Smad3 and 4 inhibit <g>ITGB6</g> transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the <g>ITGB6</g> promoter abolishes <g>TGFb</g>1-induced <g>ITGB6</g> transcriptional activity. Using chromatin immunoprecipitation we demonstrate that <g>TGFb</g>1 stimulation of lung epithelial cells results in direct binding of Smad3, and Smad4, to the <g>ITGB6</g> gene promoter within this region. Finally, using an adenoviral <g>TGFb</g>1 over-expression model of pulmonary fibrosis we demonstrate that Smad3 is crucial for <g>TGFb</g>1-induced avb6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of avb6 integrin activated <g>TGFb</g>1-induced <g>ITGB6</g> gene expression regulates epithelial basal avb6 integrin expression, and demonstrates that this occurs via Smad-dependent transcriptional regulation at a single Smad binding site in the promoter of the b6 subunit gene. Active <g>TGFb</g>1 amplifies this pathway both in vitro and in vivo, which may promote fibrosis.
27494713|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating, <d>progressive disease</d> with poor survival rates and limited treatment options. Upregulation of avb6 integrins within the alveolar epithelial cells is a characteristic feature of <d>IPF</d> and correlates with poor patient survival. The pro-fibrotic cytokine <g>TGFb</g>1 can upregulate avb6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous <g>TGFb</g>1 increases expression of the integrin b6 subunit gene <g>ITGB6</g> and avb6 integrin cell surface expression in a time- and concentration-dependent manner. <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via transcriptional activation of the <g>ITGB6</g> gene, but does not result from effects on <g>ITGB6</g> mRNA stability. Basal expression of <g>ITGB6</g> in, and avb6 integrins on, lung epithelial cells occurs via homeostatic avb6-mediated <g>TGFb</g>1 activation in the absence of exogenous stimulation, and can be amplified by <g>TGFb</g>1 activation. Fundamentally, we show for the first time that <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via canonical Smad signalling since dominant negative constructs directed against Smad3 and 4 inhibit <g>ITGB6</g> transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the <g>ITGB6</g> promoter abolishes <g>TGFb</g>1-induced <g>ITGB6</g> transcriptional activity. Using chromatin immunoprecipitation we demonstrate that <g>TGFb</g>1 stimulation of lung epithelial cells results in direct binding of Smad3, and Smad4, to the <g>ITGB6</g> gene promoter within this region. Finally, using an adenoviral <g>TGFb</g>1 over-expression model of pulmonary fibrosis we demonstrate that Smad3 is crucial for <g>TGFb</g>1-induced avb6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of avb6 integrin activated <g>TGFb</g>1-induced <g>ITGB6</g> gene expression regulates epithelial basal avb6 integrin expression, and demonstrates that this occurs via Smad-dependent transcriptional regulation at a single Smad binding site in the promoter of the b6 subunit gene. Active <g>TGFb</g>1 amplifies this pathway both in vitro and in vivo, which may promote fibrosis.
27494713|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a devastating, <d>progressive disease</d> with poor survival rates and limited treatment options. Upregulation of avb6 integrins within the alveolar epithelial cells is a characteristic feature of <d>IPF</d> and correlates with poor patient survival. The pro-fibrotic cytokine <g>TGFb</g>1 can upregulate avb6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous <g>TGFb</g>1 increases expression of the integrin b6 subunit gene <g>ITGB6</g> and avb6 integrin cell surface expression in a time- and concentration-dependent manner. <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via transcriptional activation of the <g>ITGB6</g> gene, but does not result from effects on <g>ITGB6</g> mRNA stability. Basal expression of <g>ITGB6</g> in, and avb6 integrins on, lung epithelial cells occurs via homeostatic avb6-mediated <g>TGFb</g>1 activation in the absence of exogenous stimulation, and can be amplified by <g>TGFb</g>1 activation. Fundamentally, we show for the first time that <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via canonical Smad signalling since dominant negative constructs directed against <g><g>Smad3</g> and 4</g> inhibit <g>ITGB6</g> transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the <g>ITGB6</g> promoter abolishes <g>TGFb</g>1-induced <g>ITGB6</g> transcriptional activity. Using chromatin immunoprecipitation we demonstrate that <g>TGFb</g>1 stimulation of lung epithelial cells results in direct binding of <g>Smad3</g>, and <g>Smad4</g>, to the <g>ITGB6</g> gene promoter within this region. Finally, using an adenoviral <g>TGFb</g>1 over-expression model of <d>pulmonary fibrosis</d> we demonstrate that <g>Smad3</g> is crucial for <g>TGFb</g>1-induced avb6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of avb6 integrin activated <g>TGFb</g>1-induced <g>ITGB6</g> gene expression regulates epithelial basal avb6 integrin expression, and demonstrates that this occurs via Smad-dependent transcriptional regulation at a single Smad binding site in the promoter of the b6 subunit gene. Active <g>TGFb</g>1 amplifies this pathway both in vitro and in vivo, which may promote fibrosis.
27494713|a|<d>Idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d> is a devastating, <d>progressive disease</d> with poor survival rates and limited treatment options. Upregulation of avb6 integrins within the alveolar epithelial cells is a characteristic feature of <d>IPF</d> and correlates with poor patient survival. The pro-fibrotic cytokine <g>TGFb</g>1 can upregulate avb6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous <g>TGFb</g>1 increases expression of the integrin b6 subunit gene <g>ITGB6</g> and avb6 integrin cell surface expression in a time- and concentration-dependent manner. <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via transcriptional activation of the <g>ITGB6</g> gene, but does not result from effects on <g>ITGB6</g> mRNA stability. Basal expression of <g>ITGB6</g> in, and avb6 integrins on, lung epithelial cells occurs via homeostatic avb6-mediated <g>TGFb</g>1 activation in the absence of exogenous stimulation, and can be amplified by <g>TGFb</g>1 activation. Fundamentally, we show for the first time that <g>TGFb</g>1-induced <g>ITGB6</g> expression occurs via canonical Smad signalling since dominant negative constructs directed against <g><g>Smad3</g> and 4</g> inhibit <g>ITGB6</g> transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the <g>ITGB6</g> promoter abolishes <g>TGFb</g>1-induced <g>ITGB6</g> transcriptional activity. Using chromatin immunoprecipitation we demonstrate that <g>TGFb</g>1 stimulation of lung epithelial cells results in direct binding of <g>Smad3</g>, and <g>Smad4</g>, to the <g>ITGB6</g> gene promoter within this region. Finally, using an adenoviral <g>TGFb</g>1 over-expression model of <d>pulmonary <d>fibrosis</d></d> we demonstrate that <g>Smad3</g> is crucial for <g>TGFb</g>1-induced avb6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of avb6 integrin activated <g>TGFb</g>1-induced <g>ITGB6</g> gene expression regulates epithelial basal avb6 integrin expression, and demonstrates that this occurs via Smad-dependent transcriptional regulation at a single Smad binding site in the promoter of the b6 subunit gene. Active <g>TGFb</g>1 amplifies this pathway both in vitro and in vivo, which may promote <d>fibrosis</d>.
27508041|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive lung disease involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. MicroRNAs miRNAs, as gene regulators, are assumed to regulate about one third of genes and thus play important roles in cellular functions including proliferation, growth, differentiation and apoptosis. Recent studies have indicated that some miRNAs may play critical roles in the pathogenesis of <d>pulmonary fibrosis</d>. In this study, we found that miR-338*miR-338-5p, which has been found to be associated with tumor progression, was down-regulated in fibroblasts and TGF-b-induced lung fibrotic tissues. Over-expression of miR-338* can partly prevent the fibrotic process induced by TGF-b. Moreover, LPA1 was proven to be a downstream target of miR-338*. Lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. Taken together, our results suggest that miR-338* attenuates the pathogenesis of <d>pulmonary fibrosis</d> through targeting LPA1. Thus, miR-338* can be a potential therapeutic target for the treatment of IPF.
27508041|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive lung disease involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. MicroRNAs miRNAs, as gene regulators, are assumed to regulate about one third of genes and thus play important roles in cellular functions including proliferation, growth, differentiation and apoptosis. Recent studies have indicated that some miRNAs may play critical roles in the pathogenesis of <d>pulmonary fibrosis</d>. In this study, we found that miR-338*miR-338-5p, which has been found to be associated with tumor progression, was down-regulated in fibroblasts and TGF-b-induced lung fibrotic tissues. Over-expression of miR-338* can partly prevent the fibrotic process induced by TGF-b. Moreover, <g>LPA1</g> was proven to be a downstream target of miR-338*. Lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. Taken together, our results suggest that miR-338* attenuates the pathogenesis of <d>pulmonary fibrosis</d> through targeting <g>LPA1</g>. Thus, miR-338* can be a potential therapeutic target for the treatment of <d>IPF</d>.
27508041|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>lung disease</d> involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. MicroRNAs miRNAs, as gene regulators, are assumed to regulate about one third of genes and thus play important roles in cellular functions including proliferation, growth, differentiation and apoptosis. Recent studies have indicated that some miRNAs may play critical roles in the pathogenesis of <d>pulmonary fibrosis</d>. In this study, we found that miR-338*miR-338-5p, which has been found to be associated with tumor progression, was down-regulated in fibroblasts and TGF-b-induced lung fibrotic tissues. Over-expression of miR-338* can partly prevent the fibrotic process induced by TGF-b. Moreover, <g>LPA1</g> was proven to be a downstream target of miR-338*. Lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. Taken together, our results suggest that miR-338* attenuates the pathogenesis of <d>pulmonary fibrosis</d> through targeting <g>LPA1</g>. Thus, miR-338* can be a potential therapeutic target for the treatment of <d>IPF</d>.
27508041|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive <d>lung disease</d> involving <d>pulmonary injury</d> associated with tissue repair, dysfunction and fibrosis. MicroRNAs miRNAs, as gene regulators, are assumed to regulate about one third of genes and thus play important roles in cellular functions including proliferation, growth, differentiation and apoptosis. Recent studies have indicated that some miRNAs may play critical roles in the pathogenesis of <d>pulmonary fibrosis</d>. In this study, we found that miR-338*miR-338-5p, which has been found to be associated with tumor progression, was down-regulated in fibroblasts and TGF-b-induced lung fibrotic tissues. Over-expression of miR-338* can partly prevent the fibrotic process induced by TGF-b. Moreover, <g>LPA1</g> was proven to be a downstream target of miR-338*. Lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. Taken together, our results suggest that miR-338* attenuates the pathogenesis of <d>pulmonary fibrosis</d> through targeting <g>LPA1</g>. Thus, miR-338* can be a potential therapeutic target for the treatment of <d>IPF</d>.
27508041|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive <d>lung disease</d> involving <d>pulmonary injury</d> associated with tissue repair, dysfunction and <d>fibrosis</d>. MicroRNAs miRNAs, as gene regulators, are assumed to regulate about one third of genes and thus play important roles in cellular functions including proliferation, growth, differentiation and apoptosis. Recent studies have indicated that some miRNAs may play critical roles in the pathogenesis of <d>pulmonary <d>fibrosis</d></d>. In this study, we found that miR-338*miR-338-5p, which has been found to be associated with tumor progression, was down-regulated in fibroblasts and TGF-b-induced lung fibrotic tissues. Over-expression of miR-338* can partly prevent the fibrotic process induced by TGF-b. Moreover, <g>LPA1</g> was proven to be a downstream target of miR-338*. Lentivirus-mediated over-expression of miR-338* can alleviate lung <d>fibrosis</d> induced by bleomycin in mice. Taken together, our results suggest that miR-338* attenuates the pathogenesis of <d>pulmonary <d>fibrosis</d></d> through targeting <g>LPA1</g>. Thus, miR-338* can be a potential therapeutic target for the treatment of <d>IPF</d>.
27508041|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive <d>lung disease</d> involving <d>pulmonary injury</d> associated with tissue repair, dysfunction and <d>fibrosis</d>. MicroRNAs miRNAs, as gene regulators, are assumed to regulate about one third of genes and thus play important roles in cellular functions including proliferation, growth, differentiation and apoptosis. Recent studies have indicated that some miRNAs may play critical roles in the pathogenesis of <d>pulmonary <d>fibrosis</d></d>. In this study, we found that <g>miR-338</g>*<g>miR-338</g>-5p, which has been found to be associated with <d>tumor</d> progression, was down-regulated in fibroblasts and TGF-b-induced lung fibrotic tissues. Over-expression of <g>miR-338</g>* can partly prevent the fibrotic process induced by TGF-b. Moreover, <g>LPA1</g> was proven to be a downstream target of <g>miR-338</g>*. Lentivirus-mediated over-expression of <g>miR-338</g>* can alleviate lung <d>fibrosis</d> induced by bleomycin in mice. Taken together, our results suggest that <g>miR-338</g>* attenuates the pathogenesis of <d>pulmonary <d>fibrosis</d></d> through targeting <g>LPA1</g>. Thus, <g>miR-338</g>* can be a potential therapeutic target for the treatment of <d>IPF</d>.
27508042|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a chronic lung disease involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. Recent studies indicate that some microRNAs miRNAs may play critical roles in the pathogenesis of <d>pulmonary fibrosis</d>. In this study, we aim to investigate whether miR-338* miR-338-5p, which has been found to be associated with tumor progression, is associated with pathological process of <d>pulmonary fibrosis</d>. Balb/c mice were treated with bleomycin BLM to establish IPF models. Targtscan was used to predict the downstream target of miR-338*. Morphological changes were observed with light microscope and epithelial to mesenchymal transition EMT markers were detected by western blot. The expression of miR-338* or downstream target SMO was analyzed by real-time quantitative RT-PCR, northern blot or western blot. <g>MiR-338</g>* was down-regulated in the lung tissue from mice with bleomycin-induced <d>pulmonary fibrosis</d>. The <g>smoothened</g> SMO is a direct target of miR-338*, and knocking-down the expression of SMO could partially rescue the fibrotic phenotype of TGF-b-induced NuLi-1 cells. Over-expression of SMO led to the fibrotic phenotype of NuLi-1 cells even without TGF-b treatment. These findings showed that the over-expression of SMO contributed to the fibrotic phenotype of NuLi-1 cells by affecting the epithelial-to-mesenchymal transition EMT procedure. Furthermore, in vivo, lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. In conclusion, our results suggest that miR-338* can target SMO to reduce the EMT procedure and thus postpone the development of <d>pulmonary fibrosis</d>.
27508042|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic lung disease involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. Recent studies indicate that some microRNAs miRNAs may play critical roles in the pathogenesis of <d>pulmonary fibrosis</d>. In this study, we aim to investigate whether miR-338* miR-338-5p, which has been found to be associated with tumor progression, is associated with pathological process of <d>pulmonary fibrosis</d>. Balb/c mice were treated with bleomycin BLM to establish <d>IPF</d> models. Targtscan was used to predict the downstream target of miR-338*. Morphological changes were observed with light microscope and epithelial to mesenchymal transition EMT markers were detected by western blot. The expression of miR-338* or downstream target SMO was analyzed by real-time quantitative RT-PCR, northern blot or western blot. <g>MiR-338</g>* was down-regulated in the lung tissue from mice with bleomycin-induced <d>pulmonary fibrosis</d>. The <g>smoothened</g> SMO is a direct target of miR-338*, and knocking-down the expression of SMO could partially rescue the fibrotic phenotype of TGF-b-induced NuLi-1 cells. Over-expression of SMO led to the fibrotic phenotype of NuLi-1 cells even without TGF-b treatment. These findings showed that the over-expression of SMO contributed to the fibrotic phenotype of NuLi-1 cells by affecting the epithelial-to-mesenchymal transition EMT procedure. Furthermore, in vivo, lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. In conclusion, our results suggest that miR-338* can target SMO to reduce the EMT procedure and thus postpone the development of <d>pulmonary fibrosis</d>.
27508042|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic lung disease</d> involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. Recent studies indicate that some microRNAs miRNAs may play critical roles in the pathogenesis of <d>pulmonary fibrosis</d>. In this study, we aim to investigate whether miR-338* miR-338-5p, which has been found to be associated with tumor progression, is associated with pathological process of <d>pulmonary fibrosis</d>. Balb/c mice were treated with bleomycin BLM to establish <d>IPF</d> models. Targtscan was used to predict the downstream target of miR-338*. Morphological changes were observed with light microscope and epithelial to mesenchymal transition EMT markers were detected by western blot. The expression of miR-338* or downstream target SMO was analyzed by real-time quantitative RT-PCR, northern blot or western blot. <g>MiR-338</g>* was down-regulated in the lung tissue from mice with bleomycin-induced <d>pulmonary fibrosis</d>. The <g>smoothened</g> SMO is a direct target of miR-338*, and knocking-down the expression of SMO could partially rescue the fibrotic phenotype of TGF-b-induced NuLi-1 cells. Over-expression of SMO led to the fibrotic phenotype of NuLi-1 cells even without TGF-b treatment. These findings showed that the over-expression of SMO contributed to the fibrotic phenotype of NuLi-1 cells by affecting the epithelial-to-mesenchymal transition EMT procedure. Furthermore, in vivo, lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. In conclusion, our results suggest that miR-338* can target SMO to reduce the EMT procedure and thus postpone the development of <d>pulmonary fibrosis</d>.
27508042|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic lung disease</d> involving <d>pulmonary injury</d> associated with tissue repair, dysfunction and fibrosis. Recent studies indicate that some microRNAs miRNAs may play critical roles in the pathogenesis of <d>pulmonary fibrosis</d>. In this study, we aim to investigate whether miR-338* miR-338-5p, which has been found to be associated with tumor progression, is associated with pathological process of <d>pulmonary fibrosis</d>. Balb/c mice were treated with bleomycin BLM to establish <d>IPF</d> models. Targtscan was used to predict the downstream target of miR-338*. Morphological changes were observed with light microscope and epithelial to mesenchymal transition EMT markers were detected by western blot. The expression of miR-338* or downstream target SMO was analyzed by real-time quantitative RT-PCR, northern blot or western blot. <g>MiR-338</g>* was down-regulated in the lung tissue from mice with bleomycin-induced <d>pulmonary fibrosis</d>. The <g>smoothened</g> SMO is a direct target of miR-338*, and knocking-down the expression of SMO could partially rescue the fibrotic phenotype of TGF-b-induced NuLi-1 cells. Over-expression of SMO led to the fibrotic phenotype of NuLi-1 cells even without TGF-b treatment. These findings showed that the over-expression of SMO contributed to the fibrotic phenotype of NuLi-1 cells by affecting the epithelial-to-mesenchymal transition EMT procedure. Furthermore, in vivo, lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. In conclusion, our results suggest that miR-338* can target SMO to reduce the EMT procedure and thus postpone the development of <d>pulmonary fibrosis</d>.
27508042|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>chronic lung disease</d> involving <d>pulmonary injury</d> associated with tissue repair, dysfunction and <d>fibrosis</d>. Recent studies indicate that some microRNAs miRNAs may play critical roles in the pathogenesis of <d>pulmonary <d>fibrosis</d></d>. In this study, we aim to investigate whether miR-338* miR-338-5p, which has been found to be associated with tumor progression, is associated with pathological process of <d>pulmonary <d>fibrosis</d></d>. Balb/c mice were treated with bleomycin BLM to establish <d>IPF</d> models. Targtscan was used to predict the downstream target of miR-338*. Morphological changes were observed with light microscope and epithelial to mesenchymal transition EMT markers were detected by western blot. The expression of miR-338* or downstream target SMO was analyzed by real-time quantitative RT-PCR, northern blot or western blot. <g>MiR-338</g>* was down-regulated in the lung tissue from mice with bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. The <g>smoothened</g> SMO is a direct target of miR-338*, and knocking-down the expression of SMO could partially rescue the fibrotic phenotype of TGF-b-induced NuLi-1 cells. Over-expression of SMO led to the fibrotic phenotype of NuLi-1 cells even without TGF-b treatment. These findings showed that the over-expression of SMO contributed to the fibrotic phenotype of NuLi-1 cells by affecting the epithelial-to-mesenchymal transition EMT procedure. Furthermore, in vivo, lentivirus-mediated over-expression of miR-338* can alleviate lung <d>fibrosis</d> induced by bleomycin in mice. In conclusion, our results suggest that miR-338* can target SMO to reduce the EMT procedure and thus postpone the development of <d>pulmonary <d>fibrosis</d></d>.
27508042|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>chronic lung disease</d> involving <d>pulmonary injury</d> associated with tissue repair, dysfunction and <d>fibrosis</d>. Recent studies indicate that some microRNAs miRNAs may play critical roles in the pathogenesis of <d>pulmonary <d>fibrosis</d></d>. In this study, we aim to investigate whether <g>miR-338</g>* <g>miR-338</g>-5p, which has been found to be associated with <d>tumor</d> progression, is associated with pathological process of <d>pulmonary <d>fibrosis</d></d>. Balb/c mice were treated with bleomycin BLM to establish <d>IPF</d> models. Targtscan was used to predict the downstream target of <g>miR-338</g>*. Morphological changes were observed with light microscope and epithelial to mesenchymal transition EMT markers were detected by western blot. The expression of <g>miR-338</g>* or downstream target SMO was analyzed by real-time quantitative RT-PCR, northern blot or western blot. <g>MiR-338</g>* was down-regulated in the lung tissue from mice with bleomycin-induced <d>pulmonary <d>fibrosis</d></d>. The <g>smoothened</g> SMO is a direct target of <g>miR-338</g>*, and knocking-down the expression of SMO could partially rescue the fibrotic phenotype of TGF-b-induced NuLi-1 cells. Over-expression of SMO led to the fibrotic phenotype of NuLi-1 cells even without TGF-b treatment. These findings showed that the over-expression of SMO contributed to the fibrotic phenotype of NuLi-1 cells by affecting the epithelial-to-mesenchymal transition EMT procedure. Furthermore, in vivo, lentivirus-mediated over-expression of <g>miR-338</g>* can alleviate lung <d>fibrosis</d> induced by bleomycin in mice. In conclusion, our results suggest that <g>miR-338</g>* can target SMO to reduce the EMT procedure and thus postpone the development of <d>pulmonary <d>fibrosis</d></d>.
27513632|a|MicroRNA  miR-221 plays an essential role in the epithelial-mesenchymal transition EMT. High mobility group AT-hook 2  <g>HMGA2</g>, is a key regulator of EMT. However, the role of <g>miR  -221</g> in <d>pulmonary fibrosis</d>, and the association between <g>miR  -221</g> and <g>HMGA2</g> remain largely unknown. For this purpose, we examined the expression of <g>miR  -221</g> and <g>HMGA2</g> in human idiopathic <d>pulmonary fibrosis</d>  IPF tissues and pulmonary cells, namely the adenocarcinoma  A549 and human bronchial epithelium  HBE cell lines, and found that the expression of <g>miR  -221</g> was inhibited in both tissues and cells whereas high mRNA and protein expression of <g>HMGA2</g> was observed. Additionally, transforming growth factor  -b1  TGF  -b1 induced the EMT, characterized by the upregulated expression of the mesenchymal markers, namely N  -cadherin, vimentin, a  -smooth muscle actin, collagen  I and collagen  III, and the downregulated expression of the epithelial marker E-cadherin in A549 and HBE cells. We then performed transfection with <g>miR  -221</g> mimics, and found that the expression of phosphorylated-Smad3 in <g>miR  -221</g>  -overexpressing cells was significantly downregulated, compared with that in the TGF  -b1-treated cells without transfection. Furthermore, the overexpression of <g>miR  -221</g> decreased the expression of <g>HMGA2</g>, suppressed the EMT, and inhibited the proliferation of A549 and HBE cells. <g>HMGA2</g> was directly targeted by <g>miR  -221</g> which was confirmed by the dual-luciferase reporter gene assay. Finally, a mouse model of bleomycin  BLM  -induced <d>pulmonary fibrosis</d> was used to confirm the effect of <g>miR  -221</g> on EMT. Hematoxylin and eosin staining showed that BLM induced thicker alveolar walls and more collagen deposition, whereas <g>miR  -221</g> treatment reduced lung fibrosis and the tissues exhibited thinner alveolar walls and normal lung alveoli. Furthermore, the EMT process was suppressed following <g>miR  -221</g> injection. Taken together, these findings sugest that <g>miR  -221</g> targets <g>HMGA2</g> to inhibit BLM  -induced <d>pulmonary fibrosis</d> through the TGF  -b1/Smad3 signaling pathway.
27513632|a|<g>MicroRNA  miR-221</g> plays an essential role in the epithelial-mesenchymal transition EMT. <g>High mobility group AT-hook 2</g>  <g>HMGA2</g>, is a key regulator of EMT. However, the role of <g>miR  -221</g> in <d>pulmonary fibrosis</d>, and the association between <g>miR  -221</g> and <g>HMGA2</g> remain largely unknown. For this purpose, we examined the expression of <g>miR  -221</g> and <g>HMGA2</g> in human idiopathic <d>pulmonary fibrosis</d>  <d>IPF</d> tissues and pulmonary cells, namely the adenocarcinoma  A549 and human bronchial epithelium  HBE cell lines, and found that the expression of <g>miR  -221</g> was inhibited in both tissues and cells whereas high mRNA and protein expression of <g>HMGA2</g> was observed. Additionally, transforming growth factor  -b1  <g>TGF  -b1</g> induced the EMT, characterized by the upregulated expression of the mesenchymal markers, namely N  -cadherin, vimentin, a  -smooth muscle actin, collagen  I and collagen  III, and the downregulated expression of the epithelial marker E-cadherin in A549 and HBE cells. We then performed transfection with <g>miR  -221</g> mimics, and found that the expression of phosphorylated-<g>Smad3</g> in <g>miR  -221</g>  -overexpressing cells was significantly downregulated, compared with that in the <g>TGF  -b1</g>-treated cells without transfection. Furthermore, the overexpression of <g>miR  -221</g> decreased the expression of <g>HMGA2</g>, suppressed the EMT, and inhibited the proliferation of A549 and HBE cells. <g>HMGA2</g> was directly targeted by <g>miR  -221</g> which was confirmed by the dual-luciferase reporter gene assay. Finally, a mouse model of bleomycin  BLM  -induced <d>pulmonary fibrosis</d> was used to confirm the effect of <g>miR  -221</g> on EMT. Hematoxylin and eosin staining showed that BLM induced thicker alveolar walls and more collagen deposition, whereas <g>miR  -221</g> treatment reduced lung fibrosis and the tissues exhibited thinner alveolar walls and normal lung alveoli. Furthermore, the EMT process was suppressed following <g>miR  -221</g> injection. Taken together, these findings sugest that <g>miR  -221</g> targets <g>HMGA2</g> to inhibit BLM  -induced <d>pulmonary fibrosis</d> through the <g>TGF  -b1</g>/<g>Smad3</g> signaling pathway.
27513632|a|<g>MicroRNA  miR-221</g> plays an essential role in the epithelial-mesenchymal transition EMT. <g>High mobility group AT-hook 2</g>  <g>HMGA2</g>, is a key regulator of EMT. However, the role of <g>miR  -221</g> in <d>pulmonary fibrosis</d>, and the association between <g>miR  -221</g> and <g>HMGA2</g> remain largely unknown. For this purpose, we examined the expression of <g>miR  -221</g> and <g>HMGA2</g> in human idiopathic <d>pulmonary fibrosis</d>  <d>IPF</d> tissues and pulmonary cells, namely the <d>adenocarcinoma  A549</d> and human bronchial epithelium  HBE cell lines, and found that the expression of <g>miR  -221</g> was inhibited in both tissues and cells whereas high mRNA and protein expression of <g>HMGA2</g> was observed. Additionally, transforming growth factor  -b1  <g>TGF  -b1</g> induced the EMT, characterized by the upregulated expression of the mesenchymal markers, namely N  -cadherin, vimentin, a  -smooth muscle actin, collagen  I and collagen  III, and the downregulated expression of the epithelial marker E-cadherin in A549 and HBE cells. We then performed transfection with <g>miR  -221</g> mimics, and found that the expression of phosphorylated-<g>Smad3</g> in <g>miR  -221</g>  -overexpressing cells was significantly downregulated, compared with that in the <g>TGF  -b1</g>-treated cells without transfection. Furthermore, the overexpression of <g>miR  -221</g> decreased the expression of <g>HMGA2</g>, suppressed the EMT, and inhibited the proliferation of A549 and HBE cells. <g>HMGA2</g> was directly targeted by <g>miR  -221</g> which was confirmed by the dual-luciferase reporter gene assay. Finally, a mouse model of bleomycin  BLM  -induced <d>pulmonary fibrosis</d> was used to confirm the effect of <g>miR  -221</g> on EMT. Hematoxylin and eosin staining showed that BLM induced thicker alveolar walls and more collagen deposition, whereas <g>miR  -221</g> treatment reduced lung fibrosis and the tissues exhibited thinner alveolar walls and normal lung alveoli. Furthermore, the EMT process was suppressed following <g>miR  -221</g> injection. Taken together, these findings sugest that <g>miR  -221</g> targets <g>HMGA2</g> to inhibit BLM  -induced <d>pulmonary fibrosis</d> through the <g>TGF  -b1</g>/<g>Smad3</g> signaling pathway.
27513632|a|<g>MicroRNA  miR-221</g> plays an essential role in the epithelial-mesenchymal transition EMT. <g>High mobility group AT-hook 2</g>  <g>HMGA2</g>, is a key regulator of EMT. However, the role of <g>miR  -221</g> in <d>pulmonary fibrosis</d>, and the association between <g>miR  -221</g> and <g>HMGA2</g> remain largely unknown. For this purpose, we examined the expression of <g>miR  -221</g> and <g>HMGA2</g> in human idiopathic <d>pulmonary fibrosis</d>  <d>IPF</d> tissues and pulmonary cells, namely the <d>adenocarcinoma  A549</d> and human bronchial epithelium  HBE cell lines, and found that the expression of <g>miR  -221</g> was inhibited in both tissues and cells whereas high mRNA and protein expression of <g>HMGA2</g> was observed. Additionally, <g>transforming growth factor  -b1</g>  <g>TGF  -b1</g> induced the EMT, characterized by the upregulated expression of the mesenchymal markers, namely <g>N  -cadherin</g>, <g>vimentin</g>, a  -smooth muscle actin, collagen  I and collagen  III, and the downregulated expression of the epithelial marker <g>E-cadherin</g> in A549 and HBE cells. We then performed transfection with <g>miR  -221</g> mimics, and found that the expression of phosphorylated-<g>Smad3</g> in <g>miR  -221</g>  -overexpressing cells was significantly downregulated, compared with that in the <g>TGF  -b1</g>-treated cells without transfection. Furthermore, the overexpression of <g>miR  -221</g> decreased the expression of <g>HMGA2</g>, suppressed the EMT, and inhibited the proliferation of A549 and HBE cells. <g>HMGA2</g> was directly targeted by <g>miR  -221</g> which was confirmed by the dual-luciferase reporter gene assay. Finally, a mouse model of bleomycin  BLM  -induced <d>pulmonary fibrosis</d> was used to confirm the effect of <g>miR  -221</g> on EMT. Hematoxylin and eosin staining showed that BLM induced <d>thicker alveolar walls</d> and more collagen deposition, whereas <g>miR  -221</g> treatment reduced lung fibrosis and the tissues exhibited thinner alveolar walls and normal lung alveoli. Furthermore, the EMT process was suppressed following <g>miR  -221</g> injection. Taken together, these findings sugest that <g>miR  -221</g> targets <g>HMGA2</g> to inhibit BLM  -induced <d>pulmonary fibrosis</d> through the <g>TGF  -b1</g>/<g>Smad3</g> signaling pathway.
27513632|a|<g>MicroRNA  miR-221</g> plays an essential role in the epithelial-mesenchymal transition EMT. <g>High mobility group AT-hook 2</g>  <g>HMGA2</g>, is a key regulator of EMT. However, the role of <g>miR  -221</g> in <d>pulmonary <d>fibrosis</d></d>, and the association between <g>miR  -221</g> and <g>HMGA2</g> remain largely unknown. For this purpose, we examined the expression of <g>miR  -221</g> and <g>HMGA2</g> in human idiopathic <d>pulmonary <d>fibrosis</d></d>  <d>IPF</d> tissues and pulmonary cells, namely the <d>adenocarcinoma  A549</d> and human bronchial epithelium  HBE cell lines, and found that the expression of <g>miR  -221</g> was inhibited in both tissues and cells whereas high mRNA and protein expression of <g>HMGA2</g> was observed. Additionally, <g>transforming growth factor  -b1</g>  <g>TGF  -b1</g> induced the EMT, characterized by the upregulated expression of the mesenchymal markers, namely <g>N  -cadherin</g>, <g>vimentin</g>, a  -smooth muscle actin, collagen  I and collagen  III, and the downregulated expression of the epithelial marker <g>E-cadherin</g> in A549 and HBE cells. We then performed transfection with <g>miR  -221</g> mimics, and found that the expression of phosphorylated-<g>Smad3</g> in <g>miR  -221</g>  -overexpressing cells was significantly downregulated, compared with that in the <g>TGF  -b1</g>-treated cells without transfection. Furthermore, the overexpression of <g>miR  -221</g> decreased the expression of <g>HMGA2</g>, suppressed the EMT, and inhibited the proliferation of A549 and HBE cells. <g>HMGA2</g> was directly targeted by <g>miR  -221</g> which was confirmed by the dual-luciferase reporter gene assay. Finally, a mouse model of bleomycin  BLM  -induced <d>pulmonary <d>fibrosis</d></d> was used to confirm the effect of <g>miR  -221</g> on EMT. Hematoxylin and eosin staining showed that BLM induced <d>thicker alveolar walls</d> and more collagen deposition, whereas <g>miR  -221</g> treatment reduced lung <d>fibrosis</d> and the tissues exhibited thinner alveolar walls and normal lung alveoli. Furthermore, the EMT process was suppressed following <g>miR  -221</g> injection. Taken together, these findings sugest that <g>miR  -221</g> targets <g>HMGA2</g> to inhibit BLM  -induced <d>pulmonary <d>fibrosis</d></d> through the <g>TGF  -b1</g>/<g>Smad3</g> signaling pathway.
27560128|a|RATIONALE: <d>Fibrotic disorders</d> are associated with tissue accumulation of fibroblasts. We recently showed that caveolin-1 Cav-1 gene suppression by the pro-fibrotic cytokine TGF-b1 contributes to fibroblast proliferation and apoptosis-resistance. Cav-1 has been shown to be constitutively suppressed in idiopathic pulmonary fibrosis IPF, but mechanisms for this suppression are incompletely understood. We hypothesized that epigenetic processes contribute to Cav-1 downregulation in IPF lung fibroblasts, and following fibrogenic stimuli. METHODS: Cav-1 expression levels, DNA methylation status and histone modifications associated with the Cav-1 promoter were examined by PCR, western blots, pyrosequencing or ChIP assays in IPF lung fibroblasts, normal fibroblasts following TGF-b1 stimulation, or in murine lung fibroblasts after bleomycin injury. RESULTS: Methylation-specific-PCR demonstrated methylated and unmethylated Cav-1 DNA copies in all groups. Despite significant changes in Cav-1 expression, no changes in DNA methylation were observed in CpG islands CGIs or CGI shores of the Cav-1 promoter by pyrosequencing of lung fibroblasts from IPF lungs, in response to TGF-b1, or after bleomycin-induced murine lung injury, when compared to respective controls. In contrast, the association of Cav-1 promoter with the active histone modification mark, H3K4Me3, correlated with Cav-1 downregulation in activated/fibrotic lung fibroblasts. CONCLUSION: Our data indicate that Cav-1 gene silencing in lung fibroblasts is actively regulated by epigenetic mechanisms that involve histone modifications, in particular H3K4Me3, whereas DNA methylation does not appear to be a primary mechanism. These findings support therapeutic strategies that target histone modifications to restore Cav-1 expression in fibroblasts participating in pathogenic tissue remodeling.
27560128|a|RATIONALE: <d>Fibrotic disorders</d> are associated with tissue accumulation of fibroblasts. We recently showed that <g>caveolin-1</g> Cav-1 gene suppression by the pro-fibrotic cytokine TGF-b1 contributes to fibroblast proliferation and apoptosis-resistance. Cav-1 has been shown to be constitutively suppressed in <d>idiopathic pulmonary fibrosis</d> IPF, but mechanisms for this suppression are incompletely understood. We hypothesized that epigenetic processes contribute to Cav-1 downregulation in IPF lung fibroblasts, and following fibrogenic stimuli. METHODS: Cav-1 expression levels, DNA methylation status and histone modifications associated with the Cav-1 promoter were examined by PCR, western blots, pyrosequencing or ChIP assays in IPF lung fibroblasts, normal fibroblasts following TGF-b1 stimulation, or in murine lung fibroblasts after bleomycin injury. RESULTS: Methylation-specific-PCR demonstrated methylated and unmethylated Cav-1 DNA copies in all groups. Despite significant changes in Cav-1 expression, no changes in DNA methylation were observed in CpG islands CGIs or CGI shores of the Cav-1 promoter by pyrosequencing of lung fibroblasts from IPF lungs, in response to TGF-b1, or after bleomycin-induced murine lung injury, when compared to respective controls. In contrast, the association of Cav-1 promoter with the active histone modification mark, H3K4Me3, correlated with Cav-1 downregulation in activated/fibrotic lung fibroblasts. CONCLUSION: Our data indicate that Cav-1 gene silencing in lung fibroblasts is actively regulated by epigenetic mechanisms that involve histone modifications, in particular H3K4Me3, whereas DNA methylation does not appear to be a primary mechanism. These findings support therapeutic strategies that target histone modifications to restore Cav-1 expression in fibroblasts participating in pathogenic tissue remodeling.
27560128|a|RATIONALE: <d>Fibrotic disorders</d> are associated with tissue accumulation of fibroblasts. We recently showed that <g>caveolin-1</g> Cav-1 gene suppression by the pro-fibrotic cytokine TGF-b1 contributes to fibroblast proliferation and apoptosis-resistance. Cav-1 has been shown to be constitutively suppressed in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, but mechanisms for this suppression are incompletely understood. We hypothesized that epigenetic processes contribute to Cav-1 downregulation in <d>IPF</d> lung fibroblasts, and following fibrogenic stimuli. METHODS: Cav-1 expression levels, DNA methylation status and histone modifications associated with the Cav-1 promoter were examined by PCR, western blots, pyrosequencing or ChIP assays in <d>IPF</d> lung fibroblasts, normal fibroblasts following TGF-b1 stimulation, or in murine lung fibroblasts after bleomycin injury. RESULTS: Methylation-specific-PCR demonstrated methylated and unmethylated Cav-1 DNA copies in all groups. Despite significant changes in Cav-1 expression, no changes in DNA methylation were observed in CpG islands CGIs or CGI shores of the Cav-1 promoter by pyrosequencing of lung fibroblasts from <d>IPF</d> lungs, in response to TGF-b1, or after bleomycin-induced murine lung injury, when compared to respective controls. In contrast, the association of Cav-1 promoter with the active histone modification mark, H3K4Me3, correlated with Cav-1 downregulation in activated/fibrotic lung fibroblasts. CONCLUSION: Our data indicate that Cav-1 gene silencing in lung fibroblasts is actively regulated by epigenetic mechanisms that involve histone modifications, in particular H3K4Me3, whereas DNA methylation does not appear to be a primary mechanism. These findings support therapeutic strategies that target histone modifications to restore Cav-1 expression in fibroblasts participating in pathogenic tissue remodeling.
27560128|a|RATIONALE: <d>Fibrotic disorders</d> are associated with tissue accumulation of fibroblasts. We recently showed that <g>caveolin-1</g> Cav-1 gene suppression by the pro-fibrotic cytokine TGF-b1 contributes to fibroblast proliferation and apoptosis-resistance. Cav-1 has been shown to be constitutively suppressed in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, but mechanisms for this suppression are incompletely understood. We hypothesized that epigenetic processes contribute to Cav-1 downregulation in <d>IPF</d> lung fibroblasts, and following fibrogenic stimuli. METHODS: Cav-1 expression levels, DNA methylation status and histone modifications associated with the Cav-1 promoter were examined by PCR, western blots, pyrosequencing or ChIP assays in <d>IPF</d> lung fibroblasts, normal fibroblasts following TGF-b1 stimulation, or in murine lung fibroblasts after bleomycin injury. RESULTS: Methylation-specific-PCR demonstrated methylated and unmethylated Cav-1 DNA copies in all groups. Despite significant changes in Cav-1 expression, no changes in DNA methylation were observed in CpG islands CGIs or CGI shores of the Cav-1 promoter by pyrosequencing of lung fibroblasts from <d>IPF</d> lungs, in response to TGF-b1, or after bleomycin-induced murine <d>lung injury</d>, when compared to respective controls. In contrast, the association of Cav-1 promoter with the active histone modification mark, H3K4Me3, correlated with Cav-1 downregulation in activated/fibrotic lung fibroblasts. CONCLUSION: Our data indicate that Cav-1 gene silencing in lung fibroblasts is actively regulated by epigenetic mechanisms that involve histone modifications, in particular H3K4Me3, whereas DNA methylation does not appear to be a primary mechanism. These findings support therapeutic strategies that target histone modifications to restore Cav-1 expression in fibroblasts participating in pathogenic tissue remodeling.
27576730|a|BACKGROUND: Accumulation of profibrotic myofibroblasts in fibroblastic foci FF is a crucial process for development of <d>fibrosis</d> during idiopathic pulmonary <d>fibrosis</d> IPF pathogenesis, and transforming growth factor TGF-b plays a key regulatory role in myofibroblast differentiation. Reactive oxygen species ROS has been proposed to be involved in the mechanism for TGF-b-induced myofibroblast differentiation. Metformin is a biguanide antidiabetic medication and its pharmacological action is mediated through the activation of AMP-activated protein kinase AMPK, which regulates not only energy homeostasis but also stress responses, including ROS. Therefore, we sought to investigate the inhibitory role of metformin in lung <d>fibrosis</d> development via modulating TGF-b signaling. METHODS: TGF-b-induced myofibroblast differentiation in lung fibroblasts LF was used for in vitro models. The anti-fibrotic role of metfromin was examined in a bleomycin BLM-induced lung <d>fibrosis</d> model. RESULTS: We found that TGF-b-induced myofibroblast differentiation was clearly inhibited by metformin treatment in LF. Metformin-mediated activation of AMPK was responsible for inhibiting TGF-b-induced <g>NOX4</g> expression. <g>NOX4</g> knockdown and N-acetylcysteine NAC treatment illustrated that <g>NOX4</g>-derived ROS generation was critical for TGF-b-induced SMAD phosphorylation and myofibroblast differentiation. BLM treatment induced development of lung <d>fibrosis</d> with concomitantly enhanced <g>NOX4</g> expression and SMAD phosphorylation, which was efficiently inhibited by metformin. Increased <g>NOX4</g> expression levels were also observed in FF of IPF lungs and LF isolated from IPF patients. CONCLUSIONS: These findings suggest that metformin can be a promising anti-fibrotic modality of treatment for IPF affected by TGF-b.
27576730|a|BACKGROUND: Accumulation of profibrotic myofibroblasts in fibroblastic foci FF is a crucial process for development of <d>fibrosis</d> during idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> pathogenesis, and transforming growth factor TGF-b plays a key regulatory role in myofibroblast differentiation. Reactive oxygen species ROS has been proposed to be involved in the mechanism for TGF-b-induced myofibroblast differentiation. Metformin is a biguanide antidiabetic medication and its pharmacological action is mediated through the activation of AMP-activated protein kinase AMPK, which regulates not only energy homeostasis but also stress responses, including ROS. Therefore, we sought to investigate the inhibitory role of metformin in lung <d>fibrosis</d> development via modulating TGF-b signaling. METHODS: TGF-b-induced myofibroblast differentiation in lung fibroblasts LF was used for in vitro models. The anti-fibrotic role of metfromin was examined in a bleomycin BLM-induced lung <d>fibrosis</d> model. RESULTS: We found that TGF-b-induced myofibroblast differentiation was clearly inhibited by metformin treatment in LF. Metformin-mediated activation of AMPK was responsible for inhibiting TGF-b-induced <g>NOX4</g> expression. <g>NOX4</g> knockdown and N-acetylcysteine NAC treatment illustrated that <g>NOX4</g>-derived ROS generation was critical for TGF-b-induced SMAD phosphorylation and myofibroblast differentiation. BLM treatment induced development of lung <d>fibrosis</d> with concomitantly enhanced <g>NOX4</g> expression and SMAD phosphorylation, which was efficiently inhibited by metformin. Increased <g>NOX4</g> expression levels were also observed in FF of <d>IPF</d> lungs and LF isolated from <d>IPF</d> patients. CONCLUSIONS: These findings suggest that metformin can be a promising anti-fibrotic modality of treatment for <d>IPF</d> affected by TGF-b.
27582065|a|The accumulation of fibroblasts/myofibroblasts in fibrotic foci is one of the characteristics of <d>idiopathic pulmonary fibrosis</d> IPF. Enhancer of zeste homolog 2 <g>EZH2</g> is the catalytic component of a multiprotein complex, polycomb repressive complex 2, which is involved in the trimethylation of histone H3 at lysine 27. In this study, we investigated the role and mechanisms of <g>EZH2</g> in the differentiation of fibroblasts into myofibroblasts. We found that <g>EZH2</g> was upregulated in the lungs of patients with IPF and in mice with bleomycin-induced lung fibrosis. The upregulation of <g>EZH2</g> occurred in myofibroblasts. The inhibition of <g>EZH2</g> by its inhibitor 3-deazaneplanocin A DZNep or an shRNA reduced the TGF-b1-induced differentiation of human lung fibroblasts into myofibroblasts, as demonstrated by the expression of the myofibroblast markers a-smooth muscle actin and fibronectin, and contractility. DZNep inhibited Smad2/3 nuclear translocation without affecting Smad2/3 phosphorylation. DZNep treatment attenuated bleomycin-induced pulmonary fibrosis in mice. We conclude that <g>EZH2</g> induces the differentiation of fibroblasts to myofibroblasts by enhancing Smad2/3 nuclear translocation.
27582065|a|The accumulation of fibroblasts/myofibroblasts in fibrotic foci is one of the characteristics of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Enhancer of zeste homolog 2 <g>EZH2</g> is the catalytic component of a multiprotein complex, polycomb repressive complex 2, which is involved in the trimethylation of histone H3 at lysine 27. In this study, we investigated the role and mechanisms of <g>EZH2</g> in the differentiation of fibroblasts into myofibroblasts. We found that <g>EZH2</g> was upregulated in the lungs of patients with <d>IPF</d> and in mice with bleomycin-induced lung fibrosis. The upregulation of <g>EZH2</g> occurred in myofibroblasts. The inhibition of <g>EZH2</g> by its inhibitor 3-deazaneplanocin A DZNep or an shRNA reduced the TGF-b1-induced differentiation of human lung fibroblasts into myofibroblasts, as demonstrated by the expression of the myofibroblast markers a-smooth muscle actin and fibronectin, and contractility. DZNep inhibited Smad2/3 nuclear translocation without affecting Smad2/3 phosphorylation. DZNep treatment attenuated bleomycin-induced pulmonary fibrosis in mice. We conclude that <g>EZH2</g> induces the differentiation of fibroblasts to myofibroblasts by enhancing Smad2/3 nuclear translocation.
27582065|a|The accumulation of fibroblasts/myofibroblasts in fibrotic foci is one of the characteristics of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. <g>Enhancer of zeste homolog 2</g> <g>EZH2</g> is the catalytic component of a multiprotein complex, polycomb repressive complex 2, which is involved in the trimethylation of histone H3 at lysine 27. In this study, we investigated the role and mechanisms of <g>EZH2</g> in the differentiation of fibroblasts into myofibroblasts. We found that <g>EZH2</g> was upregulated in the lungs of patients with <d>IPF</d> and in mice with bleomycin-induced <d>lung fibrosis</d>. The upregulation of <g>EZH2</g> occurred in myofibroblasts. The inhibition of <g>EZH2</g> by its inhibitor 3-deazaneplanocin A DZNep or an shRNA reduced the TGF-b1-induced differentiation of human lung fibroblasts into myofibroblasts, as demonstrated by the expression of the myofibroblast markers a-smooth muscle actin and fibronectin, and contractility. DZNep inhibited Smad2/3 nuclear translocation without affecting Smad2/3 phosphorylation. DZNep treatment attenuated bleomycin-induced pulmonary fibrosis in mice. We conclude that <g>EZH2</g> induces the differentiation of fibroblasts to myofibroblasts by enhancing Smad2/3 nuclear translocation.
27582065|a|The accumulation of fibroblasts/myofibroblasts in fibrotic foci is one of the characteristics of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. <g>Enhancer of zeste homolog 2</g> <g>EZH2</g> is the catalytic component of a multiprotein complex, polycomb repressive complex 2, which is involved in the trimethylation of histone H3 at lysine 27. In this study, we investigated the role and mechanisms of <g>EZH2</g> in the differentiation of fibroblasts into myofibroblasts. We found that <g>EZH2</g> was upregulated in the lungs of patients with <d>IPF</d> and in mice with bleomycin-induced <d>lung fibrosis</d>. The upregulation of <g>EZH2</g> occurred in myofibroblasts. The inhibition of <g>EZH2</g> by its inhibitor 3-deazaneplanocin A DZNep or an shRNA reduced the <g>TGF-b1</g>-induced differentiation of human lung fibroblasts into myofibroblasts, as demonstrated by the expression of the myofibroblast markers a-smooth muscle actin and <g>fibronectin</g>, and contractility. DZNep inhibited <g>Smad2/3</g> nuclear translocation without affecting <g>Smad2/3</g> phosphorylation. DZNep treatment attenuated bleomycin-induced <d>pulmonary fibrosis</d> in mice. We conclude that <g>EZH2</g> induces the differentiation of fibroblasts to myofibroblasts by enhancing <g>Smad2/3</g> nuclear translocation.
27583344|a|UNASSIGNED: This data article contains complementary figures related to the research article entitled, "Transforming growth factor-b-induced <g>CUX1</g> isoforms are associated with fibrosis in <d>systemic sclerosis</d> lung fibroblasts" Ikeda et al. 2016 [2], http://dx.doi.org/10.1016/j.bbrep.2016.06.022, which presents that TGF-b increased <g>CUX1</g> binding in the proximal promoter and enhancer of the COL1A2 and regulated COL1. Further, in the scleroderma SSc lung and diffuse alveolar damage lung sections, <g>CUX1</g> localized within the a- smooth muscle actin a-SMA positive cells Fragiadaki et al., 2011 [1], "High doses of TGF-beta potently suppress type I collagen via the transcription factor <g>CUX1</g>" Ikeda et al., 2016 [2]. Here we show that <g>CUX1</g> isoforms are localized within a-smooth muscle actin-positive cells in SSc skin and idiopathic pulmonary fibrosis IPF lung tissue sections. In particular, at the granular and prickle cell layers in the SSc skin sections, <g>CUX1</g> and a-SMA are co-localized. In addition, at the fibrotic loci in the IPF lung tissue sections, <g>CUX1</g> localized within the a-smooth muscle actin a-SMA positive cells.
27583344|a|UNASSIGNED: This data article contains complementary figures related to the research article entitled, "Transforming growth factor-b-induced <g>CUX1</g> isoforms are associated with <d>fibrosis</d> in <d>systemic sclerosis</d> lung fibroblasts" Ikeda et al. 2016 [2], http://dx.doi.org/10.1016/j.bbrep.2016.06.022, which presents that TGF-b increased <g>CUX1</g> binding in the proximal promoter and enhancer of the COL1A2 and regulated COL1. Further, in the scleroderma SSc lung and diffuse alveolar damage lung sections, <g>CUX1</g> localized within the a- smooth muscle actin a-SMA positive cells Fragiadaki et al., 2011 [1], "High doses of TGF-beta potently suppress type I collagen via the transcription factor <g>CUX1</g>" Ikeda et al., 2016 [2]. Here we show that <g>CUX1</g> isoforms are localized within a-smooth muscle actin-positive cells in SSc skin and idiopathic pulmonary <d>fibrosis</d> IPF lung tissue sections. In particular, at the granular and prickle cell layers in the SSc skin sections, <g>CUX1</g> and a-SMA are co-localized. In addition, at the fibrotic loci in the IPF lung tissue sections, <g>CUX1</g> localized within the a-smooth muscle actin a-SMA positive cells.
27583344|a|UNASSIGNED: This data article contains complementary figures related to the research article entitled, "Transforming growth factor-b-induced <g>CUX1</g> isoforms are associated with <d>fibrosis</d> in <d>systemic sclerosis</d> lung fibroblasts" Ikeda et al. 2016 [2], http://dx.doi.org/10.1016/j.bbrep.2016.06.022, which presents that <g>TGF-b</g> increased <g>CUX1</g> binding in the proximal promoter and enhancer of the <g>COL1A2</g> and regulated COL1. Further, in the <d>scleroderma</d> SSc lung and diffuse alveolar damage lung sections, <g>CUX1</g> localized within the a- smooth muscle actin a-SMA positive cells Fragiadaki et al., 2011 [1], "High doses of <g>TGF-b</g>eta potently suppress type I collagen via the transcription factor <g>CUX1</g>" Ikeda et al., 2016 [2]. Here we show that <g>CUX1</g> isoforms are localized within a-smooth muscle actin-positive cells in SSc skin and idiopathic pulmonary <d>fibrosis</d> IPF lung tissue sections. In particular, at the granular and prickle cell layers in the SSc skin sections, <g>CUX1</g> and a-SMA are co-localized. In addition, at the fibrotic loci in the IPF lung tissue sections, <g>CUX1</g> localized within the a-smooth muscle actin a-SMA positive cells.
27583344|a|UNASSIGNED: This data article contains complementary figures related to the research article entitled, "Transforming growth factor-b-induced <g>CUX1</g> isoforms are associated with <d>fibrosis</d> in <d>systemic sclerosis</d> lung fibroblasts" Ikeda et al. 2016 [2], http://dx.doi.org/10.1016/j.bbrep.2016.06.022, which presents that <g>TGF-b</g> increased <g>CUX1</g> binding in the proximal promoter and enhancer of the <g>COL1A2</g> and regulated COL1. Further, in the <d>scleroderma</d> SSc lung and <d>diffuse alveolar damage</d> lung sections, <g>CUX1</g> localized within the a- smooth muscle actin a-SMA positive cells Fragiadaki et al., 2011 [1], "High doses of <g>TGF-b</g>eta potently suppress type I collagen via the transcription factor <g>CUX1</g>" Ikeda et al., 2016 [2]. Here we show that <g>CUX1</g> isoforms are localized within a-smooth muscle actin-positive cells in SSc skin and idiopathic pulmonary <d>fibrosis</d> IPF lung tissue sections. In particular, at the granular and prickle cell layers in the SSc skin sections, <g>CUX1</g> and a-SMA are co-localized. In addition, at the fibrotic loci in the IPF lung tissue sections, <g>CUX1</g> localized within the a-smooth muscle actin a-SMA positive cells.
27583344|a|UNASSIGNED: This data article contains complementary figures related to the research article entitled, "Transforming growth factor-b-induced <g>CUX1</g> isoforms are associated with <d>fibrosis</d> in <d>systemic sclerosis</d> lung fibroblasts" Ikeda et al. 2016 [2], http://dx.doi.org/10.1016/j.bbrep.2016.06.022, which presents that <g>TGF-b</g> increased <g>CUX1</g> binding in the proximal promoter and enhancer of the <g>COL1A2</g> and regulated COL1. Further, in the <d>scleroderma</d> SSc lung and <d>diffuse alveolar damage</d> lung sections, <g>CUX1</g> localized within the a- smooth muscle actin <g>a-SMA</g> positive cells Fragiadaki et al., 2011 [1], "High doses of <g>TGF-b</g>eta potently suppress type I collagen via the transcription factor <g>CUX1</g>" Ikeda et al., 2016 [2]. Here we show that <g>CUX1</g> isoforms are localized within a-smooth muscle actin-positive cells in SSc skin and idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> lung tissue sections. In particular, at the granular and prickle cell layers in the SSc skin sections, <g>CUX1</g> and <g>a-SMA</g> are co-localized. In addition, at the fibrotic loci in the <d>IPF</d> lung tissue sections, <g>CUX1</g> localized within the a-smooth muscle actin <g>a-SMA</g> positive cells.
27604640|a|Transforming growth factor b-1 <g>TGFb-1</g>-induced phosphorylation of transcription factors <g>Smad2</g> and <g>Smad3</g> plays a crucial role in the pathogenesis of idiopathic <d>pulmonary fibrosis</d> IPF. However, the molecular regulation of <g>Smad2</g>/<g>Smad3</g> proteins stability remains a mystery. Here, we show that ubiquitin carboxyl-terminal hydrolase-L5 UCHL5 or UCH37 de-ubiquitinates both <g>Smad2</g> and <g>Smad3</g>, up-regulates their stability, and promotes <g>TGFb-1</g>-induced expression of profibrotic proteins, such as fibronectin FN and a-smooth muscle actin a-SMA. Inhibition or down-regulation of UCHL5 reduced <g>Smad2</g>/<g>Smad3</g> levels and <g>TGFb-1</g>-induced the expression of FN and a-SMA in human lung fibroblast. We demonstrate that <g>Smad2</g> and <g>Smad3</g> ubiquitination was diminished by over-expression of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5. UCHL5 is highly expressed in IPF lungs. UCHL5, <g>Smad2</g>, and <g>Smad3</g> levels were increased in bleomycin-injured lungs. Administration of UCHL5 inhibitor, b-AP15, reduced the expression of FN, type I collagen, <g>Smad2</g>/<g>Smad3</g>, and the deposition of collagen in lung tissues in a bleomycin-induced model of <d>pulmonary fibrosis</d>. Our studies provide a molecular mechanism by which UCHL5 mitigates <g>TGFb-1</g> signaling by stabilizing <g>Smad2</g>/<g>Smad3</g>. These data indicate that UCHL5 may contribute to the pathogenesis of IPF and may be a potential therapeutic target.
27604640|a|<g>Transforming growth factor b-1</g> <g>TGFb-1</g>-induced phosphorylation of transcription factors <g>Smad2</g> and <g>Smad3</g> plays a crucial role in the pathogenesis of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. However, the molecular regulation of <g>Smad2</g>/<g>Smad3</g> proteins stability remains a mystery. Here, we show that ubiquitin carboxyl-terminal hydrolase-L5 UCHL5 or UCH37 de-ubiquitinates both <g>Smad2</g> and <g>Smad3</g>, up-regulates their stability, and promotes <g>TGFb-1</g>-induced expression of profibrotic proteins, such as fibronectin FN and a-smooth muscle actin a-SMA. Inhibition or down-regulation of UCHL5 reduced <g>Smad2</g>/<g>Smad3</g> levels and <g>TGFb-1</g>-induced the expression of FN and a-SMA in human lung fibroblast. We demonstrate that <g>Smad2</g> and <g>Smad3</g> ubiquitination was diminished by over-expression of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5. UCHL5 is highly expressed in <d>IPF</d> lungs. UCHL5, <g>Smad2</g>, and <g>Smad3</g> levels were increased in bleomycin-injured lungs. Administration of UCHL5 inhibitor, b-AP15, reduced the expression of FN, type I collagen, <g>Smad2</g>/<g>Smad3</g>, and the deposition of collagen in lung tissues in a bleomycin-induced model of <d>pulmonary fibrosis</d>. Our studies provide a molecular mechanism by which UCHL5 mitigates <g>TGFb-1</g> signaling by stabilizing <g>Smad2</g>/<g>Smad3</g>. These data indicate that UCHL5 may contribute to the pathogenesis of <d>IPF</d> and may be a potential therapeutic target.
27658114|a|The pathogenetic heterogeneity of <d>pulmonary fibrosis</d> yields both challenges and opportunities for therapy. Its complexity implicates a variety of cellular processes, signaling pathways, and genetics as drivers of disease. TGF-b stimulation is one avenue, and is central to pro-fibrotic protein expression, leading to decreased pulmonary function. Here we report our recent findings, introducing the E3 ligase Fibrosis Inducing E3 Ligase 1 FIEL1 as an important regulator of TGF-b signaling through the selective degradation of PIAS4. FIEL1 exacerbates bleomycin-induced murine <d>pulmonary fibrosis</d>, while its silencing attenuates the fibrotic phenotype. Further, we developed a small molecule inhibitor of FIEL1 BC-1485 that inhibits the degradation of PIAS4, and ameliorates fibrosis in murine models. New understanding of this pathway illustrates the many targeting opportunities among the complexity of <d>pulmonary fibrosis</d> in the continuing search for therapy.
27658114|a|The pathogenetic heterogeneity of <d>pulmonary fibrosis</d> yields both challenges and opportunities for therapy. Its complexity implicates a variety of cellular processes, signaling pathways, and genetics as drivers of disease. <g>TGF-b</g> stimulation is one avenue, and is central to pro-fibrotic protein expression, leading to <d>decreased pulmonary function</d>. Here we report our recent findings, introducing the E3 ligase Fibrosis Inducing E3 Ligase 1 FIEL1 as an important regulator of <g>TGF-b</g> signaling through the selective degradation of PIAS4. FIEL1 exacerbates bleomycin-induced murine <d>pulmonary fibrosis</d>, while its silencing attenuates the fibrotic phenotype. Further, we developed a small molecule inhibitor of FIEL1 BC-1485 that inhibits the degradation of PIAS4, and ameliorates fibrosis in murine models. New understanding of this pathway illustrates the many targeting opportunities among the complexity of <d>pulmonary fibrosis</d> in the continuing search for therapy.
27658114|a|The pathogenetic heterogeneity of <d>pulmonary <d>fibrosis</d></d> yields both challenges and opportunities for therapy. Its complexity implicates a variety of cellular processes, signaling pathways, and genetics as drivers of disease. <g>TGF-b</g> stimulation is one avenue, and is central to pro-fibrotic protein expression, leading to <d>decreased pulmonary function</d>. Here we report our recent findings, introducing the E3 ligase Fibrosis Inducing E3 Ligase 1 <g>FIEL1</g> as an important regulator of <g>TGF-b</g> signaling through the selective degradation of <g>PIAS4</g>. <g>FIEL1</g> exacerbates bleomycin-induced murine <d>pulmonary <d>fibrosis</d></d>, while its silencing attenuates the fibrotic phenotype. Further, we developed a small molecule inhibitor of <g>FIEL1</g> BC-1485 that inhibits the degradation of <g>PIAS4</g>, and ameliorates <d>fibrosis</d> in murine models. New understanding of this pathway illustrates the many targeting opportunities among the complexity of <d>pulmonary <d>fibrosis</d></d> in the continuing search for therapy.
27746237|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF; therefore, microRNAs may reveal novel pathogenic pathways. OBJECTIVES: We sought to determine the regulatory role of microRNA miR-155 in the profibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts, and its contribution to experimental pulmonary fibrosis. METHODS: Bleomycin-induced lung fibrosis in wild-type and miR-155-/- mice was analyzed by histology, collagen, and profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in  vivo using specific inhibitors. RESULTS: miR-155-/- mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-b production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor LXRa in lung fibroblasts and macrophages. Inhibition of LXRa in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the profibrotic phenotype of IPF and miR-155-/- fibroblasts. CONCLUSIONS: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRa target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.
27746237|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to <d>IPF</d>; therefore, microRNAs may reveal novel pathogenic pathways. OBJECTIVES: We sought to determine the regulatory role of microRNA miR-155 in the profibrotic function of murine lung macrophages and fibroblasts, <d>IPF</d> lung fibroblasts, and its contribution to experimental pulmonary fibrosis. METHODS: Bleomycin-induced lung fibrosis in wild-type and miR-155-/- mice was analyzed by histology, collagen, and profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and validated in mouse lung fibroblasts and macrophages, and in <d>IPF</d> lung fibroblasts, using loss-and-gain of function assays, and in  vivo using specific inhibitors. RESULTS: miR-155-/- mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-b production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor LXRa in lung fibroblasts and macrophages. Inhibition of LXRa in experimental lung fibrosis and in <d>IPF</d> lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the profibrotic phenotype of <d>IPF</d> and miR-155-/- fibroblasts. CONCLUSIONS: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRa target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for <d>IPF</d>.
27746237|a|BACKGROUND: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to <d>IPF</d>; therefore, microRNAs may reveal novel pathogenic pathways. OBJECTIVES: We sought to determine the regulatory role of <g>microRNA miR-155</g> in the profibrotic function of murine lung macrophages and fibroblasts, <d>IPF</d> lung fibroblasts, and its contribution to experimental <d>pulmonary fibrosis</d>. METHODS: Bleomycin-induced lung fibrosis in wild-type and miR-155-/- mice was analyzed by histology, collagen, and profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and validated in mouse lung fibroblasts and macrophages, and in <d>IPF</d> lung fibroblasts, using loss-and-gain of function assays, and in  vivo using specific inhibitors. RESULTS: miR-155-/- mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-b production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor LXRa in lung fibroblasts and macrophages. Inhibition of LXRa in experimental lung fibrosis and in <d>IPF</d> lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the profibrotic phenotype of <d>IPF</d> and miR-155-/- fibroblasts. CONCLUSIONS: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRa target that when deregulated enables pathogenic <d>pulmonary fibrosis</d>. Manipulation of the miR-155/LXR pathway may have therapeutic potential for <d>IPF</d>.
27746237|a|BACKGROUND: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to <d>IPF</d>; therefore, microRNAs may reveal novel pathogenic pathways. OBJECTIVES: We sought to determine the regulatory role of <g>microRNA miR-155</g> in the profibrotic function of murine lung macrophages and fibroblasts, <d>IPF</d> lung fibroblasts, and its contribution to experimental <d>pulmonary fibrosis</d>. METHODS: Bleomycin-induced <d>lung fibrosis</d> in wild-type and miR-155-/- mice was analyzed by histology, collagen, and profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and validated in mouse lung fibroblasts and macrophages, and in <d>IPF</d> lung fibroblasts, using loss-and-gain of function assays, and in  vivo using specific inhibitors. RESULTS: miR-155-/- mice developed exacerbated <d>lung fibrosis</d>, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-b production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor LXRa in lung fibroblasts and macrophages. Inhibition of LXRa in experimental <d>lung fibrosis</d> and in <d>IPF</d> lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the profibrotic phenotype of <d>IPF</d> and miR-155-/- fibroblasts. CONCLUSIONS: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRa target that when deregulated enables pathogenic <d>pulmonary fibrosis</d>. Manipulation of the miR-155/LXR pathway may have therapeutic potential for <d>IPF</d>.
27765762|a|UNASSIGNED: MicroRNAs play an important role in the development and progression of various diseases, such as <d>idiopathic pulmonary fibrosis</d> IPF. Although the accumulation of aberrant fibroblasts resistant to apoptosis is a hallmark in IPF lungs, the mechanism regulating apoptosis susceptibility is not fully understood. Here, we investigated the role of miR-29, which is the most downregulated microRNA in IPF lungs and is also known as a regulator of extracellular matrix ECM, in the mechanism of apoptosis resistance. We found that functional inhibition of miR-29c caused resistance to Fas-mediated apoptosis in lung fibroblasts. Furthermore, experiments using miR-29c inhibitor and miR-29c mimic revealed that miR-29c regulated expression of the death receptor, Fas, and formation of death-inducing signaling complex DISC leading to extrinsic apoptosis. The representative profibrotic transforming growth factor TGF-b downregulated the expression of miR-29c as well as Fas receptor, and conferred resistance to apoptosis. We also found that introduction of miR-29c mimic abrogated these TGF-b-induced phenotypes of Fas repression and apoptosis resistance. The results presented here suggest that downregulation of miR-29 observed in IPF lungs may be associated with the apoptosis-resistant phenotype of IPF lung fibroblasts via downregulation of Fas receptor. Therefore, restoration of miR-29 expression in IPF lungs could not only inhibit the accumulation of ECM but also normalize the sensitivity to apoptosis in lung fibroblasts, which may be an effective strategy for treatment of IPF.
27765762|a|UNASSIGNED: MicroRNAs play an important role in the development and progression of various diseases, such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Although the accumulation of aberrant fibroblasts resistant to apoptosis is a hallmark in <d>IPF</d> lungs, the mechanism regulating apoptosis susceptibility is not fully understood. Here, we investigated the role of miR-29, which is the most downregulated microRNA in <d>IPF</d> lungs and is also known as a regulator of extracellular matrix ECM, in the mechanism of apoptosis resistance. We found that functional inhibition of miR-29c caused resistance to Fas-mediated apoptosis in lung fibroblasts. Furthermore, experiments using miR-29c inhibitor and miR-29c mimic revealed that miR-29c regulated expression of the death receptor, Fas, and formation of death-inducing signaling complex DISC leading to extrinsic apoptosis. The representative profibrotic transforming growth factor TGF-b downregulated the expression of miR-29c as well as Fas receptor, and conferred resistance to apoptosis. We also found that introduction of miR-29c mimic abrogated these TGF-b-induced phenotypes of Fas repression and apoptosis resistance. The results presented here suggest that downregulation of miR-29 observed in <d>IPF</d> lungs may be associated with the apoptosis-resistant phenotype of <d>IPF</d> lung fibroblasts via downregulation of Fas receptor. Therefore, restoration of miR-29 expression in <d>IPF</d> lungs could not only inhibit the accumulation of ECM but also normalize the sensitivity to apoptosis in lung fibroblasts, which may be an effective strategy for treatment of <d>IPF</d>.
27769060|a|MicroRNA signatures of BAL cells and alveolar macrophages are currently lacking in <d>IPF</d>. Here we sought to investigate the expression of fibrosis-related microRNAs in the cellular component of the BAL in <d>IPF</d>. We thus focused on microRNAs previously associated with fibrosis <g>miR-29a</g>, miR-29b, miR-29c, let-7d, and miR-21 and rapid <d>IPF</d> progression miR-185, miR-210, miR-302c-3p miR-376c and miR-423-5p. Among the tested microRNAs <g>miR-29a</g> and miR-185 were found significantly downregulated in <d>IPF</d> while miR-302c-3p and miR-376c were not expressed by BAL cells. Importantly, the downregulation of <g>miR-29a</g> inversely correlated with the significantly increased levels of COL1A1 mRNA in <d>IPF</d> BAL cells. Collagen 1 a was found mainly overexpressed in alveolar macrophages and not other cell types of the BAL by immunofluorescence. In view of the downregulation of miR-185, we tested the response of THP-1 macrophages to profibrotic cytokine TGFb and observed the downregulation of miR-185. Conversely, proinflammatory stimulation lead to miR-185 upregulation. Upon examination of the mRNA levels of known miR-185 targets <g>AKT</g>1, DNMT1 and HMGA2, no significant correlations were observed in the BAL cells. However, increased levels of total <g>AKT</g> and <g>AKT</g>ser473 phosphorylation were observed in the <d>IPF</d> BAL cells. Furthermore, miR-185 inhibition in THP-1 macrophages resulted in significant increase of <g>AKT</g>ser473 phosphorylation. Our study highlights the importance of BAL microRNA signatures in <d>IPF</d> and identifies significant differences in miR-185/<g>AKT</g> and <g>miR-29a</g>/collagen axes in the BAL cells of <d>IPF</d> patients.
27769060|a|MicroRNA signatures of BAL cells and alveolar macrophages are currently lacking in <d>IPF</d>. Here we sought to investigate the expression of <d>fibrosis</d>-related microRNAs in the cellular component of the BAL in <d>IPF</d>. We thus focused on microRNAs previously associated with <d>fibrosis</d> <g>miR-29a</g>, miR-29b, miR-29c, let-7d, and miR-21 and rapid <d>IPF</d> progression miR-185, miR-210, miR-302c-3p miR-376c and miR-423-5p. Among the tested microRNAs <g>miR-29a</g> and miR-185 were found significantly downregulated in <d>IPF</d> while miR-302c-3p and miR-376c were not expressed by BAL cells. Importantly, the downregulation of <g>miR-29a</g> inversely correlated with the significantly increased levels of COL1A1 mRNA in <d>IPF</d> BAL cells. Collagen 1 a was found mainly overexpressed in alveolar macrophages and not other cell types of the BAL by immunofluorescence. In view of the downregulation of miR-185, we tested the response of THP-1 macrophages to profibrotic cytokine TGFb and observed the downregulation of miR-185. Conversely, proinflammatory stimulation lead to miR-185 upregulation. Upon examination of the mRNA levels of known miR-185 targets <g>AKT</g>1, DNMT1 and HMGA2, no significant correlations were observed in the BAL cells. However, increased levels of total <g>AKT</g> and <g>AKT</g>ser473 phosphorylation were observed in the <d>IPF</d> BAL cells. Furthermore, miR-185 inhibition in THP-1 macrophages resulted in significant increase of <g>AKT</g>ser473 phosphorylation. Our study highlights the importance of BAL microRNA signatures in <d>IPF</d> and identifies significant differences in miR-185/<g>AKT</g> and <g>miR-29a</g>/collagen axes in the BAL cells of <d>IPF</d> patients.
27815256|a|Idiopathic pulmonary fibrosis <d>IPF</d> is a devastating lung disease with a median survival of 3 yr. <d>IPF</d> deteriorates upon viral or bacterial lung infection although pulmonary infection pneumonia in healthy lungs rarely induces fibrosis. Bacterial lipopolysaccharide LPS activates <g>Toll-like receptor 4</g> TLR4, initiating proinflammatory pathways. As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in <d>IPF</d> fibroblasts. Lung tissue sections from patients with <d>IPF</d> were analyzed for TLR4 expression. Isolated normal human lung fibroblasts NL-FB and <d>IPF</d> fibroblasts <d>IPF</d>-FB were exposed to LPS and transforming growth factor-b TGF-b before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of <d>IPF</d> lungs as well as in primary NL-FB and <d>IPF</d>-FB. As a model for a gram-negative pneumonia in the nonfibrotic lung, NL-FB and <d>IPF</d>-FB were coexposed to LPS and TGF-b. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-b stimulation alone, <d>IPF</d>-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-b receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and <d>IPF</d> fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.
27815256|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating lung disease with a median survival of 3 yr. <d>IPF</d> deteriorates upon viral or bacterial lung infection although pulmonary infection pneumonia in healthy lungs rarely induces fibrosis. Bacterial lipopolysaccharide LPS activates <g>Toll-like receptor 4</g> TLR4, initiating proinflammatory pathways. As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in <d>IPF</d> fibroblasts. Lung tissue sections from patients with <d>IPF</d> were analyzed for TLR4 expression. Isolated normal human lung fibroblasts NL-FB and <d>IPF</d> fibroblasts <d>IPF</d>-FB were exposed to LPS and transforming growth factor-b TGF-b before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of <d>IPF</d> lungs as well as in primary NL-FB and <d>IPF</d>-FB. As a model for a gram-negative pneumonia in the nonfibrotic lung, NL-FB and <d>IPF</d>-FB were coexposed to LPS and TGF-b. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-b stimulation alone, <d>IPF</d>-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-b receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and <d>IPF</d> fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.
27815256|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating <d>lung disease</d> with a median survival of 3 yr. <d>IPF</d> deteriorates upon viral or bacterial lung infection although pulmonary infection pneumonia in healthy lungs rarely induces fibrosis. Bacterial lipopolysaccharide LPS activates <g>Toll-like receptor 4</g> TLR4, initiating proinflammatory pathways. As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in <d>IPF</d> fibroblasts. Lung tissue sections from patients with <d>IPF</d> were analyzed for TLR4 expression. Isolated normal human lung fibroblasts NL-FB and <d>IPF</d> fibroblasts <d>IPF</d>-FB were exposed to LPS and transforming growth factor-b TGF-b before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of <d>IPF</d> lungs as well as in primary NL-FB and <d>IPF</d>-FB. As a model for a gram-negative pneumonia in the nonfibrotic lung, NL-FB and <d>IPF</d>-FB were coexposed to LPS and TGF-b. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-b stimulation alone, <d>IPF</d>-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-b receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and <d>IPF</d> fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.
27815256|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating <d>lung disease</d> with a median survival of 3 yr. <d>IPF</d> deteriorates upon viral or <d>bacterial lung infection</d> although pulmonary infection pneumonia in healthy lungs rarely induces fibrosis. Bacterial lipopolysaccharide LPS activates <g>Toll-like receptor 4</g> TLR4, initiating proinflammatory pathways. As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in <d>IPF</d> fibroblasts. Lung tissue sections from patients with <d>IPF</d> were analyzed for TLR4 expression. Isolated normal human lung fibroblasts NL-FB and <d>IPF</d> fibroblasts <d>IPF</d>-FB were exposed to LPS and transforming growth factor-b TGF-b before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of <d>IPF</d> lungs as well as in primary NL-FB and <d>IPF</d>-FB. As a model for a gram-negative pneumonia in the nonfibrotic lung, NL-FB and <d>IPF</d>-FB were coexposed to LPS and TGF-b. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-b stimulation alone, <d>IPF</d>-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-b receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and <d>IPF</d> fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.
27815256|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating <d>lung disease</d> with a median survival of 3 yr. <d>IPF</d> deteriorates upon viral or <d>bacterial lung infection</d> although <d>pulmonary infection</d> pneumonia in healthy lungs rarely induces fibrosis. Bacterial lipopolysaccharide LPS activates <g>Toll-like receptor 4</g> TLR4, initiating proinflammatory pathways. As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in <d>IPF</d> fibroblasts. Lung tissue sections from patients with <d>IPF</d> were analyzed for TLR4 expression. Isolated normal human lung fibroblasts NL-FB and <d>IPF</d> fibroblasts <d>IPF</d>-FB were exposed to LPS and transforming growth factor-b TGF-b before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of <d>IPF</d> lungs as well as in primary NL-FB and <d>IPF</d>-FB. As a model for a gram-negative pneumonia in the nonfibrotic lung, NL-FB and <d>IPF</d>-FB were coexposed to LPS and TGF-b. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-b stimulation alone, <d>IPF</d>-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-b receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and <d>IPF</d> fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.
27815256|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating <d>lung disease</d> with a median survival of 3 yr. <d>IPF</d> deteriorates upon viral or <d>bacterial lung infection</d> although <d>pulmonary infection</d> <d>pneumonia</d> in healthy lungs rarely induces fibrosis. Bacterial lipopolysaccharide LPS activates <g>Toll-like receptor 4</g> TLR4, initiating proinflammatory pathways. As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in <d>IPF</d> fibroblasts. Lung tissue sections from patients with <d>IPF</d> were analyzed for TLR4 expression. Isolated normal human lung fibroblasts NL-FB and <d>IPF</d> fibroblasts <d>IPF</d>-FB were exposed to LPS and transforming growth factor-b TGF-b before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of <d>IPF</d> lungs as well as in primary NL-FB and <d>IPF</d>-FB. As a model for a gram-negative <d>pneumonia</d> in the nonfibrotic lung, NL-FB and <d>IPF</d>-FB were coexposed to LPS and TGF-b. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-b stimulation alone, <d>IPF</d>-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-b receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and <d>IPF</d> fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.
27815256|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating <d>lung disease</d> with a median survival of 3 yr. <d>IPF</d> deteriorates upon viral or <d>bacterial lung infection</d> although <d>pulmonary infection</d> <d>pneumonia</d> in healthy lungs rarely induces <d>fibrosis</d>. Bacterial lipopolysaccharide LPS activates <g>Toll-like receptor 4</g> TLR4, initiating proinflammatory pathways. As TLR4 has already been linked to hepatic <d>fibrosis</d> and scleroderma, we now investigated the role of TLR4 in <d>IPF</d> fibroblasts. Lung tissue sections from patients with <d>IPF</d> were analyzed for TLR4 expression. Isolated normal human lung fibroblasts NL-FB and <d>IPF</d> fibroblasts <d>IPF</d>-FB were exposed to LPS and transforming growth factor-b TGF-b before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of <d>IPF</d> lungs as well as in primary NL-FB and <d>IPF</d>-FB. As a model for a gram-negative <d>pneumonia</d> in the nonfibrotic lung, NL-FB and <d>IPF</d>-FB were coexposed to LPS and TGF-b. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-b stimulation alone, <d>IPF</d>-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-b receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and <d>IPF</d> fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.
27815256|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a devastating <d>lung disease</d> with a median survival of 3 yr. <d>IPF</d> deteriorates upon viral or <d>bacterial lung infection</d> although <d>pulmonary infection</d> <d>pneumonia</d> in healthy lungs rarely induces <d>fibrosis</d>. Bacterial lipopolysaccharide LPS activates <g>Toll-like receptor 4</g> <g>TLR4</g>, initiating proinflammatory pathways. As <g>TLR4</g> has already been linked to hepatic <d>fibrosis</d> and <d>scleroderma</d>, we now investigated the role of <g>TLR4</g> in <d>IPF</d> fibroblasts. Lung tissue sections from patients with <d>IPF</d> were analyzed for <g>TLR4</g> expression. Isolated normal human lung fibroblasts NL-FB and <d>IPF</d> fibroblasts <d>IPF</d>-FB were exposed to LPS and transforming growth factor-b TGF-b before expression analysis of receptors, profibrotic mediators, and cytokines. <g>TLR4</g> is expressed in fibroblast foci of <d>IPF</d> lungs as well as in primary NL-FB and <d>IPF</d>-FB. As a model for a gram-negative <d>pneumonia</d> in the nonfibrotic lung, NL-FB and <d>IPF</d>-FB were coexposed to LPS and TGF-b. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-b stimulation alone, <d>IPF</d>-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-b receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and <d>IPF</d> fibroblasts thus differ in their profibrotic response upon LPS-induced <g>TLR4</g> stimulation.
27836973|a|<g>TGF-b</g> promotes excessive collagen deposition in <d>fibrotic diseases</d> such as idiopathic pulmonary fibrosis IPF. The amino acid composition of collagen is unique due to its high 33% glycine content. Here, we report that <g>TGF-b</g> induces expression of glycolytic genes and increases glycolytic flux. <g>TGF-b</g> also induces the expression of the enzymes of the de novo serine synthesis pathway phosphoglycerate dehydrogenase PHGDH, phosphoserine aminotransferase 1 PSAT1, and phosphoserine phosphatase PSPH and de novo glycine synthesis serine hydroxymethyltransferase 2 SHMT2. Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with IPF demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for <g>TGF-b</g>-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of <d>fibrotic diseases</d> including IPF.
27836973|a|<g>TGF-b</g> promotes excessive collagen deposition in <d>fibrotic diseases</d> such as <d>idiopathic pulmonary fibrosis</d> IPF. The amino acid composition of collagen is unique due to its high 33% glycine content. Here, we report that <g>TGF-b</g> induces expression of glycolytic genes and increases glycolytic flux. <g>TGF-b</g> also induces the expression of the enzymes of the de novo serine synthesis pathway phosphoglycerate dehydrogenase PHGDH, phosphoserine aminotransferase 1 PSAT1, and phosphoserine phosphatase PSPH and de novo glycine synthesis serine hydroxymethyltransferase 2 SHMT2. Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with IPF demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for <g>TGF-b</g>-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of <d>fibrotic diseases</d> including IPF.
27836973|a|<g>TGF-b</g> promotes excessive collagen deposition in <d>fibrotic diseases</d> such as <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. The amino acid composition of collagen is unique due to its high 33% glycine content. Here, we report that <g>TGF-b</g> induces expression of glycolytic genes and increases glycolytic flux. <g>TGF-b</g> also induces the expression of the enzymes of the de novo serine synthesis pathway phosphoglycerate dehydrogenase PHGDH, phosphoserine aminotransferase 1 PSAT1, and phosphoserine phosphatase PSPH and de novo glycine synthesis serine hydroxymethyltransferase 2 SHMT2. Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with <d>IPF</d> demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for <g>TGF-b</g>-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of <d>fibrotic diseases</d> including <d>IPF</d>.
27853171|a|The <g>transforming growth factor b-1</g> <g>TGFb-1</g> signaling pathway plays a central role in the pathogenesis of <d>pulmonary fibrosis</d>. Two <g>TGFb-1</g> receptors, TbRI and TbRII, mediate this pathway. TbRI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of TbRII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, <g>USP11</g>, promotes <g>TGFb-1</g> signaling through de-ubiquitination and stabilization of TbRII. We elucidate the role that mitoxantrone MTX, an <g>USP11</g> inhibitor, has in the attenuation of <g>TGFb-1</g> signaling. Inhibition or downregulation of <g>USP11</g> results in increases in TbRII ubiquitination and reduction of TbRII stability. Subsequently, <g>TGFb-1</g> signaling is greatly attenuated, as shown by the decreases in phosphorylation of SMAD2/3 levels as well as that of fibronectin FN and smooth muscle actin SMA. Overexpression of <g>USP11</g> reduces TbRII ubiquitination and increases TbRII stabilization, thereby elevating phosphorylation of SMAD2/3 and the ultimate expression of FN and SMA. Further, elevated expression of <g>USP11</g> and TbRII were detected in lung tissues from bleomycin-challenged mice and IPF patients. Therefore, <g>USP11</g> may contribute to the pathogenesis of <d>pulmonary fibrosis</d> by stabilization of TbRII and promotion of <g>TGFb-1</g> signaling. This study provides mechanistic evidence for development of <g>USP11</g> inhibitors as potential antifibrotic drugs for <d>pulmonary fibrosis</d>.
27853171|a|The <g>transforming growth factor b-1</g> <g>TGFb-1</g> signaling pathway plays a central role in the pathogenesis of <d>pulmonary fibrosis</d>. Two <g>TGFb-1</g> receptors, TbRI and TbRII, mediate this pathway. TbRI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of TbRII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, <g>USP11</g>, promotes <g>TGFb-1</g> signaling through de-ubiquitination and stabilization of TbRII. We elucidate the role that mitoxantrone MTX, an <g>USP11</g> inhibitor, has in the attenuation of <g>TGFb-1</g> signaling. Inhibition or downregulation of <g>USP11</g> results in increases in TbRII ubiquitination and reduction of TbRII stability. Subsequently, <g>TGFb-1</g> signaling is greatly attenuated, as shown by the decreases in phosphorylation of <g>SMAD2/3</g> levels as well as that of <g>fibronectin</g> FN and <d>smooth muscle actin</d> SMA. Overexpression of <g>USP11</g> reduces TbRII ubiquitination and increases TbRII stabilization, thereby elevating phosphorylation of <g>SMAD2/3</g> and the ultimate expression of FN and SMA. Further, elevated expression of <g>USP11</g> and TbRII were detected in lung tissues from bleomycin-challenged mice and IPF patients. Therefore, <g>USP11</g> may contribute to the pathogenesis of <d>pulmonary fibrosis</d> by stabilization of TbRII and promotion of <g>TGFb-1</g> signaling. This study provides mechanistic evidence for development of <g>USP11</g> inhibitors as potential antifibrotic drugs for <d>pulmonary fibrosis</d>.
27853171|a|The <g>transforming growth factor b-1</g> <g>TGFb-1</g> signaling pathway plays a central role in the pathogenesis of <d>pulmonary fibrosis</d>. Two <g>TGFb-1</g> receptors, TbRI and TbRII, mediate this pathway. TbRI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of TbRII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, <g>USP11</g>, promotes <g>TGFb-1</g> signaling through de-ubiquitination and stabilization of TbRII. We elucidate the role that mitoxantrone MTX, an <g>USP11</g> inhibitor, has in the attenuation of <g>TGFb-1</g> signaling. Inhibition or downregulation of <g>USP11</g> results in increases in TbRII ubiquitination and reduction of TbRII stability. Subsequently, <g>TGFb-1</g> signaling is greatly attenuated, as shown by the decreases in phosphorylation of <g><d>SMA</d>D2/3</g> levels as well as that of <g>fibronectin</g> FN and <d>smooth muscle actin</d> <d>SMA</d>. Overexpression of <g>USP11</g> reduces TbRII ubiquitination and increases TbRII stabilization, thereby elevating phosphorylation of <g><d>SMA</d>D2/3</g> and the ultimate expression of FN and <d>SMA</d>. Further, elevated expression of <g>USP11</g> and TbRII were detected in lung tissues from bleomycin-challenged mice and IPF patients. Therefore, <g>USP11</g> may contribute to the pathogenesis of <d>pulmonary fibrosis</d> by stabilization of TbRII and promotion of <g>TGFb-1</g> signaling. This study provides mechanistic evidence for development of <g>USP11</g> inhibitors as potential antifibrotic drugs for <d>pulmonary fibrosis</d>.
27853171|a|The <g>transforming growth factor b-1</g> <g>TGFb-1</g> signaling pathway plays a central role in the pathogenesis of <d>pulmonary fibrosis</d>. Two <g>TGFb-1</g> receptors, TbRI and TbRII, mediate this pathway. TbRI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of TbRII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, <g>USP11</g>, promotes <g>TGFb-1</g> signaling through de-ubiquitination and stabilization of TbRII. We elucidate the role that mitoxantrone MTX, an <g>USP11</g> inhibitor, has in the attenuation of <g>TGFb-1</g> signaling. Inhibition or downregulation of <g>USP11</g> results in increases in TbRII ubiquitination and reduction of TbRII stability. Subsequently, <g>TGFb-1</g> signaling is greatly attenuated, as shown by the decreases in phosphorylation of <g><d>SMA</d>D2/3</g> levels as well as that of <g>fibronectin</g> FN and <d>smooth muscle actin</d> <d>SMA</d>. Overexpression of <g>USP11</g> reduces TbRII ubiquitination and increases TbRII stabilization, thereby elevating phosphorylation of <g><d>SMA</d>D2/3</g> and the ultimate expression of FN and <d>SMA</d>. Further, elevated expression of <g>USP11</g> and TbRII were detected in lung tissues from bleomycin-challenged mice and <d>IPF</d> patients. Therefore, <g>USP11</g> may contribute to the pathogenesis of <d>pulmonary fibrosis</d> by stabilization of TbRII and promotion of <g>TGFb-1</g> signaling. This study provides mechanistic evidence for development of <g>USP11</g> inhibitors as potential antifibrotic drugs for <d>pulmonary fibrosis</d>.
27867035|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> IPF is a form of progressive interstitial lung disease with unknown etiology. Due to a lack of effective treatment, IPF is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function and hindering gas exchange. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution. Genetic engineering in mice enables the time-controlled labeling and monitoring of lipogenic or myogenic populations of lung fibroblasts during fibrosis formation and resolution. Our data demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during fibrosis formation. Conversely, we observed a myogenic-to-lipogenic switch during fibrosis resolution. Analysis of human lung tissues and primary human lung fibroblasts indicates that this fate switching is involved in IPF pathogenesis, opening potential therapeutic avenues to treat patients.
27867035|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a form of progressive interstitial lung disease with unknown etiology. Due to a lack of effective treatment, <d>IPF</d> is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function and hindering gas exchange. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution. Genetic engineering in mice enables the time-controlled labeling and monitoring of lipogenic or myogenic populations of lung fibroblasts during fibrosis formation and resolution. Our data demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during fibrosis formation. Conversely, we observed a myogenic-to-lipogenic switch during fibrosis resolution. Analysis of human lung tissues and primary human lung fibroblasts indicates that this fate switching is involved in <d>IPF</d> pathogenesis, opening potential therapeutic avenues to treat patients.
27867035|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a form of progressive <d>interstitial lung disease</d> with unknown etiology. Due to a lack of effective treatment, <d>IPF</d> is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function and hindering gas exchange. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution. Genetic engineering in mice enables the time-controlled labeling and monitoring of lipogenic or myogenic populations of lung fibroblasts during fibrosis formation and resolution. Our data demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during fibrosis formation. Conversely, we observed a myogenic-to-lipogenic switch during fibrosis resolution. Analysis of human lung tissues and primary human lung fibroblasts indicates that this fate switching is involved in <d>IPF</d> pathogenesis, opening potential therapeutic avenues to treat patients.
27867035|a|UNASSIGNED: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a form of progressive <d>interstitial lung disease</d> with unknown etiology. Due to a lack of effective treatment, <d>IPF</d> is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function and hindering gas exchange. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing <d>fibrosis</d> formation and resolution. Genetic engineering in mice enables the time-controlled labeling and monitoring of lipogenic or myogenic populations of lung fibroblasts during <d>fibrosis</d> formation and resolution. Our data demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during <d>fibrosis</d> formation. Conversely, we observed a myogenic-to-lipogenic switch during <d>fibrosis</d> resolution. Analysis of human lung tissues and primary human lung fibroblasts indicates that this fate switching is involved in <d>IPF</d> pathogenesis, opening potential therapeutic avenues to treat patients.
27869174|a|Cellular plasticity and de-differentiation are hallmarks of tissue/organ regenerative capacity in diverse species. Despite a more restricted capacity for regeneration, humans with age-related <d>chronic diseases</d>, such as cancer and fibrosis, show evidence of a recapitulation of developmental gene programs. We have previously identified a resident population of mesenchymal stromal cells MSCs in the terminal airways-alveoli by bronchoalveolar lavage BAL of human adult lungs. In this study, we characterized MSCs from BAL of patients with stable and progressive idiopathic pulmonary fibrosis IPF, defined as <5% and >= 10% decline, respectively, in forced vital capacity over the preceding 6-month period. Gene expression profiles of MSCs from IPF subjects with progressive disease were enriched for genes regulating lung development. Most notably, genes regulating early tissue patterning and branching morphogenesis were differentially regulated. Network interactive modeling of a set of these genes indicated central roles for TGF-b and SHH signaling. Importantly, fibroblast growth factor-10 FGF-10 was markedly suppressed in IPF subjects with progressive disease, and both TGF-b1 and SHH signaling were identified as critical mediators of this effect in MSCs. These findings support the concept of developmental gene re-activation in IPF, and FGF-10 deficiency as a potentially critical factor in disease progression.
27869174|a|Cellular plasticity and de-differentiation are hallmarks of tissue/organ regenerative capacity in diverse species. Despite a more restricted capacity for regeneration, humans with age-related <d>chronic diseases</d>, such as <d>cancer</d> and fibrosis, show evidence of a recapitulation of developmental gene programs. We have previously identified a resident population of mesenchymal stromal cells MSCs in the terminal airways-alveoli by bronchoalveolar lavage BAL of human adult lungs. In this study, we characterized MSCs from BAL of patients with stable and progressive idiopathic pulmonary fibrosis IPF, defined as <5% and >= 10% decline, respectively, in forced vital capacity over the preceding 6-month period. Gene expression profiles of MSCs from IPF subjects with progressive disease were enriched for genes regulating lung development. Most notably, genes regulating early tissue patterning and branching morphogenesis were differentially regulated. Network interactive modeling of a set of these genes indicated central roles for TGF-b and SHH signaling. Importantly, fibroblast growth factor-10 FGF-10 was markedly suppressed in IPF subjects with progressive disease, and both TGF-b1 and SHH signaling were identified as critical mediators of this effect in MSCs. These findings support the concept of developmental gene re-activation in IPF, and FGF-10 deficiency as a potentially critical factor in disease progression.
27869174|a|Cellular plasticity and de-differentiation are hallmarks of tissue/organ regenerative capacity in diverse species. Despite a more restricted capacity for regeneration, humans with age-related <d>chronic diseases</d>, such as <d>cancer</d> and <d>fibrosis</d>, show evidence of a recapitulation of developmental gene programs. We have previously identified a resident population of mesenchymal stromal cells MSCs in the terminal airways-alveoli by bronchoalveolar lavage BAL of human adult lungs. In this study, we characterized MSCs from BAL of patients with stable and progressive idiopathic pulmonary <d>fibrosis</d> IPF, defined as <5% and >= 10% decline, respectively, in forced vital capacity over the preceding 6-month period. Gene expression profiles of MSCs from IPF subjects with progressive disease were enriched for genes regulating lung development. Most notably, genes regulating early tissue patterning and branching morphogenesis were differentially regulated. Network interactive modeling of a set of these genes indicated central roles for TGF-b and SHH signaling. Importantly, fibroblast growth factor-10 FGF-10 was markedly suppressed in IPF subjects with progressive disease, and both TGF-b1 and SHH signaling were identified as critical mediators of this effect in MSCs. These findings support the concept of developmental gene re-activation in IPF, and FGF-10 deficiency as a potentially critical factor in disease progression.
27869174|a|Cellular plasticity and de-differentiation are hallmarks of tissue/organ regenerative capacity in diverse species. Despite a more restricted capacity for regeneration, humans with age-related <d>chronic diseases</d>, such as <d>cancer</d> and <d>fibrosis</d>, show evidence of a recapitulation of developmental gene programs. We have previously identified a resident population of mesenchymal stromal cells MSCs in the terminal airways-alveoli by bronchoalveolar lavage BAL of human adult lungs. In this study, we characterized MSCs from BAL of patients with stable and progressive idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, defined as <5% and >= 10% decline, respectively, in forced vital capacity over the preceding 6-month period. Gene expression profiles of MSCs from <d>IPF</d> subjects with progressive disease were enriched for genes regulating lung development. Most notably, genes regulating early tissue patterning and branching morphogenesis were differentially regulated. Network interactive modeling of a set of these genes indicated central roles for TGF-b and SHH signaling. Importantly, fibroblast growth factor-10 FGF-10 was markedly suppressed in <d>IPF</d> subjects with progressive disease, and both TGF-b1 and SHH signaling were identified as critical mediators of this effect in MSCs. These findings support the concept of developmental gene re-activation in <d>IPF</d>, and FGF-10 deficiency as a potentially critical factor in disease progression.
27878256|a|<d>Idiopathic pulmonary fibrosis</d> IPF is the most common interstitial lung disease. However, the pathogenesis remains to be fully elucidated. Melatonin is secreted by the pineal gland, it has a strong antioxidant effect, and exerts an anti-fibrosis effect. Whether melatonin attenuates pulm -onary fibrosis by inhibiting epithelial  -mesenchymal transition EMT requires further research. The present study aimed to investigate whether melatonin prevents transforming growth factor  -b1 TGF  -b1  -induced EMT and underlying signaling pathways using reverse transcription  -quantitative polymerase chain reaction, western blot analysis and immunofluorescence. The results demonstrated that melatonin inhibits EMT in A549 cells, and the Wnt/b  -catenin and Smad2/3 signaling pathways are involved in the EMT of the A549 cell line as they were suppressed by melatonin. The present study indicates that melatonin inhibited <g>TGFb1</g>  -induced epithelial  -mesenchymal transition in the A549 cell line and may potentially be useful in the treatment of IPF.
27878256|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is the most common interstitial lung disease. However, the pathogenesis remains to be fully elucidated. Melatonin is secreted by the pineal gland, it has a strong antioxidant effect, and exerts an anti-fibrosis effect. Whether melatonin attenuates pulm -onary fibrosis by inhibiting epithelial  -mesenchymal transition EMT requires further research. The present study aimed to investigate whether melatonin prevents transforming growth factor  -b1 TGF  -b1  -induced EMT and underlying signaling pathways using reverse transcription  -quantitative polymerase chain reaction, western blot analysis and immunofluorescence. The results demonstrated that melatonin inhibits EMT in A549 cells, and the Wnt/b  -catenin and Smad2/3 signaling pathways are involved in the EMT of the A549 cell line as they were suppressed by melatonin. The present study indicates that melatonin inhibited <g>TGFb1</g>  -induced epithelial  -mesenchymal transition in the A549 cell line and may potentially be useful in the treatment of <d>IPF</d>.
27878256|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is the most common <d>interstitial lung disease</d>. However, the pathogenesis remains to be fully elucidated. Melatonin is secreted by the pineal gland, it has a strong antioxidant effect, and exerts an anti-fibrosis effect. Whether melatonin attenuates pulm -onary fibrosis by inhibiting epithelial  -mesenchymal transition EMT requires further research. The present study aimed to investigate whether melatonin prevents transforming growth factor  -b1 TGF  -b1  -induced EMT and underlying signaling pathways using reverse transcription  -quantitative polymerase chain reaction, western blot analysis and immunofluorescence. The results demonstrated that melatonin inhibits EMT in A549 cells, and the Wnt/b  -catenin and Smad2/3 signaling pathways are involved in the EMT of the A549 cell line as they were suppressed by melatonin. The present study indicates that melatonin inhibited <g>TGFb1</g>  -induced epithelial  -mesenchymal transition in the A549 cell line and may potentially be useful in the treatment of <d>IPF</d>.
27878256|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is the most common <d>interstitial lung disease</d>. However, the pathogenesis remains to be fully elucidated. Melatonin is secreted by the pineal gland, it has a strong antioxidant effect, and exerts an anti-<d>fibrosis</d> effect. Whether melatonin attenuates pulm -onary <d>fibrosis</d> by inhibiting epithelial  -mesenchymal transition EMT requires further research. The present study aimed to investigate whether melatonin prevents transforming growth factor  -b1 TGF  -b1  -induced EMT and underlying signaling pathways using reverse transcription  -quantitative polymerase chain reaction, western blot analysis and immunofluorescence. The results demonstrated that melatonin inhibits EMT in A549 cells, and the Wnt/b  -catenin and Smad2/3 signaling pathways are involved in the EMT of the A549 cell line as they were suppressed by melatonin. The present study indicates that melatonin inhibited <g>TGFb1</g>  -induced epithelial  -mesenchymal transition in the A549 cell line and may potentially be useful in the treatment of <d>IPF</d>.
27909724|a|<d>Idiopathic pulmonary fibrosis</d>  IPF is a chronic lethal interstitial lung disease with unknown etiology. Recent studies have indicated that heat-shock protein  27  <g>HSP27</g> contributes to the pathogenesis of IPF through the regulation of epithelial-mesenchymal transition  EMT. However, the expression and role of <g>HSP27</g> in fibroblasts during pulmonary fibrogenesis has not been investigated to date, at least to the best of our knowledge. In this study, we examined the expression of <g>HSP27</g> in fibrotic lung tissue and fibroblasts from bleomycin  BLM-challenged mice and human lung fibroblasts treated with transforming growth factor-b  <g>TGF-b</g>. The results revealed that the expression of <g>HSP27</g> was significantly increased in fibrotic lung tissue and fibroblasts from BLM-challenged mice. In  vitro, <g>TGF-b</g> stimulated <g>HSP27</g> expression in and the differentiation of human lung fibroblasts. The knockdown of <g>Smad3</g> expression or nuclear factor-kB  p65 subunit attenuated the <g>TGF-b</g>-induced increase in <g>HSP27</g> expression and the differentiation of human lung fibroblasts. In addition, the knockdown of <g>HSP27</g> expression attenuated the <g>TGF-b</g>-induced activation of <g>ERK</g> and <g>Smad3</g>, and inhibited the differentiation of human lung fibroblasts. On the whole, the findings of our study demonstrate that <g>HSP27</g> expression is upregulated in lung fibroblasts during pulmonary fibrosis, and subsequently, <g>HSP27</g> modulates lung fibroblast differentiation through the <g>Smad3</g> and <g>ERK</g> pathways.
27909724|a|<d>Idiopathic pulmonary fibrosis</d>  <d>IPF</d> is a chronic lethal interstitial lung disease with unknown etiology. Recent studies have indicated that heat-shock protein  27  <g>HSP27</g> contributes to the pathogenesis of <d>IPF</d> through the regulation of epithelial-mesenchymal transition  EMT. However, the expression and role of <g>HSP27</g> in fibroblasts during pulmonary fibrogenesis has not been investigated to date, at least to the best of our knowledge. In this study, we examined the expression of <g>HSP27</g> in fibrotic lung tissue and fibroblasts from bleomycin  BLM-challenged mice and human lung fibroblasts treated with transforming growth factor-b  <g>TGF-b</g>. The results revealed that the expression of <g>HSP27</g> was significantly increased in fibrotic lung tissue and fibroblasts from BLM-challenged mice. In  vitro, <g>TGF-b</g> stimulated <g>HSP27</g> expression in and the differentiation of human lung fibroblasts. The knockdown of <g>Smad3</g> expression or nuclear factor-kB  p65 subunit attenuated the <g>TGF-b</g>-induced increase in <g>HSP27</g> expression and the differentiation of human lung fibroblasts. In addition, the knockdown of <g>HSP27</g> expression attenuated the <g>TGF-b</g>-induced activation of <g>ERK</g> and <g>Smad3</g>, and inhibited the differentiation of human lung fibroblasts. On the whole, the findings of our study demonstrate that <g>HSP27</g> expression is upregulated in lung fibroblasts during pulmonary fibrosis, and subsequently, <g>HSP27</g> modulates lung fibroblast differentiation through the <g>Smad3</g> and <g>ERK</g> pathways.
27909724|a|<d>Idiopathic pulmonary fibrosis</d>  <d>IPF</d> is a chronic lethal <d>interstitial lung disease</d> with unknown etiology. Recent studies have indicated that heat-shock protein  27  <g>HSP27</g> contributes to the pathogenesis of <d>IPF</d> through the regulation of epithelial-mesenchymal transition  EMT. However, the expression and role of <g>HSP27</g> in fibroblasts during pulmonary fibrogenesis has not been investigated to date, at least to the best of our knowledge. In this study, we examined the expression of <g>HSP27</g> in fibrotic lung tissue and fibroblasts from bleomycin  BLM-challenged mice and human lung fibroblasts treated with transforming growth factor-b  <g>TGF-b</g>. The results revealed that the expression of <g>HSP27</g> was significantly increased in fibrotic lung tissue and fibroblasts from BLM-challenged mice. In  vitro, <g>TGF-b</g> stimulated <g>HSP27</g> expression in and the differentiation of human lung fibroblasts. The knockdown of <g>Smad3</g> expression or nuclear factor-kB  p65 subunit attenuated the <g>TGF-b</g>-induced increase in <g>HSP27</g> expression and the differentiation of human lung fibroblasts. In addition, the knockdown of <g>HSP27</g> expression attenuated the <g>TGF-b</g>-induced activation of <g>ERK</g> and <g>Smad3</g>, and inhibited the differentiation of human lung fibroblasts. On the whole, the findings of our study demonstrate that <g>HSP27</g> expression is upregulated in lung fibroblasts during pulmonary fibrosis, and subsequently, <g>HSP27</g> modulates lung fibroblast differentiation through the <g>Smad3</g> and <g>ERK</g> pathways.
27909724|a|<d>Idiopathic <d>pulmonary fibrosis</d></d>  <d>IPF</d> is a chronic lethal <d>interstitial lung disease</d> with unknown etiology. Recent studies have indicated that heat-shock protein  27  <g>HSP27</g> contributes to the pathogenesis of <d>IPF</d> through the regulation of epithelial-mesenchymal transition  EMT. However, the expression and role of <g>HSP27</g> in fibroblasts during pulmonary fibrogenesis has not been investigated to date, at least to the best of our knowledge. In this study, we examined the expression of <g>HSP27</g> in fibrotic lung tissue and fibroblasts from bleomycin  BLM-challenged mice and human lung fibroblasts treated with <g>transforming growth factor-b</g>  <g>TGF-b</g>. The results revealed that the expression of <g>HSP27</g> was significantly increased in fibrotic lung tissue and fibroblasts from BLM-challenged mice. In  vitro, <g>TGF-b</g> stimulated <g>HSP27</g> expression in and the differentiation of human lung fibroblasts. The knockdown of <g>Smad3</g> expression or nuclear factor-kB  <g>p65</g> subunit attenuated the <g>TGF-b</g>-induced increase in <g>HSP27</g> expression and the differentiation of human lung fibroblasts. In addition, the knockdown of <g>HSP27</g> expression attenuated the <g>TGF-b</g>-induced activation of <g>ERK</g> and <g>Smad3</g>, and inhibited the differentiation of human lung fibroblasts. On the whole, the findings of our study demonstrate that <g>HSP27</g> expression is upregulated in lung fibroblasts during <d>pulmonary fibrosis</d>, and subsequently, <g>HSP27</g> modulates lung fibroblast differentiation through the <g>Smad3</g> and <g>ERK</g> pathways.
27937011|a|CONTEXT: Previous studies have reported that caveolin-1 Cav-1 is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic <d>pulmonary fibrosis</d> IPF is unknown. OBJECTIVE: This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF. MATERIALS AND METHODS: Rat IPF model was established by endotracheal injection of 5   mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone P, 100   mg/kg once daily, prednisone H, 5   mg/kg once daily and acetylcysteine N, 4   mg/kg 3 times per day were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-a TNF-a, transforming growth factor-b1 TGF-b1 and platelet-derived growth factor PDGF was determined by enzyme-linked immunosorbent assay. RESULTS: After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower p   <   0.05 significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-b1, TNF-a and PDGF, but the expression of Cav-1 was higher p   <   0.05. Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group p   <   0.05. Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores r   =   -0.506, p   <   0.01; r   =   -0.676, p   <   0.01 as well as expression of TGF-b1, TNF-a and PDGF r   =   -0.590, p   <   0.01; r   =   -0.530, p   <   0.01; r   =   -0.553, p   <   0.01. DISCUSSION AND CONCLUSION: Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and <d>pulmonary fibrosis</d> in rat IPF models, which may be related with enhanced caveolin-1, reduced TNF-a, TGF-b1, PDGF.
27937011|a|CONTEXT: Previous studies have reported that <g>caveolin-1</g> Cav-1 is associated with <d>lung fibrosis</d>. However, the role of Cav-1 expression in pirfenidone-treated idiopathic <d>pulmonary fibrosis</d> IPF is unknown. OBJECTIVE: This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF. MATERIALS AND METHODS: Rat IPF model was established by endotracheal injection of 5   mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone P, 100   mg/kg once daily, prednisone H, 5   mg/kg once daily and acetylcysteine N, 4   mg/kg 3 times per day were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-a TNF-a, transforming growth factor-b1 TGF-b1 and platelet-derived growth factor PDGF was determined by enzyme-linked immunosorbent assay. RESULTS: After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower p   <   0.05 significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-b1, TNF-a and PDGF, but the expression of Cav-1 was higher p   <   0.05. Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group p   <   0.05. Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores r   =   -0.506, p   <   0.01; r   =   -0.676, p   <   0.01 as well as expression of TGF-b1, TNF-a and PDGF r   =   -0.590, p   <   0.01; r   =   -0.530, p   <   0.01; r   =   -0.553, p   <   0.01. DISCUSSION AND CONCLUSION: Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and <d>pulmonary fibrosis</d> in rat IPF models, which may be related with enhanced <g>caveolin-1</g>, reduced TNF-a, TGF-b1, PDGF.
27937011|a|CONTEXT: Previous studies have reported that <g>caveolin-1</g> Cav-1 is associated with <d>lung fibrosis</d>. However, the role of Cav-1 expression in pirfenidone-treated idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is unknown. OBJECTIVE: This study investigated Cav-1 expression in pirfenidone-treated <d>IPF</d>, and compared the effects of pirfenidone with acetylcysteine and prednisone on <d>IPF</d>. MATERIALS AND METHODS: Rat <d>IPF</d> model was established by endotracheal injection of 5   mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone P, 100   mg/kg once daily, prednisone H, 5   mg/kg once daily and acetylcysteine N, 4   mg/kg 3 times per day were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without <d>IPF</d> were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-a TNF-a, transforming growth factor-b1 TGF-b1 and platelet-derived growth factor PDGF was determined by enzyme-linked immunosorbent assay. RESULTS: After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower p   <   0.05 significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-b1, TNF-a and PDGF, but the expression of Cav-1 was higher p   <   0.05. Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group p   <   0.05. Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores r   =   -0.506, p   <   0.01; r   =   -0.676, p   <   0.01 as well as expression of TGF-b1, TNF-a and PDGF r   =   -0.590, p   <   0.01; r   =   -0.530, p   <   0.01; r   =   -0.553, p   <   0.01. DISCUSSION AND CONCLUSION: Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and <d>pulmonary fibrosis</d> in rat <d>IPF</d> models, which may be related with enhanced <g>caveolin-1</g>, reduced TNF-a, TGF-b1, PDGF.
27937011|a|CONTEXT: Previous studies have reported that <g>caveolin-1</g> Cav-1 is associated with <d>lung fibrosis</d>. However, the role of Cav-1 expression in pirfenidone-treated idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is unknown. OBJECTIVE: This study investigated Cav-1 expression in pirfenidone-treated <d>IPF</d>, and compared the effects of pirfenidone with acetylcysteine and prednisone on <d>IPF</d>. MATERIALS AND METHODS: Rat <d>IPF</d> model was established by endotracheal injection of 5   mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone P, 100   mg/kg once daily, prednisone H, 5   mg/kg once daily and acetylcysteine N, 4   mg/kg 3 times per day were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without <d>IPF</d> were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of <d>tumour</d> necrosis factor-a TNF-a, transforming growth factor-b1 TGF-b1 and platelet-derived growth factor PDGF was determined by enzyme-linked immunosorbent assay. RESULTS: After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower p   <   0.05 significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-b1, TNF-a and PDGF, but the expression of Cav-1 was higher p   <   0.05. Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group p   <   0.05. Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores r   =   -0.506, p   <   0.01; r   =   -0.676, p   <   0.01 as well as expression of TGF-b1, TNF-a and PDGF r   =   -0.590, p   <   0.01; r   =   -0.530, p   <   0.01; r   =   -0.553, p   <   0.01. DISCUSSION AND CONCLUSION: Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and <d>pulmonary fibrosis</d> in rat <d>IPF</d> models, which may be related with enhanced <g>caveolin-1</g>, reduced TNF-a, TGF-b1, PDGF.
27937011|a|CONTEXT: Previous studies have reported that <g>caveolin-1</g> Cav-1 is associated with <d>lung fibrosis</d>. However, the role of Cav-1 expression in pirfenidone-treated idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is unknown. OBJECTIVE: This study investigated Cav-1 expression in pirfenidone-treated <d>IPF</d>, and compared the effects of pirfenidone with acetylcysteine and prednisone on <d>IPF</d>. MATERIALS AND METHODS: Rat <d>IPF</d> model was established by endotracheal injection of 5   mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone P, 100   mg/kg once daily, prednisone H, 5   mg/kg once daily and acetylcysteine N, 4   mg/kg 3 times per day were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without <d>IPF</d> were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of <d>tumour</d> <d>necrosis</d> factor-a TNF-a, transforming growth factor-b1 TGF-b1 and platelet-derived growth factor PDGF was determined by enzyme-linked immunosorbent assay. RESULTS: After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower p   <   0.05 significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-b1, TNF-a and PDGF, but the expression of Cav-1 was higher p   <   0.05. Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group p   <   0.05. Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores r   =   -0.506, p   <   0.01; r   =   -0.676, p   <   0.01 as well as expression of TGF-b1, TNF-a and PDGF r   =   -0.590, p   <   0.01; r   =   -0.530, p   <   0.01; r   =   -0.553, p   <   0.01. DISCUSSION AND CONCLUSION: Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and <d>pulmonary fibrosis</d> in rat <d>IPF</d> models, which may be related with enhanced <g>caveolin-1</g>, reduced TNF-a, TGF-b1, PDGF.
27937011|a|CONTEXT: Previous studies have reported that <g>caveolin-1</g> Cav-1 is associated with <d>lung <d>fibrosis</d></d>. However, the role of Cav-1 expression in pirfenidone-treated idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is unknown. OBJECTIVE: This study investigated Cav-1 expression in pirfenidone-treated <d>IPF</d>, and compared the effects of pirfenidone with acetylcysteine and prednisone on <d>IPF</d>. MATERIALS AND METHODS: Rat <d>IPF</d> model was established by endotracheal injection of 5   mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone P, 100   mg/kg once daily, prednisone H, 5   mg/kg once daily and acetylcysteine N, 4   mg/kg 3 times per day were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without <d>IPF</d> were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of <d>tumour</d> <d>necrosis</d> factor-a <g>TNF-a</g>, transforming growth factor-b1 <g>TGF-b1</g> and platelet-derived growth factor PDGF was determined by enzyme-linked immunosorbent assay. RESULTS: After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower p   <   0.05 significance of airsacculitis and <d>fibrosis</d> scores of lung tissues, as well as expression of <g>TGF-b1</g>, <g>TNF-a</g> and PDGF, but the expression of Cav-1 was higher p   <   0.05. Compared with the N group, the <d>fibrosis</d> score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group p   <   0.05. Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and <d>fibrosis</d> scores r   =   -0.506, p   <   0.01; r   =   -0.676, p   <   0.01 as well as expression of <g>TGF-b1</g>, <g>TNF-a</g> and PDGF r   =   -0.590, p   <   0.01; r   =   -0.530, p   <   0.01; r   =   -0.553, p   <   0.01. DISCUSSION AND CONCLUSION: Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and <d>pulmonary <d>fibrosis</d></d> in rat <d>IPF</d> models, which may be related with enhanced <g>caveolin-1</g>, reduced <g>TNF-a</g>, <g>TGF-b1</g>, PDGF.
27941755|a|Idiopathic pulmonary fibrosis IPF is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci FF represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: 1 from resident fibroblasts, 2 from bone marrow-derived progenitors of fibroblasts, and 3 from <d>alveolar epithelia</d>l cells that have undergone epithelial-mesenchymal transition EMT. We found that FF dissociated capillary vessels from the <d>alveolar epithelia</d>, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100    m below the <d>alveolar epithelia</d>. Furthermore, the <d>alveolar epithelia</d>l cells covering the FF exhibited a partial EMT phenotype. In addition, normal human <d>alveolar epithelia</d>l cells in vitro underwent dynamic EMT in response to transforming growth factor-b signaling within 72   h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the <d>alveolar epithelia</d> and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned <d>alveolar epithelia</d> located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the alveolar septa, thus destroying them. Consequently, collapse of the alveolar septa is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-b signaling, which can suppress EMT of the <d>alveolar epithelia</d>l cells in vitro, is a potential strategy for treating IPF.
27941755|a|Idiopathic pulmonary fibrosis IPF is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci FF represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: 1 from resident fibroblasts, 2 from bone marrow-derived progenitors of fibroblasts, and 3 from <d>alveolar epithelia</d>l cells that have undergone <d>epithelial-mesenchymal transition</d> EMT. We found that FF dissociated capillary vessels from the <d>alveolar epithelia</d>, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100    m below the <d>alveolar epithelia</d>. Furthermore, the <d>alveolar epithelia</d>l cells covering the FF exhibited a partial EMT phenotype. In addition, normal human <d>alveolar epithelia</d>l cells in vitro underwent dynamic EMT in response to transforming growth factor-b signaling within 72   h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the <d>alveolar epithelia</d> and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned <d>alveolar epithelia</d> located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the alveolar septa, thus destroying them. Consequently, collapse of the alveolar septa is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-b signaling, which can suppress EMT of the <d>alveolar epithelia</d>l cells in vitro, is a potential strategy for treating IPF.
27941755|a|Idiopathic pulmonary fibrosis IPF is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci FF represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: 1 from resident fibroblasts, 2 from bone marrow-derived progenitors of fibroblasts, and 3 from <d>alveolar epithelia</d>l cells that have undergone <d>epithelial-mesenchymal transition</d> EMT. We found that FF dissociated capillary vessels from the <d>alveolar epithelia</d>, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100    m below the <d>alveolar epithelia</d>. Furthermore, the <d>alveolar epithelia</d>l cells covering the FF exhibited a partial EMT phenotype. In addition, normal human <d>alveolar epithelia</d>l cells in vitro underwent dynamic EMT in response to transforming growth factor-b signaling within 72   h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the <d>alveolar epithelia</d> and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned <d>alveolar epithelia</d> located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the <d>alveolar septa</d>, thus destroying them. Consequently, collapse of the <d>alveolar septa</d> is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-b signaling, which can suppress EMT of the <d>alveolar epithelia</d>l cells in vitro, is a potential strategy for treating IPF.
27941755|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci FF represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: 1 from resident fibroblasts, 2 from bone marrow-derived progenitors of fibroblasts, and 3 from <d>alveolar epithelia</d>l cells that have undergone <d>epithelial-mesenchymal transition</d> EMT. We found that FF dissociated capillary vessels from the <d>alveolar epithelia</d>, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100    m below the <d>alveolar epithelia</d>. Furthermore, the <d>alveolar epithelia</d>l cells covering the FF exhibited a partial EMT phenotype. In addition, normal human <d>alveolar epithelia</d>l cells in vitro underwent dynamic EMT in response to transforming growth factor-b signaling within 72   h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the <d>alveolar epithelia</d> and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned <d>alveolar epithelia</d> located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the <d>alveolar septa</d>, thus destroying them. Consequently, collapse of the <d>alveolar septa</d> is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-b signaling, which can suppress EMT of the <d>alveolar epithelia</d>l cells in vitro, is a potential strategy for treating IPF.
27941755|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive interstitial lung disease of unknown cause. <d>IPF</d> has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci FF represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: 1 from resident fibroblasts, 2 from bone marrow-derived progenitors of fibroblasts, and 3 from <d>alveolar epithelia</d>l cells that have undergone <d>epithelial-mesenchymal transition</d> EMT. We found that FF dissociated capillary vessels from the <d>alveolar epithelia</d>, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100    m below the <d>alveolar epithelia</d>. Furthermore, the <d>alveolar epithelia</d>l cells covering the FF exhibited a partial EMT phenotype. In addition, normal human <d>alveolar epithelia</d>l cells in vitro underwent dynamic EMT in response to transforming growth factor-b signaling within 72   h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the <d>alveolar epithelia</d> and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned <d>alveolar epithelia</d> located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the <d>alveolar septa</d>, thus destroying them. Consequently, collapse of the <d>alveolar septa</d> is likely to be the first step toward honeycombing in the lung during late stage <d>IPF</d>. On the basis of these findings, inhibition of transforming growth factor-b signaling, which can suppress EMT of the <d>alveolar epithelia</d>l cells in vitro, is a potential strategy for treating <d>IPF</d>.
27941755|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive <d>interstitial lung disease</d> of unknown cause. <d>IPF</d> has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci FF represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: 1 from resident fibroblasts, 2 from bone marrow-derived progenitors of fibroblasts, and 3 from <d>alveolar epithelia</d>l cells that have undergone <d>epithelial-mesenchymal transition</d> EMT. We found that FF dissociated capillary vessels from the <d>alveolar epithelia</d>, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100    m below the <d>alveolar epithelia</d>. Furthermore, the <d>alveolar epithelia</d>l cells covering the FF exhibited a partial EMT phenotype. In addition, normal human <d>alveolar epithelia</d>l cells in vitro underwent dynamic EMT in response to transforming growth factor-b signaling within 72   h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the <d>alveolar epithelia</d> and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned <d>alveolar epithelia</d> located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the <d>alveolar septa</d>, thus destroying them. Consequently, collapse of the <d>alveolar septa</d> is likely to be the first step toward honeycombing in the lung during late stage <d>IPF</d>. On the basis of these findings, inhibition of transforming growth factor-b signaling, which can suppress EMT of the <d>alveolar epithelia</d>l cells in vitro, is a potential strategy for treating <d>IPF</d>.
27941755|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive <d>interstitial lung disease</d> of unknown cause. <d>IPF</d> has a distinct histopathological pattern of usual <d>interstitial pneumonia</d> in which fibroblastic foci FF represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: 1 from resident fibroblasts, 2 from bone marrow-derived progenitors of fibroblasts, and 3 from <d>alveolar epithelia</d>l cells that have undergone <d>epithelial-mesenchymal transition</d> EMT. We found that FF dissociated capillary vessels from the <d>alveolar epithelia</d>, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100    m below the <d>alveolar epithelia</d>. Furthermore, the <d>alveolar epithelia</d>l cells covering the FF exhibited a partial EMT phenotype. In addition, normal human <d>alveolar epithelia</d>l cells in vitro underwent dynamic EMT in response to transforming growth factor-b signaling within 72   h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the <d>alveolar epithelia</d> and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned <d>alveolar epithelia</d> located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the <d>alveolar septa</d>, thus destroying them. Consequently, collapse of the <d>alveolar septa</d> is likely to be the first step toward honeycombing in the lung during late stage <d>IPF</d>. On the basis of these findings, inhibition of transforming growth factor-b signaling, which can suppress EMT of the <d>alveolar epithelia</d>l cells in vitro, is a potential strategy for treating <d>IPF</d>.
27941755|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive <d>interstitial lung disease</d> of unknown cause. <d>IPF</d> has a distinct histopathological pattern of usual <d>interstitial pneumonia</d> in which fibroblastic foci FF represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: 1 from resident fibroblasts, 2 from bone marrow-derived progenitors of fibroblasts, and 3 from <d>alveolar epithelia</d>l cells that have undergone <d>epithelial-mesenchymal transition</d> <d>EMT</d>. We found that FF dissociated capillary vessels from the <d>alveolar epithelia</d>, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100    m below the <d>alveolar epithelia</d>. Furthermore, the <d>alveolar epithelia</d>l cells covering the FF exhibited a partial <d>EMT</d> phenotype. In addition, normal human <d>alveolar epithelia</d>l cells in vitro underwent dynamic <d>EMT</d> in response to transforming growth factor-b signaling within 72   h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the <d>alveolar epithelia</d> and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned <d>alveolar epithelia</d> located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the <d>alveolar septa</d>, thus destroying them. Consequently, collapse of the <d>alveolar septa</d> is likely to be the first step toward honeycombing in the lung during late stage <d>IPF</d>. On the basis of these findings, inhibition of transforming growth factor-b signaling, which can suppress <d>EMT</d> of the <d>alveolar epithelia</d>l cells in vitro, is a potential strategy for treating <d>IPF</d>.
27942594|a|Maladaptive epithelial repair from chronic injury is a common feature in fibrotic diseases, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs <g>miR</g>s can regulate expression of multiple genes and fundamentally alter cellular phenotypes during fibrosis. Although several <g>miR</g>s have been shown to be associated with <d>lung fibrosis</d>, the mechanisms by which <g>miR</g>s modulate epithelial behavior in <d>lung fibrosis</d> are lacking. Here, we identified <g>miR</g>-323a-3p to be downregulated in the epithelium of lungs with bronchiolitis obliterans syndrome BOS after lung transplantation, idiopathic pulmonary fibrosis IPF, and murine bleomycin-induced fibrosis. Antagomirs for <g>miR</g>-323a-3p augment, and mimics suppress, murine <d>lung fibrosis</d> after bleomycin injury, indicating that this <g>miR</g> may govern profibrotic signals. We demonstrate that <g>miR</g>-323a-3p attenuates TGF-a and TGF-b signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, <g>miR</g>-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of <g>miR</g>-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that <g>miR</g>-323a-3p has a central role in <d>lung fibrosis</d> that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.
27942594|a|Maladaptive epithelial repair from <d>chronic injury</d> is a common feature in fibrotic diseases, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs <g>miR</g>s can regulate expression of multiple genes and fundamentally alter cellular phenotypes during fibrosis. Although several <g>miR</g>s have been shown to be associated with <d>lung fibrosis</d>, the mechanisms by which <g>miR</g>s modulate epithelial behavior in <d>lung fibrosis</d> are lacking. Here, we identified <g>miR</g>-323a-3p to be downregulated in the epithelium of lungs with bronchiolitis obliterans syndrome BOS after lung transplantation, idiopathic pulmonary fibrosis IPF, and murine bleomycin-induced fibrosis. Antagomirs for <g>miR</g>-323a-3p augment, and mimics suppress, murine <d>lung fibrosis</d> after bleomycin injury, indicating that this <g>miR</g> may govern profibrotic signals. We demonstrate that <g>miR</g>-323a-3p attenuates TGF-a and TGF-b signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, <g>miR</g>-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of <g>miR</g>-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that <g>miR</g>-323a-3p has a central role in <d>lung fibrosis</d> that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.
27942594|a|Maladaptive epithelial repair from <d>chronic injury</d> is a common feature in <d>fibrotic diseases</d>, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs <g>miR</g>s can regulate expression of multiple genes and fundamentally alter cellular phenotypes during fibrosis. Although several <g>miR</g>s have been shown to be associated with <d>lung fibrosis</d>, the mechanisms by which <g>miR</g>s modulate epithelial behavior in <d>lung fibrosis</d> are lacking. Here, we identified <g>miR</g>-323a-3p to be downregulated in the epithelium of lungs with bronchiolitis obliterans syndrome BOS after lung transplantation, idiopathic pulmonary fibrosis IPF, and murine bleomycin-induced fibrosis. Antagomirs for <g>miR</g>-323a-3p augment, and mimics suppress, murine <d>lung fibrosis</d> after bleomycin injury, indicating that this <g>miR</g> may govern profibrotic signals. We demonstrate that <g>miR</g>-323a-3p attenuates TGF-a and TGF-b signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, <g>miR</g>-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of <g>miR</g>-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that <g>miR</g>-323a-3p has a central role in <d>lung fibrosis</d> that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.
27942594|a|Maladaptive epithelial repair from <d>chronic injury</d> is a common feature in <d>fibrotic diseases</d>, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs <g>miR</g>s can regulate expression of multiple genes and fundamentally alter cellular phenotypes during <d>fibrosis</d>. Although several <g>miR</g>s have been shown to be associated with <d>lung <d>fibrosis</d></d>, the mechanisms by which <g>miR</g>s modulate epithelial behavior in <d>lung <d>fibrosis</d></d> are lacking. Here, we identified <g>miR</g>-323a-3p to be downregulated in the epithelium of lungs with bronchiolitis obliterans syndrome BOS after lung transplantation, idiopathic pulmonary <d>fibrosis</d> IPF, and murine bleomycin-induced <d>fibrosis</d>. Antagomirs for <g>miR</g>-323a-3p augment, and mimics suppress, murine <d>lung <d>fibrosis</d></d> after bleomycin injury, indicating that this <g>miR</g> may govern profibrotic signals. We demonstrate that <g>miR</g>-323a-3p attenuates TGF-a and TGF-b signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, <g>miR</g>-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of <g>miR</g>-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that <g>miR</g>-323a-3p has a central role in <d>lung <d>fibrosis</d></d> that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.
27942594|a|Maladaptive epithelial repair from <d>chronic injury</d> is a common feature in <d>fibrotic diseases</d>, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs <g>miR</g>s can regulate expression of multiple genes and fundamentally alter cellular phenotypes during <d>fibrosis</d>. Although several <g>miR</g>s have been shown to be associated with <d>lung <d>fibrosis</d></d>, the mechanisms by which <g>miR</g>s modulate epithelial behavior in <d>lung <d>fibrosis</d></d> are lacking. Here, we identified <g>miR</g>-323a-3p to be downregulated in the epithelium of lungs with <d>bronchiolitis obliterans syndrome</d> BOS after lung transplantation, idiopathic pulmonary <d>fibrosis</d> IPF, and murine bleomycin-induced <d>fibrosis</d>. Antagomirs for <g>miR</g>-323a-3p augment, and mimics suppress, murine <d>lung <d>fibrosis</d></d> after bleomycin injury, indicating that this <g>miR</g> may govern profibrotic signals. We demonstrate that <g>miR</g>-323a-3p attenuates TGF-a and TGF-b signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, <g>miR</g>-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of <g>miR</g>-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that <g>miR</g>-323a-3p has a central role in <d>lung <d>fibrosis</d></d> that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.
27942594|a|Maladaptive epithelial repair from <d>chronic injury</d> is a common feature in <d>fibrotic diseases</d>, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs <g>miR</g>s can regulate expression of multiple genes and fundamentally alter cellular phenotypes during <d>fibrosis</d>. Although several <g>miR</g>s have been shown to be associated with <d>lung <d>fibrosis</d></d>, the mechanisms by which <g>miR</g>s modulate epithelial behavior in <d>lung <d>fibrosis</d></d> are lacking. Here, we identified <g>miR</g>-323a-3p to be downregulated in the epithelium of lungs with <d>bronchiolitis obliterans syndrome</d> <d>BOS</d> after lung transplantation, idiopathic pulmonary <d>fibrosis</d> IPF, and murine bleomycin-induced <d>fibrosis</d>. Antagomirs for <g>miR</g>-323a-3p augment, and mimics suppress, murine <d>lung <d>fibrosis</d></d> after bleomycin injury, indicating that this <g>miR</g> may govern profibrotic signals. We demonstrate that <g>miR</g>-323a-3p attenuates TGF-a and TGF-b signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, <g>miR</g>-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of <g>miR</g>-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that <g>miR</g>-323a-3p has a central role in <d>lung <d>fibrosis</d></d> that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.
27942594|a|Maladaptive epithelial repair from <d>chronic injury</d> is a common feature in <d>fibrotic diseases</d>, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs <g>miR</g>s can regulate expression of multiple genes and fundamentally alter cellular phenotypes during <d>fibrosis</d>. Although several <g>miR</g>s have been shown to be associated with <d>lung <d>fibrosis</d></d>, the mechanisms by which <g>miR</g>s modulate epithelial behavior in <d>lung <d>fibrosis</d></d> are lacking. Here, we identified <g>miR</g>-323a-3p to be downregulated in the epithelium of lungs with <d>bronchiolitis obliterans syndrome</d> <d>BOS</d> after lung transplantation, idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, and murine bleomycin-induced <d>fibrosis</d>. Antagomirs for <g>miR</g>-323a-3p augment, and mimics suppress, murine <d>lung <d>fibrosis</d></d> after bleomycin injury, indicating that this <g>miR</g> may govern profibrotic signals. We demonstrate that <g>miR</g>-323a-3p attenuates TGF-a and TGF-b signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, <g>miR</g>-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of <g>miR</g>-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that <g>miR</g>-323a-3p has a central role in <d>lung <d>fibrosis</d></d> that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.
27942595|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a lethal interstitial lung disease characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing scRNA-seq to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 AT2 cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in IPF. Individual IPF cells frequently coexpressed alveolar type 1 AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-b, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. The present study provides a rich data source to further explore lung health and disease.
27942595|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal interstitial lung disease characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing scRNA-seq to identify epithelial cell types and associated biological processes involved in the pathogenesis of <d>IPF</d>. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 AT2 cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of <d>IPF</d> cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in <d>IPF</d>. Individual <d>IPF</d> cells frequently coexpressed alveolar type 1 AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-b, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of <d>IPF</d>. The present study provides a rich data source to further explore lung health and disease.
27942595|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal <d>interstitial lung disease</d> characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing scRNA-seq to identify epithelial cell types and associated biological processes involved in the pathogenesis of <d>IPF</d>. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 AT2 cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of <d>IPF</d> cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in <d>IPF</d>. Individual <d>IPF</d> cells frequently coexpressed alveolar type 1 AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-b, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of <d>IPF</d>. The present study provides a rich data source to further explore lung health and disease.
27942595|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal <d>interstitial lung disease</d> characterized by airway remodeling, <d>inflammation</d>, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing scRNA-seq to identify epithelial cell types and associated biological processes involved in the pathogenesis of <d>IPF</d>. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 AT2 cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of <d>IPF</d> cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in <d>IPF</d>. Individual <d>IPF</d> cells frequently coexpressed alveolar type 1 AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-b, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of <d>IPF</d>. The present study provides a rich data source to further explore lung health and disease.
27942595|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal <d>interstitial lung disease</d> characterized by airway remodeling, <d>inflammation</d>, <d>alveolar destruction</d>, and fibrosis. We utilized single-cell RNA sequencing scRNA-seq to identify epithelial cell types and associated biological processes involved in the pathogenesis of <d>IPF</d>. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 AT2 cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of <d>IPF</d> cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in <d>IPF</d>. Individual <d>IPF</d> cells frequently coexpressed alveolar type 1 AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-b, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of <d>IPF</d>. The present study provides a rich data source to further explore lung health and disease.
27942595|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a lethal <d>interstitial lung disease</d> characterized by airway remodeling, <d>inflammation</d>, <d>alveolar destruction</d>, and <d>fibrosis</d>. We utilized single-cell RNA sequencing scRNA-seq to identify epithelial cell types and associated biological processes involved in the pathogenesis of <d>IPF</d>. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 AT2 cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of <d>IPF</d> cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in <d>IPF</d>. Individual <d>IPF</d> cells frequently coexpressed alveolar type 1 AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-b, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of <d>IPF</d>. The present study provides a rich data source to further explore lung health and disease.
27942595|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a lethal <d>interstitial lung disease</d> characterized by airway remodeling, <d>inflammation</d>, <d>alveolar destruction</d>, and <d>fibrosis</d>. We utilized single-cell RNA sequencing scRNA-seq to identify epithelial cell types and associated biological processes involved in the pathogenesis of <d>IPF</d>. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated <d>alveolar type 2</d> AT2 cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of <d>IPF</d> cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in <d>IPF</d>. Individual <d>IPF</d> cells frequently coexpressed alveolar type 1 AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-b, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of <d>IPF</d>. The present study provides a rich data source to further explore lung health and disease.
27942595|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a lethal <d>interstitial lung disease</d> characterized by airway remodeling, <d>inflammation</d>, <d>alveolar destruction</d>, and <d>fibrosis</d>. We utilized single-cell RNA sequencing scRNA-seq to identify epithelial cell types and associated biological processes involved in the pathogenesis of <d>IPF</d>. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated <d>alveolar type 2</d> <g>AT2</g> cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of <d>IPF</d> cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in <d>IPF</d>. Individual <d>IPF</d> cells frequently coexpressed alveolar type 1 <g>AT1</g>, <g>AT2</g>, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via <g>TGF-b</g>, HIPPO/<g>YAP</g>, <g>P53</g>, WNT, and <g>AKT</g>/<g>PI3K</g>. Immunofluorescence confocal microscopy identified the disruption of <d>alveolar structure</d> and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of <d>IPF</d>. The present study provides a rich data source to further explore lung health and disease.
27993290|a|BACKGROUND: Dysregulation of the prostaglandin E2 PGE2 signaling pathway has been implicated in <d>interstitial pneumonia</d> IP pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E-major urinary metabolite PGE-MUM with respect to pathogenesis and extent of chronic fibrosing IP CFIP, including idiopathic pulmonary fibrosis IPF, as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls n  =  124 and patients with lung diseases bronchial asthma BA: n  =  78, chronic obstructive pulmonary disease COPD: n  =  33, CFIP: n  =  44. Extent of lung fibrosis was assessed by fibrosing score FS of computed tomography CT FS1-4. Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in IPF. Human bronchial epithelial cells HBEC and lung fibroblasts LFB were used in in  vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CFIP. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in IP FS 1-3. COX-2 was highly expressed in metaplastic epithelial cells in IPF, but lower expression of EP2 receptor was demonstrated in LFB derived from IPF. TGF-b induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CFIP, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in IPF.
27993290|a|BACKGROUND: Dysregulation of the prostaglandin E2 PGE2 signaling pathway has been implicated in <d>interstitial pneumonia</d> <d>IP</d> pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E-major urinary metabolite PGE-MUM with respect to pathogenesis and extent of chronic fibrosing <d>IP</d> CF<d>IP</d>, including idiopathic pulmonary fibrosis <d>IP</d>F, as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls n  =  124 and patients with lung diseases bronchial asthma BA: n  =  78, chronic obstructive pulmonary disease COPD: n  =  33, CF<d>IP</d>: n  =  44. Extent of lung fibrosis was assessed by fibrosing score FS of computed tomography CT FS1-4. Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in <d>IP</d>F. Human bronchial epithelial cells HBEC and lung fibroblasts LFB were used in in  vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CF<d>IP</d>. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in <d>IP</d> FS 1-3. COX-2 was highly expressed in metaplastic epithelial cells in <d>IP</d>F, but lower expression of EP2 receptor was demonstrated in LFB derived from <d>IP</d>F. TGF-b induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CF<d>IP</d>, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in <d>IP</d>F.
27993290|a|BACKGROUND: Dysregulation of the prostaglandin E2 PGE2 signaling pathway has been implicated in <d>interstitial pneumonia</d> <d>IP</d> pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E-major urinary metabolite PGE-MUM with respect to pathogenesis and extent of chronic fibrosing <d>IP</d> CF<d>IP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IP</d>F, as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls n  =  124 and patients with lung diseases bronchial asthma BA: n  =  78, chronic obstructive pulmonary disease COPD: n  =  33, CF<d>IP</d>: n  =  44. Extent of lung fibrosis was assessed by fibrosing score FS of computed tomography CT FS1-4. Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in <d>IP</d>F. Human bronchial epithelial cells HBEC and lung fibroblasts LFB were used in in  vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CF<d>IP</d>. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in <d>IP</d> FS 1-3. COX-2 was highly expressed in metaplastic epithelial cells in <d>IP</d>F, but lower expression of EP2 receptor was demonstrated in LFB derived from <d>IP</d>F. TGF-b induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CF<d>IP</d>, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in <d>IP</d>F.
27993290|a|BACKGROUND: Dysregulation of the prostaglandin E2 PGE2 signaling pathway has been implicated in <d>interstitial pneumonia</d> <d>IP</d> pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E-major urinary metabolite PGE-MUM with respect to pathogenesis and extent of chronic fibrosing <d>IP</d> CF<d>IP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IP</d>F, as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls n  =  124 and patients with <d>lung diseases</d> bronchial asthma BA: n  =  78, chronic obstructive pulmonary disease COPD: n  =  33, CF<d>IP</d>: n  =  44. Extent of lung fibrosis was assessed by fibrosing score FS of computed tomography CT FS1-4. Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in <d>IP</d>F. Human bronchial epithelial cells HBEC and lung fibroblasts LFB were used in in  vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CF<d>IP</d>. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in <d>IP</d> FS 1-3. COX-2 was highly expressed in metaplastic epithelial cells in <d>IP</d>F, but lower expression of EP2 receptor was demonstrated in LFB derived from <d>IP</d>F. TGF-b induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CF<d>IP</d>, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in <d>IP</d>F.
27993290|a|BACKGROUND: Dysregulation of the prostaglandin E2 PGE2 signaling pathway has been implicated in <d>interstitial pneumonia</d> <d>IP</d> pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E-major urinary metabolite PGE-MUM with respect to pathogenesis and extent of chronic fibrosing <d>IP</d> CF<d>IP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IP</d>F, as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls n  =  124 and patients with <d>lung diseases</d> <d>bronchial asthma</d> BA: n  =  78, chronic obstructive pulmonary disease COPD: n  =  33, CF<d>IP</d>: n  =  44. Extent of lung fibrosis was assessed by fibrosing score FS of computed tomography CT FS1-4. Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in <d>IP</d>F. Human bronchial epithelial cells HBEC and lung fibroblasts LFB were used in in  vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CF<d>IP</d>. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in <d>IP</d> FS 1-3. COX-2 was highly expressed in metaplastic epithelial cells in <d>IP</d>F, but lower expression of EP2 receptor was demonstrated in LFB derived from <d>IP</d>F. TGF-b induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CF<d>IP</d>, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in <d>IP</d>F.
27993290|a|<d>BA</d>CKGROUND: Dysregulation of the prostaglandin E2 PGE2 signaling pathway has been implicated in <d>interstitial pneumonia</d> <d>IP</d> pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E-major urinary metabolite PGE-MUM with respect to pathogenesis and extent of chronic fibrosing <d>IP</d> CF<d>IP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IP</d>F, as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls n  =  124 and patients with <d>lung diseases</d> <d>bronchial asthma</d> <d>BA</d>: n  =  78, chronic obstructive pulmonary disease COPD: n  =  33, CF<d>IP</d>: n  =  44. Extent of lung fibrosis was assessed by fibrosing score FS of computed tomography CT FS1-4. Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in <d>IP</d>F. Human bronchial epithelial cells HBEC and lung fibroblasts LFB were used in in  vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CF<d>IP</d>. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in <d>IP</d> FS 1-3. COX-2 was highly expressed in metaplastic epithelial cells in <d>IP</d>F, but lower expression of EP2 receptor was demonstrated in LFB derived from <d>IP</d>F. TGF-b induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CF<d>IP</d>, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in <d>IP</d>F.
27993290|a|<d>BA</d>CKGROUND: Dysregulation of the prostaglandin E2 PGE2 signaling pathway has been implicated in <d>interstitial pneumonia</d> <d>IP</d> pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E-major urinary metabolite PGE-MUM with respect to pathogenesis and extent of chronic fibrosing <d>IP</d> CF<d>IP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IP</d>F, as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls n  =  124 and patients with <d>lung diseases</d> <d>bronchial asthma</d> <d>BA</d>: n  =  78, <d>chronic obstructive pulmonary disease</d> COPD: n  =  33, CF<d>IP</d>: n  =  44. Extent of lung fibrosis was assessed by fibrosing score FS of computed tomography CT FS1-4. Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in <d>IP</d>F. Human bronchial epithelial cells HBEC and lung fibroblasts LFB were used in in  vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CF<d>IP</d>. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in <d>IP</d> FS 1-3. COX-2 was highly expressed in metaplastic epithelial cells in <d>IP</d>F, but lower expression of EP2 receptor was demonstrated in LFB derived from <d>IP</d>F. TGF-b induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CF<d>IP</d>, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in <d>IP</d>F.
27993290|a|<d>BA</d>CKGROUND: Dysregulation of the prostaglandin E2 PGE2 signaling pathway has been implicated in <d>interstitial pneumonia</d> <d>IP</d> pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E-major urinary metabolite PGE-MUM with respect to pathogenesis and extent of chronic fibrosing <d>IP</d> CF<d>IP</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IP</d>F, as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls n  =  124 and patients with <d>lung diseases</d> <d>bronchial asthma</d> <d>BA</d>: n  =  78, <d>chronic obstructive pulmonary disease</d> <d>COPD</d>: n  =  33, CF<d>IP</d>: n  =  44. Extent of lung fibrosis was assessed by fibrosing score FS of computed tomography CT FS1-4. Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in <d>IP</d>F. Human bronchial epithelial cells HBEC and lung fibroblasts LFB were used in in  vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CF<d>IP</d>. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in <d>IP</d> FS 1-3. COX-2 was highly expressed in metaplastic epithelial cells in <d>IP</d>F, but lower expression of EP2 receptor was demonstrated in LFB derived from <d>IP</d>F. TGF-b induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CF<d>IP</d>, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in <d>IP</d>F.
27993290|a|<d>BA</d>CKGROUND: Dysregulation of the prostaglandin E2 PGE2 signaling pathway has been implicated in <d>interstitial pneumonia</d> <d>IP</d> pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E-major urinary metabolite PGE-MUM with respect to pathogenesis and extent of chronic fibrosing <d>IP</d> CF<d>IP</d>, including <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IP</d>F, as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls n  =  124 and patients with <d>lung diseases</d> <d>bronchial asthma</d> <d>BA</d>: n  =  78, <d>chronic obstructive pulmonary disease</d> <d>COPD</d>: n  =  33, CF<d>IP</d>: n  =  44. Extent of lung <d>fibrosis</d> was assessed by fibrosing score FS of computed tomography CT FS1-4. Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in <d>IP</d>F. Human bronchial epithelial cells HBEC and lung fibroblasts LFB were used in in  vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CF<d>IP</d>. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in <d>IP</d> FS 1-3. COX-2 was highly expressed in metaplastic epithelial cells in <d>IP</d>F, but lower expression of EP2 receptor was demonstrated in LFB derived from <d>IP</d>F. TGF-b induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CF<d>IP</d>, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in <d>IP</d>F.
28060543|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> is a chronic progressive disease of increasing prevalence marked by poor prognosis and limited treatment options. Ca2+-activated <g>KCa3.1</g> potassium channels have been shown to play a key role in the aberrant activation and responses to injury in both epithelial cells and fibroblasts, both considered key drivers in the fibrotic process of IPF. Pharmacological inhibition of IPF-derived fibroblasts is able to somewhat prevent TGF-band bFGF-dependent profibrotic responses. In the current study, we investigated whether blockade of the <g>KCa3.1</g> ion channel in-vivo with a selective inhibitor, Senicapoc, was able to attenuate both histological and physiological outcomes of early fibrosis in our large animal sheep model for pulmonary fibrosis. We also determined whether treatment was targeting the pro-fibrotic activity of sheep lung fibroblasts. Senicapoc was administered in established fibrosis, at 2 weeks after bleomycin instillation, and drug efficacy was assessed 4 weeks after treatment. Treatment with Senicapoc improved pre-established bleomycin-induced changes compared to vehicle control, leading to improved lung compliance, reduced extracellular matrix and collagen deposition, and a reduction in both alpha smooth muscle actin expression and proliferating cells, both in-vivo and in-vitro. These studies show that inhibiting the <g>KCa3.1</g> ion channel is able to attenuate the early fibrogenic phase of bleomycin-dependent fibrosis and inhibits pro-fibrotic behaviour of primary sheep lung fibroblasts. This supports the previous research conducted in human IPF-derived fibroblasts and suggests that inhibiting Kca3.1 signalling may provide a novel therapeutic approach for IPF.
28060543|a|UNASSIGNED: <d>Idiopathic pulmonary fibrosis</d> is a chronic progressive disease of increasing prevalence marked by poor prognosis and limited treatment options. Ca2+-activated <g>KCa3.1</g> potassium channels have been shown to play a key role in the aberrant activation and responses to injury in both epithelial cells and fibroblasts, both considered key drivers in the fibrotic process of <d>IPF</d>. Pharmacological inhibition of <d>IPF</d>-derived fibroblasts is able to somewhat prevent TGF-band bFGF-dependent profibrotic responses. In the current study, we investigated whether blockade of the <g>KCa3.1</g> ion channel in-vivo with a selective inhibitor, Senicapoc, was able to attenuate both histological and physiological outcomes of early fibrosis in our large animal sheep model for pulmonary fibrosis. We also determined whether treatment was targeting the pro-fibrotic activity of sheep lung fibroblasts. Senicapoc was administered in established fibrosis, at 2 weeks after bleomycin instillation, and drug efficacy was assessed 4 weeks after treatment. Treatment with Senicapoc improved pre-established bleomycin-induced changes compared to vehicle control, leading to improved lung compliance, reduced extracellular matrix and collagen deposition, and a reduction in both alpha smooth muscle actin expression and proliferating cells, both in-vivo and in-vitro. These studies show that inhibiting the <g>KCa3.1</g> ion channel is able to attenuate the early fibrogenic phase of bleomycin-dependent fibrosis and inhibits pro-fibrotic behaviour of primary sheep lung fibroblasts. This supports the previous research conducted in human <d>IPF</d>-derived fibroblasts and suggests that inhibiting Kca3.1 signalling may provide a novel therapeutic approach for <d>IPF</d>.
28060543|a|UNASSIGNED: <d>Idiopathic pulmonary <d>fibrosis</d></d> is a chronic progressive disease of increasing prevalence marked by poor prognosis and limited treatment options. Ca2+-activated <g>KCa3.1</g> potassium channels have been shown to play a key role in the aberrant activation and responses to injury in both epithelial cells and fibroblasts, both considered key drivers in the fibrotic process of <d>IPF</d>. Pharmacological inhibition of <d>IPF</d>-derived fibroblasts is able to somewhat prevent TGF-band <g>bFGF</g>-dependent profibrotic responses. In the current study, we investigated whether blockade of the <g>KCa3.1</g> ion channel in-vivo with a selective inhibitor, Senicapoc, was able to attenuate both histological and physiological outcomes of early <d>fibrosis</d> in our large animal sheep model for pulmonary <d>fibrosis</d>. We also determined whether treatment was targeting the pro-fibrotic activity of sheep lung fibroblasts. Senicapoc was administered in established <d>fibrosis</d>, at 2 weeks after bleomycin instillation, and drug efficacy was assessed 4 weeks after treatment. Treatment with Senicapoc improved pre-established bleomycin-induced changes compared to vehicle control, leading to improved lung compliance, reduced extracellular matrix and collagen deposition, and a reduction in both alpha smooth muscle actin expression and proliferating cells, both in-vivo and in-vitro. These studies show that inhibiting the <g>KCa3.1</g> ion channel is able to attenuate the early fibrogenic phase of bleomycin-dependent <d>fibrosis</d> and inhibits pro-fibrotic behaviour of primary sheep lung fibroblasts. This supports the previous research conducted in human <d>IPF</d>-derived fibroblasts and suggests that inhibiting Kca3.1 signalling may provide a novel therapeutic approach for <d>IPF</d>.
28095470|a|UNASSIGNED: <g>Semaphorin-7A</g> is a glycosylphosphatidylinositol-anchored protein, initially characterized as an axon guidance protein. <g>Semaphorin-7A</g> also contributes to immune cell regulation and may be an essential pro-fibrotic factor when expressed by non-fibroblast cell types exogenous. In mouse models, <g>semaphorin-7A</g> was shown to be important for TGF-  1-induced <d>pulmonary fibrosis</d> characterized by myofibroblast accumulation and extracellular matrix deposition, but the cell-specific role of <g>semaphorin-7A</g> was not examined in fibroblasts. The purpose of this study is to determine <g>semaphorin-7A</g> expression by fibroblasts and to investigate the function of endogenously expressed <g>semaphorin-7A</g> in primary human lung fibroblasts HLF. Herein, we show that non-fibrotic HLF expressed high levels of cell surface <g>semaphorin-7A</g> with little dependence on the percentage of serum or recombinant TGF-  1. <g>Semaphorin-7A</g> siRNA strongly decreased <g>semaphorin-7A</g> mRNA expression and reduced cell surface <g>semaphorin-7A</g>. Reduction of <g>semaphorin-7A</g> induced increased proliferation and migration of non-fibrotic HLF. Also, independent of the presence of TGF-  1, the decline of <g>semaphorin-7A</g> by siRNA was associated with increased a-smooth muscle actin production and gene expression of periostin, fibronectin, laminin, and serum response factor SRF, indicating differentiation into a myofibroblast. Conversely, overexpression of <g>semaphorin-7A</g> in the NIH3T3 fibroblast cell line reduced the production of pro-fibrotic markers. The inverse association between <g>semaphorin-7A</g> and pro-fibrotic fibroblast markers was further analyzed using HLF from idiopathic <d>pulmonary fibrosis</d> IPF n = 6 and non-fibrotic n = 7 lungs. Using these 13 fibroblast lines, we observed that <g>semaphorin-7A</g> and periostin expression were inversely correlated. In conclusion, our study indicates that endogenous <g>semaphorin-7A</g> in HLF plays a role in maintaining fibroblast homeostasis by preventing up-regulation of pro-fibrotic genes. Therefore, endogenous and exogenous <g>semaphorin-7A</g> may have opposite effects on the fibroblast phenotype.
28095470|a|UNASSIGNED: <g>Semaphorin-7A</g> is a glycosylphosphatidylinositol-anchored protein, initially characterized as an axon guidance protein. <g>Semaphorin-7A</g> also contributes to immune cell regulation and may be an essential pro-fibrotic factor when expressed by non-fibroblast cell types exogenous. In mouse models, <g>semaphorin-7A</g> was shown to be important for TGF-  1-induced <d>pulmonary fibrosis</d> characterized by myofibroblast accumulation and extracellular matrix deposition, but the cell-specific role of <g>semaphorin-7A</g> was not examined in fibroblasts. The purpose of this study is to determine <g>semaphorin-7A</g> expression by fibroblasts and to investigate the function of endogenously expressed <g>semaphorin-7A</g> in primary human lung fibroblasts <g>HLF</g>. Herein, we show that non-fibrotic <g>HLF</g> expressed high levels of cell surface <g>semaphorin-7A</g> with little dependence on the percentage of serum or recombinant TGF-  1. <g>Semaphorin-7A</g> siRNA strongly decreased <g>semaphorin-7A</g> mRNA expression and reduced cell surface <g>semaphorin-7A</g>. Reduction of <g>semaphorin-7A</g> induced increased proliferation and migration of non-fibrotic <g>HLF</g>. Also, independent of the presence of TGF-  1, the decline of <g>semaphorin-7A</g> by siRNA was associated with increased a-smooth muscle actin production and gene expression of <g>periostin</g>, <g>fibronectin</g>, laminin, and <g>serum response factor</g> <g>SRF</g>, indicating differentiation into a myofibroblast. Conversely, overexpression of <g>semaphorin-7A</g> in the NIH3T3 fibroblast cell line reduced the production of pro-fibrotic markers. The inverse association between <g>semaphorin-7A</g> and pro-fibrotic fibroblast markers was further analyzed using <g>HLF</g> from idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> n = 6 and non-fibrotic n = 7 lungs. Using these 13 fibroblast lines, we observed that <g>semaphorin-7A</g> and <g>periostin</g> expression were inversely correlated. In conclusion, our study indicates that endogenous <g>semaphorin-7A</g> in <g>HLF</g> plays a role in maintaining fibroblast homeostasis by preventing up-regulation of pro-fibrotic genes. Therefore, endogenous and exogenous <g>semaphorin-7A</g> may have opposite effects on the fibroblast phenotype.
28128990|a|This study aimed to explore the different pathogeneses of <d>combined pulmonary fibrosis and emphysema</d> CPFE from emphysema and pulmonary fibrosis. The levels of transforming growth factor-b1 TGF-b1, vascular endothelial growth factor VEGF, Krebs Von Den Lungen-6 KL-6, matrix metalloproteinase-9 MMP-9, tissue inhibitors of metalloproteinases-1 TIMP-1, cytokeratin 19 fragment CYFRA21-1, squamous cell carcinoma antigen SCC, and the telomerase activity in peripheral blood were measured in 38 CPFE patients, 50 pulmonary emphysema patients, and 34 idiopathic pulmonary fibrosis IPF patients. The results demonstrated that the levels of VEGF and TGF-b1 in IPF patients were significantly higher than those in emphysema patients p < 0.05, and no significant differences were detected between CPFE patients and other two groups p > 0.05. The levels of KL-6 and CYFRA21-1 in IPF patients were significantly higher than those in emphysema and CPFE patients p < 0.05, and the latter had the similar levels p > 0.05. Among the three groups, the levels of SCC, MMP-9, TIMP-1, MMP-9/TIMP-1 ratio, and telomerase activity were not different p > 0.05. Our study showed that VEGF, TGF-b1, KL-6, and CYFRA21-1 may play a role in the pathogenesis of pulmonary fibrosis. The lower levels of KL-6 and CYFRA21-1 in CPFE patients may be one of the reasons why these patients develop emphysema on the basis of fibrosis.
28128990|a|This study aimed to explore the different pathogeneses of <d>combined pulmonary fibrosis and emphysema</d> <d>CPFE</d> from emphysema and pulmonary fibrosis. The levels of transforming growth factor-b1 TGF-b1, vascular endothelial growth factor VEGF, Krebs Von Den Lungen-6 KL-6, matrix metalloproteinase-9 MMP-9, tissue inhibitors of metalloproteinases-1 TIMP-1, cytokeratin 19 fragment CYFRA21-1, squamous cell carcinoma antigen SCC, and the telomerase activity in peripheral blood were measured in 38 <d>CPFE</d> patients, 50 pulmonary emphysema patients, and 34 idiopathic pulmonary fibrosis IPF patients. The results demonstrated that the levels of VEGF and TGF-b1 in IPF patients were significantly higher than those in emphysema patients p < 0.05, and no significant differences were detected between <d>CPFE</d> patients and other two groups p > 0.05. The levels of KL-6 and CYFRA21-1 in IPF patients were significantly higher than those in emphysema and <d>CPFE</d> patients p < 0.05, and the latter had the similar levels p > 0.05. Among the three groups, the levels of SCC, MMP-9, TIMP-1, MMP-9/TIMP-1 ratio, and telomerase activity were not different p > 0.05. Our study showed that VEGF, TGF-b1, KL-6, and CYFRA21-1 may play a role in the pathogenesis of pulmonary fibrosis. The lower levels of KL-6 and CYFRA21-1 in <d>CPFE</d> patients may be one of the reasons why these patients develop emphysema on the basis of fibrosis.
28128990|a|This study aimed to explore the different pathogeneses of <d>combined pulmonary fibrosis and <d>emphysema</d></d> <d>CPFE</d> from <d>emphysema</d> and pulmonary fibrosis. The levels of transforming growth factor-b1 TGF-b1, vascular endothelial growth factor VEGF, Krebs Von Den Lungen-6 KL-6, matrix metalloproteinase-9 MMP-9, tissue inhibitors of metalloproteinases-1 TIMP-1, cytokeratin 19 fragment CYFRA21-1, squamous cell carcinoma antigen SCC, and the telomerase activity in peripheral blood were measured in 38 <d>CPFE</d> patients, 50 pulmonary <d>emphysema</d> patients, and 34 idiopathic pulmonary fibrosis IPF patients. The results demonstrated that the levels of VEGF and TGF-b1 in IPF patients were significantly higher than those in <d>emphysema</d> patients p < 0.05, and no significant differences were detected between <d>CPFE</d> patients and other two groups p > 0.05. The levels of KL-6 and CYFRA21-1 in IPF patients were significantly higher than those in <d>emphysema</d> and <d>CPFE</d> patients p < 0.05, and the latter had the similar levels p > 0.05. Among the three groups, the levels of SCC, MMP-9, TIMP-1, MMP-9/TIMP-1 ratio, and telomerase activity were not different p > 0.05. Our study showed that VEGF, TGF-b1, KL-6, and CYFRA21-1 may play a role in the pathogenesis of pulmonary fibrosis. The lower levels of KL-6 and CYFRA21-1 in <d>CPFE</d> patients may be one of the reasons why these patients develop <d>emphysema</d> on the basis of fibrosis.
28128990|a|This study aimed to explore the different pathogeneses of <d>combined <d>pulmonary fibrosis</d> and <d>emphysema</d></d> <d>CPFE</d> from <d>emphysema</d> and <d>pulmonary fibrosis</d>. The levels of transforming growth factor-b1 TGF-b1, vascular endothelial growth factor VEGF, Krebs Von Den Lungen-6 KL-6, matrix metalloproteinase-9 MMP-9, tissue inhibitors of metalloproteinases-1 TIMP-1, cytokeratin 19 fragment CYFRA21-1, squamous cell carcinoma antigen SCC, and the telomerase activity in peripheral blood were measured in 38 <d>CPFE</d> patients, 50 pulmonary <d>emphysema</d> patients, and 34 idiopathic <d>pulmonary fibrosis</d> IPF patients. The results demonstrated that the levels of VEGF and TGF-b1 in IPF patients were significantly higher than those in <d>emphysema</d> patients p < 0.05, and no significant differences were detected between <d>CPFE</d> patients and other two groups p > 0.05. The levels of KL-6 and CYFRA21-1 in IPF patients were significantly higher than those in <d>emphysema</d> and <d>CPFE</d> patients p < 0.05, and the latter had the similar levels p > 0.05. Among the three groups, the levels of SCC, MMP-9, TIMP-1, MMP-9/TIMP-1 ratio, and telomerase activity were not different p > 0.05. Our study showed that VEGF, TGF-b1, KL-6, and CYFRA21-1 may play a role in the pathogenesis of <d>pulmonary fibrosis</d>. The lower levels of KL-6 and CYFRA21-1 in <d>CPFE</d> patients may be one of the reasons why these patients develop <d>emphysema</d> on the basis of fibrosis.
28128990|a|This study aimed to explore the different pathogeneses of <d>combined <d>pulmonary fibrosis</d> and <d>emphysema</d></d> <d>CPFE</d> from <d>emphysema</d> and <d>pulmonary fibrosis</d>. The levels of <g>transforming growth factor-b1</g> <g>TGF-b1</g>, <g>vascular endothelial growth factor</g> <g>VEGF</g>, <g>Krebs Von Den Lungen-6</g> <g>KL-6</g>, <g>matrix metalloproteinase-9</g> <g>MMP-9</g>, <g>tissue inhibitors of metalloproteinases-1</g> <g>TIMP-1</g>, <g>cytokeratin 19</g> fragment CYFRA21-1, <d>squamous cell carcinoma</d> antigen SCC, and the telomerase activity in peripheral blood were measured in 38 <d>CPFE</d> patients, 50 pulmonary <d>emphysema</d> patients, and 34 idiopathic <d>pulmonary fibrosis</d> IPF patients. The results demonstrated that the levels of <g>VEGF</g> and <g>TGF-b1</g> in IPF patients were significantly higher than those in <d>emphysema</d> patients p < 0.05, and no significant differences were detected between <d>CPFE</d> patients and other two groups p > 0.05. The levels of <g>KL-6</g> and CYFRA21-1 in IPF patients were significantly higher than those in <d>emphysema</d> and <d>CPFE</d> patients p < 0.05, and the latter had the similar levels p > 0.05. Among the three groups, the levels of SCC, <g>MMP-9</g>, <g>TIMP-1</g>, <g>MMP-9</g>/<g>TIMP-1</g> ratio, and telomerase activity were not different p > 0.05. Our study showed that <g>VEGF</g>, <g>TGF-b1</g>, <g>KL-6</g>, and CYFRA21-1 may play a role in the pathogenesis of <d>pulmonary fibrosis</d>. The lower levels of <g>KL-6</g> and CYFRA21-1 in <d>CPFE</d> patients may be one of the reasons why these patients develop <d>emphysema</d> on the basis of fibrosis.
28128990|a|This study aimed to explore the different pathogeneses of <d>combined <d>pulmonary fibrosis</d> and <d>emphysema</d></d> <d>CPFE</d> from <d>emphysema</d> and <d>pulmonary fibrosis</d>. The levels of <g>transforming growth factor-b1</g> <g>TGF-b1</g>, <g>vascular endothelial growth factor</g> <g>VEGF</g>, <g>Krebs Von Den Lungen-6</g> <g>KL-6</g>, <g>matrix metalloproteinase-9</g> <g>MMP-9</g>, <g>tissue inhibitors of metalloproteinases-1</g> <g>TIMP-1</g>, <g>cytokeratin 19</g> fragment CYFRA21-1, <d>squamous cell carcinoma</d> antigen SCC, and the telomerase activity in peripheral blood were measured in 38 <d>CPFE</d> patients, 50 pulmonary <d>emphysema</d> patients, and 34 idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> patients. The results demonstrated that the levels of <g>VEGF</g> and <g>TGF-b1</g> in <d>IPF</d> patients were significantly higher than those in <d>emphysema</d> patients p < 0.05, and no significant differences were detected between <d>CPFE</d> patients and other two groups p > 0.05. The levels of <g>KL-6</g> and CYFRA21-1 in <d>IPF</d> patients were significantly higher than those in <d>emphysema</d> and <d>CPFE</d> patients p < 0.05, and the latter had the similar levels p > 0.05. Among the three groups, the levels of SCC, <g>MMP-9</g>, <g>TIMP-1</g>, <g>MMP-9</g>/<g>TIMP-1</g> ratio, and telomerase activity were not different p > 0.05. Our study showed that <g>VEGF</g>, <g>TGF-b1</g>, <g>KL-6</g>, and CYFRA21-1 may play a role in the pathogenesis of <d>pulmonary fibrosis</d>. The lower levels of <g>KL-6</g> and CYFRA21-1 in <d>CPFE</d> patients may be one of the reasons why these patients develop <d>emphysema</d> on the basis of fibrosis.
28128990|a|This study aimed to explore the different pathogeneses of <d>combined <d>pulmonary <d>fibrosis</d></d> and <d>emphysema</d></d> <d>CPFE</d> from <d>emphysema</d> and <d>pulmonary <d>fibrosis</d></d>. The levels of <g>transforming growth factor-b1</g> <g>TGF-b1</g>, <g>vascular endothelial growth factor</g> <g>VEGF</g>, <g>Krebs Von Den Lungen-6</g> <g>KL-6</g>, <g>matrix metalloproteinase-9</g> <g>MMP-9</g>, <g>tissue inhibitors of metalloproteinases-1</g> <g>TIMP-1</g>, <g>cytokeratin 19</g> fragment CYFRA21-1, <d>squamous cell carcinoma</d> antigen SCC, and the telomerase activity in peripheral blood were measured in 38 <d>CPFE</d> patients, 50 pulmonary <d>emphysema</d> patients, and 34 idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> patients. The results demonstrated that the levels of <g>VEGF</g> and <g>TGF-b1</g> in <d>IPF</d> patients were significantly higher than those in <d>emphysema</d> patients p < 0.05, and no significant differences were detected between <d>CPFE</d> patients and other two groups p > 0.05. The levels of <g>KL-6</g> and CYFRA21-1 in <d>IPF</d> patients were significantly higher than those in <d>emphysema</d> and <d>CPFE</d> patients p < 0.05, and the latter had the similar levels p > 0.05. Among the three groups, the levels of SCC, <g>MMP-9</g>, <g>TIMP-1</g>, <g>MMP-9</g>/<g>TIMP-1</g> ratio, and telomerase activity were not different p > 0.05. Our study showed that <g>VEGF</g>, <g>TGF-b1</g>, <g>KL-6</g>, and CYFRA21-1 may play a role in the pathogenesis of <d>pulmonary <d>fibrosis</d></d>. The lower levels of <g>KL-6</g> and CYFRA21-1 in <d>CPFE</d> patients may be one of the reasons why these patients develop <d>emphysema</d> on the basis of <d>fibrosis</d>.
28131417|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic progressive lung disease that typically leads to respiratory failure and death within 3-5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of IPF. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to pleural mesothelial cell PMC migration and sub-pleural pulmonary fibrosis. MicroRNA miRNA expression has recently been implicated in the pathogenesis of IPF. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.
28131417|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic progressive lung disease that typically leads to respiratory failure and death within 3-5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of <d>IPF</d>. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to pleural mesothelial cell PMC migration and sub-pleural pulmonary fibrosis. MicroRNA miRNA expression has recently been implicated in the pathogenesis of <d>IPF</d>. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of <d>IPF</d>.
28131417|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic progressive lung disease</d> that typically leads to respiratory failure and death within 3-5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of <d>IPF</d>. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to pleural mesothelial cell PMC migration and sub-pleural pulmonary fibrosis. MicroRNA miRNA expression has recently been implicated in the pathogenesis of <d>IPF</d>. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of <d>IPF</d>.
28131417|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic progressive lung disease</d> that typically leads to <d>respiratory failure</d> and death within 3-5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of <d>IPF</d>. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to pleural mesothelial cell PMC migration and sub-pleural pulmonary fibrosis. MicroRNA miRNA expression has recently been implicated in the pathogenesis of <d>IPF</d>. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of <d>IPF</d>.
28131417|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic progressive lung disease</d> that typically leads to <d>respiratory failure</d> and <d>death</d> within 3-5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of <d>IPF</d>. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to pleural mesothelial cell PMC migration and sub-pleural pulmonary fibrosis. MicroRNA miRNA expression has recently been implicated in the pathogenesis of <d>IPF</d>. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of <d>IPF</d>.
28131417|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic progressive lung disease</d> that typically leads to <d>respiratory failure</d> and <d>death</d> within 3-5 years of diagnosis. Sub-<d>pleural pulmonary fibrosis</d> is a pathological hallmark of <d>IPF</d>. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to pleural mesothelial cell PMC migration and sub-<d>pleural pulmonary fibrosis</d>. MicroRNA miRNA expression has recently been implicated in the pathogenesis of <d>IPF</d>. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-<d>pleural pulmonary fibrosis</d> through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of <d>IPF</d>.
28131417|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a <d>chronic progressive lung disease</d> that typically leads to <d>respiratory failure</d> and <d>death</d> within 3-5 years of diagnosis. Sub-<d>pleural <d>pulmonary fibrosis</d></d> is a pathological hallmark of <d>IPF</d>. Bleomycin treatment of mice is a an established <d>pulmonary fibrosis</d> model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to pleural mesothelial cell PMC migration and sub-<d>pleural <d>pulmonary fibrosis</d></d>. MicroRNA miRNA expression has recently been implicated in the pathogenesis of <d>IPF</d>. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a <d>pulmonary fibrosis</d> animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-<d>pleural <d>pulmonary fibrosis</d></d> through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of <d>IPF</d>.
28131417|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a <d>chronic progressive lung disease</d> that typically leads to <d>respiratory failure</d> and <d>death</d> within 3-5 years of diagnosis. Sub-<d>pleural <d>pulmonary fibrosis</d></d> is a pathological hallmark of <d>IPF</d>. Bleomycin treatment of mice is a an established <d>pulmonary fibrosis</d> model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to <d>pleural mesothelial cell</d> PMC migration and sub-<d>pleural <d>pulmonary fibrosis</d></d>. MicroRNA miRNA expression has recently been implicated in the pathogenesis of <d>IPF</d>. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a <d>pulmonary fibrosis</d> animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-<d>pleural <d>pulmonary fibrosis</d></d> through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of <d>IPF</d>.
28131417|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a <d>chronic progressive lung disease</d> that typically leads to <d>respiratory failure</d> and <d>death</d> within 3-5 years of diagnosis. Sub-<d>pleural <d>pulmonary fibrosis</d></d> is a pathological hallmark of <d>IPF</d>. Bleomycin treatment of mice is a an established <d>pulmonary fibrosis</d> model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to <d>pleural mesothelial cell</d> <d>PMC</d> migration and sub-<d>pleural <d>pulmonary fibrosis</d></d>. MicroRNA miRNA expression has recently been implicated in the pathogenesis of <d>IPF</d>. However, changes in miRNA expression in <d>PMC</d>s and sub-pleural fibrosis have not been reported. Using cultured <d>PMC</d>s and a <d>pulmonary fibrosis</d> animal model, we found that miR-18a-5p was reduced in <d>PMC</d>s treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of <d>PMC</d>s. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of <d>PMC</d> and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-<d>pleural <d>pulmonary fibrosis</d></d> through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of <d>IPF</d>.
28131417|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a <d>chronic progressive lung disease</d> that typically leads to <d>respiratory failure</d> and <d>death</d> within 3-5 years of diagnosis. Sub-<d>pleural <d>pulmonary fibrosis</d></d> is a pathological hallmark of <d>IPF</d>. Bleomycin treatment of mice is a an established <d>pulmonary fibrosis</d> model. We recently showed that bleomycin-induced epithelial-mesenchymal transition EMT contributes to <d>pleural mesothelial cell</d> <d>PMC</d> migration and sub-<d>pleural <d>pulmonary fibrosis</d></d>. MicroRNA miRNA expression has recently been implicated in the pathogenesis of <d>IPF</d>. However, changes in miRNA expression in <d>PMC</d>s and <d>sub-pleural fibrosis</d> have not been reported. Using cultured <d>PMC</d>s and a <d>pulmonary fibrosis</d> animal model, we found that miR-18a-5p was reduced in <d>PMC</d>s treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of <d>PMC</d>s. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor b receptor II <g>TGF-b</g>RII mRNA, and this is associated with reduced <g>TGF-b</g>RII expression and suppression of <g>TGF-b</g>-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of <d>PMC</d> and inhibited bleomycin-induced <d>sub-pleural fibrosis</d> in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-<d>pleural <d>pulmonary fibrosis</d></d> through upregulation of its target, <g>TGF-b</g>RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of <d>IPF</d>.
28178340|a|BACKGROUND: Idiopathic pulmonary fibrosis <d>IPF</d> is a rare lung disease of unknown origin leading rapidly to death. This paper addresses the issue of whether sputum induction is a suitable tool to study respiratory tract inflammation and potential biomarkers in <d>IPF</d> compared to COPD, a fibrosing airway wall disease. METHODS: In a cross-sectional analysis, 15 <d>IPF</d> patients, 32 COPD and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of TGF- b, IGF-1, IGF-2, IGFBP-1, IGFBP-2, IGFBP-3, IL-8, IL-13, MMP-7, MMP-9, YKL-40, TNF-a and KL-6 in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for TGF-b, MMP-7, YKL-40, IGFBP-2, IL-6, IL-8 and TNF-a. RESULTS: <d>IPF</d> patients, like COPD, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS. <d>IPF</d> sputum supernatants had increased concentrations of IGFBP-2, IL-8, TGF-b, MMP-7, MMP-9 and KL-6 p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively when compared to healthy subjects where COPD had higher IL-6 and TNF-a levels than <d>IPF</d> p<0.05 and p<0.05 respectively and HS p<0.0001 and p<0.001 respectively and higher IL-8 and MMP-9 than HS p<0.0001 and p<0.001 respectively. Conversely to IL-6 and TNF-a, MMP-7 was increased in <d>IPF</d> compared to COPD p<0.05. The KL-6 and MMP-7 protein levels in sputum were inversely correlated with total lung capacity TLC, % of predicted in <d>IPF</d> patients r = -0.73 and r = -0.53 respectively. Sputum gene expression analysis identified a significant increase for IGFBP-2, IL-6, IL-8 and MMP-7 in <d>IPF</d> compared to HS p<0.05, p<0.01, p<0.05 and p<0.0001 respectively and for IGFBP-2, YKL-40, IL-6, IL-8 and MMP-7 compared to COPD p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively. Furthermore, gene expression of TGF-b was increased in <d>IPF</d> compared to COPD p<0.001 but not to HS. CONCLUSION: Our data show clear increase in expression and production of IGFBP-2, IL-8 and MMP-7 in sputum from patients with <d>IPF</d> that may contribute to the disease.
28178340|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a rare lung disease of unknown origin leading rapidly to death. This paper addresses the issue of whether sputum induction is a suitable tool to study respiratory tract inflammation and potential biomarkers in <d>IPF</d> compared to COPD, a fibrosing airway wall disease. METHODS: In a cross-sectional analysis, 15 <d>IPF</d> patients, 32 COPD and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of TGF- b, IGF-1, IGF-2, IGFBP-1, <g>IGFBP-2</g>, IGFBP-3, <g>IL-8</g>, IL-13, <g>MMP-7</g>, MMP-9, YKL-40, TNF-a and KL-6 in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for TGF-b, <g>MMP-7</g>, YKL-40, <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and TNF-a. RESULTS: <d>IPF</d> patients, like COPD, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS. <d>IPF</d> sputum supernatants had increased concentrations of <g>IGFBP-2</g>, <g>IL-8</g>, TGF-b, <g>MMP-7</g>, MMP-9 and KL-6 p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively when compared to healthy subjects where COPD had higher IL-6 and TNF-a levels than <d>IPF</d> p<0.05 and p<0.05 respectively and HS p<0.0001 and p<0.001 respectively and higher <g>IL-8</g> and MMP-9 than HS p<0.0001 and p<0.001 respectively. Conversely to IL-6 and TNF-a, <g>MMP-7</g> was increased in <d>IPF</d> compared to COPD p<0.05. The KL-6 and <g>MMP-7</g> protein levels in sputum were inversely correlated with total lung capacity TLC, % of predicted in <d>IPF</d> patients r = -0.73 and r = -0.53 respectively. Sputum gene expression analysis identified a significant increase for <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and <g>MMP-7</g> in <d>IPF</d> compared to HS p<0.05, p<0.01, p<0.05 and p<0.0001 respectively and for <g>IGFBP-2</g>, YKL-40, IL-6, <g>IL-8</g> and <g>MMP-7</g> compared to COPD p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively. Furthermore, gene expression of TGF-b was increased in <d>IPF</d> compared to COPD p<0.001 but not to HS. CONCLUSION: Our data show clear increase in expression and production of <g>IGFBP-2</g>, <g>IL-8</g> and <g>MMP-7</g> in sputum from patients with <d>IPF</d> that may contribute to the disease.
28178340|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a rare <d>lung disease</d> of unknown origin leading rapidly to death. This paper addresses the issue of whether sputum induction is a suitable tool to study respiratory tract inflammation and potential biomarkers in <d>IPF</d> compared to COPD, a fibrosing airway wall disease. METHODS: In a cross-sectional analysis, 15 <d>IPF</d> patients, 32 COPD and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of TGF- b, IGF-1, IGF-2, IGFBP-1, <g>IGFBP-2</g>, IGFBP-3, <g>IL-8</g>, IL-13, <g>MMP-7</g>, MMP-9, YKL-40, TNF-a and KL-6 in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for TGF-b, <g>MMP-7</g>, YKL-40, <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and TNF-a. RESULTS: <d>IPF</d> patients, like COPD, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS. <d>IPF</d> sputum supernatants had increased concentrations of <g>IGFBP-2</g>, <g>IL-8</g>, TGF-b, <g>MMP-7</g>, MMP-9 and KL-6 p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively when compared to healthy subjects where COPD had higher IL-6 and TNF-a levels than <d>IPF</d> p<0.05 and p<0.05 respectively and HS p<0.0001 and p<0.001 respectively and higher <g>IL-8</g> and MMP-9 than HS p<0.0001 and p<0.001 respectively. Conversely to IL-6 and TNF-a, <g>MMP-7</g> was increased in <d>IPF</d> compared to COPD p<0.05. The KL-6 and <g>MMP-7</g> protein levels in sputum were inversely correlated with total lung capacity TLC, % of predicted in <d>IPF</d> patients r = -0.73 and r = -0.53 respectively. Sputum gene expression analysis identified a significant increase for <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and <g>MMP-7</g> in <d>IPF</d> compared to HS p<0.05, p<0.01, p<0.05 and p<0.0001 respectively and for <g>IGFBP-2</g>, YKL-40, IL-6, <g>IL-8</g> and <g>MMP-7</g> compared to COPD p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively. Furthermore, gene expression of TGF-b was increased in <d>IPF</d> compared to COPD p<0.001 but not to HS. CONCLUSION: Our data show clear increase in expression and production of <g>IGFBP-2</g>, <g>IL-8</g> and <g>MMP-7</g> in sputum from patients with <d>IPF</d> that may contribute to the disease.
28178340|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a rare <d>lung disease</d> of unknown origin leading rapidly to <d>death</d>. This paper addresses the issue of whether sputum induction is a suitable tool to study respiratory tract inflammation and potential biomarkers in <d>IPF</d> compared to COPD, a fibrosing airway wall disease. METHODS: In a cross-sectional analysis, 15 <d>IPF</d> patients, 32 COPD and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of TGF- b, IGF-1, IGF-2, IGFBP-1, <g>IGFBP-2</g>, IGFBP-3, <g>IL-8</g>, IL-13, <g>MMP-7</g>, MMP-9, YKL-40, TNF-a and KL-6 in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for TGF-b, <g>MMP-7</g>, YKL-40, <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and TNF-a. RESULTS: <d>IPF</d> patients, like COPD, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS. <d>IPF</d> sputum supernatants had increased concentrations of <g>IGFBP-2</g>, <g>IL-8</g>, TGF-b, <g>MMP-7</g>, MMP-9 and KL-6 p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively when compared to healthy subjects where COPD had higher IL-6 and TNF-a levels than <d>IPF</d> p<0.05 and p<0.05 respectively and HS p<0.0001 and p<0.001 respectively and higher <g>IL-8</g> and MMP-9 than HS p<0.0001 and p<0.001 respectively. Conversely to IL-6 and TNF-a, <g>MMP-7</g> was increased in <d>IPF</d> compared to COPD p<0.05. The KL-6 and <g>MMP-7</g> protein levels in sputum were inversely correlated with total lung capacity TLC, % of predicted in <d>IPF</d> patients r = -0.73 and r = -0.53 respectively. Sputum gene expression analysis identified a significant increase for <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and <g>MMP-7</g> in <d>IPF</d> compared to HS p<0.05, p<0.01, p<0.05 and p<0.0001 respectively and for <g>IGFBP-2</g>, YKL-40, IL-6, <g>IL-8</g> and <g>MMP-7</g> compared to COPD p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively. Furthermore, gene expression of TGF-b was increased in <d>IPF</d> compared to COPD p<0.001 but not to HS. CONCLUSION: Our data show clear increase in expression and production of <g>IGFBP-2</g>, <g>IL-8</g> and <g>MMP-7</g> in sputum from patients with <d>IPF</d> that may contribute to the disease.
28178340|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a rare <d>lung disease</d> of unknown origin leading rapidly to <d>death</d>. This paper addresses the issue of whether sputum induction is a suitable tool to study <d>respiratory tract inflammation</d> and potential biomarkers in <d>IPF</d> compared to COPD, a fibrosing airway wall disease. METHODS: In a cross-sectional analysis, 15 <d>IPF</d> patients, 32 COPD and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of TGF- b, IGF-1, IGF-2, IGFBP-1, <g>IGFBP-2</g>, IGFBP-3, <g>IL-8</g>, IL-13, <g>MMP-7</g>, MMP-9, YKL-40, TNF-a and KL-6 in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for TGF-b, <g>MMP-7</g>, YKL-40, <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and TNF-a. RESULTS: <d>IPF</d> patients, like COPD, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS. <d>IPF</d> sputum supernatants had increased concentrations of <g>IGFBP-2</g>, <g>IL-8</g>, TGF-b, <g>MMP-7</g>, MMP-9 and KL-6 p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively when compared to healthy subjects where COPD had higher IL-6 and TNF-a levels than <d>IPF</d> p<0.05 and p<0.05 respectively and HS p<0.0001 and p<0.001 respectively and higher <g>IL-8</g> and MMP-9 than HS p<0.0001 and p<0.001 respectively. Conversely to IL-6 and TNF-a, <g>MMP-7</g> was increased in <d>IPF</d> compared to COPD p<0.05. The KL-6 and <g>MMP-7</g> protein levels in sputum were inversely correlated with total lung capacity TLC, % of predicted in <d>IPF</d> patients r = -0.73 and r = -0.53 respectively. Sputum gene expression analysis identified a significant increase for <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and <g>MMP-7</g> in <d>IPF</d> compared to HS p<0.05, p<0.01, p<0.05 and p<0.0001 respectively and for <g>IGFBP-2</g>, YKL-40, IL-6, <g>IL-8</g> and <g>MMP-7</g> compared to COPD p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively. Furthermore, gene expression of TGF-b was increased in <d>IPF</d> compared to COPD p<0.001 but not to HS. CONCLUSION: Our data show clear increase in expression and production of <g>IGFBP-2</g>, <g>IL-8</g> and <g>MMP-7</g> in sputum from patients with <d>IPF</d> that may contribute to the disease.
28178340|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a rare <d>lung disease</d> of unknown origin leading rapidly to <d>death</d>. This paper addresses the issue of whether sputum induction is a suitable tool to study <d>respiratory tract inflammation</d> and potential biomarkers in <d>IPF</d> compared to <d>COPD</d>, a fibrosing airway wall disease. METHODS: In a cross-sectional analysis, 15 <d>IPF</d> patients, 32 <d>COPD</d> and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of TGF- b, IGF-1, IGF-2, IGFBP-1, <g>IGFBP-2</g>, IGFBP-3, <g>IL-8</g>, IL-13, <g>MMP-7</g>, MMP-9, YKL-40, TNF-a and KL-6 in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for TGF-b, <g>MMP-7</g>, YKL-40, <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and TNF-a. RESULTS: <d>IPF</d> patients, like <d>COPD</d>, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS. <d>IPF</d> sputum supernatants had increased concentrations of <g>IGFBP-2</g>, <g>IL-8</g>, TGF-b, <g>MMP-7</g>, MMP-9 and KL-6 p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively when compared to healthy subjects where <d>COPD</d> had higher IL-6 and TNF-a levels than <d>IPF</d> p<0.05 and p<0.05 respectively and HS p<0.0001 and p<0.001 respectively and higher <g>IL-8</g> and MMP-9 than HS p<0.0001 and p<0.001 respectively. Conversely to IL-6 and TNF-a, <g>MMP-7</g> was increased in <d>IPF</d> compared to <d>COPD</d> p<0.05. The KL-6 and <g>MMP-7</g> protein levels in sputum were inversely correlated with total lung capacity TLC, % of predicted in <d>IPF</d> patients r = -0.73 and r = -0.53 respectively. Sputum gene expression analysis identified a significant increase for <g>IGFBP-2</g>, IL-6, <g>IL-8</g> and <g>MMP-7</g> in <d>IPF</d> compared to HS p<0.05, p<0.01, p<0.05 and p<0.0001 respectively and for <g>IGFBP-2</g>, YKL-40, IL-6, <g>IL-8</g> and <g>MMP-7</g> compared to <d>COPD</d> p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively. Furthermore, gene expression of TGF-b was increased in <d>IPF</d> compared to <d>COPD</d> p<0.001 but not to HS. CONCLUSION: Our data show clear increase in expression and production of <g>IGFBP-2</g>, <g>IL-8</g> and <g>MMP-7</g> in sputum from patients with <d>IPF</d> that may contribute to the disease.
28178340|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a rare <d>lung disease</d> of unknown origin leading rapidly to <d>death</d>. This paper addresses the issue of whether sputum induction is a suitable tool to study <d>respiratory tract inflammation</d> and potential biomarkers in <d>IPF</d> compared to <d>COPD</d>, a fibrosing airway wall disease. METHODS: In a cross-sectional analysis, 15 <d>IPF</d> patients, 32 <d>COPD</d> and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of <g>TGF- b</g>, <g>IGF-1</g>, <g>IGF-2</g>, <g>IGFBP-1</g>, <g>IGFBP-2</g>, <g>IGFBP-3</g>, <g>IL-8</g>, <g>IL-13</g>, <g>MMP-7</g>, <g>MMP-9</g>, <g>YKL-40</g>, <g>TNF-a</g> and <g>KL-6</g> in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for <g>TGF-b</g>, <g>MMP-7</g>, <g>YKL-40</g>, <g>IGFBP-2</g>, <g>IL-6</g>, <g>IL-8</g> and <g>TNF-a</g>. RESULTS: <d>IPF</d> patients, like <d>COPD</d>, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to <d>HS</d>. <d>IPF</d> sputum supernatants had increased concentrations of <g>IGFBP-2</g>, <g>IL-8</g>, <g>TGF-b</g>, <g>MMP-7</g>, <g>MMP-9</g> and <g>KL-6</g> p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively when compared to healthy subjects where <d>COPD</d> had higher <g>IL-6</g> and <g>TNF-a</g> levels than <d>IPF</d> p<0.05 and p<0.05 respectively and <d>HS</d> p<0.0001 and p<0.001 respectively and higher <g>IL-8</g> and <g>MMP-9</g> than <d>HS</d> p<0.0001 and p<0.001 respectively. Conversely to <g>IL-6</g> and <g>TNF-a</g>, <g>MMP-7</g> was increased in <d>IPF</d> compared to <d>COPD</d> p<0.05. The <g>KL-6</g> and <g>MMP-7</g> protein levels in sputum were inversely correlated with total lung capacity TLC, % of predicted in <d>IPF</d> patients r = -0.73 and r = -0.53 respectively. Sputum gene expression analysis identified a significant increase for <g>IGFBP-2</g>, <g>IL-6</g>, <g>IL-8</g> and <g>MMP-7</g> in <d>IPF</d> compared to <d>HS</d> p<0.05, p<0.01, p<0.05 and p<0.0001 respectively and for <g>IGFBP-2</g>, <g>YKL-40</g>, <g>IL-6</g>, <g>IL-8</g> and <g>MMP-7</g> compared to <d>COPD</d> p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively. Furthermore, gene expression of <g>TGF-b</g> was increased in <d>IPF</d> compared to <d>COPD</d> p<0.001 but not to <d>HS</d>. CONCLUSION: Our data show clear increase in expression and production of <g>IGFBP-2</g>, <g>IL-8</g> and <g>MMP-7</g> in sputum from patients with <d>IPF</d> that may contribute to the disease.
28182573|a|Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic pulmonary fibrosis IPF, and is governed by transforming growth factor TGF-b/Smad signalling. We sought to define the role of <d>heat shock</d> protein HSP90 in profibrotic responses in IPF and to determine the therapeutic effects of HSP90 inhibition in a murine model of pulmonary fibrosis.We investigated the effects of HSP90 inhibition<i>in vitro</i>by applying 17-AAG 17-allylamino-17-demethoxygeldanamycin to lung fibroblasts and A549 cells and<i>in vivo</i>by administering 17-DMAG 17-dimethylaminoethylamino-17-demethoxygeldanamycin to mice with bleomycin-induced pulmonary fibrosis.HSP90 expression was increased in myofibroblasts from fibrotic human and mouse lungs compared with controls. 17-AAG inhibited TGF-b1-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial-mesenchymal transition of A549 cells. The antifibrotic effects were associated with TGF-b receptor disruption and inhibition of Smad2/3 activation. Co-immunoprecipitation revealed that HSP90b interacted with TGF-b receptor II and stabilised TGF-b receptors. Furthermore, 17-DMAG improved lung function and decreased fibrosis and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice.In conclusion, this is the first study to demonstrate that HSP90 inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced pulmonary fibrosis in mice.
28182573|a|Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic <d>pulmonary fibrosis</d> IPF, and is governed by transforming growth factor TGF-b/Smad signalling. We sought to define the role of <d>heat shock</d> protein HSP90 in profibrotic responses in IPF and to determine the therapeutic effects of HSP90 inhibition in a murine model of <d>pulmonary fibrosis</d>.We investigated the effects of HSP90 inhibition<i>in vitro</i>by applying 17-AAG 17-allylamino-17-demethoxygeldanamycin to lung fibroblasts and A549 cells and<i>in vivo</i>by administering 17-DMAG 17-dimethylaminoethylamino-17-demethoxygeldanamycin to mice with bleomycin-induced <d>pulmonary fibrosis</d>.HSP90 expression was increased in myofibroblasts from fibrotic human and mouse lungs compared with controls. 17-AAG inhibited TGF-b1-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial-mesenchymal transition of A549 cells. The antifibrotic effects were associated with TGF-b receptor disruption and inhibition of Smad2/3 activation. Co-immunoprecipitation revealed that HSP90b interacted with TGF-b receptor II and stabilised TGF-b receptors. Furthermore, 17-DMAG improved lung function and decreased fibrosis and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice.In conclusion, this is the first study to demonstrate that HSP90 inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced <d>pulmonary fibrosis</d> in mice.
28182573|a|Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>, and is governed by transforming growth factor TGF-b/Smad signalling. We sought to define the role of <d>heat shock</d> protein HSP90 in profibrotic responses in <d>IPF</d> and to determine the therapeutic effects of HSP90 inhibition in a murine model of <d>pulmonary fibrosis</d>.We investigated the effects of HSP90 inhibition<i>in vitro</i>by applying 17-AAG 17-allylamino-17-demethoxygeldanamycin to lung fibroblasts and A549 cells and<i>in vivo</i>by administering 17-DMAG 17-dimethylaminoethylamino-17-demethoxygeldanamycin to mice with bleomycin-induced <d>pulmonary fibrosis</d>.HSP90 expression was increased in myofibroblasts from fibrotic human and mouse lungs compared with controls. 17-AAG inhibited TGF-b1-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial-mesenchymal transition of A549 cells. The antifibrotic effects were associated with TGF-b receptor disruption and inhibition of Smad2/3 activation. Co-immunoprecipitation revealed that HSP90b interacted with TGF-b receptor II and stabilised TGF-b receptors. Furthermore, 17-DMAG improved lung function and decreased fibrosis and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice.In conclusion, this is the first study to demonstrate that HSP90 inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced <d>pulmonary fibrosis</d> in mice.
28182573|a|Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d>, and is governed by transforming growth factor <g>TGF-b</g>/Smad signalling. We sought to define the role of <d>heat shock</d> protein <g>HSP90</g> in profibrotic responses in <d>IPF</d> and to determine the therapeutic effects of <g>HSP90</g> inhibition in a murine model of <d>pulmonary <d>fibrosis</d></d>.We investigated the effects of <g>HSP90</g> inhibition<i>in vitro</i>by applying 17-<g>AAG</g> 17-allylamino-17-demethoxygeldanamycin to lung fibroblasts and A549 cells and<i>in vivo</i>by administering 17-DMAG 17-dimethylaminoethylamino-17-demethoxygeldanamycin to mice with bleomycin-induced <d>pulmonary <d>fibrosis</d></d>.<g>HSP90</g> expression was increased in myofibroblasts from fibrotic human and mouse lungs compared with controls. 17-<g>AAG</g> inhibited <g><g>TGF-b</g>1</g>-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial-mesenchymal transition of A549 cells. The antifibrotic effects were associated with <g>TGF-b</g> receptor disruption and inhibition of <g>Smad2/3</g> activation. Co-immunoprecipitation revealed that <g>HSP90</g>b interacted with <g>TGF-b</g> receptor II and stabilised <g>TGF-b</g> receptors. Furthermore, 17-DMAG improved lung function and decreased <d>fibrosis</d> and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice.In conclusion, this is the first study to demonstrate that <g>HSP90</g> inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced <d>pulmonary <d>fibrosis</d></d> in mice.
28213468|a|UNASSIGNED: Idiopathic <d>pulmonary fibrosis</d> IPF is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the pulmonary architecture and impaired gas exchange. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor TGF-b signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined if Lefty A can attenuate bleomycin BLM-induced <d>pulmonary fibrosis</d> in vivo based on a novel therapeutic strategy where HEK293 cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had one week earlier been intratracheally administered BLM to induce <d>pulmonary fibrosis</d>. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor CTGF and type I collagen messenger mRNA, lessened the morphological fibrotic effects induced by bleomycin, and increased the expression of matrix metalloproteinase MMP-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate <d>pulmonary fibrosis</d> in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses.
28213468|a|UNASSIGNED: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the pulmonary architecture and impaired gas exchange. Associated with high morbidity and mortality, <d>IPF</d> is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor TGF-b signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined if Lefty A can attenuate bleomycin BLM-induced <d>pulmonary fibrosis</d> in vivo based on a novel therapeutic strategy where HEK293 cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had one week earlier been intratracheally administered BLM to induce <d>pulmonary fibrosis</d>. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor CTGF and type I collagen messenger mRNA, lessened the morphological fibrotic effects induced by bleomycin, and increased the expression of matrix metalloproteinase MMP-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate <d>pulmonary fibrosis</d> in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses.
28213468|a|UNASSIGNED: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the <d>pulmonary architecture</d> and impaired gas exchange. Associated with high morbidity and mortality, <d>IPF</d> is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor TGF-b signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined if Lefty A can attenuate bleomycin BLM-induced <d>pulmonary fibrosis</d> in vivo based on a novel therapeutic strategy where HEK293 cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had one week earlier been intratracheally administered BLM to induce <d>pulmonary fibrosis</d>. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor CTGF and type I collagen messenger mRNA, lessened the morphological fibrotic effects induced by bleomycin, and increased the expression of matrix metalloproteinase MMP-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate <d>pulmonary fibrosis</d> in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses.
28213468|a|UNASSIGNED: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the <d>pulmonary architecture</d> and <d>impaired gas exchange</d>. Associated with high morbidity and mortality, <d>IPF</d> is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor TGF-b signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined if Lefty A can attenuate bleomycin BLM-induced <d>pulmonary fibrosis</d> in vivo based on a novel therapeutic strategy where HEK293 cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had one week earlier been intratracheally administered BLM to induce <d>pulmonary fibrosis</d>. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor CTGF and type I collagen messenger mRNA, lessened the morphological fibrotic effects induced by bleomycin, and increased the expression of matrix metalloproteinase MMP-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate <d>pulmonary fibrosis</d> in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses.
28213468|a|UNASSIGNED: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the <d>pulmonary architecture</d> and <d>impaired gas exchange</d>. Associated with high morbidity and mortality, <d>IPF</d> is generally refractory to current pharmacological therapies. <g>Lefty A</g>, a potent inhibitor of transforming growth factor TGF-b signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of <d>renal fibrosis</d> and other potential organ fibroses. Here, we determined if <g>Lefty A</g> can attenuate bleomycin BLM-induced <d>pulmonary fibrosis</d> in vivo based on a novel therapeutic strategy where HEK293 cells are genetically engineered with the <g>Lefty A</g>-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had one week earlier been intratracheally administered BLM to induce <d>pulmonary fibrosis</d>. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of <g>Lefty A</g> released from the microencapsulated cells. The engineered HEK293 cells with <g>Lefty A</g> significantly reduced the expression of connective tissue growth factor CTGF and type I collagen messenger mRNA, lessened the morphological fibrotic effects induced by bleomycin, and increased the expression of matrix metalloproteinase MMP-9. This illustrates that engineered HEK293 cells with <g>Lefty A</g> can attenuate <d>pulmonary fibrosis</d> in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses.
28213468|a|UNASSIGNED: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the <d>pulmonary architecture</d> and <d>impaired gas exchange</d>. Associated with high morbidity and mortality, <d>IPF</d> is generally refractory to current pharmacological therapies. <g>Lefty A</g>, a potent inhibitor of transforming growth factor TGF-b signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of <d>renal <d>fibrosis</d></d> and other potential organ fibroses. Here, we determined if <g>Lefty A</g> can attenuate bleomycin BLM-induced <d>pulmonary <d>fibrosis</d></d> in vivo based on a novel therapeutic strategy where HEK293 cells are genetically engineered with the <g>Lefty A</g>-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had one week earlier been intratracheally administered BLM to induce <d>pulmonary <d>fibrosis</d></d>. The severity of <d>fibrosis</d> in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of <g>Lefty A</g> released from the microencapsulated cells. The engineered HEK293 cells with <g>Lefty A</g> significantly reduced the expression of connective tissue growth factor CTGF and type I collagen messenger mRNA, lessened the morphological fibrotic effects induced by bleomycin, and increased the expression of matrix metalloproteinase MMP-9. This illustrates that engineered HEK293 cells with <g>Lefty A</g> can attenuate <d>pulmonary <d>fibrosis</d></d> in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses.
28213468|a|UNASSIGNED: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the <d>pulmonary architecture</d> and <d>impaired gas exchange</d>. Associated with high morbidity and mortality, <d>IPF</d> is generally refractory to current pharmacological therapies. <g>Lefty A</g>, a potent inhibitor of transforming growth factor TGF-b signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of <d>renal <d>fibrosis</d></d> and other potential organ fibroses. Here, we determined if <g>Lefty A</g> can attenuate bleomycin BLM-induced <d>pulmonary <d>fibrosis</d></d> in vivo based on a novel therapeutic strategy where HEK293 cells are genetically engineered with the <g>Lefty A</g>-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had one week earlier been intratracheally administered BLM to induce <d>pulmonary <d>fibrosis</d></d>. The severity of <d>fibrosis</d> in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of <g>Lefty A</g> released from the microencapsulated cells. The engineered HEK293 cells with <g>Lefty A</g> significantly reduced the expression of <g>connective tissue growth factor</g> <g>CTGF</g> and type I collagen messenger mRNA, lessened the morphological fibrotic effects induced by bleomycin, and increased the expression of <g>matrix metalloproteinase MMP-9</g>. This illustrates that engineered HEK293 cells with <g>Lefty A</g> can attenuate <d>pulmonary <d>fibrosis</d></d> in vivo, thus providing a novel method to treat human <d>pulmonary fibrotic disease</d> and other organ fibroses.
28239659|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a severe fibrotic lung disease associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix ECM production. To identify inhibitors that can attenuate fibroblast activation, we queried IPF gene signatures against a library of small-molecule-induced gene-expression profiles and identified <g>Hsp90</g> inhibitors as potential therapeutic agents that can suppress fibroblast activation in IPF. Although <g>Hsp90</g> is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in IPF. Here, we found elevated <g>Hsp90</g> staining in lung biopsies of patients with IPF. Notably, fibroblasts isolated from fibrotic lesions showed heightened <g>Hsp90</g> ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin 17-AAG, a small-molecule inhibitor of <g>Hsp90</g> ATPase activity, attenuated fibroblast activation and also TGF-b-driven effects on fibroblast to myofibroblast transformation. The loss of the <g>Hsp90</g>AB, but not the <g>Hsp90</g>AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis in a mouse model of <d>pulmonary fibrosis</d>, suggesting that targeting <g>Hsp90</g> represents an effective strategy for the treatment of fibrotic lung disease.
28239659|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a severe fibrotic lung disease associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix ECM production. To identify inhibitors that can attenuate fibroblast activation, we queried <d>IPF</d> gene signatures against a library of small-molecule-induced gene-expression profiles and identified <g>Hsp90</g> inhibitors as potential therapeutic agents that can suppress fibroblast activation in <d>IPF</d>. Although <g>Hsp90</g> is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in <d>IPF</d>. Here, we found elevated <g>Hsp90</g> staining in lung biopsies of patients with <d>IPF</d>. Notably, fibroblasts isolated from fibrotic lesions showed heightened <g>Hsp90</g> ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin 17-AAG, a small-molecule inhibitor of <g>Hsp90</g> ATPase activity, attenuated fibroblast activation and also TGF-b-driven effects on fibroblast to myofibroblast transformation. The loss of the <g>Hsp90</g>AB, but not the <g>Hsp90</g>AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis in a mouse model of <d>pulmonary fibrosis</d>, suggesting that targeting <g>Hsp90</g> represents an effective strategy for the treatment of fibrotic lung disease.
28239659|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a severe <d>fibrotic lung disease</d> associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix ECM production. To identify inhibitors that can attenuate fibroblast activation, we queried <d>IPF</d> gene signatures against a library of small-molecule-induced gene-expression profiles and identified <g>Hsp90</g> inhibitors as potential therapeutic agents that can suppress fibroblast activation in <d>IPF</d>. Although <g>Hsp90</g> is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in <d>IPF</d>. Here, we found elevated <g>Hsp90</g> staining in lung biopsies of patients with <d>IPF</d>. Notably, fibroblasts isolated from fibrotic lesions showed heightened <g>Hsp90</g> ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin 17-AAG, a small-molecule inhibitor of <g>Hsp90</g> ATPase activity, attenuated fibroblast activation and also TGF-b-driven effects on fibroblast to myofibroblast transformation. The loss of the <g>Hsp90</g>AB, but not the <g>Hsp90</g>AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis in a mouse model of <d>pulmonary fibrosis</d>, suggesting that targeting <g>Hsp90</g> represents an effective strategy for the treatment of <d>fibrotic lung disease</d>.
28239659|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a severe <d>fibrotic lung disease</d> associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix ECM production. To identify inhibitors that can attenuate fibroblast activation, we queried <d>IPF</d> gene signatures against a library of small-molecule-induced gene-expression profiles and identified <g>Hsp90</g> inhibitors as potential therapeutic agents that can suppress fibroblast activation in <d>IPF</d>. Although <g>Hsp90</g> is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in <d>IPF</d>. Here, we found elevated <g>Hsp90</g> staining in lung biopsies of patients with <d>IPF</d>. Notably, fibroblasts isolated from <d>fibrotic lesions</d> showed heightened <g>Hsp90</g> ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin 17-AAG, a small-molecule inhibitor of <g>Hsp90</g> ATPase activity, attenuated fibroblast activation and also TGF-b-driven effects on fibroblast to myofibroblast transformation. The loss of the <g>Hsp90</g>AB, but not the <g>Hsp90</g>AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis in a mouse model of <d>pulmonary fibrosis</d>, suggesting that targeting <g>Hsp90</g> represents an effective strategy for the treatment of <d>fibrotic lung disease</d>.
28239659|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a severe <d>fibrotic lung disease</d> associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix ECM production. To identify inhibitors that can attenuate fibroblast activation, we queried <d>IPF</d> gene signatures against a library of small-molecule-induced gene-expression profiles and identified <g>Hsp90</g> inhibitors as potential therapeutic agents that can suppress fibroblast activation in <d>IPF</d>. Although <g>Hsp90</g> is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in <d>IPF</d>. Here, we found elevated <g>Hsp90</g> staining in lung biopsies of patients with <d>IPF</d>. Notably, fibroblasts isolated from <d>fibrotic lesions</d> showed heightened <g>Hsp90</g> ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin 17-AAG, a small-molecule inhibitor of <g>Hsp90</g> ATPase activity, attenuated fibroblast activation and also <g>TGF-b</g>-driven effects on fibroblast to myofibroblast transformation. The loss of the <g>Hsp90</g>AB, but not the <g>Hsp90</g>AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing <d>fibrosis</d> in a mouse model of <d>pulmonary <d>fibrosis</d></d>, suggesting that targeting <g>Hsp90</g> represents an effective strategy for the treatment of <d>fibrotic lung disease</d>.
28254114|a|In this study, we aimed to explore the association of genetic polymorphism in <g>matrix metalloproteinase-9</g> MMP-9 and <g>transforming growth factor-b1</g> TGF-b1 and the susceptibility to <d>combined pulmonary fibrosis</d> and emphysema CPFE. We examined the polymorphisms of the MMP-9 C-1562T and TGF-b1 T869C in 38 CPFE patients, 50 pulmonary emphysema patients, and 34 idiopathic pulmonary fibrosis IPF patients. The frequencies of polymorphic genotypes in MMP-9 were 78.95% CC and 21.05% CT in CPFE group, 76.0% CC and 24.0% CT in emphysema group, and 100.0% CC in IPF group. There were highly statistically significant increased frequencies of the CT genotype and T allele in CPFE and emphysema groups compared with IPF group p < 0.05. The frequencies of polymorphic genotypes in TGF-b1 were 2.63% CC, 28.95% CT, 68.42% TT in CPFE group, 4.00% CC, 16.00% CT, 80.00% TT in emphysema group, and 5.88% CC, 41.18% CT, 52.94% TT in IPF group. Significant increases in the TT genotype and T allele frequencies were observed in emphysema group compared with IPF group p < 0.05. Our study has showed that T allele in MMP-9 C-1562T and T allele in TGF-b1 T869C are risk factors of pulmonary emphysema. The T allele in MMP-9 C-1562T possibly predisposes patients with pulmonary fibrosis to develop emphysema.
28254114|a|In this study, we aimed to explore the association of genetic polymorphism in <g>matrix metalloproteinase-9</g> MMP-9 and <g>transforming growth factor-b1</g> TGF-b1 and the susceptibility to <d>combined pulmonary fibrosis</d> and <d>emphysema</d> CPFE. We examined the polymorphisms of the MMP-9 C-1562T and TGF-b1 T869C in 38 CPFE patients, 50 pulmonary <d>emphysema</d> patients, and 34 idiopathic pulmonary fibrosis IPF patients. The frequencies of polymorphic genotypes in MMP-9 were 78.95% CC and 21.05% CT in CPFE group, 76.0% CC and 24.0% CT in <d>emphysema</d> group, and 100.0% CC in IPF group. There were highly statistically significant increased frequencies of the CT genotype and T allele in CPFE and <d>emphysema</d> groups compared with IPF group p < 0.05. The frequencies of polymorphic genotypes in TGF-b1 were 2.63% CC, 28.95% CT, 68.42% TT in CPFE group, 4.00% CC, 16.00% CT, 80.00% TT in <d>emphysema</d> group, and 5.88% CC, 41.18% CT, 52.94% TT in IPF group. Significant increases in the TT genotype and T allele frequencies were observed in <d>emphysema</d> group compared with IPF group p < 0.05. Our study has showed that T allele in MMP-9 C-1562T and T allele in TGF-b1 T869C are risk factors of pulmonary <d>emphysema</d>. The T allele in MMP-9 C-1562T possibly predisposes patients with pulmonary fibrosis to develop <d>emphysema</d>.
28254114|a|In this study, we aimed to explore the association of genetic polymorphism in <g>matrix metalloproteinase-9</g> <g>MMP-9</g> and <g>transforming growth factor-b1</g> <g>TGF-b1</g> and the susceptibility to <d>combined pulmonary fibrosis</d> and <d>emphysema</d> CPFE. We examined the polymorphisms of the <g>MMP-9</g> C-1562T and <g>TGF-b1</g> T869C in 38 CPFE patients, 50 pulmonary <d>emphysema</d> patients, and 34 <d>idiopathic pulmonary fibrosis</d> IPF patients. The frequencies of polymorphic genotypes in <g>MMP-9</g> were 78.95% CC and 21.05% CT in CPFE group, 76.0% CC and 24.0% CT in <d>emphysema</d> group, and 100.0% CC in IPF group. There were highly statistically significant increased frequencies of the CT genotype and T allele in CPFE and <d>emphysema</d> groups compared with IPF group p < 0.05. The frequencies of polymorphic genotypes in <g>TGF-b1</g> were 2.63% CC, 28.95% CT, 68.42% TT in CPFE group, 4.00% CC, 16.00% CT, 80.00% TT in <d>emphysema</d> group, and 5.88% CC, 41.18% CT, 52.94% TT in IPF group. Significant increases in the TT genotype and T allele frequencies were observed in <d>emphysema</d> group compared with IPF group p < 0.05. Our study has showed that T allele in <g>MMP-9</g> C-1562T and T allele in <g>TGF-b1</g> T869C are risk factors of pulmonary <d>emphysema</d>. The T allele in <g>MMP-9</g> C-1562T possibly predisposes patients with pulmonary fibrosis to develop <d>emphysema</d>.
28254114|a|In this study, we aimed to explore the association of genetic polymorphism in <g>matrix metalloproteinase-9</g> <g>MMP-9</g> and <g>transforming growth factor-b1</g> <g>TGF-b1</g> and the susceptibility to <d>combined pulmonary fibrosis</d> and <d>emphysema</d> CPFE. We examined the polymorphisms of the <g>MMP-9</g> C-1562T and <g>TGF-b1</g> T869C in 38 CPFE patients, 50 pulmonary <d>emphysema</d> patients, and 34 <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> patients. The frequencies of polymorphic genotypes in <g>MMP-9</g> were 78.95% CC and 21.05% CT in CPFE group, 76.0% CC and 24.0% CT in <d>emphysema</d> group, and 100.0% CC in <d>IPF</d> group. There were highly statistically significant increased frequencies of the CT genotype and T allele in CPFE and <d>emphysema</d> groups compared with <d>IPF</d> group p < 0.05. The frequencies of polymorphic genotypes in <g>TGF-b1</g> were 2.63% CC, 28.95% CT, 68.42% TT in CPFE group, 4.00% CC, 16.00% CT, 80.00% TT in <d>emphysema</d> group, and 5.88% CC, 41.18% CT, 52.94% TT in <d>IPF</d> group. Significant increases in the TT genotype and T allele frequencies were observed in <d>emphysema</d> group compared with <d>IPF</d> group p < 0.05. Our study has showed that T allele in <g>MMP-9</g> C-1562T and T allele in <g>TGF-b1</g> T869C are risk factors of pulmonary <d>emphysema</d>. The T allele in <g>MMP-9</g> C-1562T possibly predisposes patients with pulmonary fibrosis to develop <d>emphysema</d>.
28254114|a|In this study, we aimed to explore the association of genetic polymorphism in <g>matrix metalloproteinase-9</g> <g>MMP-9</g> and <g>transforming growth factor-b1</g> <g>TGF-b1</g> and the susceptibility to <d>combined <d>pulmonary fibrosis</d></d> and <d>emphysema</d> CPFE. We examined the polymorphisms of the <g>MMP-9</g> C-1562T and <g>TGF-b1</g> T869C in 38 CPFE patients, 50 pulmonary <d>emphysema</d> patients, and 34 <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> patients. The frequencies of polymorphic genotypes in <g>MMP-9</g> were 78.95% CC and 21.05% CT in CPFE group, 76.0% CC and 24.0% CT in <d>emphysema</d> group, and 100.0% CC in <d>IPF</d> group. There were highly statistically significant increased frequencies of the CT genotype and T allele in CPFE and <d>emphysema</d> groups compared with <d>IPF</d> group p < 0.05. The frequencies of polymorphic genotypes in <g>TGF-b1</g> were 2.63% CC, 28.95% CT, 68.42% TT in CPFE group, 4.00% CC, 16.00% CT, 80.00% TT in <d>emphysema</d> group, and 5.88% CC, 41.18% CT, 52.94% TT in <d>IPF</d> group. Significant increases in the TT genotype and T allele frequencies were observed in <d>emphysema</d> group compared with <d>IPF</d> group p < 0.05. Our study has showed that T allele in <g>MMP-9</g> C-1562T and T allele in <g>TGF-b1</g> T869C are risk factors of pulmonary <d>emphysema</d>. The T allele in <g>MMP-9</g> C-1562T possibly predisposes patients with <d>pulmonary fibrosis</d> to develop <d>emphysema</d>.
28259823|a|INTRODUCTION: <d>Idiopathic pulmonary fibrosis</d> IPF is a lethal lung disease, which is accompanied by changes in lung structure. With regard to treatment, aerosolized drugs administered intrapulmonarily are rapidly distributed into the plasma and do not remain in the lungs due to damage to the alveolar epithelium that occurs from pulmonary fibrosis. In this study, we sought to develop an in vitro model of respiratory epithelial cells in IPF for the evaluation of the intrapulmonary distribution of aerosolized drugs. We investigated transforming growth factor TGF-b1-induced epithelial-mesenchymal transition EMT and permeability alteration in A549, NCI-H441, and Calu-3 cell monolayers. METHODS: After TGF-b1 treatment of A549, NCI-H441, and Calu-3 cells, EMT markers including E-cadherin and vimentin and tight junction proteins including claudins-1, -3, and -5 were stained using immunofluorescence methods and detected using immunoblotting methods. Transport experiments were performed using TGF-b1-treated cell monolayers and fluorescein isothiocyanate dextrans FD; 4.4, 10, and 70kDa. In addition, TGF-b1-induced apoptosis and necrosis were evaluated by flow cytometry using Annexin V and ethidium homodimer III, respectively. RESULTS: In NCI-H441 cells, incomplete EMT, destruction of claudins-1 and -3, and enhancement of FD permeability were caused by TGF-b1 treatment. In A549 cells, complete EMT occurred but was not adequate for transport experiments because of low transepithelial electrical resistance. Whereas in Calu-3 cells, no changes were observed. TGF-b1-induced apoptosis and necrosis were not observed in any of the cell lines. DISCUSSION: Incomplete EMT and permeability enhancement were observed in the alveolar epithelium of IPF. Therefore, our results indicate that TGF-b1-treated NCI-H441 cell monolayers may serve as a useful in vitro model of respiratory epithelial cells for IPF.
28259823|a|INTRODUCTION: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal lung disease, which is accompanied by changes in lung structure. With regard to treatment, aerosolized drugs administered intrapulmonarily are rapidly distributed into the plasma and do not remain in the lungs due to damage to the alveolar epithelium that occurs from pulmonary fibrosis. In this study, we sought to develop an in vitro model of respiratory epithelial cells in <d>IPF</d> for the evaluation of the intrapulmonary distribution of aerosolized drugs. We investigated transforming growth factor TGF-b1-induced epithelial-mesenchymal transition EMT and permeability alteration in A549, NCI-H441, and Calu-3 cell monolayers. METHODS: After TGF-b1 treatment of A549, NCI-H441, and Calu-3 cells, EMT markers including E-cadherin and vimentin and tight junction proteins including claudins-1, -3, and -5 were stained using immunofluorescence methods and detected using immunoblotting methods. Transport experiments were performed using TGF-b1-treated cell monolayers and fluorescein isothiocyanate dextrans FD; 4.4, 10, and 70kDa. In addition, TGF-b1-induced apoptosis and necrosis were evaluated by flow cytometry using Annexin V and ethidium homodimer III, respectively. RESULTS: In NCI-H441 cells, incomplete EMT, destruction of claudins-1 and -3, and enhancement of FD permeability were caused by TGF-b1 treatment. In A549 cells, complete EMT occurred but was not adequate for transport experiments because of low transepithelial electrical resistance. Whereas in Calu-3 cells, no changes were observed. TGF-b1-induced apoptosis and necrosis were not observed in any of the cell lines. DISCUSSION: Incomplete EMT and permeability enhancement were observed in the alveolar epithelium of <d>IPF</d>. Therefore, our results indicate that TGF-b1-treated NCI-H441 cell monolayers may serve as a useful in vitro model of respiratory epithelial cells for <d>IPF</d>.
28259823|a|INTRODUCTION: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal <d>lung disease</d>, which is accompanied by changes in lung structure. With regard to treatment, aerosolized drugs administered intrapulmonarily are rapidly distributed into the plasma and do not remain in the lungs due to damage to the alveolar epithelium that occurs from pulmonary fibrosis. In this study, we sought to develop an in vitro model of respiratory epithelial cells in <d>IPF</d> for the evaluation of the intrapulmonary distribution of aerosolized drugs. We investigated transforming growth factor TGF-b1-induced epithelial-mesenchymal transition EMT and permeability alteration in A549, NCI-H441, and Calu-3 cell monolayers. METHODS: After TGF-b1 treatment of A549, NCI-H441, and Calu-3 cells, EMT markers including E-cadherin and vimentin and tight junction proteins including claudins-1, -3, and -5 were stained using immunofluorescence methods and detected using immunoblotting methods. Transport experiments were performed using TGF-b1-treated cell monolayers and fluorescein isothiocyanate dextrans FD; 4.4, 10, and 70kDa. In addition, TGF-b1-induced apoptosis and necrosis were evaluated by flow cytometry using Annexin V and ethidium homodimer III, respectively. RESULTS: In NCI-H441 cells, incomplete EMT, destruction of claudins-1 and -3, and enhancement of FD permeability were caused by TGF-b1 treatment. In A549 cells, complete EMT occurred but was not adequate for transport experiments because of low transepithelial electrical resistance. Whereas in Calu-3 cells, no changes were observed. TGF-b1-induced apoptosis and necrosis were not observed in any of the cell lines. DISCUSSION: Incomplete EMT and permeability enhancement were observed in the alveolar epithelium of <d>IPF</d>. Therefore, our results indicate that TGF-b1-treated NCI-H441 cell monolayers may serve as a useful in vitro model of respiratory epithelial cells for <d>IPF</d>.
28259823|a|INTRODUCTION: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a lethal <d>lung disease</d>, which is accompanied by changes in lung structure. With regard to treatment, aerosolized drugs administered intrapulmonarily are rapidly distributed into the plasma and do not remain in the lungs due to damage to the alveolar epithelium that occurs from <d>pulmonary fibrosis</d>. In this study, we sought to develop an in vitro model of respiratory epithelial cells in <d>IPF</d> for the evaluation of the intrapulmonary distribution of aerosolized drugs. We investigated transforming growth factor TGF-b1-induced epithelial-mesenchymal transition EMT and permeability alteration in A549, NCI-H441, and Calu-3 cell monolayers. METHODS: After TGF-b1 treatment of A549, NCI-H441, and Calu-3 cells, EMT markers including E-cadherin and vimentin and tight junction proteins including claudins-1, -3, and -5 were stained using immunofluorescence methods and detected using immunoblotting methods. Transport experiments were performed using TGF-b1-treated cell monolayers and fluorescein isothiocyanate dextrans FD; 4.4, 10, and 70kDa. In addition, TGF-b1-induced apoptosis and necrosis were evaluated by flow cytometry using Annexin V and ethidium homodimer III, respectively. RESULTS: In NCI-H441 cells, incomplete EMT, destruction of claudins-1 and -3, and enhancement of FD permeability were caused by TGF-b1 treatment. In A549 cells, complete EMT occurred but was not adequate for transport experiments because of low transepithelial electrical resistance. Whereas in Calu-3 cells, no changes were observed. TGF-b1-induced apoptosis and necrosis were not observed in any of the cell lines. DISCUSSION: Incomplete EMT and permeability enhancement were observed in the alveolar epithelium of <d>IPF</d>. Therefore, our results indicate that TGF-b1-treated NCI-H441 cell monolayers may serve as a useful in vitro model of respiratory epithelial cells for <d>IPF</d>.
28259823|a|INTRODUCTION: <d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a lethal <d>lung disease</d>, which is accompanied by changes in lung structure. With regard to treatment, aerosolized drugs administered intrapulmonarily are rapidly distributed into the plasma and do not remain in the lungs due to damage to the alveolar epithelium that occurs from <d>pulmonary fibrosis</d>. In this study, we sought to develop an in vitro model of respiratory epithelial cells in <d>IPF</d> for the evaluation of the intrapulmonary distribution of aerosolized drugs. We investigated transforming growth factor <g>TGF-b1</g>-induced epithelial-mesenchymal transition EMT and permeability alteration in A549, NCI-H441, and Calu-3 cell monolayers. METHODS: After <g>TGF-b1</g> treatment of A549, NCI-H441, and Calu-3 cells, EMT markers including <g>E-cadherin</g> and <g>vimentin</g> and tight junction proteins including <g>claudins-1, -3, and -5</g> were stained using immunofluorescence methods and detected using immunoblotting methods. Transport experiments were performed using <g>TGF-b1</g>-treated cell monolayers and fluorescein isothiocyanate dextrans FD; 4.4, 10, and 70kDa. In addition, <g>TGF-b1</g>-induced apoptosis and <d>necrosis</d> were evaluated by flow cytometry using Annexin V and ethidium homodimer III, respectively. RESULTS: In NCI-H441 cells, incomplete EMT, destruction of claudins-1 and -3, and enhancement of FD permeability were caused by <g>TGF-b1</g> treatment. In A549 cells, complete EMT occurred but was not adequate for transport experiments because of low transepithelial electrical resistance. Whereas in Calu-3 cells, no changes were observed. <g>TGF-b1</g>-induced apoptosis and <d>necrosis</d> were not observed in any of the cell lines. DISCUSSION: Incomplete EMT and permeability enhancement were observed in the alveolar epithelium of <d>IPF</d>. Therefore, our results indicate that <g>TGF-b1</g>-treated NCI-H441 cell monolayers may serve as a useful in vitro model of respiratory epithelial cells for <d>IPF</d>.
28292882|a|Idiopathic pulmonary <d>fibrosis</d> IPF involves collagen deposition that results in a progressive decline in lung function. This process involves activation of Smad2/3 by transforming growth factor TGF-b and Wnt signaling pathways. Collagen Triple Helix Repeat-Containing-1 <g>Cthrc1</g> protein inhibits Smad2/3 activation. To test the hypothesis that <g>Cthrc1</g> limits collagen deposition and the decline of lung function, <g>Cthrc1</g> knockout <g>Cthrc1</g>-/- and wild-type mice WT received intratracheal injections of 2.5  U/kg bleomycin or saline. Lungs were harvested after 14  days and Bronchoalveolar lavage BAL TGF-b, IL1-b, hydroxyproline and lung compliance were assessed. TGF-b was significantly higher in <g>Cthrc1</g>-/- compared to WT 53.45      6.15  ng/mL vs. 34.48      11.05 after saline injection. Bleomycin injection increased TGF-b in both <g>Cthrc1</g>-/- 66.37      8.54  ng/mL and WT 63.64      8.09  ng/mL. Hydroxyproline was significantly higher in <g>Cthrc1</g>-/- compared to WT after bleomycin-injection 2.676      0.527   g/mg vs. 1.889      0.520, P  =  0.028. Immunohistochemistry of <g>Cthrc1</g>-/- lung sections showed intracellular localization and activation of b-catenin Y654 in areas of tissue remodeling that was not evident in WT Lung compliance was significantly reduced by bleomycin in <g>Cthrc1</g>-/- but there was no effect in WT animals. These data suggest <g>Cthrc1</g> reduces fibrotic tissue formation in bleomycin-induced lung <d>fibrosis</d> and the effect is potent enough to limit the decline in lung function. We conclude that <g>Cthrc1</g> plays a protective role, limiting collagen deposition and could form the basis of a novel therapy for pulmonary <d>fibrosis</d>.
28292882|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> involves collagen deposition that results in a progressive decline in lung function. This process involves activation of Smad2/3 by transforming growth factor TGF-b and Wnt signaling pathways. Collagen Triple Helix Repeat-Containing-1 <g>Cthrc1</g> protein inhibits Smad2/3 activation. To test the hypothesis that <g>Cthrc1</g> limits collagen deposition and the decline of lung function, <g>Cthrc1</g> knockout <g>Cthrc1</g>-/- and wild-type mice WT received intratracheal injections of 2.5  U/kg bleomycin or saline. Lungs were harvested after 14  days and Bronchoalveolar lavage BAL TGF-b, IL1-b, hydroxyproline and lung compliance were assessed. TGF-b was significantly higher in <g>Cthrc1</g>-/- compared to WT 53.45      6.15  ng/mL vs. 34.48      11.05 after saline injection. Bleomycin injection increased TGF-b in both <g>Cthrc1</g>-/- 66.37      8.54  ng/mL and WT 63.64      8.09  ng/mL. Hydroxyproline was significantly higher in <g>Cthrc1</g>-/- compared to WT after bleomycin-injection 2.676      0.527   g/mg vs. 1.889      0.520, P  =  0.028. Immunohistochemistry of <g>Cthrc1</g>-/- lung sections showed intracellular localization and activation of b-catenin Y654 in areas of tissue remodeling that was not evident in WT Lung compliance was significantly reduced by bleomycin in <g>Cthrc1</g>-/- but there was no effect in WT animals. These data suggest <g>Cthrc1</g> reduces fibrotic tissue formation in bleomycin-induced lung <d>fibrosis</d> and the effect is potent enough to limit the decline in lung function. We conclude that <g>Cthrc1</g> plays a protective role, limiting collagen deposition and could form the basis of a novel therapy for pulmonary <d>fibrosis</d>.
28292882|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> involves collagen deposition that results in a progressive <d>decline in lung function</d>. This process involves activation of Smad2/3 by transforming growth factor TGF-b and Wnt signaling pathways. Collagen Triple Helix Repeat-Containing-1 <g>Cthrc1</g> protein inhibits Smad2/3 activation. To test the hypothesis that <g>Cthrc1</g> limits collagen deposition and the decline of lung function, <g>Cthrc1</g> knockout <g>Cthrc1</g>-/- and wild-type mice WT received intratracheal injections of 2.5  U/kg bleomycin or saline. Lungs were harvested after 14  days and Bronchoalveolar lavage BAL TGF-b, IL1-b, hydroxyproline and lung compliance were assessed. TGF-b was significantly higher in <g>Cthrc1</g>-/- compared to WT 53.45      6.15  ng/mL vs. 34.48      11.05 after saline injection. Bleomycin injection increased TGF-b in both <g>Cthrc1</g>-/- 66.37      8.54  ng/mL and WT 63.64      8.09  ng/mL. Hydroxyproline was significantly higher in <g>Cthrc1</g>-/- compared to WT after bleomycin-injection 2.676      0.527   g/mg vs. 1.889      0.520, P  =  0.028. Immunohistochemistry of <g>Cthrc1</g>-/- lung sections showed intracellular localization and activation of b-catenin Y654 in areas of tissue remodeling that was not evident in WT Lung compliance was significantly reduced by bleomycin in <g>Cthrc1</g>-/- but there was no effect in WT animals. These data suggest <g>Cthrc1</g> reduces fibrotic tissue formation in bleomycin-induced lung <d>fibrosis</d> and the effect is potent enough to limit the <d>decline in lung function</d>. We conclude that <g>Cthrc1</g> plays a protective role, limiting collagen deposition and could form the basis of a novel therapy for pulmonary <d>fibrosis</d>.
28292882|a|Idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> involves collagen deposition that results in a progressive <d>decline in lung function</d>. This process involves activation of <g>Smad2/3</g> by transforming growth factor TGF-b and Wnt signaling pathways. <g>Collagen Triple Helix Repeat-Containing-1</g> <g>Cthrc1</g> protein inhibits <g>Smad2/3</g> activation. To test the hypothesis that <g>Cthrc1</g> limits collagen deposition and the decline of lung function, <g>Cthrc1</g> knockout <g>Cthrc1</g>-/- and wild-type mice <d>WT</d> received intratracheal injections of 2.5  U/kg bleomycin or saline. Lungs were harvested after 14  days and Bronchoalveolar lavage BAL TGF-b, IL1-b, hydroxyproline and lung compliance were assessed. TGF-b was significantly higher in <g>Cthrc1</g>-/- compared to <d>WT</d> 53.45      6.15  ng/mL vs. 34.48      11.05 after saline injection. Bleomycin injection increased TGF-b in both <g>Cthrc1</g>-/- 66.37      8.54  ng/mL and <d>WT</d> 63.64      8.09  ng/mL. Hydroxyproline was significantly higher in <g>Cthrc1</g>-/- compared to <d>WT</d> after bleomycin-injection 2.676      0.527   g/mg vs. 1.889      0.520, P  =  0.028. Immunohistochemistry of <g>Cthrc1</g>-/- lung sections showed intracellular localization and activation of b-catenin Y654 in areas of tissue remodeling that was not evident in <d>WT</d> Lung compliance was significantly reduced by bleomycin in <g>Cthrc1</g>-/- but there was no effect in <d>WT</d> animals. These data suggest <g>Cthrc1</g> reduces fibrotic tissue formation in bleomycin-induced lung <d>fibrosis</d> and the effect is potent enough to limit the <d>decline in lung function</d>. We conclude that <g>Cthrc1</g> plays a protective role, limiting collagen deposition and could form the basis of a novel therapy for pulmonary <d>fibrosis</d>.
28314802|a|IPF is a devastating chronic interstitial lung disease ILD characterized by lung tissue scarring and high morbidity. Lung epithelial injury, myofibroblast activation, and deranged repair are believed to be key processes involved in disease onset and progression but the exact molecular mechanisms behind IPF remain unclear. Several drugs have been shown to slow disease progression, but treatments which halt or reverse IPF progression have not been identified. Ex vivo models of human lung have been proposed for drug discovery, one of which is precision-cut lung slices PCLS. Although PCLS production from IPF explants is possible, IPF explants are rare and typically represent end-stage disease. Here we present a novel model of early <d>fibrosis</d>-like changes in human PCLS derived from patients without ILD/IPF using a combination of profibrotic growth factors and signaling molecules. Fibrotic-like changes of PCLS were qualitatively analyzed by histology and immunofluorescence and quantitatively by WST1, RT-qPCR, WB, and ELISA. PCLS remained viable after 5 days of treatment and fibrotic gene expression FN1, SERPINE1, COL1A1, CTGF, MMP7 and ACTA2 increased as early as 24h of treatment, with increases in protein levels at 48 hours and increased deposition of extracellular matrix. Alveolar epithelium reprogramming was evident by decreases in SFTPC and loss of HOPX In summary, using human-derived PCLS from patients without ILD/IPF, we established a novel ex vivo model which displays characteristics of early <d>fibrosis</d> and could be used to evaluate novel therapies and study early-stage IPF pathomechanisms.
28314802|a|<d>IPF</d> is a devastating chronic interstitial lung disease ILD characterized by lung tissue scarring and high morbidity. Lung epithelial injury, myofibroblast activation, and deranged repair are believed to be key processes involved in disease onset and progression but the exact molecular mechanisms behind <d>IPF</d> remain unclear. Several drugs have been shown to slow disease progression, but treatments which halt or reverse <d>IPF</d> progression have not been identified. Ex vivo models of human lung have been proposed for drug discovery, one of which is precision-cut lung slices PCLS. Although PCLS production from <d>IPF</d> explants is possible, <d>IPF</d> explants are rare and typically represent end-stage disease. Here we present a novel model of early <d>fibrosis</d>-like changes in human PCLS derived from patients without ILD/<d>IPF</d> using a combination of profibrotic growth factors and signaling molecules. Fibrotic-like changes of PCLS were qualitatively analyzed by histology and immunofluorescence and quantitatively by WST1, RT-qPCR, WB, and ELISA. PCLS remained viable after 5 days of treatment and fibrotic gene expression FN1, SERPINE1, COL1A1, CTGF, MMP7 and ACTA2 increased as early as 24h of treatment, with increases in protein levels at 48 hours and increased deposition of extracellular matrix. Alveolar epithelium reprogramming was evident by decreases in SFTPC and loss of HOPX In summary, using human-derived PCLS from patients without ILD/<d>IPF</d>, we established a novel ex vivo model which displays characteristics of early <d>fibrosis</d> and could be used to evaluate novel therapies and study early-stage <d>IPF</d> pathomechanisms.
28314802|a|<d>IPF</d> is a devastating chronic <d>interstitial lung disease</d> ILD characterized by lung tissue scarring and high morbidity. Lung epithelial injury, myofibroblast activation, and deranged repair are believed to be key processes involved in disease onset and progression but the exact molecular mechanisms behind <d>IPF</d> remain unclear. Several drugs have been shown to slow disease progression, but treatments which halt or reverse <d>IPF</d> progression have not been identified. Ex vivo models of human lung have been proposed for drug discovery, one of which is precision-cut lung slices PCLS. Although PCLS production from <d>IPF</d> explants is possible, <d>IPF</d> explants are rare and typically represent end-stage disease. Here we present a novel model of early <d>fibrosis</d>-like changes in human PCLS derived from patients without ILD/<d>IPF</d> using a combination of profibrotic growth factors and signaling molecules. Fibrotic-like changes of PCLS were qualitatively analyzed by histology and immunofluorescence and quantitatively by WST1, RT-qPCR, WB, and ELISA. PCLS remained viable after 5 days of treatment and fibrotic gene expression FN1, SERPINE1, COL1A1, CTGF, MMP7 and ACTA2 increased as early as 24h of treatment, with increases in protein levels at 48 hours and increased deposition of extracellular matrix. Alveolar epithelium reprogramming was evident by decreases in SFTPC and loss of HOPX In summary, using human-derived PCLS from patients without ILD/<d>IPF</d>, we established a novel ex vivo model which displays characteristics of early <d>fibrosis</d> and could be used to evaluate novel therapies and study early-stage <d>IPF</d> pathomechanisms.
28314802|a|<d>IPF</d> is a devastating chronic <d>interstitial lung disease</d> <d>ILD</d> characterized by lung tissue scarring and high morbidity. Lung epithelial injury, myofibroblast activation, and deranged repair are believed to be key processes involved in disease onset and progression but the exact molecular mechanisms behind <d>IPF</d> remain unclear. Several drugs have been shown to slow disease progression, but treatments which halt or reverse <d>IPF</d> progression have not been identified. Ex vivo models of human lung have been proposed for drug discovery, one of which is precision-cut lung slices PCLS. Although PCLS production from <d>IPF</d> explants is possible, <d>IPF</d> explants are rare and typically represent end-stage disease. Here we present a novel model of early <d>fibrosis</d>-like changes in human PCLS derived from patients without <d>ILD</d>/<d>IPF</d> using a combination of profibrotic growth factors and signaling molecules. Fibrotic-like changes of PCLS were qualitatively analyzed by histology and immunofluorescence and quantitatively by WST1, RT-qPCR, WB, and ELISA. PCLS remained viable after 5 days of treatment and fibrotic gene expression FN1, SERPINE1, COL1A1, CTGF, MMP7 and ACTA2 increased as early as 24h of treatment, with increases in protein levels at 48 hours and increased deposition of extracellular matrix. Alveolar epithelium reprogramming was evident by decreases in SFTPC and loss of HOPX In summary, using human-derived PCLS from patients without <d>ILD</d>/<d>IPF</d>, we established a novel ex vivo model which displays characteristics of early <d>fibrosis</d> and could be used to evaluate novel therapies and study early-stage <d>IPF</d> pathomechanisms.
28360109|a|Alveolar epithelial cell AEC <d>injury and apoptosis</d> are prominent pathological features of idiopathic pulmonary fibrosis IPF. There is evidence of AEC plasticity in lung injury repair response and in IPF. In this report, we explore the role of focal adhesion kinase FAK signaling in determining the fate of lung epithelial cells in response to transforming growth factor-b1 <g>TGF-b</g>1. Rat type II alveolar epithelial cells RLE-6TN were treated with or without <g>TGF-b</g>1, and the expressions of mesenchymal markers, phenotype, and function were analyzed. Pharmacological protein kinase inhibitors were utilized to screen for SMAD-dependent and -independent pathways. SMAD and FAK signaling was analyzed using siRNA knockdown, inhibitors, and expression of a mutant construct of FAK. Apoptosis was measured using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL staining. <g>TGF-b</g>1 induced the acquisition of mesenchymal markers, including a-smooth muscle actin, in RLE-6TN cells and enhanced the contraction of three-dimensional collagen gels. This phenotypical transition or plasticity, epithelial-myofibroblast plasticity EMP, is dependent on SMAD3 and FAK signaling. FAK activation was found to be dependent on ALK5/SMAD3 signaling. We observed that <g>TGF-b</g>1 induces both EMP and apoptosis in the same cell culture system but not in the same cell. While blockade of SMAD signaling inhibited EMP, it had a minimal effect on apoptosis; in contrast, inhibition of FAK signaling markedly shifted to an apoptotic fate. The data support that FAK activation determines whether AECs undergo EMP vs. apoptosis in response to <g>TGF-b</g>1 stimulation. <g>TGF-b</g>1-induced EMP is FAK- dependent, whereas <g>TGF-b</g>1-induced apoptosis is favored when FAK signaling is inhibited.
28360109|a|Alveolar epithelial cell AEC <d>injury and apoptosis</d> are prominent pathological features of <d>idiopathic pulmonary fibrosis</d> IPF. There is evidence of AEC plasticity in lung injury repair response and in IPF. In this report, we explore the role of focal adhesion kinase FAK signaling in determining the fate of lung epithelial cells in response to transforming growth factor-b1 <g>TGF-b</g>1. Rat type II alveolar epithelial cells RLE-6TN were treated with or without <g>TGF-b</g>1, and the expressions of mesenchymal markers, phenotype, and function were analyzed. Pharmacological protein kinase inhibitors were utilized to screen for SMAD-dependent and -independent pathways. SMAD and FAK signaling was analyzed using siRNA knockdown, inhibitors, and expression of a mutant construct of FAK. Apoptosis was measured using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL staining. <g>TGF-b</g>1 induced the acquisition of mesenchymal markers, including a-smooth muscle actin, in RLE-6TN cells and enhanced the contraction of three-dimensional collagen gels. This phenotypical transition or plasticity, epithelial-myofibroblast plasticity EMP, is dependent on SMAD3 and FAK signaling. FAK activation was found to be dependent on ALK5/SMAD3 signaling. We observed that <g>TGF-b</g>1 induces both EMP and apoptosis in the same cell culture system but not in the same cell. While blockade of SMAD signaling inhibited EMP, it had a minimal effect on apoptosis; in contrast, inhibition of FAK signaling markedly shifted to an apoptotic fate. The data support that FAK activation determines whether AECs undergo EMP vs. apoptosis in response to <g>TGF-b</g>1 stimulation. <g>TGF-b</g>1-induced EMP is FAK- dependent, whereas <g>TGF-b</g>1-induced apoptosis is favored when FAK signaling is inhibited.
28360109|a|Alveolar epithelial cell AEC <d>injury and apoptosis</d> are prominent pathological features of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. There is evidence of AEC plasticity in lung injury repair response and in <d>IPF</d>. In this report, we explore the role of focal adhesion kinase FAK signaling in determining the fate of lung epithelial cells in response to transforming growth factor-b1 <g>TGF-b</g>1. Rat type II alveolar epithelial cells RLE-6TN were treated with or without <g>TGF-b</g>1, and the expressions of mesenchymal markers, phenotype, and function were analyzed. Pharmacological protein kinase inhibitors were utilized to screen for SMAD-dependent and -independent pathways. SMAD and FAK signaling was analyzed using siRNA knockdown, inhibitors, and expression of a mutant construct of FAK. Apoptosis was measured using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL staining. <g>TGF-b</g>1 induced the acquisition of mesenchymal markers, including a-smooth muscle actin, in RLE-6TN cells and enhanced the contraction of three-dimensional collagen gels. This phenotypical transition or plasticity, epithelial-myofibroblast plasticity EMP, is dependent on SMAD3 and FAK signaling. FAK activation was found to be dependent on ALK5/SMAD3 signaling. We observed that <g>TGF-b</g>1 induces both EMP and apoptosis in the same cell culture system but not in the same cell. While blockade of SMAD signaling inhibited EMP, it had a minimal effect on apoptosis; in contrast, inhibition of FAK signaling markedly shifted to an apoptotic fate. The data support that FAK activation determines whether AECs undergo EMP vs. apoptosis in response to <g>TGF-b</g>1 stimulation. <g>TGF-b</g>1-induced EMP is FAK- dependent, whereas <g>TGF-b</g>1-induced apoptosis is favored when FAK signaling is inhibited.
28360109|a|Alveolar epithelial cell AEC <d>injury and apoptosis</d> are prominent pathological features of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. There is evidence of AEC plasticity in <d>lung injury</d> repair response and in <d>IPF</d>. In this report, we explore the role of focal adhesion kinase FAK signaling in determining the fate of lung epithelial cells in response to transforming growth factor-b1 <g>TGF-b</g>1. Rat type II alveolar epithelial cells RLE-6TN were treated with or without <g>TGF-b</g>1, and the expressions of mesenchymal markers, phenotype, and function were analyzed. Pharmacological protein kinase inhibitors were utilized to screen for SMAD-dependent and -independent pathways. SMAD and FAK signaling was analyzed using siRNA knockdown, inhibitors, and expression of a mutant construct of FAK. Apoptosis was measured using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL staining. <g>TGF-b</g>1 induced the acquisition of mesenchymal markers, including a-smooth muscle actin, in RLE-6TN cells and enhanced the contraction of three-dimensional collagen gels. This phenotypical transition or plasticity, epithelial-myofibroblast plasticity EMP, is dependent on SMAD3 and FAK signaling. FAK activation was found to be dependent on ALK5/SMAD3 signaling. We observed that <g>TGF-b</g>1 induces both EMP and apoptosis in the same cell culture system but not in the same cell. While blockade of SMAD signaling inhibited EMP, it had a minimal effect on apoptosis; in contrast, inhibition of FAK signaling markedly shifted to an apoptotic fate. The data support that FAK activation determines whether AECs undergo EMP vs. apoptosis in response to <g>TGF-b</g>1 stimulation. <g>TGF-b</g>1-induced EMP is FAK- dependent, whereas <g>TGF-b</g>1-induced apoptosis is favored when FAK signaling is inhibited.
28360109|a|Alveolar epithelial cell AEC <d>injury and apoptosis</d> are prominent pathological features of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. There is evidence of AEC plasticity in <d>lung injury</d> repair response and in <d>IPF</d>. In this report, we explore the role of <g>focal adhesion kinase</g> <g>FAK</g> signaling in determining the fate of lung epithelial cells in response to <g>transforming growth factor-b1</g> <g>TGF-b</g>1. Rat type II alveolar epithelial cells RLE-6TN were treated with or without <g>TGF-b</g>1, and the expressions of mesenchymal markers, phenotype, and function were analyzed. Pharmacological protein kinase inhibitors were utilized to screen for SMAD-dependent and -independent pathways. SMAD and <g>FAK</g> signaling was analyzed using siRNA knockdown, inhibitors, and expression of a mutant construct of <g>FAK</g>. Apoptosis was measured using cleaved caspase-3 and <g>terminal deoxynucleotidyl transferase</g> dUTP nick end labeling TUNEL staining. <g>TGF-b</g>1 induced the acquisition of mesenchymal markers, including a-smooth muscle actin, in RLE-6TN cells and enhanced the contraction of three-dimensional collagen gels. This phenotypical transition or plasticity, <d>epithelial-myofibroblast plasticity</d> EMP, is dependent on SMAD3 and <g>FAK</g> signaling. <g>FAK</g> activation was found to be dependent on ALK5/SMAD3 signaling. We observed that <g>TGF-b</g>1 induces both EMP and apoptosis in the same cell culture system but not in the same cell. While blockade of SMAD signaling inhibited EMP, it had a minimal effect on apoptosis; in contrast, inhibition of <g>FAK</g> signaling markedly shifted to an apoptotic fate. The data support that <g>FAK</g> activation determines whether AECs undergo EMP vs. apoptosis in response to <g>TGF-b</g>1 stimulation. <g>TGF-b</g>1-induced EMP is <g>FAK</g>- dependent, whereas <g>TGF-b</g>1-induced apoptosis is favored when <g>FAK</g> signaling is inhibited.
28360109|a|Alveolar epithelial cell AEC <d>injury and apoptosis</d> are prominent pathological features of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. There is evidence of AEC plasticity in <d>lung injury</d> repair response and in <d>IPF</d>. In this report, we explore the role of <g>focal adhesion kinase</g> <g>FAK</g> signaling in determining the fate of lung epithelial cells in response to <g>transforming growth factor-b1</g> <g>TGF-b</g>1. Rat type II alveolar epithelial cells RLE-6TN were treated with or without <g>TGF-b</g>1, and the expressions of mesenchymal markers, phenotype, and function were analyzed. Pharmacological protein kinase inhibitors were utilized to screen for SMAD-dependent and -independent pathways. SMAD and <g>FAK</g> signaling was analyzed using siRNA knockdown, inhibitors, and expression of a mutant construct of <g>FAK</g>. Apoptosis was measured using cleaved caspase-3 and <g>terminal deoxynucleotidyl transferase</g> dUTP nick end labeling TUNEL staining. <g>TGF-b</g>1 induced the acquisition of mesenchymal markers, including a-smooth muscle actin, in RLE-6TN cells and enhanced the contraction of three-dimensional collagen gels. This phenotypical transition or plasticity, <d>epithelial-myofibroblast plasticity</d> <d>EMP</d>, is dependent on SMAD3 and <g>FAK</g> signaling. <g>FAK</g> activation was found to be dependent on ALK5/SMAD3 signaling. We observed that <g>TGF-b</g>1 induces both <d>EMP</d> and apoptosis in the same cell culture system but not in the same cell. While blockade of SMAD signaling inhibited <d>EMP</d>, it had a minimal effect on apoptosis; in contrast, inhibition of <g>FAK</g> signaling markedly shifted to an apoptotic fate. The data support that <g>FAK</g> activation determines whether AECs undergo <d>EMP</d> vs. apoptosis in response to <g>TGF-b</g>1 stimulation. <g>TGF-b</g>1-induced <d>EMP</d> is <g>FAK</g>- dependent, whereas <g>TGF-b</g>1-induced apoptosis is favored when <g>FAK</g> signaling is inhibited.
28389561|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblast phenotype has prevented the development of targeted therapies for IPF. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 CD44 variant containing exon 6, which enhances the <g>TGFb1</g> autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. NADPH oxidase 4 <g>NOX4</g> enzyme, which catalyzes the reduction of O2 to hydrogen peroxide H2O2, has been implicated in the cardiac and lung myofibroblast phenotype. However, whether CD44V6 regulates <g>NOX4</g> to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how TGF-b-1-induced CD44V6 regulates the <g>NOX4</g>/reactive oxygen species ROS signaling that mediates the myofibroblast differentiation. Specifically, we found that <g>NOX4</g>/ROS regulates hyaluronan synthesis and the transcription of CD44V6 via an effect upon AP-1 activity. Further, CD44V6 is part of a positive-feedback loop with <g>TGFb1</g>/TGFbRI signaling that acts to increase <g>NOX4</g>/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both <g>NOX4</g> and CD44v6 are up-regulated in the lungs of mice subjected to experimental lung injury and in cases of human IPF. Genetic CD44v6 shRNA or a small molecule inhibitor CD44v6 peptide targeting of CD44v6 abrogates fibrogenesis in murine models of lung injury. These studies support a function for CD44V6 in lung fibrosis and offer proof of concept for therapeutic targeting of CD44V6 in lung fibrosis disorders.
28389561|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblast phenotype has prevented the development of targeted therapies for <d>IPF</d>. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 CD44 variant containing exon 6, which enhances the <g>TGFb1</g> autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. NADPH oxidase 4 <g>NOX4</g> enzyme, which catalyzes the reduction of O2 to hydrogen peroxide H2O2, has been implicated in the cardiac and lung myofibroblast phenotype. However, whether CD44V6 regulates <g>NOX4</g> to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how TGF-b-1-induced CD44V6 regulates the <g>NOX4</g>/reactive oxygen species ROS signaling that mediates the myofibroblast differentiation. Specifically, we found that <g>NOX4</g>/ROS regulates hyaluronan synthesis and the transcription of CD44V6 via an effect upon AP-1 activity. Further, CD44V6 is part of a positive-feedback loop with <g>TGFb1</g>/TGFbRI signaling that acts to increase <g>NOX4</g>/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both <g>NOX4</g> and CD44v6 are up-regulated in the lungs of mice subjected to experimental lung injury and in cases of human <d>IPF</d>. Genetic CD44v6 shRNA or a small molecule inhibitor CD44v6 peptide targeting of CD44v6 abrogates fibrogenesis in murine models of lung injury. These studies support a function for CD44V6 in lung fibrosis and offer proof of concept for therapeutic targeting of CD44V6 in lung fibrosis disorders.
28389561|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain <d>fibrosis</d> and the myofibroblast phenotype has prevented the development of targeted therapies for <d>IPF</d>. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 CD44 variant containing exon 6, which enhances the <g>TGFb1</g> autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. NADPH oxidase 4 <g>NOX4</g> enzyme, which catalyzes the reduction of O2 to hydrogen peroxide H2O2, has been implicated in the cardiac and lung myofibroblast phenotype. However, whether CD44V6 regulates <g>NOX4</g> to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how TGF-b-1-induced CD44V6 regulates the <g>NOX4</g>/reactive oxygen species ROS signaling that mediates the myofibroblast differentiation. Specifically, we found that <g>NOX4</g>/ROS regulates hyaluronan synthesis and the transcription of CD44V6 via an effect upon AP-1 activity. Further, CD44V6 is part of a positive-feedback loop with <g>TGFb1</g>/TGFbRI signaling that acts to increase <g>NOX4</g>/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both <g>NOX4</g> and CD44v6 are up-regulated in the lungs of mice subjected to experimental lung injury and in cases of human <d>IPF</d>. Genetic CD44v6 shRNA or a small molecule inhibitor CD44v6 peptide targeting of CD44v6 abrogates fibrogenesis in murine models of lung injury. These studies support a function for CD44V6 in lung <d>fibrosis</d> and offer proof of concept for therapeutic targeting of CD44V6 in lung <d>fibrosis</d> disorders.
28389561|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain <d>fibrosis</d> and the myofibroblast phenotype has prevented the development of targeted therapies for <d>IPF</d>. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, <g>CD44</g>V6 <g>CD44</g> variant containing exon 6, which enhances the <g>TGFb1</g> autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. <g>NADPH oxidase 4</g> <g>NOX4</g> enzyme, which catalyzes the reduction of O2 to hydrogen peroxide H2O2, has been implicated in the cardiac and lung myofibroblast phenotype. However, whether <g>CD44</g>V6 regulates <g>NOX4</g> to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how <g>TGF-b-1</g>-induced <g>CD44</g>V6 regulates the <g>NOX4</g>/reactive oxygen species ROS signaling that mediates the myofibroblast differentiation. Specifically, we found that <g>NOX4</g>/ROS regulates hyaluronan synthesis and the transcription of <g>CD44</g>V6 via an effect upon AP-1 activity. Further, <g>CD44</g>V6 is part of a positive-feedback loop with <g>TGFb1</g>/TGFbRI signaling that acts to increase <g>NOX4</g>/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both <g>NOX4</g> and <g>CD44</g>v6 are up-regulated in the lungs of mice subjected to experimental <d>lung injury</d> and in cases of human <d>IPF</d>. Genetic <g>CD44</g>v6 shRNA or a small molecule inhibitor <g>CD44</g>v6 peptide targeting of <g>CD44</g>v6 abrogates fibrogenesis in murine models of <d>lung injury</d>. These studies support a function for <g>CD44</g>V6 in lung <d>fibrosis</d> and offer proof of concept for therapeutic targeting of <g>CD44</g>V6 in lung <d>fibrosis</d> disorders.
28446589|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic lung disorder that is characterized by aberrant tissue remodeling and the formation of fibroblastic foci that are composed of fibrogenic myofibroblasts. <g>TGF-b1</g> is one of the factors that are responsible for fibrosis as it promotes fibroblast to myofibroblast differentiation FMD and is associated with up-regulation of a-smooth muscle actin. Therefore, inhibition of FMD may represent an effective strategy for the treatment of IPF. Here, we describe the treatment of human lung fibroblasts WI-38 and HFL-1 cells with <g>cyclosporine A</g> CsA, which reduces <g>TGF-b1</g>-induced FMD via degradation of <g>hypoxia-inducible factor-1a</g> HIF-1a. In addition, in primary myofibroblast-like cells that were obtained from a patient with pulmonary fibrosis, treatment with CsA and an HIF-1a inhibitor HIFi decreased the expression levels of a-smooth muscle actin and fibronectin, which indicated that CsA and HIFi promote dedifferentiation of myofibroblasts. In mice intratracheally administered CsA or HIFi at an early fibrotic stage [7, 8, and 9 d postinstillation dpi of bleomycin], marked alleviation of lung fibrosis was observed at 14 dpi. These results suggest that CsA exhibits antifibrotic effects by degrading HIF-1a and that the CsA-HIF-1a axis provides new insights into therapeutic options for the treatment of IPF.-Yamazaki, R., Kasuya, Y., Fujita, T., Umezawa, H., Yanagihara, M., Nakamura, H., Yoshino, I., Tatsumi, K., Murayama, T. Antifibrotic effects of <g>cyclosporine A</g> on <g>TGF-b1</g>-treated lung fibroblasts and lungs from bleomycin-treated mice: role of <g>hypoxia-inducible factor-1a</g>.
28446589|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic lung disorder that is characterized by aberrant tissue remodeling and the formation of fibroblastic foci that are composed of fibrogenic myofibroblasts. <g>TGF-b1</g> is one of the factors that are responsible for fibrosis as it promotes fibroblast to myofibroblast differentiation FMD and is associated with up-regulation of a-smooth muscle actin. Therefore, inhibition of FMD may represent an effective strategy for the treatment of <d>IPF</d>. Here, we describe the treatment of human lung fibroblasts WI-38 and HFL-1 cells with <g>cyclosporine A</g> CsA, which reduces <g>TGF-b1</g>-induced FMD via degradation of <g>hypoxia-inducible factor-1a</g> HIF-1a. In addition, in primary myofibroblast-like cells that were obtained from a patient with pulmonary fibrosis, treatment with CsA and an HIF-1a inhibitor HIFi decreased the expression levels of a-smooth muscle actin and fibronectin, which indicated that CsA and HIFi promote dedifferentiation of myofibroblasts. In mice intratracheally administered CsA or HIFi at an early fibrotic stage [7, 8, and 9 d postinstillation dpi of bleomycin], marked alleviation of lung fibrosis was observed at 14 dpi. These results suggest that CsA exhibits antifibrotic effects by degrading HIF-1a and that the CsA-HIF-1a axis provides new insights into therapeutic options for the treatment of <d>IPF</d>.-Yamazaki, R., Kasuya, Y., Fujita, T., Umezawa, H., Yanagihara, M., Nakamura, H., Yoshino, I., Tatsumi, K., Murayama, T. Antifibrotic effects of <g>cyclosporine A</g> on <g>TGF-b1</g>-treated lung fibroblasts and lungs from bleomycin-treated mice: role of <g>hypoxia-inducible factor-1a</g>.
28446589|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a <d>chronic lung disorder</d> that is characterized by aberrant tissue remodeling and the formation of fibroblastic foci that are composed of fibrogenic myofibroblasts. <g>TGF-b1</g> is one of the factors that are responsible for fibrosis as it promotes fibroblast to myofibroblast differentiation FMD and is associated with up-regulation of a-smooth muscle actin. Therefore, inhibition of FMD may represent an effective strategy for the treatment of <d>IPF</d>. Here, we describe the treatment of human lung fibroblasts WI-38 and HFL-1 cells with <g>cyclosporine A</g> CsA, which reduces <g>TGF-b1</g>-induced FMD via degradation of <g>hypoxia-inducible factor-1a</g> HIF-1a. In addition, in primary myofibroblast-like cells that were obtained from a patient with pulmonary fibrosis, treatment with CsA and an HIF-1a inhibitor HIFi decreased the expression levels of a-smooth muscle actin and fibronectin, which indicated that CsA and HIFi promote dedifferentiation of myofibroblasts. In mice intratracheally administered CsA or HIFi at an early fibrotic stage [7, 8, and 9 d postinstillation dpi of bleomycin], marked alleviation of lung fibrosis was observed at 14 dpi. These results suggest that CsA exhibits antifibrotic effects by degrading HIF-1a and that the CsA-HIF-1a axis provides new insights into therapeutic options for the treatment of <d>IPF</d>.-Yamazaki, R., Kasuya, Y., Fujita, T., Umezawa, H., Yanagihara, M., Nakamura, H., Yoshino, I., Tatsumi, K., Murayama, T. Antifibrotic effects of <g>cyclosporine A</g> on <g>TGF-b1</g>-treated lung fibroblasts and lungs from bleomycin-treated mice: role of <g>hypoxia-inducible factor-1a</g>.
28446589|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>chronic lung disorder</d> that is characterized by aberrant tissue remodeling and the formation of fibroblastic foci that are composed of fibrogenic myofibroblasts. <g>TGF-b1</g> is one of the factors that are responsible for <d>fibrosis</d> as it promotes fibroblast to myofibroblast differentiation FMD and is associated with up-regulation of a-smooth muscle actin. Therefore, inhibition of FMD may represent an effective strategy for the treatment of <d>IPF</d>. Here, we describe the treatment of human lung fibroblasts WI-38 and HFL-1 cells with <g>cyclosporine A</g> CsA, which reduces <g>TGF-b1</g>-induced FMD via degradation of <g>hypoxia-inducible factor-1a</g> HIF-1a. In addition, in primary myofibroblast-like cells that were obtained from a patient with pulmonary <d>fibrosis</d>, treatment with CsA and an HIF-1a inhibitor HIFi decreased the expression levels of a-smooth muscle actin and fibronectin, which indicated that CsA and HIFi promote dedifferentiation of myofibroblasts. In mice intratracheally administered CsA or HIFi at an early fibrotic stage [7, 8, and 9 d postinstillation dpi of bleomycin], marked alleviation of lung <d>fibrosis</d> was observed at 14 dpi. These results suggest that CsA exhibits antifibrotic effects by degrading HIF-1a and that the CsA-HIF-1a axis provides new insights into therapeutic options for the treatment of <d>IPF</d>.-Yamazaki, R., Kasuya, Y., Fujita, T., Umezawa, H., Yanagihara, M., Nakamura, H., Yoshino, I., Tatsumi, K., Murayama, T. Antifibrotic effects of <g>cyclosporine A</g> on <g>TGF-b1</g>-treated lung fibroblasts and lungs from bleomycin-treated mice: role of <g>hypoxia-inducible factor-1a</g>.
28446589|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>chronic lung disorder</d> that is characterized by aberrant tissue remodeling and the formation of fibroblastic foci that are composed of fibrogenic myofibroblasts. <g>TGF-b1</g> is one of the factors that are responsible for <d>fibrosis</d> as it promotes <d>fibroblast to myofibroblast differentiation</d> FMD and is associated with up-regulation of a-smooth muscle actin. Therefore, inhibition of FMD may represent an effective strategy for the treatment of <d>IPF</d>. Here, we describe the treatment of human lung fibroblasts WI-38 and HFL-1 cells with <g>cyclosporine A</g> CsA, which reduces <g>TGF-b1</g>-induced FMD via degradation of <g>hypoxia-inducible factor-1a</g> HIF-1a. In addition, in primary myofibroblast-like cells that were obtained from a patient with pulmonary <d>fibrosis</d>, treatment with CsA and an HIF-1a inhibitor HIFi decreased the expression levels of a-smooth muscle actin and fibronectin, which indicated that CsA and HIFi promote dedifferentiation of myofibroblasts. In mice intratracheally administered CsA or HIFi at an early fibrotic stage [7, 8, and 9 d postinstillation dpi of bleomycin], marked alleviation of lung <d>fibrosis</d> was observed at 14 dpi. These results suggest that CsA exhibits antifibrotic effects by degrading HIF-1a and that the CsA-HIF-1a axis provides new insights into therapeutic options for the treatment of <d>IPF</d>.-Yamazaki, R., Kasuya, Y., Fujita, T., Umezawa, H., Yanagihara, M., Nakamura, H., Yoshino, I., Tatsumi, K., Murayama, T. Antifibrotic effects of <g>cyclosporine A</g> on <g>TGF-b1</g>-treated lung fibroblasts and lungs from bleomycin-treated mice: role of <g>hypoxia-inducible factor-1a</g>.
28446589|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a <d>chronic lung disorder</d> that is characterized by aberrant tissue remodeling and the formation of fibroblastic foci that are composed of fibrogenic myofibroblasts. <g>TGF-b1</g> is one of the factors that are responsible for <d>fibrosis</d> as it promotes <d>fibroblast to myofibroblast differentiation</d> <d>FMD</d> and is associated with up-regulation of a-smooth muscle actin. Therefore, inhibition of <d>FMD</d> may represent an effective strategy for the treatment of <d>IPF</d>. Here, we describe the treatment of human lung fibroblasts WI-38 and HFL-1 cells with <g>cyclosporine A</g> CsA, which reduces <g>TGF-b1</g>-induced <d>FMD</d> via degradation of <g>hypoxia-inducible factor-1a</g> HIF-1a. In addition, in primary myofibroblast-like cells that were obtained from a patient with pulmonary <d>fibrosis</d>, treatment with CsA and an HIF-1a inhibitor HIFi decreased the expression levels of a-smooth muscle actin and fibronectin, which indicated that CsA and HIFi promote dedifferentiation of myofibroblasts. In mice intratracheally administered CsA or HIFi at an early fibrotic stage [7, 8, and 9 d postinstillation dpi of bleomycin], marked alleviation of lung <d>fibrosis</d> was observed at 14 dpi. These results suggest that CsA exhibits antifibrotic effects by degrading HIF-1a and that the CsA-HIF-1a axis provides new insights into therapeutic options for the treatment of <d>IPF</d>.-Yamazaki, R., Kasuya, Y., Fujita, T., Umezawa, H., Yanagihara, M., Nakamura, H., Yoshino, I., Tatsumi, K., Murayama, T. Antifibrotic effects of <g>cyclosporine A</g> on <g>TGF-b1</g>-treated lung fibroblasts and lungs from bleomycin-treated mice: role of <g>hypoxia-inducible factor-1a</g>.
28455433|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a highly lethal pathological process that is characterized by inflammation, fibroblast accumulation, and excessive collagen deposition. Although <g>AKT2</g>-mediated signaling pathways modulate inflammatory responses, their role in IPF has not been defined. We report that <g>AKT2</g> deficiency Akt2-/- protected against bleomycin-induced pulmonary fibrosis and inflammation. Adoptive transfer of wild-type macrophages or administration of IL-13 to Akt2-/- mice could restore pulmonary fibrosis. In response to IL-33 treatment, Akt2-/- macrophages displayed decreased production of IL-13 and TGF-b1 and attenuated phosphorylation of FoxO3a compared with Akt2+/+ macrophages. Furthermore, the expression of IL-13 was increased by small interfering RNA knockdown of FoxO3a or in FoxO3a-deficient macrophages. By evaluating lung sections from pulmonary fibrosis patients, we found that the phosphorylation of <g>AKT2</g> and FoxO3a was remarkably upregulated. Collectively, these results indicate that <g>AKT2</g> modulates pulmonary fibrosis through inducing TGF-b1 and IL-13 production by macrophages, and inhibition of <g>AKT2</g> may be a potential strategy for treating IPF.
28455433|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a highly lethal pathological process that is characterized by inflammation, fibroblast accumulation, and excessive collagen deposition. Although <g>AKT2</g>-mediated signaling pathways modulate inflammatory responses, their role in <d>IPF</d> has not been defined. We report that <g>AKT2</g> deficiency Akt2-/- protected against bleomycin-induced pulmonary fibrosis and inflammation. Adoptive transfer of wild-type macrophages or administration of IL-13 to Akt2-/- mice could restore pulmonary fibrosis. In response to IL-33 treatment, Akt2-/- macrophages displayed decreased production of IL-13 and TGF-b1 and attenuated phosphorylation of FoxO3a compared with Akt2+/+ macrophages. Furthermore, the expression of IL-13 was increased by small interfering RNA knockdown of FoxO3a or in FoxO3a-deficient macrophages. By evaluating lung sections from pulmonary fibrosis patients, we found that the phosphorylation of <g>AKT2</g> and FoxO3a was remarkably upregulated. Collectively, these results indicate that <g>AKT2</g> modulates pulmonary fibrosis through inducing TGF-b1 and IL-13 production by macrophages, and inhibition of <g>AKT2</g> may be a potential strategy for treating <d>IPF</d>.
28455433|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a highly lethal pathological process that is characterized by <d>inflammation</d>, fibroblast accumulation, and excessive collagen deposition. Although <g>AKT2</g>-mediated signaling pathways modulate inflammatory responses, their role in <d>IPF</d> has not been defined. We report that <g>AKT2</g> deficiency Akt2-/- protected against bleomycin-induced pulmonary fibrosis and <d>inflammation</d>. Adoptive transfer of wild-type macrophages or administration of IL-13 to Akt2-/- mice could restore pulmonary fibrosis. In response to IL-33 treatment, Akt2-/- macrophages displayed decreased production of IL-13 and TGF-b1 and attenuated phosphorylation of FoxO3a compared with Akt2+/+ macrophages. Furthermore, the expression of IL-13 was increased by small interfering RNA knockdown of FoxO3a or in FoxO3a-deficient macrophages. By evaluating lung sections from pulmonary fibrosis patients, we found that the phosphorylation of <g>AKT2</g> and FoxO3a was remarkably upregulated. Collectively, these results indicate that <g>AKT2</g> modulates pulmonary fibrosis through inducing TGF-b1 and IL-13 production by macrophages, and inhibition of <g>AKT2</g> may be a potential strategy for treating <d>IPF</d>.
28455433|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a highly lethal pathological process that is characterized by <d>inflammation</d>, fibroblast accumulation, and excessive collagen deposition. Although <g>AKT2</g>-mediated signaling pathways modulate inflammatory responses, their role in <d>IPF</d> has not been defined. We report that <g>AKT2</g> deficiency <g>Akt2</g>-/- protected against bleomycin-induced <d>pulmonary fibrosis</d> and <d>inflammation</d>. Adoptive transfer of wild-type macrophages or administration of IL-13 to <g>Akt2</g>-/- mice could restore <d>pulmonary fibrosis</d>. In response to IL-33 treatment, <g>Akt2</g>-/- macrophages displayed decreased production of IL-13 and TGF-b1 and attenuated phosphorylation of FoxO3a compared with <g>Akt2</g>+/+ macrophages. Furthermore, the expression of IL-13 was increased by small interfering RNA knockdown of FoxO3a or in FoxO3a-deficient macrophages. By evaluating lung sections from <d>pulmonary fibrosis</d> patients, we found that the phosphorylation of <g>AKT2</g> and FoxO3a was remarkably upregulated. Collectively, these results indicate that <g>AKT2</g> modulates <d>pulmonary fibrosis</d> through inducing TGF-b1 and IL-13 production by macrophages, and inhibition of <g>AKT2</g> may be a potential strategy for treating <d>IPF</d>.
28469072|a|Fibrotic lung disease, most notably idiopathic pulmonary fibrosis IPF, is thought to result from aberrant wound-healing responses to repetitive lung injury. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to <d>lung fibrosis</d> is unknown. We previously described a model in which exaggeration of vascular leak after lung injury shifts the outcome of wound-healing responses from normal repair to pathological fibrosis. Here we report that the fibrosis produced in this model is highly dependent on <g>thrombin</g> activity and its downstream signaling pathways. Direct <g>thrombin</g> inhibition with dabigatran significantly inhibited protease-activated receptor-1 PAR1 activation, integrin avb6 induction, TGF-b activation, and the development of pulmonary fibrosis in this vascular leak-dependent model. We used a potentially novel imaging method - ultashort echo time UTE lung magnetic resonance imaging MRI with the gadolinium-based, fibrin-specific probe EP-2104R - to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of <g>thrombin</g> can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/avb6/TGF-b axis or significantly protect against fibrosis. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in IPF, and the clinical availability of direct <g>thrombin</g> inhibitors that our data suggest could benefit these patients.
28469072|a|<d>Fibrotic lung disease</d>, most notably idiopathic pulmonary fibrosis IPF, is thought to result from aberrant wound-healing responses to repetitive lung injury. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to <d>lung fibrosis</d> is unknown. We previously described a model in which exaggeration of vascular leak after lung injury shifts the outcome of wound-healing responses from normal repair to pathological fibrosis. Here we report that the fibrosis produced in this model is highly dependent on <g>thrombin</g> activity and its downstream signaling pathways. Direct <g>thrombin</g> inhibition with dabigatran significantly inhibited protease-activated receptor-1 PAR1 activation, integrin avb6 induction, TGF-b activation, and the development of pulmonary fibrosis in this vascular leak-dependent model. We used a potentially novel imaging method - ultashort echo time UTE lung magnetic resonance imaging MRI with the gadolinium-based, fibrin-specific probe EP-2104R - to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of <g>thrombin</g> can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/avb6/TGF-b axis or significantly protect against fibrosis. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in IPF, and the clinical availability of direct <g>thrombin</g> inhibitors that our data suggest could benefit these patients.
28469072|a|<d>Fibrotic lung disease</d>, most notably <d>idiopathic pulmonary fibrosis</d> IPF, is thought to result from aberrant wound-healing responses to repetitive lung injury. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to <d>lung fibrosis</d> is unknown. We previously described a model in which exaggeration of vascular leak after lung injury shifts the outcome of wound-healing responses from normal repair to pathological fibrosis. Here we report that the fibrosis produced in this model is highly dependent on <g>thrombin</g> activity and its downstream signaling pathways. Direct <g>thrombin</g> inhibition with dabigatran significantly inhibited protease-activated receptor-1 PAR1 activation, integrin avb6 induction, TGF-b activation, and the development of pulmonary fibrosis in this vascular leak-dependent model. We used a potentially novel imaging method - ultashort echo time UTE lung magnetic resonance imaging MRI with the gadolinium-based, fibrin-specific probe EP-2104R - to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of <g>thrombin</g> can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/avb6/TGF-b axis or significantly protect against fibrosis. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in IPF, and the clinical availability of direct <g>thrombin</g> inhibitors that our data suggest could benefit these patients.
28469072|a|<d>Fibrotic lung disease</d>, most notably <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, is thought to result from aberrant wound-healing responses to repetitive lung injury. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to <d>lung fibrosis</d> is unknown. We previously described a model in which exaggeration of vascular leak after lung injury shifts the outcome of wound-healing responses from normal repair to pathological fibrosis. Here we report that the fibrosis produced in this model is highly dependent on <g>thrombin</g> activity and its downstream signaling pathways. Direct <g>thrombin</g> inhibition with dabigatran significantly inhibited protease-activated receptor-1 PAR1 activation, integrin avb6 induction, TGF-b activation, and the development of pulmonary fibrosis in this vascular leak-dependent model. We used a potentially novel imaging method - ultashort echo time UTE lung magnetic resonance imaging MRI with the gadolinium-based, fibrin-specific probe EP-2104R - to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of <g>thrombin</g> can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/avb6/TGF-b axis or significantly protect against fibrosis. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in <d>IPF</d>, and the clinical availability of direct <g>thrombin</g> inhibitors that our data suggest could benefit these patients.
28469072|a|<d>Fibrotic lung disease</d>, most notably <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, is thought to result from aberrant wound-healing responses to repetitive <d>lung injury</d>. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to <d>lung fibrosis</d> is unknown. We previously described a model in which exaggeration of vascular leak after <d>lung injury</d> shifts the outcome of wound-healing responses from normal repair to pathological fibrosis. Here we report that the fibrosis produced in this model is highly dependent on <g>thrombin</g> activity and its downstream signaling pathways. Direct <g>thrombin</g> inhibition with dabigatran significantly inhibited protease-activated receptor-1 PAR1 activation, integrin avb6 induction, TGF-b activation, and the development of pulmonary fibrosis in this vascular leak-dependent model. We used a potentially novel imaging method - ultashort echo time UTE lung magnetic resonance imaging MRI with the gadolinium-based, fibrin-specific probe EP-2104R - to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of <g>thrombin</g> can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/avb6/TGF-b axis or significantly protect against fibrosis. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in <d>IPF</d>, and the clinical availability of direct <g>thrombin</g> inhibitors that our data suggest could benefit these patients.
28469072|a|<d>Fibrotic lung disease</d>, most notably <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>, is thought to result from aberrant wound-healing responses to repetitive <d>lung injury</d>. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to <d>lung <d>fibrosis</d></d> is unknown. We previously described a model in which exaggeration of vascular leak after <d>lung injury</d> shifts the outcome of wound-healing responses from normal repair to pathological <d>fibrosis</d>. Here we report that the <d>fibrosis</d> produced in this model is highly dependent on <g>thrombin</g> activity and its downstream signaling pathways. Direct <g>thrombin</g> inhibition with dabigatran significantly inhibited protease-activated receptor-1 PAR1 activation, integrin avb6 induction, TGF-b activation, and the development of pulmonary <d>fibrosis</d> in this vascular leak-dependent model. We used a potentially novel imaging method - ultashort echo time UTE lung magnetic resonance imaging MRI with the gadolinium-based, fibrin-specific probe EP-2104R - to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of <g>thrombin</g> can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/avb6/TGF-b axis or significantly protect against <d>fibrosis</d>. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in <d>IPF</d>, and the clinical availability of direct <g>thrombin</g> inhibitors that our data suggest could benefit these patients.
28493530|a|<d>IPF</d> is characterized by fibroblast accumulation, collagen deposition and ECM remodeling, with myofibroblasts believed to be the effector cell type. Myofibroblasts develop due to <g>EMT</g> of lung alveolar epithelial cells, which can be induced by <g>TGF-b</g>. M2 macrophages, a macrophage subpopulation, secrete large amounts of <g>TGF-b</g>. To clarify the relationship between <d>IPF</d>, <g>EMT</g>, <g>TGF-b</g> and M2 macrophages, a bleomycin-induced pulmonary fibrosis mouse model was used. Seventeen days after mice were treated with bleomycin, the successful establishment of a pulmonary fibrosis model was confirmed by HE stain and Masson's trichrome stain. We found evidence in support of <g>EMT</g>, such as elevated protein levels of a-SMA in lung tissue and decreased levels of E-cadherin and CK-18. Additionally, increased <g>TGF-b</g> levels and <g>TGF-b</g>/<g>Smad2</g> signaling activation was observed. Macrophages were recruited to pulmonary alveoli. Alveolar macrophages were phenotyped and identified as M2 macrophages, with up-regulated CD206 on the cell surfaces. For in vitro studies, we treated RAW 264.7 cells with IL-4 for 24 h, and the cells were then utilized as M2 macrophages. <g>TGF-b</g> levels increased significantly in the culture supernatant. Forty-eight hours after lung epithelial cells MLE-12 were co-cultured with the M2 macrophages, the expression of a-SMA increased, and E-cadherin and CK-18 decreased. When a <g>TGF-b</g> receptor inhibitor, LY2109761 was used, the <g>EMT</g> induced by M2 macrophages was blocked. In conclusion, we demonstrated that M2 macrophages induce <g>EMT</g> through the <g>TGF-b</g>/<g>Smad2</g> signaling pathway.
28493530|a|<d>IPF</d> is characterized by fibroblast accumulation, collagen deposition and ECM remodeling, with myofibroblasts believed to be the effector cell type. Myofibroblasts develop due to <g>EMT</g> of lung alveolar epithelial cells, which can be induced by <g>TGF-b</g>. M2 macrophages, a macrophage subpopulation, secrete large amounts of <g>TGF-b</g>. To clarify the relationship between <d>IPF</d>, <g>EMT</g>, <g>TGF-b</g> and M2 macrophages, a bleomycin-induced <d>pulmonary fibrosis</d> mouse model was used. Seventeen days after mice were treated with bleomycin, the successful establishment of a <d>pulmonary fibrosis</d> model was confirmed by HE stain and Masson's trichrome stain. We found evidence in support of <g>EMT</g>, such as elevated protein levels of a-SMA in lung tissue and decreased levels of E-cadherin and CK-18. Additionally, increased <g>TGF-b</g> levels and <g>TGF-b</g>/<g>Smad2</g> signaling activation was observed. Macrophages were recruited to pulmonary alveoli. Alveolar macrophages were phenotyped and identified as M2 macrophages, with up-regulated CD206 on the cell surfaces. For in vitro studies, we treated RAW 264.7 cells with IL-4 for 24 h, and the cells were then utilized as M2 macrophages. <g>TGF-b</g> levels increased significantly in the culture supernatant. Forty-eight hours after lung epithelial cells MLE-12 were co-cultured with the M2 macrophages, the expression of a-SMA increased, and E-cadherin and CK-18 decreased. When a <g>TGF-b</g> receptor inhibitor, LY2109761 was used, the <g>EMT</g> induced by M2 macrophages was blocked. In conclusion, we demonstrated that M2 macrophages induce <g>EMT</g> through the <g>TGF-b</g>/<g>Smad2</g> signaling pathway.
28495857|a|Transforming growth factor <g>TGF-b1</g> has long been regarded as a central mediator of tissue <d>fibrosis</d>. Follistatin-like 1 <g>Fstl1</g> is a crucial profibrotic glycoprotein that is upregulated in fibrotic lung tissues, and it promotes fibrogenesis via facilitating TGF-b signaling. Here we examined the signaling pathway by which <g>TGF-b1</g> upregulates <g>Fstl1</g> expression in mouse pulmonary fibroblasts. <g>TGF-b1</g> regulated <g>Fstl1</g> expression at both the transcriptional and translational levels. Although <g>TGF-b1</g> rapidly activated the Smad, MAPK, and Akt pathways in lung fibroblasts, only Smad2/3 inhibition eliminated <g>TGF-b1</g>-induced <g>Fstl1</g> expression. Analysis of the luciferase reporter activity identified a functional <g>c-Jun</g> transcription site in the <g>Fstl1</g> promoter. Our results suggested a critical role for the <g>Smad3</g>-<g>c-Jun</g> pathway in the regulation of <g>Fstl1</g> expression by <g>TGF-b1</g> during fibrogenesis.
28557137|a|Idiopathic <d>pulmonary fibrosis</d> IPF is a deadly, progressive lung disease with very few treatment options till now. Bleomycin-induced <d>pulmonary fibrosis</d> BIPF is a commonly used mice model in IPF research. <g>TGF-b</g>1 has been shown to play a key role in <d>pulmonary fibrosis</d> PF. Dendritic cell DC acts as a bridge between innate and adaptive immune systems. The coexistence of chronic inflammation sustained by mature DCs with fibrosis suggests that inflammatory phenomenon has key importance in the pathogenesis of <d>pulmonary fibrosis</d>. Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to <g>TGF-b</g> in PF. First, we established BIPF model in mice and blocked <g>TGF-b</g> expression by the use of inhibitor SB431542. Accumulation of lung <g>CD11c</g>+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of <g>TGF-b</g>. <g>TGF-b</g> initiates up-regulation of costimulatory molecules CD86 and CD80 in the inflammatory phases of the disease but not so at fibrotic stage. Expression of lung DC subset <g>CD11c</g>+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of BIPF. Blocking of <g>TGF-b</g> causes decreased expression of <g>CD11c</g>+CD103+ DCs. Another important lung DC subset <g>CD11c</g>+CD11b+ expression is suppressed by the absence of <g>TGF-b</g> after bleomycin administration. <g>CD11c</g>+CD103+ DCs might have anti-inflammatory as well as anti-fibrotic nature in PF. All these data demonstrate differential modulation of <g>CD11c</g>+ lung DCs by <g>TGF-b</g> in experimental PF.
28557137|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a deadly, progressive lung disease with very few treatment options till now. Bleomycin-induced <d>pulmonary fibrosis</d> B<d>IPF</d> is a commonly used mice model in <d>IPF</d> research. <g>TGF-b</g>1 has been shown to play a key role in <d>pulmonary fibrosis</d> PF. Dendritic cell DC acts as a bridge between innate and adaptive immune systems. The coexistence of chronic inflammation sustained by mature DCs with fibrosis suggests that inflammatory phenomenon has key importance in the pathogenesis of <d>pulmonary fibrosis</d>. Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to <g>TGF-b</g> in PF. First, we established B<d>IPF</d> model in mice and blocked <g>TGF-b</g> expression by the use of inhibitor SB431542. Accumulation of lung <g>CD11c</g>+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of <g>TGF-b</g>. <g>TGF-b</g> initiates up-regulation of costimulatory molecules CD86 and CD80 in the inflammatory phases of the disease but not so at fibrotic stage. Expression of lung DC subset <g>CD11c</g>+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of B<d>IPF</d>. Blocking of <g>TGF-b</g> causes decreased expression of <g>CD11c</g>+CD103+ DCs. Another important lung DC subset <g>CD11c</g>+CD11b+ expression is suppressed by the absence of <g>TGF-b</g> after bleomycin administration. <g>CD11c</g>+CD103+ DCs might have anti-inflammatory as well as anti-fibrotic nature in PF. All these data demonstrate differential modulation of <g>CD11c</g>+ lung DCs by <g>TGF-b</g> in experimental PF.
28557137|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a deadly, progressive <d>lung disease</d> with very few treatment options till now. Bleomycin-induced <d>pulmonary fibrosis</d> B<d>IPF</d> is a commonly used mice model in <d>IPF</d> research. <g>TGF-b</g>1 has been shown to play a key role in <d>pulmonary fibrosis</d> PF. Dendritic cell DC acts as a bridge between innate and adaptive immune systems. The coexistence of chronic inflammation sustained by mature DCs with fibrosis suggests that inflammatory phenomenon has key importance in the pathogenesis of <d>pulmonary fibrosis</d>. Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to <g>TGF-b</g> in PF. First, we established B<d>IPF</d> model in mice and blocked <g>TGF-b</g> expression by the use of inhibitor SB431542. Accumulation of lung <g>CD11c</g>+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of <g>TGF-b</g>. <g>TGF-b</g> initiates up-regulation of costimulatory molecules CD86 and CD80 in the inflammatory phases of the disease but not so at fibrotic stage. Expression of lung DC subset <g>CD11c</g>+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of B<d>IPF</d>. Blocking of <g>TGF-b</g> causes decreased expression of <g>CD11c</g>+CD103+ DCs. Another important lung DC subset <g>CD11c</g>+CD11b+ expression is suppressed by the absence of <g>TGF-b</g> after bleomycin administration. <g>CD11c</g>+CD103+ DCs might have anti-inflammatory as well as anti-fibrotic nature in PF. All these data demonstrate differential modulation of <g>CD11c</g>+ lung DCs by <g>TGF-b</g> in experimental PF.
28557137|a|Idiopathic <d>pulmonary fibrosis</d> <d>I<d>PF</d></d> is a deadly, progressive <d>lung disease</d> with very few treatment options till now. Bleomycin-induced <d>pulmonary fibrosis</d> B<d>I<d>PF</d></d> is a commonly used mice model in <d>I<d>PF</d></d> research. <g>TGF-b</g>1 has been shown to play a key role in <d>pulmonary fibrosis</d> <d>PF</d>. Dendritic cell DC acts as a bridge between innate and adaptive immune systems. The coexistence of chronic inflammation sustained by mature DCs with fibrosis suggests that inflammatory phenomenon has key importance in the pathogenesis of <d>pulmonary fibrosis</d>. Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to <g>TGF-b</g> in <d>PF</d>. First, we established B<d>I<d>PF</d></d> model in mice and blocked <g>TGF-b</g> expression by the use of inhibitor SB431542. Accumulation of lung <g>CD11c</g>+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of <g>TGF-b</g>. <g>TGF-b</g> initiates up-regulation of costimulatory molecules CD86 and CD80 in the inflammatory phases of the disease but not so at fibrotic stage. Expression of lung DC subset <g>CD11c</g>+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of B<d>I<d>PF</d></d>. Blocking of <g>TGF-b</g> causes decreased expression of <g>CD11c</g>+CD103+ DCs. Another important lung DC subset <g>CD11c</g>+CD11b+ expression is suppressed by the absence of <g>TGF-b</g> after bleomycin administration. <g>CD11c</g>+CD103+ DCs might have anti-inflammatory as well as anti-fibrotic nature in <d>PF</d>. All these data demonstrate differential modulation of <g>CD11c</g>+ lung DCs by <g>TGF-b</g> in experimental <d>PF</d>.
28557137|a|Idiopathic <d>pulmonary fibrosis</d> <d>I<d>PF</d></d> is a deadly, progressive <d>lung disease</d> with very few treatment options till now. Bleomycin-induced <d>pulmonary fibrosis</d> B<d>I<d>PF</d></d> is a commonly used mice model in <d>I<d>PF</d></d> research. <g>TGF-b</g>1 has been shown to play a key role in <d>pulmonary fibrosis</d> <d>PF</d>. Dendritic cell DC acts as a bridge between innate and adaptive immune systems. The coexistence of chronic <d>inflammation</d> sustained by mature DCs with fibrosis suggests that inflammatory phenomenon has key importance in the pathogenesis of <d>pulmonary fibrosis</d>. Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to <g>TGF-b</g> in <d>PF</d>. First, we established B<d>I<d>PF</d></d> model in mice and blocked <g>TGF-b</g> expression by the use of inhibitor SB431542. Accumulation of lung <g>CD11c</g>+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of <g>TGF-b</g>. <g>TGF-b</g> initiates up-regulation of costimulatory molecules CD86 and CD80 in the inflammatory phases of the disease but not so at fibrotic stage. Expression of lung DC subset <g>CD11c</g>+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of B<d>I<d>PF</d></d>. Blocking of <g>TGF-b</g> causes decreased expression of <g>CD11c</g>+CD103+ DCs. Another important lung DC subset <g>CD11c</g>+CD11b+ expression is suppressed by the absence of <g>TGF-b</g> after bleomycin administration. <g>CD11c</g>+CD103+ DCs might have anti-inflammatory as well as anti-fibrotic nature in <d>PF</d>. All these data demonstrate differential modulation of <g>CD11c</g>+ lung DCs by <g>TGF-b</g> in experimental <d>PF</d>.
28557137|a|Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>I<d>PF</d></d> is a deadly, progressive <d>lung disease</d> with very few treatment options till now. Bleomycin-induced <d>pulmonary <d>fibrosis</d></d> B<d>I<d>PF</d></d> is a commonly used mice model in <d>I<d>PF</d></d> research. <g>TGF-b</g>1 has been shown to play a key role in <d>pulmonary <d>fibrosis</d></d> <d>PF</d>. Dendritic cell DC acts as a bridge between innate and adaptive immune systems. The coexistence of chronic <d>inflammation</d> sustained by mature DCs with <d>fibrosis</d> suggests that inflammatory phenomenon has key importance in the pathogenesis of <d>pulmonary <d>fibrosis</d></d>. Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to <g>TGF-b</g> in <d>PF</d>. First, we established B<d>I<d>PF</d></d> model in mice and blocked <g>TGF-b</g> expression by the use of inhibitor SB431542. Accumulation of lung <g>CD11c</g>+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of <g>TGF-b</g>. <g>TGF-b</g> initiates up-regulation of costimulatory molecules CD86 and CD80 in the inflammatory phases of the disease but not so at fibrotic stage. Expression of lung DC subset <g>CD11c</g>+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of B<d>I<d>PF</d></d>. Blocking of <g>TGF-b</g> causes decreased expression of <g>CD11c</g>+CD103+ DCs. Another important lung DC subset <g>CD11c</g>+CD11b+ expression is suppressed by the absence of <g>TGF-b</g> after bleomycin administration. <g>CD11c</g>+CD103+ DCs might have anti-inflammatory as well as anti-fibrotic nature in <d>PF</d>. All these data demonstrate differential modulation of <g>CD11c</g>+ lung DCs by <g>TGF-b</g> in experimental <d>PF</d>.
28573228|a|BACKGROUND: An increasing number of people suffered <d>idiopathic fibrosis</d> IPF and the current treatment was far from clinical satisfaction. Moxibustion, another effective and safe unconventional therapy, had been introduced to treat this refractory disease. The study aimed to investigate the effect of moxibustion on a bleomycin A5-induced pulmonary fibrosis model. MATERIALS AND METHODS: Sprague-dawley SD rats were randomly allocated to the blank group, model group, moxibustion group, and prednisone group, for which they received no treatment, modeling, moxibustion treatment and prednisone treatment. After four-week treatment, the rats were euthanized for Hematoxylin and Eosin H.E. staining, and TGF-b1 and IFN-y protein and mRNA detection in lungs. RESULTS: In the model group, TGF-b1 was significantly increased and IFN-y was significantly decreased at both protein and mRNA levels in comparison to the blank group. In the moxibustion and prednisone group, however, TGF-b1 was decreased and IFN-y was increased at both protein and mRNA levels in comparison to the model groups. Compared with prednisone, moxibustion showed comparable effect in lowing TGF-b1 P>0.05 and better effect in up-regulating IFN-y P>0.05. CONCLUSION: The study concludes moxibustion protected pulmonary fibrosis by downregulating TGF-b1 and upregulating IFN-y cytokines at both mRNA and protein levels, and the effect was comparable to prednisone. Moxibustion could be used as a therapeutic alternative treatment for pulmonary fibrosis.
28573228|a|BACKGROUND: An increasing number of people suffered <d>idiopathic fibrosis</d> <d>IPF</d> and the current treatment was far from clinical satisfaction. Moxibustion, another effective and safe unconventional therapy, had been introduced to treat this refractory disease. The study aimed to investigate the effect of moxibustion on a bleomycin A5-induced pulmonary fibrosis model. MATERIALS AND METHODS: Sprague-dawley SD rats were randomly allocated to the blank group, model group, moxibustion group, and prednisone group, for which they received no treatment, modeling, moxibustion treatment and prednisone treatment. After four-week treatment, the rats were euthanized for Hematoxylin and Eosin H.E. staining, and TGF-b1 and IFN-y protein and mRNA detection in lungs. RESULTS: In the model group, TGF-b1 was significantly increased and IFN-y was significantly decreased at both protein and mRNA levels in comparison to the blank group. In the moxibustion and prednisone group, however, TGF-b1 was decreased and IFN-y was increased at both protein and mRNA levels in comparison to the model groups. Compared with prednisone, moxibustion showed comparable effect in lowing TGF-b1 P>0.05 and better effect in up-regulating IFN-y P>0.05. CONCLUSION: The study concludes moxibustion protected pulmonary fibrosis by downregulating TGF-b1 and upregulating IFN-y cytokines at both mRNA and protein levels, and the effect was comparable to prednisone. Moxibustion could be used as a therapeutic alternative treatment for pulmonary fibrosis.
28573228|a|BACKGROUND: An increasing number of people suffered <d>idiopathic fibrosis</d> <d>IPF</d> and the current treatment was far from clinical satisfaction. Moxibustion, another effective and safe unconventional therapy, had been introduced to treat this refractory disease. The study aimed to investigate the effect of moxibustion on a bleomycin A5-induced <d>pulmonary fibrosis</d> model. MATERIALS AND METHODS: Sprague-dawley SD rats were randomly allocated to the blank group, model group, moxibustion group, and prednisone group, for which they received no treatment, modeling, moxibustion treatment and prednisone treatment. After four-week treatment, the rats were euthanized for Hematoxylin and Eosin H.E. staining, and TGF-b1 and IFN-y protein and mRNA detection in lungs. RESULTS: In the model group, TGF-b1 was significantly increased and IFN-y was significantly decreased at both protein and mRNA levels in comparison to the blank group. In the moxibustion and prednisone group, however, TGF-b1 was decreased and IFN-y was increased at both protein and mRNA levels in comparison to the model groups. Compared with prednisone, moxibustion showed comparable effect in lowing TGF-b1 P>0.05 and better effect in up-regulating IFN-y P>0.05. CONCLUSION: The study concludes moxibustion protected <d>pulmonary fibrosis</d> by downregulating TGF-b1 and upregulating IFN-y cytokines at both mRNA and protein levels, and the effect was comparable to prednisone. Moxibustion could be used as a therapeutic alternative treatment for <d>pulmonary fibrosis</d>.
28577568|a|BACKGROUND: Pirfenidone PFD is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis IPF, but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species ROS-mediated platelet-derived growth factor receptor PDGFR activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts LF was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. METHODS: Transforming growth factor-b TGF-b-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin BLM-induced <d>lung fibrosis</d> model using PARK2 knockout KO mice. RESULTS: We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-b. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of <d>lung fibrosis</d> and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. CONCLUSIONS: These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits <d>lung fibrosis</d> development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.
28577568|a|BACKGROUND: Pirfenidone PFD is an anti-fibrotic agent used to treat <d>idiopathic pulmonary fibrosis</d> IPF, but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species ROS-mediated platelet-derived growth factor receptor PDGFR activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts LF was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. METHODS: Transforming growth factor-b TGF-b-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin BLM-induced <d>lung fibrosis</d> model using PARK2 knockout KO mice. RESULTS: We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-b. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of <d>lung fibrosis</d> and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. CONCLUSIONS: These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits <d>lung fibrosis</d> development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.
28577568|a|BACKGROUND: Pirfenidone PFD is an anti-fibrotic agent used to treat <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in <d>IPF</d>. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in <d>IPF</d> pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species ROS-mediated platelet-derived growth factor receptor PDGFR activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts LF was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. METHODS: Transforming growth factor-b TGF-b-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin BLM-induced <d>lung fibrosis</d> model using PARK2 knockout KO mice. RESULTS: We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-b. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of <d>lung fibrosis</d> and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. CONCLUSIONS: These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits <d>lung fibrosis</d> development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for <d>IPF</d> treatment.
28613983|a|Accumulation of profibrotic myofibroblasts is involved in the process of <d>fibrosis</d> development during idiopathic pulmonary <d>fibrosis</d> IPF pathogenesis. TGFB transforming growth factor b is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 NADPH oxidase 4 has an essential role in TGFB-mediated cell signaling. Azithromycin AZM, a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung <d>fibrosis</d> development. Human lung fibroblasts LF were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response UPR, and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin BLM-induced lung <d>fibrosis</d> mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 STIP1 homology and U-box containing protein 1, an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung <d>fibrosis</d> development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting proteasomal degradation, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung <d>fibrosis</d> development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF.
28613983|a|Accumulation of profibrotic myofibroblasts is involved in the process of <d>fibrosis</d> development during idiopathic pulmonary <d>fibrosis</d> IPF pathogenesis. TGFB transforming growth factor b is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 NADPH oxidase 4 has an essential role in TGFB-mediated cell signaling. Azithromycin AZM, a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung <d>fibrosis</d> development. Human lung fibroblasts LF were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response UPR, and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin BLM-induced lung <d>fibrosis</d> mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 STIP1 homology and U-box containing protein 1, an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung <d>fibrosis</d> development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting <d>proteasomal degradation</d>, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung <d>fibrosis</d> development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF.
28613983|a|Accumulation of profibrotic myofibroblasts is involved in the process of <d>fibrosis</d> development during idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> pathogenesis. TGFB transforming growth factor b is one of the major profibrotic cytokines for myofibroblast differentiation and <g>NOX4</g> NADPH oxidase 4 has an essential role in TGFB-mediated cell signaling. Azithromycin AZM, a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate <g>NOX4</g> levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung <d>fibrosis</d> development. Human lung fibroblasts LF were used to evaluate TGFB-induced myofibroblast differentiation. With respect to <g>NOX4</g> regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response UPR, and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin BLM-induced lung <d>fibrosis</d> mouse models. TGFB-induced <g>NOX4</g> and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated <g>NOX4</g> reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of <g>NOX4</g> via increased protein levels of STUB1 STIP1 homology and U-box containing protein 1, an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung <d>fibrosis</d> development induced by BLM with concomitantly reduced <g>NOX4</g> protein levels and enhanced proteasome activation. These results suggest that AZM suppresses <g>NOX4</g> by promoting <d>proteasomal degradation</d>, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung <d>fibrosis</d> development. AZM may be a candidate for the treatment of the fibrotic lung disease <d>IPF</d>.
28613983|a|Accumulation of profibrotic myofibroblasts is involved in the process of <d>fibrosis</d> development during idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> pathogenesis. <g>TGFB</g> <g>transforming growth factor b</g> is one of the major profibrotic cytokines for myofibroblast differentiation and <g>NOX4</g> <g>NADPH oxidase 4</g> has an essential role in <g>TGFB</g>-mediated cell signaling. Azithromycin AZM, a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including <d>proteostasis</d>. Hence, we hypothesized that AZM may regulate <g>NOX4</g> levels by modulating <d>proteostasis</d> machineries, resulting in inhibition of <g>TGFB</g>-associated lung <d>fibrosis</d> development. Human lung fibroblasts LF were used to evaluate <g>TGFB</g>-induced myofibroblast differentiation. With respect to <g>NOX4</g> regulation via <d>proteostasis</d>, assays for macroautophagy/autophagy, the unfolded protein response UPR, and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin BLM-induced lung <d>fibrosis</d> mouse models. <g>TGFB</g>-induced <g>NOX4</g> and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated <g>NOX4</g> reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of <g>NOX4</g> via increased protein levels of STUB1 STIP1 homology and U-box containing protein 1, an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung <d>fibrosis</d> development induced by BLM with concomitantly reduced <g>NOX4</g> protein levels and enhanced proteasome activation. These results suggest that AZM suppresses <g>NOX4</g> by promoting <d>proteasomal degradation</d>, resulting in inhibition of <g>TGFB</g>-induced myofibroblast differentiation and lung <d>fibrosis</d> development. AZM may be a candidate for the treatment of the fibrotic lung disease <d>IPF</d>.
28613983|a|Accumulation of profibrotic myofibroblasts is involved in the process of <d>fibrosis</d> development during idiopathic pulmonary <d>fibrosis</d> <d>IPF</d> pathogenesis. <g>TGFB</g> <g>transforming growth factor b</g> is one of the major profibrotic cytokines for myofibroblast differentiation and <g>NOX4</g> <g>NADPH oxidase 4</g> has an essential role in <g>TGFB</g>-mediated cell signaling. Azithromycin AZM, a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including <d>proteostasis</d>. Hence, we hypothesized that AZM may regulate <g>NOX4</g> levels by modulating <d>proteostasis</d> machineries, resulting in inhibition of <g>TGFB</g>-associated lung <d>fibrosis</d> development. Human lung fibroblasts LF were used to evaluate <g>TGFB</g>-induced myofibroblast differentiation. With respect to <g>NOX4</g> regulation via <d>proteostasis</d>, assays for macroautophagy/autophagy, the unfolded protein response UPR, and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin BLM-induced lung <d>fibrosis</d> mouse models. <g>TGFB</g>-induced <g>NOX4</g> and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated <g>NOX4</g> reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of <g>NOX4</g> via increased protein levels of <g>STUB1</g> <g>STIP1</g> homology and U-box containing protein 1, an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung <d>fibrosis</d> development induced by BLM with concomitantly reduced <g>NOX4</g> protein levels and enhanced proteasome activation. These results suggest that AZM suppresses <g>NOX4</g> by promoting <d>proteasomal degradation</d>, resulting in inhibition of <g>TGFB</g>-induced myofibroblast differentiation and lung <d>fibrosis</d> development. AZM may be a candidate for the treatment of the <d>fibrotic lung disease</d> <d>IPF</d>.
28662409|a|Pulmonary fibrosis is a progressive lung disease that its pathogenic mechanism currently is incompletely understood. Toll-like receptor TLR signaling has recently been identified as a regulator of <d>inflammation</d> and pulmonary fibrosis. In addition, mesenchymal stem cells MSCs of different origins offer a great promise in treatment of idiopathic pulmonary fibrosis IPF. However mechanisms of pathogenic roles of TLR signaling and therapeutic effects of MSCs in the IPF remain elusive. In present study, the involvement of TLR signaling and the therapeutic role of MSCs were interrogated in MyD88-deficient mice using human placental MSCs of fetal origins hfPMSCs. The results showed an alleviated pulmonary <d>inflammation</d> and fibrosis in myeloid differentiation primary response gene 88 MyD88-deficient mice treated with bleomycin BLM, accompanied with a reduced TGF-b signaling and production of pro-fibrotic cytokines, including TNF-a, IL-1b. An exposure of HLF1 lung fibroblasts, A549 epithelial cells and RAW264.7 macrophages to BLM led an increased expression of key components of MyD88 and TGF-b signaling cascades. Of interest, enforced expression and inhibition of MyD88 protein resulted in an enhanced and a reduced TGF-b signaling in above cells in the presence of BLM, respectively. However, the addition of TGF-b1 showed a marginally inhibitory effect on MyD88 signaling in these cells in the absence of BLM. Importantly, the administration of hfPMSCs could significantly attenuate BLM-induced pulmonary fibrosis in mice, along with a reduced hydroxyproline HYP deposition, MyD88 and TGF-b signaling activation, and production of pro-fibrotic cytokines. These results may suggest an importance of MyD88/TGF-b signaling axis in the tissue homeostasis and functional integrity of lung in response to injury, which may offer a novel target for treatment of pulmonary fibrosis.
28662409|a|Pulmonary <d>fibrosis</d> is a progressive lung disease that its pathogenic mechanism currently is incompletely understood. Toll-like receptor TLR signaling has recently been identified as a regulator of <d>inflammation</d> and pulmonary <d>fibrosis</d>. In addition, mesenchymal stem cells MSCs of different origins offer a great promise in treatment of idiopathic pulmonary <d>fibrosis</d> IPF. However mechanisms of pathogenic roles of TLR signaling and therapeutic effects of MSCs in the IPF remain elusive. In present study, the involvement of TLR signaling and the therapeutic role of MSCs were interrogated in MyD88-deficient mice using human placental MSCs of fetal origins hfPMSCs. The results showed an alleviated pulmonary <d>inflammation</d> and <d>fibrosis</d> in myeloid differentiation primary response gene 88 MyD88-deficient mice treated with bleomycin BLM, accompanied with a reduced TGF-b signaling and production of pro-fibrotic cytokines, including TNF-a, IL-1b. An exposure of HLF1 lung fibroblasts, A549 epithelial cells and RAW264.7 macrophages to BLM led an increased expression of key components of MyD88 and TGF-b signaling cascades. Of interest, enforced expression and inhibition of MyD88 protein resulted in an enhanced and a reduced TGF-b signaling in above cells in the presence of BLM, respectively. However, the addition of TGF-b1 showed a marginally inhibitory effect on MyD88 signaling in these cells in the absence of BLM. Importantly, the administration of hfPMSCs could significantly attenuate BLM-induced pulmonary <d>fibrosis</d> in mice, along with a reduced hydroxyproline HYP deposition, MyD88 and TGF-b signaling activation, and production of pro-fibrotic cytokines. These results may suggest an importance of MyD88/TGF-b signaling axis in the tissue homeostasis and functional integrity of lung in response to injury, which may offer a novel target for treatment of pulmonary <d>fibrosis</d>.
28662409|a|Pulmonary <d>fibrosis</d> is a progressive <d>lung disease</d> that its pathogenic mechanism currently is incompletely understood. Toll-like receptor TLR signaling has recently been identified as a regulator of <d>inflammation</d> and pulmonary <d>fibrosis</d>. In addition, mesenchymal stem cells MSCs of different origins offer a great promise in treatment of idiopathic pulmonary <d>fibrosis</d> IPF. However mechanisms of pathogenic roles of TLR signaling and therapeutic effects of MSCs in the IPF remain elusive. In present study, the involvement of TLR signaling and the therapeutic role of MSCs were interrogated in <g>MyD88</g>-deficient mice using human placental MSCs of fetal origins hfPMSCs. The results showed an alleviated pulmonary <d>inflammation</d> and <d>fibrosis</d> in myeloid differentiation primary response gene 88 <g>MyD88</g>-deficient mice treated with bleomycin BLM, accompanied with a reduced TGF-b signaling and production of pro-fibrotic cytokines, including TNF-a, IL-1b. An exposure of HLF1 lung fibroblasts, A549 epithelial cells and RAW264.7 macrophages to BLM led an increased expression of key components of <g>MyD88</g> and TGF-b signaling cascades. Of interest, enforced expression and inhibition of <g>MyD88</g> protein resulted in an enhanced and a reduced TGF-b signaling in above cells in the presence of BLM, respectively. However, the addition of TGF-b1 showed a marginally inhibitory effect on <g>MyD88</g> signaling in these cells in the absence of BLM. Importantly, the administration of hfPMSCs could significantly attenuate BLM-induced pulmonary <d>fibrosis</d> in mice, along with a reduced hydroxyproline HYP deposition, <g>MyD88</g> and TGF-b signaling activation, and production of pro-fibrotic cytokines. These results may suggest an importance of <g>MyD88</g>/TGF-b signaling axis in the tissue homeostasis and functional integrity of lung in response to injury, which may offer a novel target for treatment of pulmonary <d>fibrosis</d>.
28662409|a|Pulmonary <d>fibrosis</d> is a progressive <d>lung disease</d> that its pathogenic mechanism currently is incompletely understood. Toll-like receptor TLR signaling has recently been identified as a regulator of <d>inflammation</d> and pulmonary <d>fibrosis</d>. In addition, mesenchymal stem cells MSCs of different origins offer a great promise in treatment of idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>. However mechanisms of pathogenic roles of TLR signaling and therapeutic effects of MSCs in the <d>IPF</d> remain elusive. In present study, the involvement of TLR signaling and the therapeutic role of MSCs were interrogated in <g>MyD88</g>-deficient mice using human placental MSCs of fetal origins hfPMSCs. The results showed an alleviated pulmonary <d>inflammation</d> and <d>fibrosis</d> in myeloid differentiation primary response gene 88 <g>MyD88</g>-deficient mice treated with bleomycin BLM, accompanied with a reduced TGF-b signaling and production of pro-fibrotic cytokines, including TNF-a, IL-1b. An exposure of HLF1 lung fibroblasts, A549 epithelial cells and RAW264.7 macrophages to BLM led an increased expression of key components of <g>MyD88</g> and TGF-b signaling cascades. Of interest, enforced expression and inhibition of <g>MyD88</g> protein resulted in an enhanced and a reduced TGF-b signaling in above cells in the presence of BLM, respectively. However, the addition of TGF-b1 showed a marginally inhibitory effect on <g>MyD88</g> signaling in these cells in the absence of BLM. Importantly, the administration of hfPMSCs could significantly attenuate BLM-induced pulmonary <d>fibrosis</d> in mice, along with a reduced hydroxyproline HYP deposition, <g>MyD88</g> and TGF-b signaling activation, and production of pro-fibrotic cytokines. These results may suggest an importance of <g>MyD88</g>/TGF-b signaling axis in the tissue homeostasis and functional integrity of lung in response to injury, which may offer a novel target for treatment of pulmonary <d>fibrosis</d>.
28667660|a|Idiopathic pulmonary fibrosis <d>IPF</d> and hypersensitivity pneumonitis HP belong to heterogenic group of interstitial lung diseases ILD. For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in inflammation, fibrosis and EMT processes, so important in the course of ILD: TNF-a/NFkb, TGF-b/SMAD, Wnt-b-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of <d>IPF</d> and HP. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of ILD.
28667660|a|Idiopathic pulmonary fibrosis <d>IPF</d> and <d>hypersensitivity pneumonitis</d> HP belong to heterogenic group of interstitial lung diseases ILD. For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in inflammation, fibrosis and EMT processes, so important in the course of ILD: TNF-a/NFkb, TGF-b/SMAD, Wnt-b-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of <d>IPF</d> and HP. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of ILD.
28667660|a|Idiopathic pulmonary fibrosis <d>IPF</d> and <d>hypersensitivity pneumonitis</d> <d>HP</d> belong to heterogenic group of interstitial lung diseases ILD. For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in inflammation, fibrosis and EMT processes, so important in the course of ILD: TNF-a/NFkb, TGF-b/SMAD, Wnt-b-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of <d>IPF</d> and <d>HP</d>. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of ILD.
28667660|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>hypersensitivity pneumonitis</d> <d>HP</d> belong to heterogenic group of interstitial lung diseases ILD. For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in inflammation, fibrosis and EMT processes, so important in the course of ILD: TNF-a/NFkb, TGF-b/SMAD, Wnt-b-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of <d>IPF</d> and <d>HP</d>. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of ILD.
28667660|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>hypersensitivity pneumonitis</d> <d>HP</d> belong to heterogenic group of <d>interstitial lung diseases</d> ILD. For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in inflammation, fibrosis and EMT processes, so important in the course of ILD: TNF-a/NFkb, TGF-b/SMAD, Wnt-b-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of <d>IPF</d> and <d>HP</d>. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of ILD.
28667660|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>hypersensitivity pneumonitis</d> <d>HP</d> belong to heterogenic group of <d>interstitial lung diseases</d> <d>ILD</d>. For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in inflammation, fibrosis and EMT processes, so important in the course of <d>ILD</d>: TNF-a/NFkb, TGF-b/SMAD, Wnt-b-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of <d>IPF</d> and <d>HP</d>. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of <d>ILD</d>.
28667660|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>hypersensitivity pneumonitis</d> <d>HP</d> belong to heterogenic group of <d>interstitial lung diseases</d> <d>ILD</d>. For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in <d>inflammation</d>, fibrosis and EMT processes, so important in the course of <d>ILD</d>: TNF-a/NFkb, TGF-b/SMAD, Wnt-b-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of <d>IPF</d> and <d>HP</d>. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of <d>ILD</d>.
28667660|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> and <d>hypersensitivity pneumonitis</d> <d>HP</d> belong to heterogenic group of <d>interstitial lung diseases</d> <d>ILD</d>. For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in <d>inflammation</d>, <d>fibrosis</d> and EMT processes, so important in the course of <d>ILD</d>: TNF-a/NFkb, TGF-b/SMAD, Wnt-b-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of <d>IPF</d> and <d>HP</d>. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of <d>ILD</d>.
28678431|a|Lung adenocarcinoma cells with activating epidermal growth factor receptor <g>EGFR</g> mutations are highly dependent upon <g>EGFR</g> signaling for survival and undergo apoptosis when <g>EGFR</g> signaling is inhibited by tyrosine kinase inhibitor TKI treatment. Paradoxically, <g>EGFR</g>-mutant <d>lung adenocarcinoma</d>s have subpopulations of cells that can survive independently of activated <g>EGFR</g>. Such <g>EGFR</g>-independent <g>EGFR</g>-mutant cancer cells include cells that have undergone epithelial-to-mesenchymal transition EMT or transformed to small cell lung cancer, which almost completely lack <g>EGFR</g> dependency. The presence of such cells suggests that <g>EGFR</g> TKIs cannot eradicate <g>EGFR</g>-mutant <d>lung adenocarcinoma</d> cells. However, little is known about whether and to what extent normal peripheral lung epithelial cells, not <d>lung adenocarcinoma</d> cells, can undergo EMT. We have recently reported that normal peripheral lung epithelial cells can undergo dynamic EMT within 72   h in response to transforming growth factor-b signaling. This finding reinforced the hypothesis that alveolar epithelial cells that have undergone EMT contribute to the formation of fibroblastic foci, the leading edge of fibrotic destruction in lungs affected by idiopathic pulmonary fibrosis. This review focuses on the role of EMT in neoplastic and non-neoplastic peripheral lung epithelial cells.   .
28678431|a|Lung adenocarcinoma cells with activating epidermal growth factor receptor <g>EGFR</g> mutations are highly dependent upon <g>EGFR</g> signaling for survival and undergo apoptosis when <g>EGFR</g> signaling is inhibited by tyrosine kinase inhibitor TKI treatment. Paradoxically, <g>EGFR</g>-mutant <d>lung adenocarcinoma</d>s have subpopulations of cells that can survive independently of activated <g>EGFR</g>. Such <g>EGFR</g>-independent <g>EGFR</g>-mutant cancer cells include cells that have undergone epithelial-to-mesenchymal transition EMT or transformed to small cell lung cancer, which almost completely lack <g>EGFR</g> dependency. The presence of such cells suggests that <g>EGFR</g> TKIs cannot eradicate <g>EGFR</g>-mutant <d>lung adenocarcinoma</d> cells. However, little is known about whether and to what extent normal peripheral lung epithelial cells, not <d>lung adenocarcinoma</d> cells, can undergo EMT. We have recently reported that normal peripheral lung epithelial cells can undergo dynamic EMT within 72   h in response to transforming growth factor-b signaling. This finding reinforced the hypothesis that alveolar epithelial cells that have undergone EMT contribute to the formation of fibroblastic foci, the leading edge of fibrotic destruction in lungs affected by <d>idiopathic pulmonary fibrosis</d>. This review focuses on the role of EMT in neoplastic and non-neoplastic peripheral lung epithelial cells.   .
28678431|a|<d>Lung adenocarcinoma</d> cells with activating epidermal growth factor receptor <g>EGFR</g> mutations are highly dependent upon <g>EGFR</g> signaling for survival and undergo apoptosis when <g>EGFR</g> signaling is inhibited by tyrosine kinase inhibitor TKI treatment. Paradoxically, <g>EGFR</g>-mutant <d>lung adenocarcinoma</d>s have subpopulations of cells that can survive independently of activated <g>EGFR</g>. Such <g>EGFR</g>-independent <g>EGFR</g>-mutant cancer cells include cells that have undergone epithelial-to-mesenchymal transition EMT or transformed to small cell lung cancer, which almost completely lack <g>EGFR</g> dependency. The presence of such cells suggests that <g>EGFR</g> TKIs cannot eradicate <g>EGFR</g>-mutant <d>lung adenocarcinoma</d> cells. However, little is known about whether and to what extent normal peripheral lung epithelial cells, not <d>lung adenocarcinoma</d> cells, can undergo EMT. We have recently reported that normal peripheral lung epithelial cells can undergo dynamic EMT within 72   h in response to transforming growth factor-b signaling. This finding reinforced the hypothesis that alveolar epithelial cells that have undergone EMT contribute to the formation of fibroblastic foci, the leading edge of fibrotic destruction in lungs affected by <d>idiopathic pulmonary fibrosis</d>. This review focuses on the role of EMT in neoplastic and non-neoplastic peripheral lung epithelial cells.   .
28678431|a|<d>Lung adenocarcinoma</d> cells with activating <g>epidermal growth factor receptor</g> <g>EGFR</g> mutations are highly dependent upon <g>EGFR</g> signaling for survival and undergo apoptosis when <g>EGFR</g> signaling is inhibited by tyrosine kinase inhibitor TKI treatment. Paradoxically, <g>EGFR</g>-mutant <d>lung adenocarcinoma</d>s have subpopulations of cells that can survive independently of activated <g>EGFR</g>. Such <g>EGFR</g>-independent <g>EGFR</g>-mutant <d>cancer</d> cells include cells that have undergone epithelial-to-mesenchymal transition EMT or transformed to small cell lung <d>cancer</d>, which almost completely lack <g>EGFR</g> dependency. The presence of such cells suggests that <g>EGFR</g> TKIs cannot eradicate <g>EGFR</g>-mutant <d>lung adenocarcinoma</d> cells. However, little is known about whether and to what extent normal peripheral lung epithelial cells, not <d>lung adenocarcinoma</d> cells, can undergo EMT. We have recently reported that normal peripheral lung epithelial cells can undergo dynamic EMT within 72   h in response to transforming growth factor-b signaling. This finding reinforced the hypothesis that alveolar epithelial cells that have undergone EMT contribute to the formation of fibroblastic foci, the leading edge of fibrotic destruction in lungs affected by <d>idiopathic pulmonary fibrosis</d>. This review focuses on the role of EMT in neoplastic and non-neoplastic peripheral lung epithelial cells.   .
28678431|a|<d>Lung adenocarcinoma</d> cells with activating <g>epidermal growth factor receptor</g> <g>EGFR</g> mutations are highly dependent upon <g>EGFR</g> signaling for survival and undergo apoptosis when <g>EGFR</g> signaling is inhibited by tyrosine kinase inhibitor TKI treatment. Paradoxically, <g>EGFR</g>-mutant <d>lung adenocarcinoma</d>s have subpopulations of cells that can survive independently of activated <g>EGFR</g>. Such <g>EGFR</g>-independent <g>EGFR</g>-mutant <d>cancer</d> cells include cells that have undergone epithelial-to-mesenchymal transition EMT or transformed to small cell lung <d>cancer</d>, which almost completely lack <g>EGFR</g> dependency. The presence of such cells suggests that <g>EGFR</g> TKIs cannot eradicate <g>EGFR</g>-mutant <d>lung adenocarcinoma</d> cells. However, little is known about whether and to what extent normal peripheral lung epithelial cells, not <d>lung adenocarcinoma</d> cells, can undergo EMT. We have recently reported that normal peripheral lung epithelial cells can undergo dynamic EMT within 72   h in response to transforming growth factor-b signaling. This finding reinforced the hypothesis that alveolar epithelial cells that have undergone EMT contribute to the formation of fibroblastic foci, the leading edge of <d>fibrotic destruction</d> in lungs affected by <d>idiopathic pulmonary fibrosis</d>. This review focuses on the role of EMT in neoplastic and non-neoplastic peripheral lung epithelial cells.   .
28754682|a|<d>Autoimmunity</d> has been implicated in the pathogenesis of idiopathic pulmonary fibrosis IPF; however, the repertoire of autoantigens involved in this disease and the clinical relevance of these autoimmune responses are still being explored. Our initial discovery assays demonstrated that circulating and intrapulmonary vimentin levels are increased in IPF patients. Subsequent studies showed native vimentin induced HLA-DR-dependent in vitro proliferation of CD4 T cells from IPF patients and enhanced the production of IL-4, IL-17, and TGF-b1 by these lymphocytes in contrast to normal control specimens. Vimentin supplementation of IPF PBMC cultures also resulted in HLA-DR-dependent production of IgG with anti-vimentin specificities. Circulating anti-vimentin IgG autoantibody levels were much greater in IPF subjects from the University of Alabama at Birmingham n = 102 and the University of Pittsburgh U. Pitt., n = 70 than in normal controls. Anti-vimentin autoantibody levels in IPF patients were HLA biased and inversely correlated with physiological measurements of lung function i.e., forced expiratory volumes and diffusing capacities. Despite considerable intergroup differences in transplant-free survival between these two independent IPF cohorts, serious adverse outcomes were most frequent among the patients within each population that had the highest anti-vimentin autoantibody levels University of Alabama at Birmingham: hazard ratio 2.5, 95% confidence interval 1.2-5.3, p = 0.012; University of Pittsburgh: hazard ratio 2.7, 95% confidence interval 1.3-5.5, p = 0.006. These data show that anti-vimentin autoreactivity is prevalent in IPF patients and is strongly associated with disease manifestations. These findings have implications with regard to the pathogenesis of this enigmatic disease and raise the possibility that therapies specifically directed at these autoimmune processes could have therapeutic efficacy.
28754682|a|<d>Autoimmunity</d> has been implicated in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF; however, the repertoire of autoantigens involved in this disease and the clinical relevance of these autoimmune responses are still being explored. Our initial discovery assays demonstrated that circulating and intrapulmonary vimentin levels are increased in IPF patients. Subsequent studies showed native vimentin induced HLA-DR-dependent in vitro proliferation of CD4 T cells from IPF patients and enhanced the production of IL-4, IL-17, and TGF-b1 by these lymphocytes in contrast to normal control specimens. Vimentin supplementation of IPF PBMC cultures also resulted in HLA-DR-dependent production of IgG with anti-vimentin specificities. Circulating anti-vimentin IgG autoantibody levels were much greater in IPF subjects from the University of Alabama at Birmingham n = 102 and the University of Pittsburgh U. Pitt., n = 70 than in normal controls. Anti-vimentin autoantibody levels in IPF patients were HLA biased and inversely correlated with physiological measurements of lung function i.e., forced expiratory volumes and diffusing capacities. Despite considerable intergroup differences in transplant-free survival between these two independent IPF cohorts, serious adverse outcomes were most frequent among the patients within each population that had the highest anti-vimentin autoantibody levels University of Alabama at Birmingham: hazard ratio 2.5, 95% confidence interval 1.2-5.3, p = 0.012; University of Pittsburgh: hazard ratio 2.7, 95% confidence interval 1.3-5.5, p = 0.006. These data show that anti-vimentin autoreactivity is prevalent in IPF patients and is strongly associated with disease manifestations. These findings have implications with regard to the pathogenesis of this enigmatic disease and raise the possibility that therapies specifically directed at these autoimmune processes could have therapeutic efficacy.
28754682|a|<d>Autoimmunity</d> has been implicated in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>; however, the repertoire of autoantigens involved in this disease and the clinical relevance of these autoimmune responses are still being explored. Our initial discovery assays demonstrated that circulating and intrapulmonary vimentin levels are increased in <d>IPF</d> patients. Subsequent studies showed native vimentin induced HLA-DR-dependent in vitro proliferation of CD4 T cells from <d>IPF</d> patients and enhanced the production of IL-4, IL-17, and TGF-b1 by these lymphocytes in contrast to normal control specimens. Vimentin supplementation of <d>IPF</d> PBMC cultures also resulted in HLA-DR-dependent production of IgG with anti-vimentin specificities. Circulating anti-vimentin IgG autoantibody levels were much greater in <d>IPF</d> subjects from the University of Alabama at Birmingham n = 102 and the University of Pittsburgh U. Pitt., n = 70 than in normal controls. Anti-vimentin autoantibody levels in <d>IPF</d> patients were HLA biased and inversely correlated with physiological measurements of lung function i.e., forced expiratory volumes and diffusing capacities. Despite considerable intergroup differences in transplant-free survival between these two independent <d>IPF</d> cohorts, serious adverse outcomes were most frequent among the patients within each population that had the highest anti-vimentin autoantibody levels University of Alabama at Birmingham: hazard ratio 2.5, 95% confidence interval 1.2-5.3, p = 0.012; University of Pittsburgh: hazard ratio 2.7, 95% confidence interval 1.3-5.5, p = 0.006. These data show that anti-vimentin autoreactivity is prevalent in <d>IPF</d> patients and is strongly associated with disease manifestations. These findings have implications with regard to the pathogenesis of this enigmatic disease and raise the possibility that therapies specifically directed at these autoimmune processes could have therapeutic efficacy.
28810065|a|BACKGROUND AND PURPOSE: Idiopathic <d>pulmonary fibrosis</d> IPF is a fatal respiratory disease characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of b2 -adrenoceptors b2 -AR has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of b2 -adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti-fibrotic activity of the long-acting b2 -adrenoceptor agonist olodaterol in primary human lung fibroblasts HLF and in murine models of <d>pulmonary fibrosis</d>. EXPERIMENTAL APPROACH: We assessed the activity of olodaterol to inhibit various pro-fibrotic mechanisms, induced by different pro-fibrotic mediators, in primary HLF from control donors and patients with IPF IPF-LF. The in vivo anti-fibrotic activity of olodaterol, given once daily by inhalation in either a preventive or therapeutic treatment regimen, was explored in murine models of lung fibrosis induced by either bleomycin or the overexpression of TGF-b1. KEY RESULTS: In both HLF and IPF-LF, olodaterol attenuated TGF-b-induced expression of a-smooth muscle actin, fibronectin and endothelin-1 ET-1, FGF- and PDGF-induced motility and proliferation and TGF-b/ET-1-induced contraction. In vivo olodaterol significantly attenuated the bleomycin-induced increase in lung weight, reduced bronchoalveolar lavage cell counts and inhibited release of pro-fibrotic mediators TGF-  , MMP-9 and tissue inhibitor of metalloproteinase-1. Forced vital capacity was increased only with the preventive treatment regimen. In the TGF-b-overexpressing model, olodaterol additionally reduced the Col3A1 mRNA expression. CONCLUSION AND IMPLICATIONS: Olodaterol showed anti-fibrotic properties in primary HLF from control and IPF patients and in murine models of lung fibrosis.
28810065|a|BACKGROUND AND PURPOSE: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a fatal respiratory disease characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of b2 -adrenoceptors b2 -AR has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of b2 -adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti-fibrotic activity of the long-acting b2 -adrenoceptor agonist olodaterol in primary human lung fibroblasts HLF and in murine models of <d>pulmonary fibrosis</d>. EXPERIMENTAL APPROACH: We assessed the activity of olodaterol to inhibit various pro-fibrotic mechanisms, induced by different pro-fibrotic mediators, in primary HLF from control donors and patients with <d>IPF</d> <d>IPF</d>-LF. The in vivo anti-fibrotic activity of olodaterol, given once daily by inhalation in either a preventive or therapeutic treatment regimen, was explored in murine models of lung fibrosis induced by either bleomycin or the overexpression of TGF-b1. KEY RESULTS: In both HLF and <d>IPF</d>-LF, olodaterol attenuated TGF-b-induced expression of a-smooth muscle actin, fibronectin and endothelin-1 ET-1, FGF- and PDGF-induced motility and proliferation and TGF-b/ET-1-induced contraction. In vivo olodaterol significantly attenuated the bleomycin-induced increase in lung weight, reduced bronchoalveolar lavage cell counts and inhibited release of pro-fibrotic mediators TGF-  , MMP-9 and tissue inhibitor of metalloproteinase-1. Forced vital capacity was increased only with the preventive treatment regimen. In the TGF-b-overexpressing model, olodaterol additionally reduced the Col3A1 mRNA expression. CONCLUSION AND IMPLICATIONS: Olodaterol showed anti-fibrotic properties in primary HLF from control and <d>IPF</d> patients and in murine models of lung fibrosis.
28810065|a|BACKGROUND AND PURPOSE: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a fatal <d>respiratory disease</d> characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of b2 -adrenoceptors b2 -AR has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of b2 -adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti-fibrotic activity of the long-acting b2 -adrenoceptor agonist olodaterol in primary human lung fibroblasts HLF and in murine models of <d>pulmonary fibrosis</d>. EXPERIMENTAL APPROACH: We assessed the activity of olodaterol to inhibit various pro-fibrotic mechanisms, induced by different pro-fibrotic mediators, in primary HLF from control donors and patients with <d>IPF</d> <d>IPF</d>-LF. The in vivo anti-fibrotic activity of olodaterol, given once daily by inhalation in either a preventive or therapeutic treatment regimen, was explored in murine models of lung fibrosis induced by either bleomycin or the overexpression of TGF-b1. KEY RESULTS: In both HLF and <d>IPF</d>-LF, olodaterol attenuated TGF-b-induced expression of a-smooth muscle actin, fibronectin and endothelin-1 ET-1, FGF- and PDGF-induced motility and proliferation and TGF-b/ET-1-induced contraction. In vivo olodaterol significantly attenuated the bleomycin-induced increase in lung weight, reduced bronchoalveolar lavage cell counts and inhibited release of pro-fibrotic mediators TGF-  , MMP-9 and tissue inhibitor of metalloproteinase-1. Forced vital capacity was increased only with the preventive treatment regimen. In the TGF-b-overexpressing model, olodaterol additionally reduced the Col3A1 mRNA expression. CONCLUSION AND IMPLICATIONS: Olodaterol showed anti-fibrotic properties in primary HLF from control and <d>IPF</d> patients and in murine models of lung fibrosis.
28810065|a|BACKGROUND AND PURPOSE: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a fatal <d>respiratory disease</d> characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of <g>b2 -adrenoceptors</g> <g>b2 -AR</g> has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of b2 -adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti-fibrotic activity of the long-acting b2 -adrenoceptor agonist olodaterol in primary human lung fibroblasts <g>HLF</g> and in murine models of <d>pulmonary fibrosis</d>. EXPERIMENTAL APPROACH: We assessed the activity of olodaterol to inhibit various pro-fibrotic mechanisms, induced by different pro-fibrotic mediators, in primary <g>HLF</g> from control donors and patients with <d>IPF</d> <d>IPF</d>-LF. The in vivo anti-fibrotic activity of olodaterol, given once daily by inhalation in either a preventive or therapeutic treatment regimen, was explored in murine models of <d>lung fibrosis</d> induced by either bleomycin or the overexpression of TGF-b1. KEY RESULTS: In both <g>HLF</g> and <d>IPF</d>-LF, olodaterol attenuated TGF-b-induced expression of a-smooth muscle actin, fibronectin and endothelin-1 ET-1, FGF- and PDGF-induced motility and proliferation and TGF-b/ET-1-induced contraction. In vivo olodaterol significantly attenuated the bleomycin-induced increase in lung weight, reduced bronchoalveolar lavage cell counts and inhibited release of pro-fibrotic mediators TGF-  , MMP-9 and tissue inhibitor of metalloproteinase-1. Forced vital capacity was increased only with the preventive treatment regimen. In the TGF-b-overexpressing model, olodaterol additionally reduced the Col3A1 mRNA expression. CONCLUSION AND IMPLICATIONS: Olodaterol showed anti-fibrotic properties in primary <g>HLF</g> from control and <d>IPF</d> patients and in murine models of <d>lung fibrosis</d>.
28810065|a|BACKGROUND AND PURPOSE: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a fatal <d>respiratory disease</d> characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of <g>b2 -adrenoceptors</g> <g>b2 -AR</g> has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of b2 -adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti-fibrotic activity of the long-acting b2 -adrenoceptor agonist olodaterol in primary human lung fibroblasts <g>HLF</g> and in murine models of <d>pulmonary fibrosis</d>. EXPERIMENTAL APPROACH: We assessed the activity of olodaterol to inhibit various pro-fibrotic mechanisms, induced by different pro-fibrotic mediators, in primary <g>HLF</g> from control donors and patients with <d>IPF</d> <d>IPF</d>-LF. The in vivo anti-fibrotic activity of olodaterol, given once daily by inhalation in either a preventive or therapeutic treatment regimen, was explored in murine models of <d>lung fibrosis</d> induced by either bleomycin or the overexpression of <g><g>TGF-b</g>1</g>. KEY RESULTS: In both <g>HLF</g> and <d>IPF</d>-LF, olodaterol attenuated <g>TGF-b</g>-induced expression of a-smooth muscle actin, <g>fibronectin</g> and <g>endothelin-1</g> <g>ET-1</g>, FGF- and PDGF-induced motility and proliferation and <g>TGF-b</g>/<g>ET-1</g>-induced contraction. In vivo olodaterol significantly attenuated the bleomycin-induced increase in lung weight, <d>reduced bronchoalveolar lavage</d> cell counts and inhibited release of pro-fibrotic mediators TGF-  , MMP-9 and tissue inhibitor of metalloproteinase-1. Forced vital capacity was increased only with the preventive treatment regimen. In the <g>TGF-b</g>-overexpressing model, olodaterol additionally reduced the Col3A1 mRNA expression. CONCLUSION AND IMPLICATIONS: Olodaterol showed anti-fibrotic properties in primary <g>HLF</g> from control and <d>IPF</d> patients and in murine models of <d>lung fibrosis</d>.
28816543|a|AIM OF THE STUDY: Idiopathic pulmonary fibrosis IPF is a lethal human disease with short survival time and few treatment options. In this study, we aim to demonstrate that cyclic nucleotide phosphodiesterase 1A PDE1A, a Ca2+/calmodulin-stimulating PDE family member, plays a critical role in the induction of fibrosis and angiogenesis in the lung. MATERIALS AND METHODS: To induce pulmonary damage, adult male SD rats were treated with bleomycin in a dose of 6 mg/kg body weight by a single intratracheal instillation. For in vivo silencing of PDE1A in rat lung, a nonspecific control siRNA or PDE1A-specific siRNA was used to treat rat through nasal instillation. Human normal pulmonary fibroblasts MRC-5 and hFL1 and rat lung fibroblasts were used as in vitro model. Immunohistochemistry and immunoflurescence staining were performed to detect PDE1A and a-SMA expression. Reverse transcription-qPCR was performed to detect microRNA and mRNA expression. In vitro wound healing assay was performed to detect pulmonary fibroblasts'mortality ability. RESULTS: In vitro studies showed that PDE1A can stimulate lung fibroblasts to undergo myofibroblastic changes. This led to the identification of miR-541-5p as one of the miRNA candidates associated with bleomycin response. We found that miR-541-5p expression is downregulated in TGF-b-treated lung fibroblasts and the rat pulmonary fibrosis model. Overexpression of miR-541-5p in lung fibroblasts inhibited mortality of human lung fibroblasts. CONCLUSIONS: MiR-541-5p is a key effector in lung fibroblastsby by regulating PDE1A expression at protein translation level and its overexpression is protective against bleomycin-induced <d>lung fibrosis</d>.
28816543|a|AIM OF THE STUDY: <d>Idiopathic pulmonary fibrosis</d> IPF is a lethal human disease with short survival time and few treatment options. In this study, we aim to demonstrate that cyclic nucleotide phosphodiesterase 1A PDE1A, a Ca2+/calmodulin-stimulating PDE family member, plays a critical role in the induction of fibrosis and angiogenesis in the lung. MATERIALS AND METHODS: To induce pulmonary damage, adult male SD rats were treated with bleomycin in a dose of 6 mg/kg body weight by a single intratracheal instillation. For in vivo silencing of PDE1A in rat lung, a nonspecific control siRNA or PDE1A-specific siRNA was used to treat rat through nasal instillation. Human normal pulmonary fibroblasts MRC-5 and hFL1 and rat lung fibroblasts were used as in vitro model. Immunohistochemistry and immunoflurescence staining were performed to detect PDE1A and a-SMA expression. Reverse transcription-qPCR was performed to detect microRNA and mRNA expression. In vitro wound healing assay was performed to detect pulmonary fibroblasts'mortality ability. RESULTS: In vitro studies showed that PDE1A can stimulate lung fibroblasts to undergo myofibroblastic changes. This led to the identification of miR-541-5p as one of the miRNA candidates associated with bleomycin response. We found that miR-541-5p expression is downregulated in TGF-b-treated lung fibroblasts and the rat pulmonary fibrosis model. Overexpression of miR-541-5p in lung fibroblasts inhibited mortality of human lung fibroblasts. CONCLUSIONS: MiR-541-5p is a key effector in lung fibroblastsby by regulating PDE1A expression at protein translation level and its overexpression is protective against bleomycin-induced <d>lung fibrosis</d>.
28816543|a|AIM OF THE STUDY: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal human disease with short survival time and few treatment options. In this study, we aim to demonstrate that cyclic nucleotide phosphodiesterase 1A PDE1A, a Ca2+/calmodulin-stimulating PDE family member, plays a critical role in the induction of fibrosis and angiogenesis in the lung. MATERIALS AND METHODS: To induce pulmonary damage, adult male SD rats were treated with bleomycin in a dose of 6 mg/kg body weight by a single intratracheal instillation. For in vivo silencing of PDE1A in rat lung, a nonspecific control siRNA or PDE1A-specific siRNA was used to treat rat through nasal instillation. Human normal pulmonary fibroblasts MRC-5 and hFL1 and rat lung fibroblasts were used as in vitro model. Immunohistochemistry and immunoflurescence staining were performed to detect PDE1A and a-SMA expression. Reverse transcription-qPCR was performed to detect microRNA and mRNA expression. In vitro wound healing assay was performed to detect pulmonary fibroblasts'mortality ability. RESULTS: In vitro studies showed that PDE1A can stimulate lung fibroblasts to undergo myofibroblastic changes. This led to the identification of miR-541-5p as one of the miRNA candidates associated with bleomycin response. We found that miR-541-5p expression is downregulated in TGF-b-treated lung fibroblasts and the rat pulmonary fibrosis model. Overexpression of miR-541-5p in lung fibroblasts inhibited mortality of human lung fibroblasts. CONCLUSIONS: MiR-541-5p is a key effector in lung fibroblastsby by regulating PDE1A expression at protein translation level and its overexpression is protective against bleomycin-induced <d>lung fibrosis</d>.
28816543|a|AIM OF THE STUDY: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a lethal human disease with short survival time and few treatment options. In this study, we aim to demonstrate that cyclic nucleotide phosphodiesterase 1A <g><d>PDE</d>1A</g>, a Ca2+/calmodulin-stimulating <d>PDE</d> family member, plays a critical role in the induction of fibrosis and angiogenesis in the lung. MATERIALS AND METHODS: To induce pulmonary damage, adult male SD rats were treated with bleomycin in a dose of 6 mg/kg body weight by a single intratracheal instillation. For in vivo silencing of <g><d>PDE</d>1A</g> in rat lung, a nonspecific control siRNA or <g><d>PDE</d>1A</g>-specific siRNA was used to treat rat through nasal instillation. Human normal pulmonary fibroblasts MRC-5 and hFL1 and rat lung fibroblasts were used as in vitro model. Immunohistochemistry and immunoflurescence staining were performed to detect <g><d>PDE</d>1A</g> and a-SMA expression. Reverse transcription-qPCR was performed to detect microRNA and mRNA expression. In vitro wound healing assay was performed to detect pulmonary fibroblasts'mortality ability. RESULTS: In vitro studies showed that <g><d>PDE</d>1A</g> can stimulate lung fibroblasts to undergo myofibroblastic changes. This led to the identification of miR-541-5p as one of the miRNA candidates associated with bleomycin response. We found that miR-541-5p expression is downregulated in TGF-b-treated lung fibroblasts and the rat pulmonary fibrosis model. Overexpression of miR-541-5p in lung fibroblasts inhibited mortality of human lung fibroblasts. CONCLUSIONS: MiR-541-5p is a key effector in lung fibroblastsby by regulating <g><d>PDE</d>1A</g> expression at protein translation level and its overexpression is protective against bleomycin-induced <d>lung fibrosis</d>.
28816543|a|AIM OF THE STUDY: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a lethal human disease with short survival time and few treatment options. In this study, we aim to demonstrate that cyclic nucleotide phosphodiesterase 1A <g><d>PDE</d>1A</g>, a Ca2+/calmodulin-stimulating <d>PDE</d> family member, plays a critical role in the induction of <d>fibrosis</d> and angiogenesis in the lung. MATERIALS AND METHODS: To induce pulmonary damage, adult male SD rats were treated with bleomycin in a dose of 6 mg/kg body weight by a single intratracheal instillation. For in vivo silencing of <g><d>PDE</d>1A</g> in rat lung, a nonspecific control siRNA or <g><d>PDE</d>1A</g>-specific siRNA was used to treat rat through nasal instillation. Human normal pulmonary fibroblasts MRC-5 and hFL1 and rat lung fibroblasts were used as in vitro model. Immunohistochemistry and immunoflurescence staining were performed to detect <g><d>PDE</d>1A</g> and a-SMA expression. Reverse transcription-qPCR was performed to detect microRNA and mRNA expression. In vitro wound healing assay was performed to detect pulmonary fibroblasts'mortality ability. RESULTS: In vitro studies showed that <g><d>PDE</d>1A</g> can stimulate lung fibroblasts to undergo myofibroblastic changes. This led to the identification of miR-541-5p as one of the miRNA candidates associated with bleomycin response. We found that miR-541-5p expression is downregulated in TGF-b-treated lung fibroblasts and the rat pulmonary <d>fibrosis</d> model. Overexpression of miR-541-5p in lung fibroblasts inhibited mortality of human lung fibroblasts. CONCLUSIONS: MiR-541-5p is a key effector in lung fibroblastsby by regulating <g><d>PDE</d>1A</g> expression at protein translation level and its overexpression is protective against bleomycin-induced <d>lung <d>fibrosis</d></d>.
28816543|a|AIM OF THE STUDY: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is a lethal human disease with short survival time and few treatment options. In this study, we aim to demonstrate that cyclic nucleotide phosphodiesterase 1A <g><d>PDE</d>1A</g>, a Ca2+/calmodulin-stimulating <d>PDE</d> family member, plays a critical role in the induction of <d>fibrosis</d> and angiogenesis in the lung. MATERIALS AND METHODS: To induce <d>pulmonary damage</d>, adult male SD rats were treated with bleomycin in a dose of 6 mg/kg body weight by a single intratracheal instillation. For in vivo silencing of <g><d>PDE</d>1A</g> in rat lung, a nonspecific control siRNA or <g><d>PDE</d>1A</g>-specific siRNA was used to treat rat through nasal instillation. Human normal pulmonary fibroblasts MRC-5 and hFL1 and rat lung fibroblasts were used as in vitro model. Immunohistochemistry and immunoflurescence staining were performed to detect <g><d>PDE</d>1A</g> and a-SMA expression. Reverse transcription-qPCR was performed to detect microRNA and mRNA expression. In vitro wound healing assay was performed to detect pulmonary fibroblasts'mortality ability. RESULTS: In vitro studies showed that <g><d>PDE</d>1A</g> can stimulate lung fibroblasts to undergo myofibroblastic changes. This led to the identification of miR-541-5p as one of the miRNA candidates associated with bleomycin response. We found that miR-541-5p expression is downregulated in TGF-b-treated lung fibroblasts and the rat pulmonary <d>fibrosis</d> model. Overexpression of miR-541-5p in lung fibroblasts inhibited mortality of human lung fibroblasts. CONCLUSIONS: MiR-541-5p is a key effector in lung fibroblastsby by regulating <g><d>PDE</d>1A</g> expression at protein translation level and its overexpression is protective against bleomycin-induced <d>lung <d>fibrosis</d></d>.
28821630|a|Interleukin 17A <g>IL-17A</g> and complement C' activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis IPF. We have reported that <g>IL-17A</g> induces epithelial injury via TGF-b in murine bronchiolitis obliterans; that TGF-b and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates <d>lung fibrosis</d>. In the present study, we investigated the role of <g>IL-17A</g> in regulating C' in <d>lung fibrosis</d>. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that <g>IL-17A</g> 100 ng/ml; 24 h; n = 5 donor lungs induces C' components C' factor B, C3, and GPCR kinase isoform 5, cytokines IL8, -6, and -1B, and cytokine ligands CXCL1, -2, -3, -5, -6, and -16. <g>IL-17A</g> induces protein and mRNA regulation of C' components and the synthesis of active C' 3a C3a in normal primary human alveolar type II epithelial cells AECs. Wild-type mice subjected to <g>IL-17A</g> neutralization and <g>IL-17A</g> knockout il17a-/-  mice were protected against bleomycin BLEO-induced fibrosis and collagen deposition. Further, BLEO-injured il17a-/- mice had diminished levels of circulating Krebs Von Den Lungen 6 alveolar epithelial injury marker, local caspase-3/7, and local endoplasmic reticular stress-related genes. BLEO-induced local C' activation [C3a, C5a, and terminal C' complex C5b-9] was attenuated in il17a-/- mice, and <g>IL-17A</g> neutralization prevented the loss of epithelial C' inhibitors C' receptor-1 related isoform Y and decay accelerating factor, and an increase in local TUNEL levels. RNAi-mediated gene silencing of il17a in fibrotic mice arrested the progression of <d>lung fibrosis</d>, attenuated cellular apoptosis caspase-3/7 and lung deposition of collagen and C' C5b-9. Compared to normals, plasma from IPF patients showed significantly higher hemolytic activity. Our findings demonstrate that limiting complement activation by neutralizing <g>IL-17A</g> is a potential mechanism in ameliorating <d>lung fibrosis</d>.-Cipolla, E., Fisher, A. J., Gu, H., Mickler, E. A., Agarwal, M., Wilke, C. A., Kim, K. K., Moore, B. B., Vittal, R. <g>IL-17A</g> deficiency mitigates bleomycin-induced complement activation during <d>lung fibrosis</d>.
28821630|a|<g>Interleukin 17A</g> <g>IL-17A</g> and complement C' activation have each been implicated in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> IPF. We have reported that <g>IL-17A</g> induces epithelial injury via TGF-b in murine bronchiolitis obliterans; that TGF-b and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates <d>lung fibrosis</d>. In the present study, we investigated the role of <g>IL-17A</g> in regulating C' in <d>lung fibrosis</d>. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that <g>IL-17A</g> 100 ng/ml; 24 h; n = 5 donor lungs induces C' components C' factor B, C3, and GPCR kinase isoform 5, cytokines IL8, -6, and -1B, and cytokine ligands CXCL1, -2, -3, -5, -6, and -16. <g>IL-17A</g> induces protein and mRNA regulation of C' components and the synthesis of active C' 3a C3a in normal primary human alveolar type II epithelial cells AECs. Wild-type mice subjected to <g>IL-17A</g> neutralization and <g>IL-17A</g> knockout il17a-/-  mice were protected against bleomycin BLEO-induced fibrosis and collagen deposition. Further, BLEO-injured il17a-/- mice had diminished levels of circulating Krebs Von Den Lungen 6 alveolar epithelial injury marker, local caspase-3/7, and local endoplasmic reticular stress-related genes. BLEO-induced local C' activation [C3a, C5a, and terminal C' complex C5b-9] was attenuated in il17a-/- mice, and <g>IL-17A</g> neutralization prevented the loss of epithelial C' inhibitors C' receptor-1 related isoform Y and decay accelerating factor, and an increase in local TUNEL levels. RNAi-mediated gene silencing of il17a in fibrotic mice arrested the progression of <d>lung fibrosis</d>, attenuated cellular apoptosis caspase-3/7 and lung deposition of collagen and C' C5b-9. Compared to normals, plasma from IPF patients showed significantly higher hemolytic activity. Our findings demonstrate that limiting complement activation by neutralizing <g>IL-17A</g> is a potential mechanism in ameliorating <d>lung fibrosis</d>.-Cipolla, E., Fisher, A. J., Gu, H., Mickler, E. A., Agarwal, M., Wilke, C. A., Kim, K. K., Moore, B. B., Vittal, R. <g>IL-17A</g> deficiency mitigates bleomycin-induced complement activation during <d>lung fibrosis</d>.
28821630|a|<g>Interleukin 17A</g> <g>IL-17A</g> and complement C' activation have each been implicated in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. We have reported that <g>IL-17A</g> induces epithelial injury via TGF-b in murine bronchiolitis obliterans; that TGF-b and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates <d>lung fibrosis</d>. In the present study, we investigated the role of <g>IL-17A</g> in regulating C' in <d>lung fibrosis</d>. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that <g>IL-17A</g> 100 ng/ml; 24 h; n = 5 donor lungs induces C' components C' factor B, C3, and GPCR kinase isoform 5, cytokines IL8, -6, and -1B, and cytokine ligands CXCL1, -2, -3, -5, -6, and -16. <g>IL-17A</g> induces protein and mRNA regulation of C' components and the synthesis of active C' 3a C3a in normal primary human alveolar type II epithelial cells AECs. Wild-type mice subjected to <g>IL-17A</g> neutralization and <g>IL-17A</g> knockout il17a-/-  mice were protected against bleomycin BLEO-induced fibrosis and collagen deposition. Further, BLEO-injured il17a-/- mice had diminished levels of circulating Krebs Von Den Lungen 6 alveolar epithelial injury marker, local caspase-3/7, and local endoplasmic reticular stress-related genes. BLEO-induced local C' activation [C3a, C5a, and terminal C' complex C5b-9] was attenuated in il17a-/- mice, and <g>IL-17A</g> neutralization prevented the loss of epithelial C' inhibitors C' receptor-1 related isoform Y and decay accelerating factor, and an increase in local TUNEL levels. RNAi-mediated gene silencing of il17a in fibrotic mice arrested the progression of <d>lung fibrosis</d>, attenuated cellular apoptosis caspase-3/7 and lung deposition of collagen and C' C5b-9. Compared to normals, plasma from <d>IPF</d> patients showed significantly higher hemolytic activity. Our findings demonstrate that limiting complement activation by neutralizing <g>IL-17A</g> is a potential mechanism in ameliorating <d>lung fibrosis</d>.-Cipolla, E., Fisher, A. J., Gu, H., Mickler, E. A., Agarwal, M., Wilke, C. A., Kim, K. K., Moore, B. B., Vittal, R. <g>IL-17A</g> deficiency mitigates bleomycin-induced complement activation during <d>lung fibrosis</d>.
28821630|a|<g>Interleukin 17A</g> <g>IL-17A</g> and complement C' activation have each been implicated in the pathogenesis of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. We have reported that <g>IL-17A</g> induces epithelial injury via <g>TGF-b</g> in murine <d>bronchiolitis obliterans</d>; that <g>TGF-b</g> and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates <d>lung fibrosis</d>. In the present study, we investigated the role of <g>IL-17A</g> in regulating C' in <d>lung fibrosis</d>. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that <g>IL-17A</g> 100 ng/ml; 24 h; n = 5 donor lungs induces C' components C' factor B, C3, and GPCR kinase isoform 5, cytokines IL8, -6, and -1B, and cytokine ligands CXCL1, -2, -3, -5, -6, and -16. <g>IL-17A</g> induces protein and mRNA regulation of C' components and the synthesis of active C' 3a C3a in normal primary human alveolar type II epithelial cells AECs. Wild-type mice subjected to <g>IL-17A</g> neutralization and <g>IL-17A</g> knockout il17a-/-  mice were protected against bleomycin BLEO-induced fibrosis and collagen deposition. Further, BLEO-injured il17a-/- mice had diminished levels of circulating Krebs Von Den Lungen 6 alveolar epithelial injury marker, local caspase-3/7, and local endoplasmic reticular stress-related genes. BLEO-induced local C' activation [C3a, C5a, and terminal C' complex C5b-9] was attenuated in il17a-/- mice, and <g>IL-17A</g> neutralization prevented the loss of epithelial C' inhibitors C' receptor-1 related isoform Y and decay accelerating factor, and an increase in local TUNEL levels. RNAi-mediated gene silencing of il17a in fibrotic mice arrested the progression of <d>lung fibrosis</d>, attenuated cellular apoptosis caspase-3/7 and lung deposition of collagen and C' C5b-9. Compared to normals, plasma from <d>IPF</d> patients showed significantly higher hemolytic activity. Our findings demonstrate that limiting complement activation by neutralizing <g>IL-17A</g> is a potential mechanism in ameliorating <d>lung fibrosis</d>.-Cipolla, E., Fisher, A. J., Gu, H., Mickler, E. A., Agarwal, M., Wilke, C. A., Kim, K. K., Moore, B. B., Vittal, R. <g>IL-17A</g> deficiency mitigates bleomycin-induced complement activation during <d>lung fibrosis</d>.
28821630|a|<g>Interleukin 17A</g> <g>IL-17A</g> and complement C' activation have each been implicated in the pathogenesis of <d>idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d>. We have reported that <g>IL-17A</g> induces epithelial injury via <g>TGF-b</g> in murine <d>bronchiolitis obliterans</d>; that <g>TGF-b</g> and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates <d>lung <d>fibrosis</d></d>. In the present study, we investigated the role of <g>IL-17A</g> in regulating C' in <d>lung <d>fibrosis</d></d>. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that <g>IL-17A</g> 100 ng/ml; 24 h; n = 5 donor lungs induces C' components C' factor B, C3, and GPCR kinase isoform 5, cytokines <g>IL8, -6, and -1B</g>, and cytokine ligands <g>CXCL1</g>, -2, -3, -5, -6, and -16. <g>IL-17A</g> induces protein and mRNA regulation of C' components and the synthesis of active C' 3a C3a in normal primary human alveolar type II epithelial cells AECs. Wild-type mice subjected to <g>IL-17A</g> neutralization and <g>IL-17A</g> knockout <g>il17a</g>-/-  mice were protected against bleomycin BLEO-induced <d>fibrosis</d> and collagen deposition. Further, BLEO-injured <g>il17a</g>-/- mice had diminished levels of circulating Krebs Von Den Lungen 6 alveolar epithelial injury marker, local caspase-3/7, and local endoplasmic reticular stress-related genes. BLEO-induced local C' activation [C3a, C5a, and terminal C' complex C5b-9] was attenuated in <g>il17a</g>-/- mice, and <g>IL-17A</g> neutralization prevented the loss of epithelial C' inhibitors C' receptor-1 related isoform Y and decay accelerating factor, and an increase in local TUNEL levels. RNAi-mediated gene silencing of <g>il17a</g> in fibrotic mice arrested the progression of <d>lung <d>fibrosis</d></d>, attenuated cellular apoptosis caspase-3/7 and lung deposition of collagen and C' C5b-9. Compared to normals, plasma from <d>IPF</d> patients showed significantly higher hemolytic activity. Our findings demonstrate that limiting complement activation by neutralizing <g>IL-17A</g> is a potential mechanism in ameliorating <d>lung <d>fibrosis</d></d>.-Cipolla, E., Fisher, A. J., Gu, H., Mickler, E. A., Agarwal, M., Wilke, C. A., Kim, K. K., Moore, B. B., Vittal, R. <g>IL-17A</g> deficiency mitigates bleomycin-induced complement activation during <d>lung <d>fibrosis</d></d>.
28847533|a|INTRODUCTION: Controversy exists about the pathogenesis of <d>idiopathic pulmonary fibrosis</d> acute exacerbations IPF-AEs. According to one hypothesis IPF-AEs represent the development of any etiology diffuse alveolar damage DAD upon usual interstitial pneumonia UIP, whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated IPF patients. METHODS: Consecutive IPF patients referred to our department were included. Diagnoses of IPF and IPF-AE were based on international guidelines and consensus criteria. The interleukins IL-4, <g>IL-6</g>, <g>IL-8</g>, IL-10, and IL-13 as well asactive transforming growth factor-beta TGF-b were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. RESULTS: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The <g>IL-6</g> and <g>IL-8</g> levels were significantly higher in exacerbated patients p=0.002 and p=0.046, respectively. An increase in either <g>IL-6</g> or <g>IL-8</g> by 1pg/ml increases the odds of death by 5.6% p=0.021 and 6.7% p=0.013, respectively, in all patients. No differences were detected for the other cytokines. CONCLUSION: High levels of <g>IL-6</g> and <g>IL-8</g> characterize early-on IPF-AEs and an increase in the levels of <g>IL-6</g> and <g>IL-8</g> associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-b, IL-10, IL-4 and IL-13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of <g>IL-6</g> further studies are necessary to clarify the enigma of IPF-AEs etiopathogenesis.
28847533|a|INTRODUCTION: Controversy exists about the pathogenesis of <d>idiopathic pulmonary fibrosis</d> acute exacerbations <d>IPF</d>-AEs. According to one hypothesis <d>IPF</d>-AEs represent the development of any etiology diffuse alveolar damage DAD upon usual interstitial pneumonia UIP, whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated <d>IPF</d> patients. METHODS: Consecutive <d>IPF</d> patients referred to our department were included. Diagnoses of <d>IPF</d> and <d>IPF</d>-AE were based on international guidelines and consensus criteria. The interleukins IL-4, <g>IL-6</g>, <g>IL-8</g>, IL-10, and IL-13 as well asactive transforming growth factor-beta TGF-b were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. RESULTS: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The <g>IL-6</g> and <g>IL-8</g> levels were significantly higher in exacerbated patients p=0.002 and p=0.046, respectively. An increase in either <g>IL-6</g> or <g>IL-8</g> by 1pg/ml increases the odds of death by 5.6% p=0.021 and 6.7% p=0.013, respectively, in all patients. No differences were detected for the other cytokines. CONCLUSION: High levels of <g>IL-6</g> and <g>IL-8</g> characterize early-on <d>IPF</d>-AEs and an increase in the levels of <g>IL-6</g> and <g>IL-8</g> associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-b, IL-10, IL-4 and IL-13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of <g>IL-6</g> further studies are necessary to clarify the enigma of <d>IPF</d>-AEs etiopathogenesis.
28847533|a|INTRODUCTION: Controversy exists about the pathogenesis of <d>idiopathic pulmonary fibrosis</d> acute exacerbations <d>IPF</d>-AEs. According to one hypothesis <d>IPF</d>-AEs represent the development of any etiology <d>diffuse alveolar damage</d> DAD upon usual interstitial pneumonia UIP, whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated <d>IPF</d> patients. METHODS: Consecutive <d>IPF</d> patients referred to our department were included. Diagnoses of <d>IPF</d> and <d>IPF</d>-AE were based on international guidelines and consensus criteria. The interleukins IL-4, <g>IL-6</g>, <g>IL-8</g>, IL-10, and IL-13 as well asactive transforming growth factor-beta TGF-b were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. RESULTS: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The <g>IL-6</g> and <g>IL-8</g> levels were significantly higher in exacerbated patients p=0.002 and p=0.046, respectively. An increase in either <g>IL-6</g> or <g>IL-8</g> by 1pg/ml increases the odds of death by 5.6% p=0.021 and 6.7% p=0.013, respectively, in all patients. No differences were detected for the other cytokines. CONCLUSION: High levels of <g>IL-6</g> and <g>IL-8</g> characterize early-on <d>IPF</d>-AEs and an increase in the levels of <g>IL-6</g> and <g>IL-8</g> associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-b, IL-10, IL-4 and IL-13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of <g>IL-6</g> further studies are necessary to clarify the enigma of <d>IPF</d>-AEs etiopathogenesis.
28847533|a|INTRODUCTION: Controversy exists about the pathogenesis of <d>idiopathic pulmonary fibrosis</d> acute exacerbations <d>IPF</d>-AEs. According to one hypothesis <d>IPF</d>-AEs represent the development of any etiology <d>diffuse alveolar damage</d> <d>DAD</d> upon usual interstitial pneumonia UIP, whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated <d>IPF</d> patients. METHODS: Consecutive <d>IPF</d> patients referred to our department were included. Diagnoses of <d>IPF</d> and <d>IPF</d>-AE were based on international guidelines and consensus criteria. The interleukins IL-4, <g>IL-6</g>, <g>IL-8</g>, IL-10, and IL-13 as well asactive transforming growth factor-beta TGF-b were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. RESULTS: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The <g>IL-6</g> and <g>IL-8</g> levels were significantly higher in exacerbated patients p=0.002 and p=0.046, respectively. An increase in either <g>IL-6</g> or <g>IL-8</g> by 1pg/ml increases the odds of death by 5.6% p=0.021 and 6.7% p=0.013, respectively, in all patients. No differences were detected for the other cytokines. CONCLUSION: High levels of <g>IL-6</g> and <g>IL-8</g> characterize early-on <d>IPF</d>-AEs and an increase in the levels of <g>IL-6</g> and <g>IL-8</g> associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-b, IL-10, IL-4 and IL-13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of <g>IL-6</g> further studies are necessary to clarify the enigma of <d>IPF</d>-AEs etiopathogenesis.
28847533|a|INTRODUCTION: Controversy exists about the pathogenesis of <d>idiopathic pulmonary fibrosis</d> acute exacerbations <d>IPF</d>-AEs. According to one hypothesis <d>IPF</d>-AEs represent the development of any etiology <d>diffuse alveolar damage</d> <d>DAD</d> upon <d>usual interstitial pneumonia</d> UIP, whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated <d>IPF</d> patients. METHODS: Consecutive <d>IPF</d> patients referred to our department were included. Diagnoses of <d>IPF</d> and <d>IPF</d>-AE were based on international guidelines and consensus criteria. The interleukins IL-4, <g>IL-6</g>, <g>IL-8</g>, IL-10, and IL-13 as well asactive transforming growth factor-beta TGF-b were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. RESULTS: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The <g>IL-6</g> and <g>IL-8</g> levels were significantly higher in exacerbated patients p=0.002 and p=0.046, respectively. An increase in either <g>IL-6</g> or <g>IL-8</g> by 1pg/ml increases the odds of death by 5.6% p=0.021 and 6.7% p=0.013, respectively, in all patients. No differences were detected for the other cytokines. CONCLUSION: High levels of <g>IL-6</g> and <g>IL-8</g> characterize early-on <d>IPF</d>-AEs and an increase in the levels of <g>IL-6</g> and <g>IL-8</g> associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-b, IL-10, IL-4 and IL-13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of <g>IL-6</g> further studies are necessary to clarify the enigma of <d>IPF</d>-AEs etiopathogenesis.
28847533|a|INTRODUCTION: Controversy exists about the pathogenesis of <d>idiopathic pulmonary fibrosis</d> acute exacerbations <d>IPF</d>-AEs. According to one hypothesis <d>IPF</d>-AEs represent the development of any etiology <d>diffuse alveolar damage</d> <d>DAD</d> upon <d>usual interstitial pneumonia</d> <d>UIP</d>, whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated <d>IPF</d> patients. METHODS: Consecutive <d>IPF</d> patients referred to our department were included. Diagnoses of <d>IPF</d> and <d>IPF</d>-AE were based on international guidelines and consensus criteria. The interleukins IL-4, <g>IL-6</g>, <g>IL-8</g>, IL-10, and IL-13 as well asactive transforming growth factor-beta TGF-b were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. RESULTS: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The <g>IL-6</g> and <g>IL-8</g> levels were significantly higher in exacerbated patients p=0.002 and p=0.046, respectively. An increase in either <g>IL-6</g> or <g>IL-8</g> by 1pg/ml increases the odds of death by 5.6% p=0.021 and 6.7% p=0.013, respectively, in all patients. No differences were detected for the other cytokines. CONCLUSION: High levels of <g>IL-6</g> and <g>IL-8</g> characterize early-on <d>IPF</d>-AEs and an increase in the levels of <g>IL-6</g> and <g>IL-8</g> associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-b, IL-10, IL-4 and IL-13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of <g>IL-6</g> further studies are necessary to clarify the enigma of <d>IPF</d>-AEs etiopathogenesis.
28847533|a|INTRODUCTION: Controversy exists about the pathogenesis of <d>idiopathic pulmonary fibrosis</d> acute exacerbations <d>IPF</d>-AEs. According to one hypothesis <d>IPF</d>-AEs represent the development of any etiology <d>diffuse alveolar damage</d> <d>DAD</d> upon <d>usual interstitial pneumonia</d> <d>UIP</d>, whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated <d>IPF</d> patients. METHODS: Consecutive <d>IPF</d> patients referred to our department were included. Diagnoses of <d>IPF</d> and <d>IPF</d>-AE were based on international guidelines and consensus criteria. The interleukins IL-4, <g>IL-6</g>, <g>IL-8</g>, <g>IL-10</g>, and <g>IL-13</g> as well asactive <g>transforming growth factor-beta</g> <g>TGF-b</g> were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. RESULTS: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The <g>IL-6</g> and <g>IL-8</g> levels were significantly higher in exacerbated patients p=0.002 and p=0.046, respectively. An increase in either <g>IL-6</g> or <g>IL-8</g> by 1pg/ml increases the odds of <d>death</d> by 5.6% p=0.021 and 6.7% p=0.013, respectively, in all patients. No differences were detected for the other cytokines. CONCLUSION: High levels of <g>IL-6</g> and <g>IL-8</g> characterize early-on <d>IPF</d>-AEs and an increase in the levels of <g>IL-6</g> and <g>IL-8</g> associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, <g>TGF-b</g>, <g>IL-10</g>, IL-4 and <g>IL-13</g> were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of <g>IL-6</g> further studies are necessary to clarify the enigma of <d>IPF</d>-AEs etiopathogenesis.
28873461|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a chronic and usually progressive lung disease and the epithelial-mesenchymal transition EMT may play an important role in the pathogenesis of pulmonary fibrosis. IL-17 is a proinflammatory cytokine which promotes EMT profiles in lung inflammatory diseases. In this study, we investigated the effect of IL-17 on EMT in alveolar epithelial cell line A549 and the role of TGFb1-Smad and ERK signaling pathways in the process. Morphological observation on the cells was performed under inverted microscope. The mRNA and protein expressions of E-cad and a-SMA were detected by quantitative RT-PCR and western blotting. The mRNA and protein expressions of <g>TGF-b1</g> were analyzed via quantitative RT-PCR and ELISA. Expressions of <g>Smad2/3</g>, p-<g>Smad2/3</g>, <g>ERK1/2</g>, p-<g>ERK1/2</g> and p-JNK were examined by western blotting. The results indicated that IL-17 can induce A549 cells to undergo morphological changes and phenotypic markers changes, such as down-regulated E-cad expression and up-regulated a-SMA expression. Additionally, IL-17 enhanced <g>TGF-b1</g> expression and stimulated <g>Smad2/3</g> and <g>ERK1/2</g> phosphorylation in A549 cells. However, there were no significant differences in the expression of phosphorylated JNK in A549 cells with or without IL-17 treatment. SB431542 or U0126 treated cells showed inhibited morphological changes and phenotypic markers expression, such as up-regulated E-cad expression and down-regulated a-SMA expression. In summary, our results suggest that IL-17 can induce A549 alveolar epithelial cells to undergo EMT via the <g>TGF-b1</g> mediated <g>Smad2/3</g> and <g>ERK1/2</g> activation.
28873461|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and usually progressive lung disease and the epithelial-mesenchymal transition EMT may play an important role in the pathogenesis of pulmonary fibrosis. IL-17 is a proinflammatory cytokine which promotes EMT profiles in lung inflammatory diseases. In this study, we investigated the effect of IL-17 on EMT in alveolar epithelial cell line A549 and the role of TGFb1-Smad and ERK signaling pathways in the process. Morphological observation on the cells was performed under inverted microscope. The mRNA and protein expressions of E-cad and a-SMA were detected by quantitative RT-PCR and western blotting. The mRNA and protein expressions of <g>TGF-b1</g> were analyzed via quantitative RT-PCR and ELISA. Expressions of <g>Smad2/3</g>, p-<g>Smad2/3</g>, <g>ERK1/2</g>, p-<g>ERK1/2</g> and p-JNK were examined by western blotting. The results indicated that IL-17 can induce A549 cells to undergo morphological changes and phenotypic markers changes, such as down-regulated E-cad expression and up-regulated a-SMA expression. Additionally, IL-17 enhanced <g>TGF-b1</g> expression and stimulated <g>Smad2/3</g> and <g>ERK1/2</g> phosphorylation in A549 cells. However, there were no significant differences in the expression of phosphorylated JNK in A549 cells with or without IL-17 treatment. SB431542 or U0126 treated cells showed inhibited morphological changes and phenotypic markers expression, such as up-regulated E-cad expression and down-regulated a-SMA expression. In summary, our results suggest that IL-17 can induce A549 alveolar epithelial cells to undergo EMT via the <g>TGF-b1</g> mediated <g>Smad2/3</g> and <g>ERK1/2</g> activation.
28873461|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a chronic and usually progressive <d>lung disease</d> and the epithelial-mesenchymal transition EMT may play an important role in the pathogenesis of pulmonary fibrosis. IL-17 is a proinflammatory cytokine which promotes EMT profiles in lung inflammatory diseases. In this study, we investigated the effect of IL-17 on EMT in alveolar epithelial cell line A549 and the role of TGFb1-Smad and ERK signaling pathways in the process. Morphological observation on the cells was performed under inverted microscope. The mRNA and protein expressions of E-cad and a-SMA were detected by quantitative RT-PCR and western blotting. The mRNA and protein expressions of <g>TGF-b1</g> were analyzed via quantitative RT-PCR and ELISA. Expressions of <g>Smad2/3</g>, p-<g>Smad2/3</g>, <g>ERK1/2</g>, p-<g>ERK1/2</g> and p-JNK were examined by western blotting. The results indicated that IL-17 can induce A549 cells to undergo morphological changes and phenotypic markers changes, such as down-regulated E-cad expression and up-regulated a-SMA expression. Additionally, IL-17 enhanced <g>TGF-b1</g> expression and stimulated <g>Smad2/3</g> and <g>ERK1/2</g> phosphorylation in A549 cells. However, there were no significant differences in the expression of phosphorylated JNK in A549 cells with or without IL-17 treatment. SB431542 or U0126 treated cells showed inhibited morphological changes and phenotypic markers expression, such as up-regulated E-cad expression and down-regulated a-SMA expression. In summary, our results suggest that IL-17 can induce A549 alveolar epithelial cells to undergo EMT via the <g>TGF-b1</g> mediated <g>Smad2/3</g> and <g>ERK1/2</g> activation.
28873461|a|<d>Idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> is a chronic and usually progressive <d>lung disease</d> and the epithelial-mesenchymal transition EMT may play an important role in the pathogenesis of <d>pulmonary fibrosis</d>. IL-17 is a proinflammatory cytokine which promotes EMT profiles in lung inflammatory diseases. In this study, we investigated the effect of IL-17 on EMT in alveolar epithelial cell line A549 and the role of TGFb1-Smad and ERK signaling pathways in the process. Morphological observation on the cells was performed under inverted microscope. The mRNA and protein expressions of E-cad and a-SMA were detected by quantitative RT-PCR and western blotting. The mRNA and protein expressions of <g>TGF-b1</g> were analyzed via quantitative RT-PCR and ELISA. Expressions of <g>Smad2/3</g>, p-<g>Smad2/3</g>, <g>ERK1/2</g>, p-<g>ERK1/2</g> and p-JNK were examined by western blotting. The results indicated that IL-17 can induce A549 cells to undergo morphological changes and phenotypic markers changes, such as down-regulated E-cad expression and up-regulated a-SMA expression. Additionally, IL-17 enhanced <g>TGF-b1</g> expression and stimulated <g>Smad2/3</g> and <g>ERK1/2</g> phosphorylation in A549 cells. However, there were no significant differences in the expression of phosphorylated JNK in A549 cells with or without IL-17 treatment. SB431542 or U0126 treated cells showed inhibited morphological changes and phenotypic markers expression, such as up-regulated E-cad expression and down-regulated a-SMA expression. In summary, our results suggest that IL-17 can induce A549 alveolar epithelial cells to undergo EMT via the <g>TGF-b1</g> mediated <g>Smad2/3</g> and <g>ERK1/2</g> activation.
28922731|a|Fibroblast is believed to be the primary effector in <d>idiopathic pulmonary fibrosis</d> IPF, a progressive lung disorder characterized by aberrant tissue remodeling and the formation of fibroblastic foci. Due to the complicated etiology and mechanism, there are few effective drugs for this fatal disease. Shikonin SHI, which is the major ingredient isolated from the plant Lithospermum Erythrorhizon, has long been used as traditional medicine for many diseases including inflammation and cancer. The roles of SHI in attenuating skin scar and renal fibrosis by reducing TGFb1-stimulated fibroblast activation are also reported. But whether SHI works on IPF which exhibits both inflammatory and carcinoma-like features remains unknown. In this study, using isolated pulmonary fibroblasts, we demonstrated that SHI inhibited the proliferation, migration of fibroblasts, enhanced cell apoptosis and led to cell cycle arrest at G1 and G2/M phase. Moreover, SHI reduced the production of a-SMA, fibronectin, collagen I and III in response to TGF-b induction in pulmonary fibroblasts, and all of these gene production is the key component of extracellular matrix for tissue remodeling for IPF. The phosphorylation of <g>Akt</g> was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments. The phosphorylation of both <g>p38</g> MAPK and <g>Akt</g> stimulated by TGF-b was reduced after SHI treatments. Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting <g>Akt</g> activation signaling pathway, and attenuates TGF-b induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of <g>p38</g> MAPK and <g>Akt</g>. SHI might serve as a therapeutically candidate for IPF patients.
28922731|a|Fibroblast is believed to be the primary effector in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a progressive lung disorder characterized by aberrant tissue remodeling and the formation of fibroblastic foci. Due to the complicated etiology and mechanism, there are few effective drugs for this fatal disease. Shikonin SHI, which is the major ingredient isolated from the plant Lithospermum Erythrorhizon, has long been used as traditional medicine for many diseases including inflammation and cancer. The roles of SHI in attenuating skin scar and renal fibrosis by reducing TGFb1-stimulated fibroblast activation are also reported. But whether SHI works on <d>IPF</d> which exhibits both inflammatory and carcinoma-like features remains unknown. In this study, using isolated pulmonary fibroblasts, we demonstrated that SHI inhibited the proliferation, migration of fibroblasts, enhanced cell apoptosis and led to cell cycle arrest at G1 and G2/M phase. Moreover, SHI reduced the production of a-SMA, fibronectin, collagen I and III in response to TGF-b induction in pulmonary fibroblasts, and all of these gene production is the key component of extracellular matrix for tissue remodeling for <d>IPF</d>. The phosphorylation of <g>Akt</g> was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments. The phosphorylation of both <g>p38</g> MAPK and <g>Akt</g> stimulated by TGF-b was reduced after SHI treatments. Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting <g>Akt</g> activation signaling pathway, and attenuates TGF-b induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of <g>p38</g> MAPK and <g>Akt</g>. SHI might serve as a therapeutically candidate for <d>IPF</d> patients.
28922731|a|Fibroblast is believed to be the primary effector in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive lung disorder</d> characterized by aberrant tissue remodeling and the formation of fibroblastic foci. Due to the complicated etiology and mechanism, there are few effective drugs for this fatal disease. Shikonin SHI, which is the major ingredient isolated from the plant Lithospermum Erythrorhizon, has long been used as traditional medicine for many diseases including inflammation and cancer. The roles of SHI in attenuating skin scar and renal fibrosis by reducing TGFb1-stimulated fibroblast activation are also reported. But whether SHI works on <d>IPF</d> which exhibits both inflammatory and carcinoma-like features remains unknown. In this study, using isolated pulmonary fibroblasts, we demonstrated that SHI inhibited the proliferation, migration of fibroblasts, enhanced cell apoptosis and led to cell cycle arrest at G1 and G2/M phase. Moreover, SHI reduced the production of a-SMA, fibronectin, collagen I and III in response to TGF-b induction in pulmonary fibroblasts, and all of these gene production is the key component of extracellular matrix for tissue remodeling for <d>IPF</d>. The phosphorylation of <g>Akt</g> was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments. The phosphorylation of both <g>p38</g> MAPK and <g>Akt</g> stimulated by TGF-b was reduced after SHI treatments. Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting <g>Akt</g> activation signaling pathway, and attenuates TGF-b induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of <g>p38</g> MAPK and <g>Akt</g>. SHI might serve as a therapeutically candidate for <d>IPF</d> patients.
28922731|a|Fibroblast is believed to be the primary effector in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive lung disorder</d> characterized by aberrant tissue remodeling and the formation of fibroblastic foci. Due to the complicated etiology and mechanism, there are few effective drugs for this fatal disease. Shikonin SHI, which is the major ingredient isolated from the plant Lithospermum Erythrorhizon, has long been used as traditional medicine for many diseases including <d>inflammation</d> and cancer. The roles of SHI in attenuating skin scar and renal fibrosis by reducing TGFb1-stimulated fibroblast activation are also reported. But whether SHI works on <d>IPF</d> which exhibits both inflammatory and carcinoma-like features remains unknown. In this study, using isolated pulmonary fibroblasts, we demonstrated that SHI inhibited the proliferation, migration of fibroblasts, enhanced cell apoptosis and led to cell cycle arrest at G1 and G2/M phase. Moreover, SHI reduced the production of a-SMA, fibronectin, collagen I and III in response to TGF-b induction in pulmonary fibroblasts, and all of these gene production is the key component of extracellular matrix for tissue remodeling for <d>IPF</d>. The phosphorylation of <g>Akt</g> was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments. The phosphorylation of both <g>p38</g> MAPK and <g>Akt</g> stimulated by TGF-b was reduced after SHI treatments. Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting <g>Akt</g> activation signaling pathway, and attenuates TGF-b induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of <g>p38</g> MAPK and <g>Akt</g>. SHI might serve as a therapeutically candidate for <d>IPF</d> patients.
28922731|a|Fibroblast is believed to be the primary effector in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive lung disorder</d> characterized by aberrant tissue remodeling and the formation of fibroblastic foci. Due to the complicated etiology and mechanism, there are few effective drugs for this fatal disease. Shikonin SHI, which is the major ingredient isolated from the plant Lithospermum Erythrorhizon, has long been used as traditional medicine for many diseases including <d>inflammation</d> and <d>cancer</d>. The roles of SHI in attenuating skin scar and renal fibrosis by reducing TGFb1-stimulated fibroblast activation are also reported. But whether SHI works on <d>IPF</d> which exhibits both inflammatory and carcinoma-like features remains unknown. In this study, using isolated pulmonary fibroblasts, we demonstrated that SHI inhibited the proliferation, migration of fibroblasts, enhanced cell apoptosis and led to cell cycle arrest at G1 and G2/M phase. Moreover, SHI reduced the production of a-SMA, fibronectin, collagen I and III in response to TGF-b induction in pulmonary fibroblasts, and all of these gene production is the key component of extracellular matrix for tissue remodeling for <d>IPF</d>. The phosphorylation of <g>Akt</g> was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments. The phosphorylation of both <g>p38</g> MAPK and <g>Akt</g> stimulated by TGF-b was reduced after SHI treatments. Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting <g>Akt</g> activation signaling pathway, and attenuates TGF-b induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of <g>p38</g> MAPK and <g>Akt</g>. SHI might serve as a therapeutically candidate for <d>IPF</d> patients.
28922731|a|Fibroblast is believed to be the primary effector in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive lung disorder</d> characterized by aberrant tissue remodeling and the formation of fibroblastic foci. Due to the complicated etiology and mechanism, there are few effective drugs for this fatal disease. Shikonin SHI, which is the major ingredient isolated from the plant Lithospermum Erythrorhizon, has long been used as traditional medicine for many diseases including <d>inflammation</d> and <d>cancer</d>. The roles of SHI in attenuating <d>skin scar</d> and renal fibrosis by reducing TGFb1-stimulated fibroblast activation are also reported. But whether SHI works on <d>IPF</d> which exhibits both inflammatory and carcinoma-like features remains unknown. In this study, using isolated pulmonary fibroblasts, we demonstrated that SHI inhibited the proliferation, migration of fibroblasts, enhanced cell apoptosis and led to cell cycle arrest at G1 and G2/M phase. Moreover, SHI reduced the production of a-SMA, fibronectin, collagen I and III in response to TGF-b induction in pulmonary fibroblasts, and all of these gene production is the key component of extracellular matrix for tissue remodeling for <d>IPF</d>. The phosphorylation of <g>Akt</g> was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments. The phosphorylation of both <g>p38</g> MAPK and <g>Akt</g> stimulated by TGF-b was reduced after SHI treatments. Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting <g>Akt</g> activation signaling pathway, and attenuates TGF-b induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of <g>p38</g> MAPK and <g>Akt</g>. SHI might serve as a therapeutically candidate for <d>IPF</d> patients.
28922731|a|Fibroblast is believed to be the primary effector in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive lung disorder</d> characterized by aberrant tissue remodeling and the formation of fibroblastic foci. Due to the complicated etiology and mechanism, there are few effective drugs for this fatal disease. Shikonin SHI, which is the major ingredient isolated from the plant Lithospermum Erythrorhizon, has long been used as traditional medicine for many diseases including <d>inflammation</d> and <d>cancer</d>. The roles of SHI in attenuating <d>skin scar</d> and <d>renal fibrosis</d> by reducing TGFb1-stimulated fibroblast activation are also reported. But whether SHI works on <d>IPF</d> which exhibits both inflammatory and carcinoma-like features remains unknown. In this study, using isolated pulmonary fibroblasts, we demonstrated that SHI inhibited the proliferation, migration of fibroblasts, enhanced cell apoptosis and led to cell cycle arrest at G1 and G2/M phase. Moreover, SHI reduced the production of a-SMA, fibronectin, collagen I and III in response to TGF-b induction in pulmonary fibroblasts, and all of these gene production is the key component of extracellular matrix for tissue remodeling for <d>IPF</d>. The phosphorylation of <g>Akt</g> was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments. The phosphorylation of both <g>p38</g> MAPK and <g>Akt</g> stimulated by TGF-b was reduced after SHI treatments. Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting <g>Akt</g> activation signaling pathway, and attenuates TGF-b induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of <g>p38</g> MAPK and <g>Akt</g>. SHI might serve as a therapeutically candidate for <d>IPF</d> patients.
28922731|a|Fibroblast is believed to be the primary effector in <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>, a <d>progressive lung disorder</d> characterized by aberrant tissue remodeling and the formation of fibroblastic foci. Due to the complicated etiology and mechanism, there are few effective drugs for this fatal disease. Shikonin SHI, which is the major ingredient isolated from the plant Lithospermum Erythrorhizon, has long been used as traditional medicine for many diseases including <d>inflammation</d> and <d>cancer</d>. The roles of SHI in attenuating <d>skin scar</d> and <d>renal fibrosis</d> by reducing <g>TGFb1</g>-stimulated fibroblast activation are also reported. But whether SHI works on <d>IPF</d> which exhibits both inflammatory and <d>carcinoma</d>-like features remains unknown. In this study, using isolated pulmonary fibroblasts, we demonstrated that SHI inhibited the proliferation, migration of fibroblasts, enhanced cell apoptosis and led to cell cycle arrest at G1 and G2/M phase. Moreover, SHI reduced the production of a-SMA, fibronectin, collagen I and III in response to TGF-b induction in pulmonary fibroblasts, and all of these gene production is the key component of extracellular matrix for tissue remodeling for <d>IPF</d>. The phosphorylation of <g>Akt</g> was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments. The phosphorylation of both <g>p38</g> MAPK and <g>Akt</g> stimulated by TGF-b was reduced after SHI treatments. Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting <g>Akt</g> activation signaling pathway, and attenuates TGF-b induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of <g>p38</g> MAPK and <g>Akt</g>. SHI might serve as a therapeutically candidate for <d>IPF</d> patients.
29019702|a|Organ <d>fibrosis</d>, including idiopathic pulmonary <d>fibrosis</d> IPF, is associated with significant morbidity and mortality. Since currently available therapies have limited effect, there is need to better understand the mechanisms by which organ <d>fibrosis</d> occurs. We have recently reported that TGF-b, a key cytokine which promotes fibrogenesis, induces the expression of the enzymes of the de novo serine and glycine synthesis pathway in human lung fibroblasts and that phosphoglycerate dehydrogenase <g>PHGDH</g>, the first and rate limiting enzyme of the pathway is required to promote collagen protein synthesis downstream of TGF-b. In this study, we investigated whether inhibition of de novo serine and glycine synthesis attenuates lung <d>fibrosis</d> in vivo. We found that TGF-b induces mRNA and protein expression of <g>PHGDH</g> in murine fibroblasts. Similarly, intratracheal administration of bleomycin resulted in increased expression of <g>PHGDH</g> in mouse lungs, localized to fibrotic regions. Using a newly developed small molecule inhibitor of <g>PHGDH</g> NCT-503, we tested whether pharmacologic inhibition of <g>PHGDH</g> could inhibit fibrogenesis both in vitro and in vivo. Treatment of murine and human lung fibroblasts with NCT-503 decreased TGF-b-induced collagen protein synthesis. Mice treated with the <g>PHGDH</g> inhibitor beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung <d>fibrosis</d>. These results indicate that the de novo serine synthesis pathway is necessary for TGF-b-induced collagen synthesis and bleomycin-induced pulmonary <d>fibrosis</d>. <g>PHGDH</g> and other enzymes in the de novo serine synthesis pathway may be a therapeutic target for treatment of fibrotic diseases, including IPF.
29019702|a|Organ <d>fibrosis</d>, including idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, is associated with significant morbidity and mortality. Since currently available therapies have limited effect, there is need to better understand the mechanisms by which organ <d>fibrosis</d> occurs. We have recently reported that TGF-b, a key cytokine which promotes fibrogenesis, induces the expression of the enzymes of the de novo serine and glycine synthesis pathway in human lung fibroblasts and that phosphoglycerate dehydrogenase <g>PHGDH</g>, the first and rate limiting enzyme of the pathway is required to promote collagen protein synthesis downstream of TGF-b. In this study, we investigated whether inhibition of de novo serine and glycine synthesis attenuates lung <d>fibrosis</d> in vivo. We found that TGF-b induces mRNA and protein expression of <g>PHGDH</g> in murine fibroblasts. Similarly, intratracheal administration of bleomycin resulted in increased expression of <g>PHGDH</g> in mouse lungs, localized to fibrotic regions. Using a newly developed small molecule inhibitor of <g>PHGDH</g> NCT-503, we tested whether pharmacologic inhibition of <g>PHGDH</g> could inhibit fibrogenesis both in vitro and in vivo. Treatment of murine and human lung fibroblasts with NCT-503 decreased TGF-b-induced collagen protein synthesis. Mice treated with the <g>PHGDH</g> inhibitor beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung <d>fibrosis</d>. These results indicate that the de novo serine synthesis pathway is necessary for TGF-b-induced collagen synthesis and bleomycin-induced pulmonary <d>fibrosis</d>. <g>PHGDH</g> and other enzymes in the de novo serine synthesis pathway may be a therapeutic target for treatment of fibrotic diseases, including <d>IPF</d>.
29019702|a|Organ <d>fibrosis</d>, including idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, is associated with significant morbidity and mortality. Since currently available therapies have limited effect, there is need to better understand the mechanisms by which organ <d>fibrosis</d> occurs. We have recently reported that <g>TGF-b</g>, a key cytokine which promotes fibrogenesis, induces the expression of the enzymes of the de novo serine and glycine synthesis pathway in human lung fibroblasts and that <g>phosphoglycerate dehydrogenase</g> <g>PHGDH</g>, the first and rate limiting enzyme of the pathway is required to promote collagen protein synthesis downstream of <g>TGF-b</g>. In this study, we investigated whether inhibition of de novo serine and glycine synthesis attenuates lung <d>fibrosis</d> in vivo. We found that <g>TGF-b</g> induces mRNA and protein expression of <g>PHGDH</g> in murine fibroblasts. Similarly, intratracheal administration of bleomycin resulted in increased expression of <g>PHGDH</g> in mouse lungs, localized to fibrotic regions. Using a newly developed small molecule inhibitor of <g>PHGDH</g> NCT-503, we tested whether pharmacologic inhibition of <g>PHGDH</g> could inhibit fibrogenesis both in vitro and in vivo. Treatment of murine and human lung fibroblasts with NCT-503 decreased <g>TGF-b</g>-induced collagen protein synthesis. Mice treated with the <g>PHGDH</g> inhibitor beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung <d>fibrosis</d>. These results indicate that the de novo serine synthesis pathway is necessary for <g>TGF-b</g>-induced collagen synthesis and bleomycin-induced pulmonary <d>fibrosis</d>. <g>PHGDH</g> and other enzymes in the de novo serine synthesis pathway may be a therapeutic target for treatment of <d>fibrotic diseases</d>, including <d>IPF</d>.
29031221|a|OBJECTIVE: To investigate the impacts of particulate matter 2.5 PM2.5 from straw burning on the acute exacerbation of <d>lung fibrosis</d> in mice and the preventive effects of N-acetylcysteine NAC. METHODS: The composition, particle size, and 30-min concentration change in an exposure system of the PM2.5 from straw-burning were determined. Forty C57BL male mice were equally randomized to two groups: bleomycin BLM-induced <d>lung fibrosis</d> with an exposure to air BLM+air and BLM+PM2.5 groups. On day 7 after receiving intratracheal injection of BLM, mice were exposed to air or PM2.5 in an exposure system for 30min twice daily and then sacrificed after one-week or four-week exposure 10 mice/group. Mouse survival, lung histopathology, macrophage accumulation in the lung, and pro-inflammatory cytokine levels in alveolar lavage fluid ALF were determined. RESULTS: PM2.5 from straw burning were mainly composed of organic matter 74.1%; 10.92% of the inorganic matter of the PM2.5 were chloride ion; 4.64% were potassium ion; other components were sulfate, nitrate, and nitrite. Particle size was 10nm-2 m. Histopathology revealed a greater extent of inflammatory cell infiltration in the lung, widened alveolar septum, and <d>lung fibrosis</d> in the BLM+PM2.5 group than in the BLM+air group and a greater extent of those adverse effects after four-week than after one-week exposure to PM2.5. The BLM+PM2.5 group also showed macrophages containing particular matter and increased pulmonary collagen deposition as the exposure to PM2.5 increased. Interleukin IL-6 and TNF-a levels in ALF were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05 and significantly higher after four-week exposure than after one-week exposure to PM2.5 P<0.05. TGF-b levels in ALF after four-week exposure were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05. The levels of IL-6, TNF-a, and TGF-b in peripheral serum were not significantly different in the BLM+PM2.5 and BLM+air groups. Lung hydroxyproline contents increased as the exposure to PM2.5 increased and were significantly higher after four-week than after one-week exposure P=0.019. Exposure to PM2.5 did not affect the survival of normal mice 100% but reduced the survival of mice with BLM-induced IPF 30%, whereas NAC extended the survival 70%, vs. BLM+PM2.5, P=0.032. CONCLUSION: Exposure of mice with BLM-induced IPF to PM2.5 from straw burning exacerbated lung inflammation and fibrosis and increased mortality; NAC increased the mouse survival, indicating protective effects.
29031221|a|OBJECTIVE: To investigate the impacts of particulate matter 2.5 PM2.5 from straw burning on the acute exacerbation of <d>lung fibrosis</d> in mice and the preventive effects of N-acetylcysteine NAC. METHODS: The composition, particle size, and 30-min concentration change in an exposure system of the PM2.5 from straw-burning were determined. Forty C57BL male mice were equally randomized to two groups: bleomycin BLM-induced <d>lung fibrosis</d> with an exposure to air BLM+air and BLM+PM2.5 groups. On day 7 after receiving intratracheal injection of BLM, mice were exposed to air or PM2.5 in an exposure system for 30min twice daily and then sacrificed after one-week or four-week exposure 10 mice/group. Mouse survival, lung histopathology, macrophage accumulation in the lung, and pro-inflammatory cytokine levels in <d>alveolar lavage fluid</d> ALF were determined. RESULTS: PM2.5 from straw burning were mainly composed of organic matter 74.1%; 10.92% of the inorganic matter of the PM2.5 were chloride ion; 4.64% were potassium ion; other components were sulfate, nitrate, and nitrite. Particle size was 10nm-2 m. Histopathology revealed a greater extent of inflammatory cell infiltration in the lung, widened alveolar septum, and <d>lung fibrosis</d> in the BLM+PM2.5 group than in the BLM+air group and a greater extent of those adverse effects after four-week than after one-week exposure to PM2.5. The BLM+PM2.5 group also showed macrophages containing particular matter and increased pulmonary collagen deposition as the exposure to PM2.5 increased. Interleukin IL-6 and TNF-a levels in ALF were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05 and significantly higher after four-week exposure than after one-week exposure to PM2.5 P<0.05. TGF-b levels in ALF after four-week exposure were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05. The levels of IL-6, TNF-a, and TGF-b in peripheral serum were not significantly different in the BLM+PM2.5 and BLM+air groups. Lung hydroxyproline contents increased as the exposure to PM2.5 increased and were significantly higher after four-week than after one-week exposure P=0.019. Exposure to PM2.5 did not affect the survival of normal mice 100% but reduced the survival of mice with BLM-induced IPF 30%, whereas NAC extended the survival 70%, vs. BLM+PM2.5, P=0.032. CONCLUSION: Exposure of mice with BLM-induced IPF to PM2.5 from straw burning exacerbated lung inflammation and fibrosis and increased mortality; NAC increased the mouse survival, indicating protective effects.
29031221|a|OBJECTIVE: To investigate the impacts of particulate matter 2.5 PM2.5 from straw burning on the acute exacerbation of <d>lung fibrosis</d> in mice and the preventive effects of N-acetylcysteine NAC. METHODS: The composition, particle size, and 30-min concentration change in an exposure system of the PM2.5 from straw-burning were determined. Forty C57BL male mice were equally randomized to two groups: bleomycin BLM-induced <d>lung fibrosis</d> with an exposure to air BLM+air and BLM+PM2.5 groups. On day 7 after receiving intratracheal injection of BLM, mice were exposed to air or PM2.5 in an exposure system for 30min twice daily and then sacrificed after one-week or four-week exposure 10 mice/group. Mouse survival, lung histopathology, macrophage accumulation in the lung, and pro-inflammatory cytokine levels in <d>alveolar lavage fluid</d> <d>ALF</d> were determined. RESULTS: PM2.5 from straw burning were mainly composed of organic matter 74.1%; 10.92% of the inorganic matter of the PM2.5 were chloride ion; 4.64% were potassium ion; other components were sulfate, nitrate, and nitrite. Particle size was 10nm-2 m. Histopathology revealed a greater extent of inflammatory cell infiltration in the lung, widened alveolar septum, and <d>lung fibrosis</d> in the BLM+PM2.5 group than in the BLM+air group and a greater extent of those adverse effects after four-week than after one-week exposure to PM2.5. The BLM+PM2.5 group also showed macrophages containing particular matter and increased pulmonary collagen deposition as the exposure to PM2.5 increased. Interleukin IL-6 and TNF-a levels in <d>ALF</d> were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05 and significantly higher after four-week exposure than after one-week exposure to PM2.5 P<0.05. TGF-b levels in <d>ALF</d> after four-week exposure were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05. The levels of IL-6, TNF-a, and TGF-b in peripheral serum were not significantly different in the BLM+PM2.5 and BLM+air groups. Lung hydroxyproline contents increased as the exposure to PM2.5 increased and were significantly higher after four-week than after one-week exposure P=0.019. Exposure to PM2.5 did not affect the survival of normal mice 100% but reduced the survival of mice with BLM-induced IPF 30%, whereas NAC extended the survival 70%, vs. BLM+PM2.5, P=0.032. CONCLUSION: Exposure of mice with BLM-induced IPF to PM2.5 from straw burning exacerbated lung inflammation and fibrosis and increased mortality; NAC increased the mouse survival, indicating protective effects.
29031221|a|OBJECTIVE: To investigate the impacts of particulate matter 2.5 PM2.5 from straw burning on the acute exacerbation of <d>lung fibrosis</d> in mice and the preventive effects of N-acetylcysteine NAC. METHODS: The composition, particle size, and 30-min concentration change in an exposure system of the PM2.5 from straw-burning were determined. Forty C57BL male mice were equally randomized to two groups: bleomycin BLM-induced <d>lung fibrosis</d> with an exposure to air BLM+air and BLM+PM2.5 groups. On day 7 after receiving intratracheal injection of BLM, mice were exposed to air or PM2.5 in an exposure system for 30min twice daily and then sacrificed after one-week or four-week exposure 10 mice/group. Mouse survival, lung histopathology, macrophage accumulation in the lung, and pro-inflammatory cytokine levels in <d>alveolar lavage fluid</d> <d>ALF</d> were determined. RESULTS: PM2.5 from straw burning were mainly composed of organic matter 74.1%; 10.92% of the inorganic matter of the PM2.5 were chloride ion; 4.64% were potassium ion; other components were sulfate, nitrate, and nitrite. Particle size was 10nm-2 m. Histopathology revealed a greater extent of inflammatory cell infiltration in the lung, widened <d>alveolar septum</d>, and <d>lung fibrosis</d> in the BLM+PM2.5 group than in the BLM+air group and a greater extent of those adverse effects after four-week than after one-week exposure to PM2.5. The BLM+PM2.5 group also showed macrophages containing particular matter and increased pulmonary collagen deposition as the exposure to PM2.5 increased. Interleukin IL-6 and TNF-a levels in <d>ALF</d> were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05 and significantly higher after four-week exposure than after one-week exposure to PM2.5 P<0.05. TGF-b levels in <d>ALF</d> after four-week exposure were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05. The levels of IL-6, TNF-a, and TGF-b in peripheral serum were not significantly different in the BLM+PM2.5 and BLM+air groups. Lung hydroxyproline contents increased as the exposure to PM2.5 increased and were significantly higher after four-week than after one-week exposure P=0.019. Exposure to PM2.5 did not affect the survival of normal mice 100% but reduced the survival of mice with BLM-induced IPF 30%, whereas NAC extended the survival 70%, vs. BLM+PM2.5, P=0.032. CONCLUSION: Exposure of mice with BLM-induced IPF to PM2.5 from straw burning exacerbated lung inflammation and fibrosis and increased mortality; NAC increased the mouse survival, indicating protective effects.
29031221|a|OBJECTIVE: To investigate the impacts of particulate matter 2.5 PM2.5 from straw burning on the acute exacerbation of <d>lung fibrosis</d> in mice and the preventive effects of N-acetylcysteine NAC. METHODS: The composition, particle size, and 30-min concentration change in an exposure system of the PM2.5 from straw-burning were determined. Forty C57BL male mice were equally randomized to two groups: bleomycin BLM-induced <d>lung fibrosis</d> with an exposure to air BLM+air and BLM+PM2.5 groups. On day 7 after receiving intratracheal injection of BLM, mice were exposed to air or PM2.5 in an exposure system for 30min twice daily and then sacrificed after one-week or four-week exposure 10 mice/group. Mouse survival, lung histopathology, macrophage accumulation in the lung, and pro-inflammatory cytokine levels in <d>alveolar lavage fluid</d> <d>ALF</d> were determined. RESULTS: PM2.5 from straw burning were mainly composed of organic matter 74.1%; 10.92% of the inorganic matter of the PM2.5 were chloride ion; 4.64% were potassium ion; other components were sulfate, nitrate, and nitrite. Particle size was 10nm-2 m. Histopathology revealed a greater extent of inflammatory cell infiltration in the lung, widened <d>alveolar septum</d>, and <d>lung fibrosis</d> in the BLM+PM2.5 group than in the BLM+air group and a greater extent of those adverse effects after four-week than after one-week exposure to PM2.5. The BLM+PM2.5 group also showed macrophages containing particular matter and increased pulmonary collagen deposition as the exposure to PM2.5 increased. <g>Interleukin <g>IL-6</g></g> and <g>TNF-a</g> levels in <d>ALF</d> were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05 and significantly higher after four-week exposure than after one-week exposure to PM2.5 P<0.05. <g>TGF-b</g> levels in <d>ALF</d> after four-week exposure were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05. The levels of <g>IL-6</g>, <g>TNF-a</g>, and <g>TGF-b</g> in peripheral serum were not significantly different in the BLM+PM2.5 and BLM+air groups. Lung hydroxyproline contents increased as the exposure to PM2.5 increased and were significantly higher after four-week than after one-week exposure P=0.019. Exposure to PM2.5 did not affect the survival of normal mice 100% but reduced the survival of mice with BLM-induced <d>IPF</d> 30%, whereas NAC extended the survival 70%, vs. BLM+PM2.5, P=0.032. CONCLUSION: Exposure of mice with BLM-induced <d>IPF</d> to PM2.5 from straw burning exacerbated lung inflammation and fibrosis and increased mortality; NAC increased the mouse survival, indicating protective effects.
29031221|a|OBJECTIVE: To investigate the impacts of particulate matter 2.5 PM2.5 from straw burning on the acute exacerbation of <d>lung fibrosis</d> in mice and the preventive effects of N-acetylcysteine NAC. METHODS: The composition, particle size, and 30-min concentration change in an exposure system of the PM2.5 from straw-burning were determined. Forty C57BL male mice were equally randomized to two groups: bleomycin BLM-induced <d>lung fibrosis</d> with an exposure to air BLM+air and BLM+PM2.5 groups. On day 7 after receiving intratracheal injection of BLM, mice were exposed to air or PM2.5 in an exposure system for 30min twice daily and then sacrificed after one-week or four-week exposure 10 mice/group. Mouse survival, lung histopathology, macrophage accumulation in the lung, and pro-inflammatory cytokine levels in <d>alveolar lavage fluid</d> <d>ALF</d> were determined. RESULTS: PM2.5 from straw burning were mainly composed of organic matter 74.1%; 10.92% of the inorganic matter of the PM2.5 were chloride ion; 4.64% were potassium ion; other components were sulfate, nitrate, and nitrite. Particle size was 10nm-2 m. Histopathology revealed a greater extent of inflammatory cell infiltration in the lung, widened <d>alveolar septum</d>, and <d>lung fibrosis</d> in the BLM+PM2.5 group than in the BLM+air group and a greater extent of those adverse effects after four-week than after one-week exposure to PM2.5. The BLM+PM2.5 group also showed macrophages containing particular matter and increased pulmonary collagen deposition as the exposure to PM2.5 increased. <g>Interleukin <g>IL-6</g></g> and <g>TNF-a</g> levels in <d>ALF</d> were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05 and significantly higher after four-week exposure than after one-week exposure to PM2.5 P<0.05. <g>TGF-b</g> levels in <d>ALF</d> after four-week exposure were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05. The levels of <g>IL-6</g>, <g>TNF-a</g>, and <g>TGF-b</g> in peripheral serum were not significantly different in the BLM+PM2.5 and BLM+air groups. Lung hydroxyproline contents increased as the exposure to PM2.5 increased and were significantly higher after four-week than after one-week exposure P=0.019. Exposure to PM2.5 did not affect the survival of normal mice 100% but reduced the survival of mice with BLM-induced <d>IPF</d> 30%, whereas NAC extended the survival 70%, vs. BLM+PM2.5, P=0.032. CONCLUSION: Exposure of mice with BLM-induced <d>IPF</d> to PM2.5 from straw burning exacerbated <d>lung inflammation</d> and fibrosis and increased mortality; NAC increased the mouse survival, indicating protective effects.
29031221|a|OBJECTIVE: To investigate the impacts of particulate matter 2.5 PM2.5 from straw burning on the acute exacerbation of <d>lung <d>fibrosis</d></d> in mice and the preventive effects of N-acetylcysteine NAC. METHODS: The composition, particle size, and 30-min concentration change in an exposure system of the PM2.5 from straw-burning were determined. Forty C57BL male mice were equally randomized to two groups: bleomycin BLM-induced <d>lung <d>fibrosis</d></d> with an exposure to air BLM+air and BLM+PM2.5 groups. On day 7 after receiving intratracheal injection of BLM, mice were exposed to air or PM2.5 in an exposure system for 30min twice daily and then sacrificed after one-week or four-week exposure 10 mice/group. Mouse survival, lung histopathology, macrophage accumulation in the lung, and pro-inflammatory cytokine levels in <d>alveolar lavage fluid</d> <d>ALF</d> were determined. RESULTS: PM2.5 from straw burning were mainly composed of organic matter 74.1%; 10.92% of the inorganic matter of the PM2.5 were chloride ion; 4.64% were potassium ion; other components were sulfate, nitrate, and nitrite. Particle size was 10nm-2 m. Histopathology revealed a greater extent of inflammatory cell infiltration in the lung, widened <d>alveolar septum</d>, and <d>lung <d>fibrosis</d></d> in the BLM+PM2.5 group than in the BLM+air group and a greater extent of those adverse effects after four-week than after one-week exposure to PM2.5. The BLM+PM2.5 group also showed macrophages containing particular matter and increased pulmonary collagen deposition as the exposure to PM2.5 increased. <g>Interleukin <g>IL-6</g></g> and <g>TNF-a</g> levels in <d>ALF</d> were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05 and significantly higher after four-week exposure than after one-week exposure to PM2.5 P<0.05. <g>TGF-b</g> levels in <d>ALF</d> after four-week exposure were significantly higher in the BLM+PM2.5 group than in the BLM+air group P<0.05. The levels of <g>IL-6</g>, <g>TNF-a</g>, and <g>TGF-b</g> in peripheral serum were not significantly different in the BLM+PM2.5 and BLM+air groups. Lung hydroxyproline contents increased as the exposure to PM2.5 increased and were significantly higher after four-week than after one-week exposure P=0.019. Exposure to PM2.5 did not affect the survival of normal mice 100% but reduced the survival of mice with BLM-induced <d>IPF</d> 30%, whereas NAC extended the survival 70%, vs. BLM+PM2.5, P=0.032. CONCLUSION: Exposure of mice with BLM-induced <d>IPF</d> to PM2.5 from straw burning exacerbated <d>lung inflammation</d> and <d>fibrosis</d> and increased mortality; NAC increased the mouse survival, indicating protective effects.
29045477|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> IPF is a chronic, progressive and fatal disease. Histone deacetylase 6 HDAC6 alters function and fate of various proteins via deacetylation of lysine residues, and is implicated in TGF-b1-induced EMT epithelial-mesenchymal transition. However, the role of HDAC6 in <d>pulmonary fibrosis</d> is unknown. METHODS: HDAC6 expression in IPF and control lungs was assessed by quantitative real-time PCR qRT-PCR and immunoblots. Lung fibroblasts were treated with TGF-b1    HDAC6 inhibitors Tubacin, Tubastatin, ACY1215, or MC1568, and fibrotic markers such as type I collagen were assessed using qRT-PCR and immunoblots. Mice were treated with bleomycin oropharyngeal aspiration; single dose    Tubastatin intraperitoneally injection; daily for 21 days, and lung collagen expression was gauged using immunoblots and trichrome staining. In a separate experiment, HDAC6 wild-type WT and knockout KO mice were administered bleomycin, and lungs were evaluated in the same manner. RESULTS: HDAC6 expression was deregulated in IPF lungs. Among the HDAC6 inhibitors tested, only Tubastatin significantly repressed TGF-b1-induced expression of type-1 collagen in lung fibroblasts, and this finding was coupled with decreased Akt phosphorylation and increased Akt-PHLPP PH domain and Leucine rich repeat Protein Phosphatase association. Tubastatin repressed TGF-b1-induced S6K phosphorylation, HIF-1a expression, and VEGF expression. Tubastatin also repressed TGF-b1-induced inhibition of LC3B-II a marker of autophagosome formation. In bleomycin-treated mouse lungs, HDAC6 expression was increased, and Tubastatin repressed type-1 collagen expression. However, in HDAC6 KO mice, bleomycin-induced type-1 collagen expression was not repressed compared to WT mice. Knockdown of HDAC6, as well as HDAC10, another potential Tubastatin target, did not inhibit TGF-b1-induced collagen expression in lung fibroblasts. CONCLUSIONS: HDAC6 expression is altered during lung fibrogenesis. Tubastatin represses TGF-b1-induced collagen expression, by diminishing Akt phosphorylation and regulating downstream targets such as HIF-1a-VEGF axis and autophagy. Tubastatin-treated WT mice are protected against bleomycin-induced fibrosis, but HDAC6 KO mice are not. Our data suggest that Tubastatin ameliorates <d>pulmonary fibrosis</d>, by targeting the TGFb-PI3K-Akt pathway, likely via an HDAC6-independent mechanism.
29045477|a|BACKGROUND: Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> is a chronic, progressive and fatal disease. Histone deacetylase 6 HDAC6 alters function and fate of various proteins via deacetylation of lysine residues, and is implicated in TGF-b1-induced EMT epithelial-mesenchymal transition. However, the role of HDAC6 in <d>pulmonary fibrosis</d> is unknown. METHODS: HDAC6 expression in <d>IPF</d> and control lungs was assessed by quantitative real-time PCR qRT-PCR and immunoblots. Lung fibroblasts were treated with TGF-b1    HDAC6 inhibitors Tubacin, Tubastatin, ACY1215, or MC1568, and fibrotic markers such as type I collagen were assessed using qRT-PCR and immunoblots. Mice were treated with bleomycin oropharyngeal aspiration; single dose    Tubastatin intraperitoneally injection; daily for 21 days, and lung collagen expression was gauged using immunoblots and trichrome staining. In a separate experiment, HDAC6 wild-type WT and knockout KO mice were administered bleomycin, and lungs were evaluated in the same manner. RESULTS: HDAC6 expression was deregulated in <d>IPF</d> lungs. Among the HDAC6 inhibitors tested, only Tubastatin significantly repressed TGF-b1-induced expression of type-1 collagen in lung fibroblasts, and this finding was coupled with decreased <g>Akt</g> phosphorylation and increased <g>Akt</g>-PHLPP PH domain and Leucine rich repeat Protein Phosphatase association. Tubastatin repressed TGF-b1-induced S6K phosphorylation, HIF-1a expression, and VEGF expression. Tubastatin also repressed TGF-b1-induced inhibition of LC3B-II a marker of autophagosome formation. In bleomycin-treated mouse lungs, HDAC6 expression was increased, and Tubastatin repressed type-1 collagen expression. However, in HDAC6 KO mice, bleomycin-induced type-1 collagen expression was not repressed compared to WT mice. Knockdown of HDAC6, as well as HDAC10, another potential Tubastatin target, did not inhibit TGF-b1-induced collagen expression in lung fibroblasts. CONCLUSIONS: HDAC6 expression is altered during lung fibrogenesis. Tubastatin represses TGF-b1-induced collagen expression, by diminishing <g>Akt</g> phosphorylation and regulating downstream targets such as HIF-1a-VEGF axis and autophagy. Tubastatin-treated WT mice are protected against bleomycin-induced fibrosis, but HDAC6 KO mice are not. Our data suggest that Tubastatin ameliorates <d>pulmonary fibrosis</d>, by targeting the TGFb-PI3K-<g>Akt</g> pathway, likely via an HDAC6-independent mechanism.
29045477|a|BACKGROUND: Idiopathic <d>pulmonary <d>fibrosis</d></d> <d>IPF</d> is a chronic, progressive and fatal disease. <g>Histone deacetylase 6</g> <g>HDAC6</g> alters function and fate of various proteins via deacetylation of lysine residues, and is implicated in <g>TGF-b1</g>-induced EMT epithelial-mesenchymal transition. However, the role of <g>HDAC6</g> in <d>pulmonary <d>fibrosis</d></d> is unknown. METHODS: <g>HDAC6</g> expression in <d>IPF</d> and control lungs was assessed by quantitative real-time PCR qRT-PCR and immunoblots. Lung fibroblasts were treated with <g>TGF-b1</g>    <g>HDAC6</g> inhibitors Tubacin, Tubastatin, ACY1215, or MC1568, and fibrotic markers such as type I collagen were assessed using qRT-PCR and immunoblots. Mice were treated with bleomycin oropharyngeal aspiration; single dose    Tubastatin intraperitoneally injection; daily for 21 days, and lung collagen expression was gauged using immunoblots and trichrome staining. In a separate experiment, <g>HDAC6</g> wild-type WT and knockout KO mice were administered bleomycin, and lungs were evaluated in the same manner. RESULTS: <g>HDAC6</g> expression was deregulated in <d>IPF</d> lungs. Among the <g>HDAC6</g> inhibitors tested, only Tubastatin significantly repressed <g>TGF-b1</g>-induced expression of type-1 collagen in lung fibroblasts, and this finding was coupled with decreased <g>Akt</g> phosphorylation and increased <g>Akt</g>-<g>PHLPP</g> PH domain and Leucine rich repeat Protein Phosphatase association. Tubastatin repressed <g>TGF-b1</g>-induced S6K phosphorylation, <g>HIF-1a</g> expression, and <g>VEGF</g> expression. Tubastatin also repressed <g>TGF-b1</g>-induced inhibition of LC3B-II a marker of autophagosome formation. In bleomycin-treated mouse lungs, <g>HDAC6</g> expression was increased, and Tubastatin repressed type-1 collagen expression. However, in <g>HDAC6</g> KO mice, bleomycin-induced type-1 collagen expression was not repressed compared to WT mice. Knockdown of <g>HDAC6</g>, as well as <g>HDAC10</g>, another potential Tubastatin target, did not inhibit <g>TGF-b1</g>-induced collagen expression in lung fibroblasts. CONCLUSIONS: <g>HDAC6</g> expression is altered during lung fibrogenesis. Tubastatin represses <g>TGF-b1</g>-induced collagen expression, by diminishing <g>Akt</g> phosphorylation and regulating downstream targets such as <g>HIF-1a</g>-<g>VEGF</g> axis and autophagy. Tubastatin-treated WT mice are protected against bleomycin-induced <d>fibrosis</d>, but <g>HDAC6</g> KO mice are not. Our data suggest that Tubastatin ameliorates <d>pulmonary <d>fibrosis</d></d>, by targeting the TGFb-PI3K-<g>Akt</g> pathway, likely via an <g>HDAC6</g>-independent mechanism.
29046395|a|The contribution of epithelial-to-mesenchymal transition EMT to the pro-fibrotic stiff microenvironment and myofibroblast accumulation in pulmonary <d>fibrosis</d> remains unclear. We examined EMT-competent lung epithelial cells and lung fibroblasts from control <d>fibrosis</d>-free donors or patients with idiopathic pulmonary <d>fibrosis</d> IPF, which is a very aggressive fibrotic disorder. Cells were cultured on pro-fibrotic conditions including stiff substrata and TGF-b1, and analyzed in terms of morphology, stiffness and expression of EMT/myofibroblast markers and fibrillar collagens. All fibroblasts acquired a robust myofibroblast phenotype upon TGF-b1 stimulation. Yet, IPF-myofibroblasts exhibited higher stiffness and expression of fibrillar collagens than control fibroblasts, concomitantly with enhanced FAKY397 activity. FAK inhibition was sufficient to decrease fibroblast stiffness and collagen expression, supporting that FAKY397 hyperactivation may underlie the aberrant mechanobiology of IPF-fibroblasts. In contrast, cells undergoing EMT failed to reach the values exhibited by IPF-myofibroblasts in all parameters examined. Likewise, EMT could be distinguished from non-activated control fibroblasts, suggesting that EMT does not elicit myofibroblast precursors either. Our data suggest that EMT does not contribute directly to the myofibroblast population, and may contribute to the stiff fibrotic microenvironment through their own stiffness but not their collagen expression. Our results also support that targeting FAKY397 may rescue normal mechanobiology in IPF.
29046395|a|The contribution of epithelial-to-mesenchymal transition EMT to the pro-fibrotic stiff microenvironment and myofibroblast accumulation in pulmonary <d>fibrosis</d> remains unclear. We examined EMT-competent lung epithelial cells and lung fibroblasts from control <d>fibrosis</d>-free donors or patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, which is a very aggressive fibrotic disorder. Cells were cultured on pro-fibrotic conditions including stiff substrata and TGF-b1, and analyzed in terms of morphology, stiffness and expression of EMT/myofibroblast markers and fibrillar collagens. All fibroblasts acquired a robust myofibroblast phenotype upon TGF-b1 stimulation. Yet, <d>IPF</d>-myofibroblasts exhibited higher stiffness and expression of fibrillar collagens than control fibroblasts, concomitantly with enhanced FAKY397 activity. FAK inhibition was sufficient to decrease fibroblast stiffness and collagen expression, supporting that FAKY397 hyperactivation may underlie the aberrant mechanobiology of <d>IPF</d>-fibroblasts. In contrast, cells undergoing EMT failed to reach the values exhibited by <d>IPF</d>-myofibroblasts in all parameters examined. Likewise, EMT could be distinguished from non-activated control fibroblasts, suggesting that EMT does not elicit myofibroblast precursors either. Our data suggest that EMT does not contribute directly to the myofibroblast population, and may contribute to the stiff fibrotic microenvironment through their own stiffness but not their collagen expression. Our results also support that targeting FAKY397 may rescue normal mechanobiology in <d>IPF</d>.
29046395|a|The contribution of epithelial-to-mesenchymal transition EMT to the pro-fibrotic stiff microenvironment and myofibroblast accumulation in pulmonary <d>fibrosis</d> remains unclear. We examined EMT-competent lung epithelial cells and lung fibroblasts from control <d>fibrosis</d>-free donors or patients with idiopathic pulmonary <d>fibrosis</d> <d>IPF</d>, which is a <d>very aggressive fibrotic disorder</d>. Cells were cultured on pro-fibrotic conditions including stiff substrata and TGF-b1, and analyzed in terms of morphology, stiffness and expression of EMT/myofibroblast markers and fibrillar collagens. All fibroblasts acquired a robust myofibroblast phenotype upon TGF-b1 stimulation. Yet, <d>IPF</d>-myofibroblasts exhibited higher stiffness and expression of fibrillar collagens than control fibroblasts, concomitantly with enhanced FAKY397 activity. FAK inhibition was sufficient to decrease fibroblast stiffness and collagen expression, supporting that FAKY397 hyperactivation may underlie the aberrant mechanobiology of <d>IPF</d>-fibroblasts. In contrast, cells undergoing EMT failed to reach the values exhibited by <d>IPF</d>-myofibroblasts in all parameters examined. Likewise, EMT could be distinguished from non-activated control fibroblasts, suggesting that EMT does not elicit myofibroblast precursors either. Our data suggest that EMT does not contribute directly to the myofibroblast population, and may contribute to the stiff fibrotic microenvironment through their own stiffness but not their collagen expression. Our results also support that targeting FAKY397 may rescue normal mechanobiology in <d>IPF</d>.
29067109|a|The differentiation of fibroblasts to myofibroblasts is critical for the development of idiopathic <d>pulmonary fibrosis</d> IPF. T-cell lymphoma invasion and metastasis 1 <g>TIAM1</g> is known to be associated with amyotrophic lateral sclerosis 1 and colorectal cancer; however, its role in IPF is unclear. The aim of the present study was to investigate the expression and roles of <g>TIAM1</g> in lung fibroblasts during <d>pulmonary fibrosis</d>. It was demonstrated that <g>TIAM1</g> expression was significantly increased in fibrotic lung tissue and lung fibroblasts from bleomycin BLM-treated mice compared with control mice P<0.05. <g>TIAM1</g> expression and differentiation were significantly upregulated in human lung fibroblasts challenged with transforming growth factor-b TGF-b compared with unchallenged cells P<0.05. Furthermore, inhibition of the nuclear factor NF-kB signaling pathway significantly attenuated TGF-b-induced <g>TIAM1</g> expression and decreased fibroblast differentiation in human lung fibroblasts P<0.05. Similarly, overexpression of <g>TIAM1</g> significantly inhibited TGF-b-induced fibroblast differentiation, as indicated by decreased expression of fibronectin and a-smooth muscle actin SMA; P<0.05. The results of the present study also demonstrated that <g>TIAM1</g> knockdown increased TGF-b-induced fibroblast differentiation P<0.05. These findings suggest that <g>TIAM1</g> expression is associated with lung fibroblast differentiation in <d>pulmonary fibrosis</d> via an NF-kB-dependent pathway, and that <g>TIAM1</g> inhibits lung fibroblast differentiation in <d>pulmonary fibrosis</d>.
29067109|a|The differentiation of fibroblasts to myofibroblasts is critical for the development of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. T-cell lymphoma invasion and metastasis 1 <g>TIAM1</g> is known to be associated with amyotrophic lateral sclerosis 1 and colorectal cancer; however, its role in <d>IPF</d> is unclear. The aim of the present study was to investigate the expression and roles of <g>TIAM1</g> in lung fibroblasts during <d>pulmonary fibrosis</d>. It was demonstrated that <g>TIAM1</g> expression was significantly increased in fibrotic lung tissue and lung fibroblasts from bleomycin BLM-treated mice compared with control mice P<0.05. <g>TIAM1</g> expression and differentiation were significantly upregulated in human lung fibroblasts challenged with transforming growth factor-b TGF-b compared with unchallenged cells P<0.05. Furthermore, inhibition of the nuclear factor NF-kB signaling pathway significantly attenuated TGF-b-induced <g>TIAM1</g> expression and decreased fibroblast differentiation in human lung fibroblasts P<0.05. Similarly, overexpression of <g>TIAM1</g> significantly inhibited TGF-b-induced fibroblast differentiation, as indicated by decreased expression of fibronectin and a-smooth muscle actin SMA; P<0.05. The results of the present study also demonstrated that <g>TIAM1</g> knockdown increased TGF-b-induced fibroblast differentiation P<0.05. These findings suggest that <g>TIAM1</g> expression is associated with lung fibroblast differentiation in <d>pulmonary fibrosis</d> via an NF-kB-dependent pathway, and that <g>TIAM1</g> inhibits lung fibroblast differentiation in <d>pulmonary fibrosis</d>.
29067109|a|The differentiation of fibroblasts to myofibroblasts is critical for the development of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. <g>T-cell lymphoma invasion and metastasis 1</g> <g>TIAM1</g> is known to be associated with <d>amyotrophic lateral sclerosis</d> 1 and colorectal cancer; however, its role in <d>IPF</d> is unclear. The aim of the present study was to investigate the expression and roles of <g>TIAM1</g> in lung fibroblasts during <d>pulmonary fibrosis</d>. It was demonstrated that <g>TIAM1</g> expression was significantly increased in fibrotic lung tissue and lung fibroblasts from bleomycin BLM-treated mice compared with control mice P<0.05. <g>TIAM1</g> expression and differentiation were significantly upregulated in human lung fibroblasts challenged with transforming growth factor-b TGF-b compared with unchallenged cells P<0.05. Furthermore, inhibition of the nuclear factor NF-kB signaling pathway significantly attenuated TGF-b-induced <g>TIAM1</g> expression and decreased fibroblast differentiation in human lung fibroblasts P<0.05. Similarly, overexpression of <g>TIAM1</g> significantly inhibited TGF-b-induced fibroblast differentiation, as indicated by decreased expression of fibronectin and a-smooth muscle actin SMA; P<0.05. The results of the present study also demonstrated that <g>TIAM1</g> knockdown increased TGF-b-induced fibroblast differentiation P<0.05. These findings suggest that <g>TIAM1</g> expression is associated with lung fibroblast differentiation in <d>pulmonary fibrosis</d> via an NF-kB-dependent pathway, and that <g>TIAM1</g> inhibits lung fibroblast differentiation in <d>pulmonary fibrosis</d>.
29067109|a|The differentiation of fibroblasts to myofibroblasts is critical for the development of idiopathic <d>pulmonary fibrosis</d> <d>IPF</d>. <g>T-cell lymphoma invasion and metastasis 1</g> <g>TIAM1</g> is known to be associated with <d>amyotrophic lateral sclerosis</d> 1 and <d>colorectal cancer</d>; however, its role in <d>IPF</d> is unclear. The aim of the present study was to investigate the expression and roles of <g>TIAM1</g> in lung fibroblasts during <d>pulmonary fibrosis</d>. It was demonstrated that <g>TIAM1</g> expression was significantly increased in fibrotic lung tissue and lung fibroblasts from bleomycin BLM-treated mice compared with control mice P<0.05. <g>TIAM1</g> expression and differentiation were significantly upregulated in human lung fibroblasts challenged with transforming growth factor-b TGF-b compared with unchallenged cells P<0.05. Furthermore, inhibition of the nuclear factor NF-kB signaling pathway significantly attenuated TGF-b-induced <g>TIAM1</g> expression and decreased fibroblast differentiation in human lung fibroblasts P<0.05. Similarly, overexpression of <g>TIAM1</g> significantly inhibited TGF-b-induced fibroblast differentiation, as indicated by decreased expression of fibronectin and a-smooth muscle actin SMA; P<0.05. The results of the present study also demonstrated that <g>TIAM1</g> knockdown increased TGF-b-induced fibroblast differentiation P<0.05. These findings suggest that <g>TIAM1</g> expression is associated with lung fibroblast differentiation in <d>pulmonary fibrosis</d> via an NF-kB-dependent pathway, and that <g>TIAM1</g> inhibits lung fibroblast differentiation in <d>pulmonary fibrosis</d>.
29113323|a|Idiopathic <d>pulmonary fibrosis</d> IPF and idiopathic nonspecific interstitial pneumonia INSIP are two related diseases involving varying degrees of <d>pulmonary fibrosis</d> with no effective cure. Bone morphogenetic protein 3 <g>BMP3</g> is a member of the transforming growth factor-b TGF-b super-family, which has not been implicated in <d>pulmonary fibrosis</d> previously. In this study, we aimed to investigate the potential role of <g>BMP3</g> playing in <d>pulmonary fibrosis</d> from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of <g>BMP3</g> was evaluated in 83 cases of IPF and INSIP by immunohistochemistry. The function of <g>BMP3</g> was investigated in both fibroblast cells and a bleomycin-induced murine <d>pulmonary fibrosis</d> model. The clinical relevance of <g>BMP3</g> expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that <g>BMP3</g> was significantly down-regulated in lung tissues of patients with IPF and INSIP. Consistently, lower expression of <g>BMP3</g> also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of <g>BMP3</g> prevented <d>pulmonary fibrosis</d> processing through inhibiting cellular proliferation of fibroblasts as well as TGF-b1 signal transduction. Finally, the relatively higher expression of <g>BMP3</g> in IPF patients was associated with less/worse mortality. Intravenous injection of recombinant <g>BMP3</g>. Taken together, our results suggested that the low expression level of <g>BMP3</g> may indicate the unfavorable prognosis of IPF patients, targeting <g>BMP3</g> may represent a novel potential therapeutic method for <d>pulmonary fibrosis</d> management.
29113323|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> and idiopathic nonspecific interstitial pneumonia INSIP are two related diseases involving varying degrees of <d>pulmonary fibrosis</d> with no effective cure. Bone morphogenetic protein 3 <g>BMP3</g> is a member of the transforming growth factor-b TGF-b super-family, which has not been implicated in <d>pulmonary fibrosis</d> previously. In this study, we aimed to investigate the potential role of <g>BMP3</g> playing in <d>pulmonary fibrosis</d> from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of <g>BMP3</g> was evaluated in 83 cases of <d>IPF</d> and INSIP by immunohistochemistry. The function of <g>BMP3</g> was investigated in both fibroblast cells and a bleomycin-induced murine <d>pulmonary fibrosis</d> model. The clinical relevance of <g>BMP3</g> expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that <g>BMP3</g> was significantly down-regulated in lung tissues of patients with <d>IPF</d> and INSIP. Consistently, lower expression of <g>BMP3</g> also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of <g>BMP3</g> prevented <d>pulmonary fibrosis</d> processing through inhibiting cellular proliferation of fibroblasts as well as TGF-b1 signal transduction. Finally, the relatively higher expression of <g>BMP3</g> in <d>IPF</d> patients was associated with less/worse mortality. Intravenous injection of recombinant <g>BMP3</g>. Taken together, our results suggested that the low expression level of <g>BMP3</g> may indicate the unfavorable prognosis of <d>IPF</d> patients, targeting <g>BMP3</g> may represent a novel potential therapeutic method for <d>pulmonary fibrosis</d> management.
29113323|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> and <d>idiopathic nonspecific interstitial pneumonia</d> INSIP are two related diseases involving varying degrees of <d>pulmonary fibrosis</d> with no effective cure. Bone morphogenetic protein 3 <g>BMP3</g> is a member of the transforming growth factor-b TGF-b super-family, which has not been implicated in <d>pulmonary fibrosis</d> previously. In this study, we aimed to investigate the potential role of <g>BMP3</g> playing in <d>pulmonary fibrosis</d> from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of <g>BMP3</g> was evaluated in 83 cases of <d>IPF</d> and INSIP by immunohistochemistry. The function of <g>BMP3</g> was investigated in both fibroblast cells and a bleomycin-induced murine <d>pulmonary fibrosis</d> model. The clinical relevance of <g>BMP3</g> expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that <g>BMP3</g> was significantly down-regulated in lung tissues of patients with <d>IPF</d> and INSIP. Consistently, lower expression of <g>BMP3</g> also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of <g>BMP3</g> prevented <d>pulmonary fibrosis</d> processing through inhibiting cellular proliferation of fibroblasts as well as TGF-b1 signal transduction. Finally, the relatively higher expression of <g>BMP3</g> in <d>IPF</d> patients was associated with less/worse mortality. Intravenous injection of recombinant <g>BMP3</g>. Taken together, our results suggested that the low expression level of <g>BMP3</g> may indicate the unfavorable prognosis of <d>IPF</d> patients, targeting <g>BMP3</g> may represent a novel potential therapeutic method for <d>pulmonary fibrosis</d> management.
29113323|a|Idiopathic <d>pulmonary fibrosis</d> <d>IPF</d> and <d>idiopathic nonspecific interstitial pneumonia</d> <d>INSIP</d> are two related diseases involving varying degrees of <d>pulmonary fibrosis</d> with no effective cure. Bone morphogenetic protein 3 <g>BMP3</g> is a member of the transforming growth factor-b TGF-b super-family, which has not been implicated in <d>pulmonary fibrosis</d> previously. In this study, we aimed to investigate the potential role of <g>BMP3</g> playing in <d>pulmonary fibrosis</d> from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of <g>BMP3</g> was evaluated in 83 cases of <d>IPF</d> and <d>INSIP</d> by immunohistochemistry. The function of <g>BMP3</g> was investigated in both fibroblast cells and a bleomycin-induced murine <d>pulmonary fibrosis</d> model. The clinical relevance of <g>BMP3</g> expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that <g>BMP3</g> was significantly down-regulated in lung tissues of patients with <d>IPF</d> and <d>INSIP</d>. Consistently, lower expression of <g>BMP3</g> also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of <g>BMP3</g> prevented <d>pulmonary fibrosis</d> processing through inhibiting cellular proliferation of fibroblasts as well as TGF-b1 signal transduction. Finally, the relatively higher expression of <g>BMP3</g> in <d>IPF</d> patients was associated with less/worse mortality. Intravenous injection of recombinant <g>BMP3</g>. Taken together, our results suggested that the low expression level of <g>BMP3</g> may indicate the unfavorable prognosis of <d>IPF</d> patients, targeting <g>BMP3</g> may represent a novel potential therapeutic method for <d>pulmonary fibrosis</d> management.
29118928|a|<d>Idiopathic pulmonary fibrosis</d> IPF is a devastating disease and the pathogenesis of IPF remains unclear. Our previous study indicated that miR-5100 promotes the proliferation and metastasis of lung epithelial cells. In this study, we investigated the effect and mechanism of miR-5100 on bleomycin BLM-induced mouse lung fibrosis and transforming growth factor b TGF-b1 or epidermal growth factor EGF induced EMT-model in A549 and Beas-2B cells. The elevated level of miR-5100 was observed in both the mouse lung fibrosis tissues and EMT cell model. Furthermore, the exogenous expression of miR-5100 promoted the EMT-related changes, enhanced TGF-b1 or EGF-induced EMT and activated the <g>smad2/3</g> in lung epithelial cells, while silencing miR-5100 had the converse effects. In addition, transwell assay showed that miR-5100 can enhance cell migration. Using target prediction software and luciferase reporter assays, we identified <g>TOB2</g> as a specific target of miR-5100 and miR-5100 can decrease the accumulation of endogenous <g>TOB2</g> in A549 and Beas-2B cells. Moreover, the exogenous expression of <g>TOB2</g> relieves the promotion of miR-5100 on EMT process and migration ability. Taken together, our results indicate that miR-5100 promotes the EMT process by targeting <g>TOB2</g> associated with activating <g>smad2/3</g> in lung epithlium cells. Our findings may provide novel insights into the pathogenesis of IPF.
29118928|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating disease and the pathogenesis of <d>IPF</d> remains unclear. Our previous study indicated that miR-5100 promotes the proliferation and metastasis of lung epithelial cells. In this study, we investigated the effect and mechanism of miR-5100 on bleomycin BLM-induced mouse lung fibrosis and transforming growth factor b TGF-b1 or epidermal growth factor EGF induced EMT-model in A549 and Beas-2B cells. The elevated level of miR-5100 was observed in both the mouse lung fibrosis tissues and EMT cell model. Furthermore, the exogenous expression of miR-5100 promoted the EMT-related changes, enhanced TGF-b1 or EGF-induced EMT and activated the <g>smad2/3</g> in lung epithelial cells, while silencing miR-5100 had the converse effects. In addition, transwell assay showed that miR-5100 can enhance cell migration. Using target prediction software and luciferase reporter assays, we identified <g>TOB2</g> as a specific target of miR-5100 and miR-5100 can decrease the accumulation of endogenous <g>TOB2</g> in A549 and Beas-2B cells. Moreover, the exogenous expression of <g>TOB2</g> relieves the promotion of miR-5100 on EMT process and migration ability. Taken together, our results indicate that miR-5100 promotes the EMT process by targeting <g>TOB2</g> associated with activating <g>smad2/3</g> in lung epithlium cells. Our findings may provide novel insights into the pathogenesis of <d>IPF</d>.
29118928|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is a devastating disease and the pathogenesis of <d>IPF</d> remains unclear. Our previous study indicated that <g>miR-5100</g> promotes the proliferation and <d>metastasis</d> of lung epithelial cells. In this study, we investigated the effect and mechanism of <g>miR-5100</g> on bleomycin BLM-induced mouse lung fibrosis and transforming growth factor b TGF-b1 or epidermal growth factor EGF induced EMT-model in A549 and Beas-2B cells. The elevated level of <g>miR-5100</g> was observed in both the mouse lung fibrosis tissues and EMT cell model. Furthermore, the exogenous expression of <g>miR-5100</g> promoted the EMT-related changes, enhanced TGF-b1 or EGF-induced EMT and activated the <g>smad2/3</g> in lung epithelial cells, while silencing <g>miR-5100</g> had the converse effects. In addition, transwell assay showed that <g>miR-5100</g> can enhance cell migration. Using target prediction software and luciferase reporter assays, we identified <g>TOB2</g> as a specific target of <g>miR-5100</g> and <g>miR-5100</g> can decrease the accumulation of endogenous <g>TOB2</g> in A549 and Beas-2B cells. Moreover, the exogenous expression of <g>TOB2</g> relieves the promotion of <g>miR-5100</g> on EMT process and migration ability. Taken together, our results indicate that <g>miR-5100</g> promotes the EMT process by targeting <g>TOB2</g> associated with activating <g>smad2/3</g> in lung epithlium cells. Our findings may provide novel insights into the pathogenesis of <d>IPF</d>.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic pulmonary diseases including chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD chronic obstructive pulmonary disease CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic pulmonary fibrosis ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD chronic obstructive pulmonary disease CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic pulmonary fibrosis ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, asthma and pulmonary fibrosis. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic pulmonary fibrosis ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and pulmonary fibrosis. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic pulmonary fibrosis ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic <d>pulmonary fibrosis</d> ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic <d>pulmonary fibrosis</d> ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic <d>pulmonary fibrosis</d> ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic <d>pulmonary fibrosis</d> ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic <d>pulmonary fibrosis</d> ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related <d>CF cystic fibrosis</d> CFTR cystic fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic <d>pulmonary fibrosis</d> ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related <d>CF <d>cystic</d> fibrosis</d> CFTR <d>cystic</d> fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic <d>pulmonary fibrosis</d> ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related <d>CF <d>cystic</d> fibrosis</d> CFTR <d>cystic</d> fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent <d>hypoxia</d> IPF idiopathic <d>pulmonary fibrosis</d> ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related <d>CF <d>cystic</d> fibrosis</d> CFTR <d>cystic</d> fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent <d>hypoxia</d> IPF idiopathic <d>pulmonary fibrosis</d> ILD <d>interstitial lung disease</d> MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related <d>CF <d>cystic</d> fibrosis</d> CFTR <d>cystic</d> fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent <d>hypoxia</d> IPF idiopathic <d>pulmonary fibrosis</d> ILD <d>interstitial lung disease</d> MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps <d>OSA obstructive sleep apnea</d> PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related <d>CF <d>cystic</d> fibrosis</d> CFTR <d>cystic</d> fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent <d>hypoxia</d> IPF idiopathic <d>pulmonary fibrosis</d> ILD <d>interstitial lung disease</d> MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps <d>OSA obstructive sleep apnea</d> PAH <d>pulmonary arterial hypertension</d> PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related <d>CF <d>cystic</d> fibrosis</d> CFTR <d>cystic</d> fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent <d>hypoxia</d> IPF idiopathic <d>pulmonary fibrosis</d> ILD <d>interstitial lung disease</d> MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps <d>OSA obstructive sleep apnea</d> PAH <d>pulmonary arterial hypertension</d> PH <d>pulmonary hypertension</d> ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related <d>CF <d>cystic</d> fibrosis</d> CFTR <d>cystic</d> fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent <d>hypoxia</d> IPF idiopathic <d>pulmonary fibrosis</d> ILD <d>interstitial lung disease</d> MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps <d>OSA obstructive sleep apnea</d> PAH <d>pulmonary arterial hypertension</d> PH <d>pulmonary hypertension</d> ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF <d>tumor</d> necrosis factor.
29130366|a|Persistent <d>inflammation</d> within the respiratory tract underlies the pathogenesis of numerous chronic <d>pulmonary diseases</d> including <d>chronic obstructive pulmonary disease</d>, <d>asthma</d> and <d>pulmonary fibrosis</d>. Chronic <d>inflammation</d> in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to <d>infection</d> and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary <d>inflammation</d> and fundamental for the response of pulmonary leukocytes to <d>infection</d>; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting <d>lung injury</d>. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic <d>lung diseases</d> with a focus on potential avenues for therapeutic targeting. Abbreviations <d>AR allergic rhinitis</d> AM alveolar macrophage ATG autophagy-related <d>CF <d>cystic</d> fibrosis</d> CFTR <d>cystic</d> fibrosis transmembrane conductance regulator COPD <d>chronic obstructive pulmonary disease</d> CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent <d>hypoxia</d> IPF idiopathic <d>pulmonary fibrosis</d> ILD <d>interstitial lung disease</d> MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps <d>OSA obstructive sleep apnea</d> PAH <d>pulmonary arterial hypertension</d> PH <d>pulmonary hypertension</d> ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF <d>tumor</d> <d>necrosis</d> factor.
29144435|a|<d>Idiopathic pulmonary fibrosis</d> IPF is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and <g>TGF-b1</g> cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from IPF patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide PAA gels. We found that <g>TGF-b1</g> consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the <g>FAK</g>/<g>Akt</g> pathway, whereas <g>FAK</g> depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and <g>TGF-b1</g> that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by <g>TGF-b1</g> alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger <g>FAK</g> and <g>Akt</g> activities in the former cells. These findings provide new insights on how matrix stiffening and <g>TGF-b1</g> cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the <g>FAK</g>/<g>Akt</g> pathway in this cooperation.
29144435|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and <g>TGF-b1</g> cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from <d>IPF</d> patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide PAA gels. We found that <g>TGF-b1</g> consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the <g>FAK</g>/<g>Akt</g> pathway, whereas <g>FAK</g> depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and <g>TGF-b1</g> that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by <g>TGF-b1</g> alone or synergistically with matrix stiffening were higher in <d>IPF</d>-fibroblasts compared to control fibroblasts in association with larger <g>FAK</g> and <g>Akt</g> activities in the former cells. These findings provide new insights on how matrix stiffening and <g>TGF-b1</g> cooperate to elicit excessive collagen-I deposition in <d>IPF</d>, and support a major role of the <g>FAK</g>/<g>Akt</g> pathway in this cooperation.
29144435|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is an <d>aggressive disease</d> in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and <g>TGF-b1</g> cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from <d>IPF</d> patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide PAA gels. We found that <g>TGF-b1</g> consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the <g>FAK</g>/<g>Akt</g> pathway, whereas <g>FAK</g> depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and <g>TGF-b1</g> that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by <g>TGF-b1</g> alone or synergistically with matrix stiffening were higher in <d>IPF</d>-fibroblasts compared to control fibroblasts in association with larger <g>FAK</g> and <g>Akt</g> activities in the former cells. These findings provide new insights on how matrix stiffening and <g>TGF-b1</g> cooperate to elicit excessive collagen-I deposition in <d>IPF</d>, and support a major role of the <g>FAK</g>/<g>Akt</g> pathway in this cooperation.
29144435|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is an <d>aggressive disease</d> in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and <g>TGF-b1</g> cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from <d>IPF</d> patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide PAA gels. We found that <g>TGF-b1</g> consistently increased <g>COL1A1</g> while decreasing <g>MMP1</g> mRNA levels in hydrogels exhibiting pre-fibrotic or <d>fibrotic-like rigidities</d> concomitantly with an enhanced activation of the <g>FAK</g>/<g>Akt</g> pathway, whereas <g>FAK</g> depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and <g>TGF-b1</g> that was positive for <g>COL1A1</g> and negative for <g>MMP1</g>. Remarkably, the <g>COL1A1</g> expression upregulation elicited by <g>TGF-b1</g> alone or synergistically with matrix stiffening were higher in <d>IPF</d>-fibroblasts compared to control fibroblasts in association with larger <g>FAK</g> and <g>Akt</g> activities in the former cells. These findings provide new insights on how matrix stiffening and <g>TGF-b1</g> cooperate to elicit excessive collagen-I deposition in <d>IPF</d>, and support a major role of the <g>FAK</g>/<g>Akt</g> pathway in this cooperation.
29195901|a|<d>Idiopathic pulmonary fibrosis</d> IPF and tumor are highly similar to abnormal cell proliferation that damages the body. This malignant cell evolution in a stressful environment closely resembles that of epithelial-mesenchymal transition EMT. As a popular EMT-inducing factor, TGFb plays an important role in the progression of multiple diseases. However, the drugs that target <g>TGFB1</g> are limited. In this study, we found that triptolide TPL, a Chinese medicine extract, exerts an anti-lung fibrosis effect by inhibiting the EMT of lung epithelial cells. In addition, triptolide directly binds to TGFb and subsequently increase E-cadherin expression and decrease vimentin expression. In in vivo studies, TPL improves the survival state and inhibits lung fibrosis in mice. In summary, this study revealed the potential therapeutic effect of paraquat induced TPL in lung fibrosis by regulating TGFb-dependent EMT progression.
29195901|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> and tumor are highly similar to abnormal cell proliferation that damages the body. This malignant cell evolution in a stressful environment closely resembles that of epithelial-mesenchymal transition EMT. As a popular EMT-inducing factor, TGFb plays an important role in the progression of multiple diseases. However, the drugs that target <g>TGFB1</g> are limited. In this study, we found that triptolide TPL, a Chinese medicine extract, exerts an anti-lung fibrosis effect by inhibiting the EMT of lung epithelial cells. In addition, triptolide directly binds to TGFb and subsequently increase E-cadherin expression and decrease vimentin expression. In in vivo studies, TPL improves the survival state and inhibits lung fibrosis in mice. In summary, this study revealed the potential therapeutic effect of paraquat induced TPL in lung fibrosis by regulating TGFb-dependent EMT progression.
29195901|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>tumor</d> are highly similar to abnormal cell proliferation that damages the body. This malignant cell evolution in a stressful environment closely resembles that of epithelial-mesenchymal transition EMT. As a popular EMT-inducing factor, TGFb plays an important role in the progression of multiple diseases. However, the drugs that target <g>TGFB1</g> are limited. In this study, we found that triptolide TPL, a Chinese medicine extract, exerts an anti-lung fibrosis effect by inhibiting the EMT of lung epithelial cells. In addition, triptolide directly binds to TGFb and subsequently increase E-cadherin expression and decrease vimentin expression. In in vivo studies, TPL improves the survival state and inhibits lung fibrosis in mice. In summary, this study revealed the potential therapeutic effect of paraquat induced TPL in lung fibrosis by regulating TGFb-dependent EMT progression.
29195901|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> and <d>tumor</d> are highly similar to abnormal cell proliferation that damages the body. This malignant cell evolution in a stressful environment closely resembles that of epithelial-mesenchymal transition EMT. As a popular EMT-inducing factor, <g>TGFb</g> plays an important role in the progression of <d>multiple diseases</d>. However, the drugs that target <g>TGFB1</g> are limited. In this study, we found that triptolide TPL, a Chinese medicine extract, exerts an anti-lung fibrosis effect by inhibiting the EMT of lung epithelial cells. In addition, triptolide directly binds to <g>TGFb</g> and subsequently increase E-cadherin expression and decrease vimentin expression. In in vivo studies, TPL improves the survival state and inhibits lung fibrosis in mice. In summary, this study revealed the potential therapeutic effect of paraquat induced TPL in lung fibrosis by regulating <g>TGFb</g>-dependent EMT progression.
29195901|a|<d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> and <d>tumor</d> are highly similar to abnormal cell proliferation that damages the body. This malignant cell evolution in a stressful environment closely resembles that of epithelial-mesenchymal transition EMT. As a popular EMT-inducing factor, <g>TGFb</g> plays an important role in the progression of <d>multiple diseases</d>. However, the drugs that target <g>TGFB1</g> are limited. In this study, we found that triptolide TPL, a Chinese medicine extract, exerts an anti-lung <d>fibrosis</d> effect by inhibiting the EMT of lung epithelial cells. In addition, triptolide directly binds to <g>TGFb</g> and subsequently increase E-cadherin expression and decrease vimentin expression. In in vivo studies, TPL improves the survival state and inhibits lung <d>fibrosis</d> in mice. In summary, this study revealed the potential therapeutic effect of paraquat induced TPL in lung <d>fibrosis</d> by regulating <g>TGFb</g>-dependent EMT progression.
29279415|a|TGF-b has an important role in fibrotic diseases, including idiopathic pulmonary fibrosis IPF. Detailed analysis of TGF-b signaling in pulmonary fibrosis at the molecular level is needed to identify novel therapeutic targets. Recently, leucine-rich alpha-2 glycoprotein LRG was reported to function as a modulator of TGF-b signaling in angiogenesis and tumor progression. However, the involvement of LRG in fibrotic disorders, including IPF, has not yet been investigated. In this study, we investigated the role of LRG in fibrosis by analyzing LRG knockout KO mice with bleomycin-induced <d>lung fibrosis</d>, an animal model of pulmonary fibrosis. The amount of LRG in the lungs of wild-type WT mice was increased by bleomycin administration prior to fibrosis development. In LRG KO mice, <d>lung fibrosis</d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of LRG KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in WT mice. In vitro experiments indicated that LRG enhanced the TGF-b-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory TGF-b receptor, is essential for LRG to promote TGF-b signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of LRG to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that LRG promotes <d>lung fibrosis</d> by modulating TGF-b-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29279415|a|<g>TGF-b</g> has an important role in <d>fibrotic diseases</d>, including idiopathic pulmonary fibrosis IPF. Detailed analysis of <g>TGF-b</g> signaling in pulmonary fibrosis at the molecular level is needed to identify novel therapeutic targets. Recently, leucine-rich alpha-2 glycoprotein LRG was reported to function as a modulator of <g>TGF-b</g> signaling in angiogenesis and tumor progression. However, the involvement of LRG in fibrotic disorders, including IPF, has not yet been investigated. In this study, we investigated the role of LRG in fibrosis by analyzing LRG knockout KO mice with bleomycin-induced <d>lung fibrosis</d>, an animal model of pulmonary fibrosis. The amount of LRG in the lungs of wild-type WT mice was increased by bleomycin administration prior to fibrosis development. In LRG KO mice, <d>lung fibrosis</d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of LRG KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in WT mice. In vitro experiments indicated that LRG enhanced the <g>TGF-b</g>-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory <g>TGF-b</g> receptor, is essential for LRG to promote <g>TGF-b</g> signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of LRG to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that LRG promotes <d>lung fibrosis</d> by modulating <g>TGF-b</g>-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29279415|a|<g>TGF-b</g> has an important role in <d>fibrotic diseases</d>, including <d>idiopathic pulmonary fibrosis</d> IPF. Detailed analysis of <g>TGF-b</g> signaling in pulmonary fibrosis at the molecular level is needed to identify novel therapeutic targets. Recently, leucine-rich alpha-2 glycoprotein LRG was reported to function as a modulator of <g>TGF-b</g> signaling in angiogenesis and tumor progression. However, the involvement of LRG in fibrotic disorders, including IPF, has not yet been investigated. In this study, we investigated the role of LRG in fibrosis by analyzing LRG knockout KO mice with bleomycin-induced <d>lung fibrosis</d>, an animal model of pulmonary fibrosis. The amount of LRG in the lungs of wild-type WT mice was increased by bleomycin administration prior to fibrosis development. In LRG KO mice, <d>lung fibrosis</d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of LRG KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in WT mice. In vitro experiments indicated that LRG enhanced the <g>TGF-b</g>-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory <g>TGF-b</g> receptor, is essential for LRG to promote <g>TGF-b</g> signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of LRG to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that LRG promotes <d>lung fibrosis</d> by modulating <g>TGF-b</g>-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29279415|a|<g>TGF-b</g> has an important role in <d>fibrotic diseases</d>, including <d>idiopathic pulmonary fibrosis</d> <d>IPF</d>. Detailed analysis of <g>TGF-b</g> signaling in pulmonary fibrosis at the molecular level is needed to identify novel therapeutic targets. Recently, leucine-rich alpha-2 glycoprotein LRG was reported to function as a modulator of <g>TGF-b</g> signaling in angiogenesis and tumor progression. However, the involvement of LRG in fibrotic disorders, including <d>IPF</d>, has not yet been investigated. In this study, we investigated the role of LRG in fibrosis by analyzing LRG knockout KO mice with bleomycin-induced <d>lung fibrosis</d>, an animal model of pulmonary fibrosis. The amount of LRG in the lungs of wild-type WT mice was increased by bleomycin administration prior to fibrosis development. In LRG KO mice, <d>lung fibrosis</d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of LRG KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in WT mice. In vitro experiments indicated that LRG enhanced the <g>TGF-b</g>-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory <g>TGF-b</g> receptor, is essential for LRG to promote <g>TGF-b</g> signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of LRG to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that LRG promotes <d>lung fibrosis</d> by modulating <g>TGF-b</g>-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29279415|a|<g>TGF-b</g> has an important role in <d>fibrotic diseases</d>, including <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. Detailed analysis of <g>TGF-b</g> signaling in <d>pulmonary fibrosis</d> at the molecular level is needed to identify novel therapeutic targets. Recently, leucine-rich alpha-2 glycoprotein LRG was reported to function as a modulator of <g>TGF-b</g> signaling in angiogenesis and tumor progression. However, the involvement of LRG in fibrotic disorders, including <d>IPF</d>, has not yet been investigated. In this study, we investigated the role of LRG in fibrosis by analyzing LRG knockout KO mice with bleomycin-induced <d>lung fibrosis</d>, an animal model of <d>pulmonary fibrosis</d>. The amount of LRG in the lungs of wild-type WT mice was increased by bleomycin administration prior to fibrosis development. In LRG KO mice, <d>lung fibrosis</d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of LRG KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in WT mice. In vitro experiments indicated that LRG enhanced the <g>TGF-b</g>-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory <g>TGF-b</g> receptor, is essential for LRG to promote <g>TGF-b</g> signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of LRG to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that LRG promotes <d>lung fibrosis</d> by modulating <g>TGF-b</g>-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29279415|a|<g>TGF-b</g> has an important role in <d>fibrotic diseases</d>, including <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. Detailed analysis of <g>TGF-b</g> signaling in <d>pulmonary fibrosis</d> at the molecular level is needed to identify novel therapeutic targets. Recently, <g>leucine-rich alpha-2 glycoprotein</g> <g>LRG</g> was reported to function as a modulator of <g>TGF-b</g> signaling in angiogenesis and <d>tumor</d> progression. However, the involvement of <g>LRG</g> in fibrotic disorders, including <d>IPF</d>, has not yet been investigated. In this study, we investigated the role of <g>LRG</g> in fibrosis by analyzing <g>LRG</g> knockout KO mice with bleomycin-induced <d>lung fibrosis</d>, an animal model of <d>pulmonary fibrosis</d>. The amount of <g>LRG</g> in the lungs of wild-type WT mice was increased by bleomycin administration prior to fibrosis development. In <g>LRG</g> KO mice, <d>lung fibrosis</d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of <g>LRG</g> KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in WT mice. In vitro experiments indicated that <g>LRG</g> enhanced the <g>TGF-b</g>-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory <g>TGF-b</g> receptor, is essential for <g>LRG</g> to promote <g>TGF-b</g> signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of <g>LRG</g> to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that <g>LRG</g> promotes <d>lung fibrosis</d> by modulating <g>TGF-b</g>-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29279415|a|<g>TGF-b</g> has an important role in <d>fibrotic diseases</d>, including <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d>. Detailed analysis of <g>TGF-b</g> signaling in <d>pulmonary fibrosis</d> at the molecular level is needed to identify novel therapeutic targets. Recently, <g>leucine-rich alpha-2 glycoprotein</g> <g>LRG</g> was reported to function as a modulator of <g>TGF-b</g> signaling in angiogenesis and <d>tumor</d> progression. However, the involvement of <g>LRG</g> in <d>fibrotic disorders</d>, including <d>IPF</d>, has not yet been investigated. In this study, we investigated the role of <g>LRG</g> in fibrosis by analyzing <g>LRG</g> knockout KO mice with bleomycin-induced <d>lung fibrosis</d>, an animal model of <d>pulmonary fibrosis</d>. The amount of <g>LRG</g> in the lungs of wild-type WT mice was increased by bleomycin administration prior to fibrosis development. In <g>LRG</g> KO mice, <d>lung fibrosis</d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of <g>LRG</g> KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in WT mice. In vitro experiments indicated that <g>LRG</g> enhanced the <g>TGF-b</g>-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory <g>TGF-b</g> receptor, is essential for <g>LRG</g> to promote <g>TGF-b</g> signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of <g>LRG</g> to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that <g>LRG</g> promotes <d>lung fibrosis</d> by modulating <g>TGF-b</g>-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29279415|a|<g>TGF-b</g> has an important role in <d>fibrotic diseases</d>, including <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d>. Detailed analysis of <g>TGF-b</g> signaling in <d>pulmonary <d>fibrosis</d></d> at the molecular level is needed to identify novel therapeutic targets. Recently, <g>leucine-rich alpha-2 glycoprotein</g> <g>LRG</g> was reported to function as a modulator of <g>TGF-b</g> signaling in angiogenesis and <d>tumor</d> progression. However, the involvement of <g>LRG</g> in <d>fibrotic disorders</d>, including <d>IPF</d>, has not yet been investigated. In this study, we investigated the role of <g>LRG</g> in <d>fibrosis</d> by analyzing <g>LRG</g> knockout KO mice with bleomycin-induced <d>lung <d>fibrosis</d></d>, an animal model of <d>pulmonary <d>fibrosis</d></d>. The amount of <g>LRG</g> in the lungs of wild-type WT mice was increased by bleomycin administration prior to <d>fibrosis</d> development. In <g>LRG</g> KO mice, <d>lung <d>fibrosis</d></d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of <g>LRG</g> KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in WT mice. In vitro experiments indicated that <g>LRG</g> enhanced the <g>TGF-b</g>-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory <g>TGF-b</g> receptor, is essential for <g>LRG</g> to promote <g>TGF-b</g> signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of <g>LRG</g> to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that <g>LRG</g> promotes <d>lung <d>fibrosis</d></d> by modulating <g>TGF-b</g>-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29279415|a|<g>TGF-b</g> has an important role in <d>fibrotic diseases</d>, including <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d>. Detailed analysis of <g>TGF-b</g> signaling in <d>pulmonary <d>fibrosis</d></d> at the molecular level is needed to identify novel therapeutic targets. Recently, <g>leucine-rich alpha-2 glycoprotein</g> <g>LRG</g> was reported to function as a modulator of <g>TGF-b</g> signaling in angiogenesis and <d>tumor</d> progression. However, the involvement of <g>LRG</g> in <d>fibrotic disorders</d>, including <d>IPF</d>, has not yet been investigated. In this study, we investigated the role of <g>LRG</g> in <d>fibrosis</d> by analyzing <g>LRG</g> knockout KO mice with bleomycin-induced <d>lung <d>fibrosis</d></d>, an animal model of <d>pulmonary <d>fibrosis</d></d>. The amount of <g>LRG</g> in the lungs of <d>wild-type</d> WT mice was increased by bleomycin administration prior to <d>fibrosis</d> development. In <g>LRG</g> KO mice, <d>lung <d>fibrosis</d></d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of <g>LRG</g> KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in WT mice. In vitro experiments indicated that <g>LRG</g> enhanced the <g>TGF-b</g>-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory <g>TGF-b</g> receptor, is essential for <g>LRG</g> to promote <g>TGF-b</g> signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of <g>LRG</g> to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that <g>LRG</g> promotes <d>lung <d>fibrosis</d></d> by modulating <g>TGF-b</g>-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29279415|a|<g>TGF-b</g> has an important role in <d>fibrotic diseases</d>, including <d>idiopathic <d>pulmonary <d>fibrosis</d></d></d> <d>IPF</d>. Detailed analysis of <g>TGF-b</g> signaling in <d>pulmonary <d>fibrosis</d></d> at the molecular level is needed to identify novel therapeutic targets. Recently, <g>leucine-rich alpha-2 glycoprotein</g> <g>LRG</g> was reported to function as a modulator of <g>TGF-b</g> signaling in angiogenesis and <d>tumor</d> progression. However, the involvement of <g>LRG</g> in <d>fibrotic disorders</d>, including <d>IPF</d>, has not yet been investigated. In this study, we investigated the role of <g>LRG</g> in <d>fibrosis</d> by analyzing <g>LRG</g> knockout KO mice with bleomycin-induced <d>lung <d>fibrosis</d></d>, an animal model of <d>pulmonary <d>fibrosis</d></d>. The amount of <g>LRG</g> in the lungs of <d>wild-type</d> <d>WT</d> mice was increased by bleomycin administration prior to <d>fibrosis</d> development. In <g>LRG</g> KO mice, <d>lung <d>fibrosis</d></d> was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in <d>WT</d> mice. Moreover, in the lungs of <g>LRG</g> KO mice, phosphorylation of Smad2 was reduced and expression of a-SMA was decreased relative to those in <d>WT</d> mice. In vitro experiments indicated that <g>LRG</g> enhanced the <g>TGF-b</g>-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory <g>TGF-b</g> receptor, is essential for <g>LRG</g> to promote <g>TGF-b</g> signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of <g>LRG</g> to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that <g>LRG</g> promotes <d>lung <d>fibrosis</d></d> by modulating <g>TGF-b</g>-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.
29351434|a|Fibroblasts are thought to be the prime cell type for producing and secreting extracellular matrix ECM proteins in the connective tissue. The profibrotic cytokine, <g>transforming growth factor-beta 1</g> <g>TGFb1</g> activates and transdifferentiates fibroblasts into aSMA-expressing myofibroblasts, which exhibit increased ECM secretion, in particular collagens. Little information, however, exists about cell-surface molecules on fibroblasts that mediate this transdifferentiation process. We recently identified, using unbiased cell-surface proteome analysis, <g>Cub domain containing protein 1</g> <g>CDCP1</g> to be strongly downregulated by <g>TGFb1</g>. <g>CDCP1</g> is a transmembrane glycoprotein, the expression and role of which has not been investigated in lung fibroblasts to date. Here, we characterized, in detail, the effect of <g>TGFb1</g> on <g>CDCP1</g> expression and function, using immunofluorescence, FACS, immunoblotting, and siRNA-mediated knockdown of <g>CDCP1</g>. <g>CDCP1</g> is present on interstitial fibroblasts, but not myofibroblasts, in the normal and <d>IPF</d> lung. In vitro, <g>TGFb1</g> decreased <g>CDCP1</g> expression in a time-dependent manner by impacting mRNA and protein levels. Knockdown of <g>CDCP1</g> enhanced a <g>TGFb1</g>-mediated cell adhesion of fibroblasts. Importantly, <g>CDCP1</g>-depleted cells displayed an enhanced expression of profibrotic markers, such as collagen V or aSMA, which was found to be independent of <g>TGFb1</g>. Our data show, for the very first time, that loss of <g>CDCP1</g> contributes to fibroblast to myofibroblast differentiation via a potential negative feedback loop between <g>CDCP1</g> expression and <g>TGFb1</g> stimulation.
29351444|a|In <d>pulmonary fibrosis</d> PF, fibroblasts and myofibroblasts proliferate and deposit excessive extracellular matrix in the interstitium, impairing normal lung function. As most forms of PF have a poor prognosis and limited treatment options, PF represents an urgent unmet need for novel, effective therapeutics. While the role of immune cells in lung fibrosis is unclear, recent studies suggest that T lymphocyte T cell activation may be impaired in PF patients. Further, we have previously shown that activated T cells can produce prostaglandins with anti-scarring potential. Here, we test the hypothesis that activated T cells directly inhibit myofibroblast differentiation using a co-culture system. Co-culture with activated primary blood-derived T cells, from both healthy human donors and PF patients, inhibited transforming growth factor beta-induced myofibroblast differentiation in primary human lung fibroblasts isolated from either normal or PF lung tissue. Co-culture supernatants contained anti-fibrotic prostaglandins D2 and E2, and the inhibitory effect of co-culture on myofibroblast differentiation was largely reversed when prostaglandin production was abrogated either by resting the T cells prior to co-culture, or via specific pharmacological inhibitors. Moreover, co-culture conditions induced COX-2 in HLFs, but not in T cells, suggesting that T cells deliver an activating signal to HLFs, which in turn produce anti-fibrotic prostaglandins. We show for the first time that co-culture with activated primary human T lymphocytes strongly inhibits myofibroblast differentiation, revealing a novel cell-to-cell communication network with therapeutic implications for fibrotic lung diseases.
29351444|a|In <d>pulmonary fibrosis</d> <d>PF</d>, fibroblasts and myofibroblasts proliferate and deposit excessive extracellular matrix in the interstitium, impairing normal lung function. As most forms of <d>PF</d> have a poor prognosis and limited treatment options, <d>PF</d> represents an urgent unmet need for novel, effective therapeutics. While the role of immune cells in lung fibrosis is unclear, recent studies suggest that T lymphocyte T cell activation may be impaired in <d>PF</d> patients. Further, we have previously shown that activated T cells can produce prostaglandins with anti-scarring potential. Here, we test the hypothesis that activated T cells directly inhibit myofibroblast differentiation using a co-culture system. Co-culture with activated primary blood-derived T cells, from both healthy human donors and <d>PF</d> patients, inhibited transforming growth factor beta-induced myofibroblast differentiation in primary human lung fibroblasts isolated from either normal or <d>PF</d> lung tissue. Co-culture supernatants contained anti-fibrotic prostaglandins D2 and E2, and the inhibitory effect of co-culture on myofibroblast differentiation was largely reversed when prostaglandin production was abrogated either by resting the T cells prior to co-culture, or via specific pharmacological inhibitors. Moreover, co-culture conditions induced COX-2 in HLFs, but not in T cells, suggesting that T cells deliver an activating signal to HLFs, which in turn produce anti-fibrotic prostaglandins. We show for the first time that co-culture with activated primary human T lymphocytes strongly inhibits myofibroblast differentiation, revealing a novel cell-to-cell communication network with therapeutic implications for fibrotic lung diseases.
29351444|a|In <d>pulmonary <d>fibrosis</d></d> <d>PF</d>, fibroblasts and myofibroblasts proliferate and deposit excessive extracellular matrix in the interstitium, impairing normal lung function. As most forms of <d>PF</d> have a poor prognosis and limited treatment options, <d>PF</d> represents an urgent unmet need for novel, effective therapeutics. While the role of immune cells in lung <d>fibrosis</d> is unclear, recent studies suggest that T lymphocyte T cell activation may be impaired in <d>PF</d> patients. Further, we have previously shown that activated T cells can produce prostaglandins with anti-scarring potential. Here, we test the hypothesis that activated T cells directly inhibit myofibroblast differentiation using a co-culture system. Co-culture with activated primary blood-derived T cells, from both healthy human donors and <d>PF</d> patients, inhibited transforming growth factor beta-induced myofibroblast differentiation in primary human lung fibroblasts isolated from either normal or <d>PF</d> lung tissue. Co-culture supernatants contained anti-fibrotic prostaglandins D2 and E2, and the inhibitory effect of co-culture on myofibroblast differentiation was largely reversed when prostaglandin production was abrogated either by resting the T cells prior to co-culture, or via specific pharmacological inhibitors. Moreover, co-culture conditions induced COX-2 in HLFs, but not in T cells, suggesting that T cells deliver an activating signal to HLFs, which in turn produce anti-fibrotic prostaglandins. We show for the first time that co-culture with activated primary human T lymphocytes strongly inhibits myofibroblast differentiation, revealing a novel cell-to-cell communication network with therapeutic implications for fibrotic lung diseases.
29351444|a|In <d>pulmonary <d>fibrosis</d></d> <d>PF</d>, fibroblasts and myofibroblasts proliferate and deposit excessive extracellular matrix in the interstitium, impairing normal lung function. As most forms of <d>PF</d> have a poor prognosis and limited treatment options, <d>PF</d> represents an urgent unmet need for novel, effective therapeutics. While the role of immune cells in lung <d>fibrosis</d> is unclear, recent studies suggest that T lymphocyte T cell activation may be impaired in <d>PF</d> patients. Further, we have previously shown that activated T cells can produce prostaglandins with anti-scarring potential. Here, we test the hypothesis that activated T cells directly inhibit myofibroblast differentiation using a co-culture system. Co-culture with activated primary blood-derived T cells, from both healthy human donors and <d>PF</d> patients, inhibited transforming growth factor beta-induced myofibroblast differentiation in primary human lung fibroblasts isolated from either normal or <d>PF</d> lung tissue. Co-culture supernatants contained anti-fibrotic prostaglandins D2 and E2, and the inhibitory effect of co-culture on myofibroblast differentiation was largely reversed when prostaglandin production was abrogated either by resting the T cells prior to co-culture, or via specific pharmacological inhibitors. Moreover, co-culture conditions induced <g>COX-2</g> in HLFs, but not in T cells, suggesting that T cells deliver an activating signal to HLFs, which in turn produce anti-fibrotic prostaglandins. We show for the first time that co-culture with activated primary human T lymphocytes strongly inhibits myofibroblast differentiation, revealing a novel cell-to-cell communication network with therapeutic implications for <d>fibrotic lung diseases</d>.
29409529|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> IPF is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 STAT3 protein is activated in lung fibroblasts and alveolar type II cells ATII, thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 <g>JAK2</g> has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze <g>JAK2</g> activation in IPF, and to determine whether <g>JAK2</g>/STAT3 inhibition is a potential therapeutic strategy for this disease. METHODS AND RESULTS: <g>JAK2</g>/p-<g>JAK2</g> and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue n   =   10 both proteins were upregulated in the lung tissue of IPF patients n   =   12. Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin IL-6/IL-13 activated <g>JAK2</g> and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-<g>JAK2</g>/p-STAT3 inhibition with JSI-124 or silencing of <g>JAK2</g> and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using <g>JAK2</g> or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-<g>JAK2</g>/p-STAT3, at a dose of 1  mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were <g>JAK2</g> and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. CONCLUSIONS: <g>JAK2</g> and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease.
29409529|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 STAT3 protein is activated in lung fibroblasts and alveolar type II cells ATII, thereby contributing to lung fibrosis in <d>IPF</d>. Although activation of Janus kinase 2 <g>JAK2</g> has been implicated in proliferative disorders, its role in <d>IPF</d> is unknown. The aim of this study was to analyze <g>JAK2</g> activation in <d>IPF</d>, and to determine whether <g>JAK2</g>/STAT3 inhibition is a potential therapeutic strategy for this disease. METHODS AND RESULTS: <g>JAK2</g>/p-<g>JAK2</g> and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue n   =   10 both proteins were upregulated in the lung tissue of <d>IPF</d> patients n   =   12. Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin IL-6/IL-13 activated <g>JAK2</g> and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-<g>JAK2</g>/p-STAT3 inhibition with JSI-124 or silencing of <g>JAK2</g> and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using <g>JAK2</g> or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-<g>JAK2</g>/p-STAT3, at a dose of 1  mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were <g>JAK2</g> and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. CONCLUSIONS: <g>JAK2</g> and STAT3 are activated in <d>IPF</d>, and their dual inhibition may be an attractive strategy for treating this disease.
29409529|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is the most rapidly progressive and fatal <d>fibrotic disorder</d>, with no curative therapies. The signal transducer and activator of transcription 3 STAT3 protein is activated in lung fibroblasts and alveolar type II cells ATII, thereby contributing to lung fibrosis in <d>IPF</d>. Although activation of Janus kinase 2 <g>JAK2</g> has been implicated in proliferative disorders, its role in <d>IPF</d> is unknown. The aim of this study was to analyze <g>JAK2</g> activation in <d>IPF</d>, and to determine whether <g>JAK2</g>/STAT3 inhibition is a potential therapeutic strategy for this disease. METHODS AND RESULTS: <g>JAK2</g>/p-<g>JAK2</g> and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue n   =   10 both proteins were upregulated in the lung tissue of <d>IPF</d> patients n   =   12. Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin IL-6/IL-13 activated <g>JAK2</g> and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-<g>JAK2</g>/p-STAT3 inhibition with JSI-124 or silencing of <g>JAK2</g> and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using <g>JAK2</g> or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-<g>JAK2</g>/p-STAT3, at a dose of 1  mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were <g>JAK2</g> and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. CONCLUSIONS: <g>JAK2</g> and STAT3 are activated in <d>IPF</d>, and their dual inhibition may be an attractive strategy for treating this disease.
29409529|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is the most rapidly progressive and fatal <d>fibrotic disorder</d>, with no curative therapies. The <g>signal transducer and activator of transcription 3</g> <g>STAT3</g> protein is activated in lung fibroblasts and alveolar type II cells ATII, thereby contributing to <d>lung fibrosis</d> in <d>IPF</d>. Although activation of Janus kinase 2 <g>JAK2</g> has been implicated in proliferative disorders, its role in <d>IPF</d> is unknown. The aim of this study was to analyze <g>JAK2</g> activation in <d>IPF</d>, and to determine whether <g>JAK2</g>/<g>STAT3</g> inhibition is a potential therapeutic strategy for this disease. METHODS AND RESULTS: <g>JAK2</g>/p-<g>JAK2</g> and <g>STAT3</g>/p<g>STAT3</g> expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue n   =   10 both proteins were upregulated in the lung tissue of <d>IPF</d> patients n   =   12. Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin IL-6/IL-13 activated <g>JAK2</g> and <g>STAT3</g>, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-<g>JAK2</g>/p-<g>STAT3</g> inhibition with JSI-124 or silencing of <g>JAK2</g> and <g>STAT3</g> genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using <g>JAK2</g> or <g>STAT3</g> inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-<g>JAK2</g>/p-<g>STAT3</g>, at a dose of 1  mg/kg/day, bleomycin-induced <d>lung fibrosis</d> was reduced and collagen deposition in the lung was inhibited, as were <g>JAK2</g> and <g>STAT3</g> activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. CONCLUSIONS: <g>JAK2</g> and <g>STAT3</g> are activated in <d>IPF</d>, and their dual inhibition may be an attractive strategy for treating this disease.
29409529|a|BACKGROUND: <d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is the most rapidly progressive and fatal <d>fibrotic disorder</d>, with no curative therapies. The <g>signal transducer and activator of transcription 3</g> <g>STAT3</g> protein is activated in lung fibroblasts and alveolar type II cells ATII, thereby contributing to <d>lung fibrosis</d> in <d>IPF</d>. Although activation of <g>Janus kinase 2</g> <g>JAK2</g> has been implicated in <d>proliferative disorders</d>, its role in <d>IPF</d> is unknown. The aim of this study was to analyze <g>JAK2</g> activation in <d>IPF</d>, and to determine whether <g>JAK2</g>/<g>STAT3</g> inhibition is a potential therapeutic strategy for this disease. METHODS AND RESULTS: <g>JAK2</g>/p-<g>JAK2</g> and <g>STAT3</g>/p<g>STAT3</g> expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue n   =   10 both proteins were upregulated in the lung tissue of <d>IPF</d> patients n   =   12. Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin IL-6/IL-13 activated <g>JAK2</g> and <g>STAT3</g>, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-<g>JAK2</g>/p-<g>STAT3</g> inhibition with JSI-124 or silencing of <g>JAK2</g> and <g>STAT3</g> genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using <g>JAK2</g> or <g>STAT3</g> inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-<g>JAK2</g>/p-<g>STAT3</g>, at a dose of 1  mg/kg/day, bleomycin-induced <d>lung fibrosis</d> was reduced and collagen deposition in the lung was inhibited, as were <g>JAK2</g> and <g>STAT3</g> activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. CONCLUSIONS: <g>JAK2</g> and <g>STAT3</g> are activated in <d>IPF</d>, and their dual inhibition may be an attractive strategy for treating this disease.
29409529|a|BACKGROUND: <d>Idiopathic pulmonary <d>fibrosis</d></d> <d>IPF</d> is the most rapidly progressive and fatal <d>fibrotic disorder</d>, with no curative therapies. The <g>signal transducer and activator of transcription 3</g> <g>STAT3</g> protein is activated in lung fibroblasts and alveolar type II cells ATII, thereby contributing to <d>lung <d>fibrosis</d></d> in <d>IPF</d>. Although activation of <g>Janus kinase 2</g> <g>JAK2</g> has been implicated in <d>proliferative disorders</d>, its role in <d>IPF</d> is unknown. The aim of this study was to analyze <g>JAK2</g> activation in <d>IPF</d>, and to determine whether <g>JAK2</g>/<g>STAT3</g> inhibition is a potential therapeutic strategy for this disease. METHODS AND RESULTS: <g>JAK2</g>/p-<g>JAK2</g> and <g>STAT3</g>/p<g>STAT3</g> expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue n   =   10 both proteins were upregulated in the lung tissue of <d>IPF</d> patients n   =   12. Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin IL-6/IL-13 activated <g>JAK2</g> and <g>STAT3</g>, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-<g>JAK2</g>/p-<g>STAT3</g> inhibition with JSI-124 or silencing of <g>JAK2</g> and <g>STAT3</g> genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using <g>JAK2</g> or <g>STAT3</g> inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and <g>Bcl-2</g> expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-<g>JAK2</g>/p-<g>STAT3</g>, at a dose of 1  mg/kg/day, bleomycin-induced <d>lung <d>fibrosis</d></d> was reduced and collagen deposition in the lung was inhibited, as were <g>JAK2</g> and <g>STAT3</g> activation and several markers of <d>fibrosis</d>, autophagy, senescence, and anti-apoptosis. CONCLUSIONS: <g>JAK2</g> and <g>STAT3</g> are activated in <d>IPF</d>, and their dual inhibition may be an attractive strategy for treating this disease.
29411215|a|<d>Idiopathic pulmonary fibrosis</d> IPF is characterized by lung fibroblasts accumulation and extracellular matrix ECM deposition. Recently, long-noncoding RNAs lncRNAs have emerged as critical regulators and prognostic markers in several diseases including IPF. In the present study, we found that the expression of <g>H19</g> was significantly increased in transforming growth factor-b TGF-b-induced fibroblast proliferation and bleomycin-BLM induced lung fibrosis p   <   0.05. We further demonstrated that <g>H19</g> was a direct target of miR-196a and was associated with <g>COL1A1</g> expression by sponging miR-196a. Moreover, downregulation of <g>H19</g> alleviated fibroblast activation and lung fibrosis, and this effect was blocked by a miR-196a inhibitor. In conclusion, our results suggest that lncRNA <g>H19</g> has a promotive effect on BLM-induced IPF, and it functions as a molecular sponge of miR-196a, which provides a novel therapeutic target for IPF.
29411215|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by lung fibroblasts accumulation and extracellular matrix ECM deposition. Recently, long-noncoding RNAs lncRNAs have emerged as critical regulators and prognostic markers in several diseases including <d>IPF</d>. In the present study, we found that the expression of <g>H19</g> was significantly increased in transforming growth factor-b TGF-b-induced fibroblast proliferation and bleomycin-BLM induced lung fibrosis p   <   0.05. We further demonstrated that <g>H19</g> was a direct target of miR-196a and was associated with <g>COL1A1</g> expression by sponging miR-196a. Moreover, downregulation of <g>H19</g> alleviated fibroblast activation and lung fibrosis, and this effect was blocked by a miR-196a inhibitor. In conclusion, our results suggest that lncRNA <g>H19</g> has a promotive effect on BLM-induced <d>IPF</d>, and it functions as a molecular sponge of miR-196a, which provides a novel therapeutic target for <d>IPF</d>.
29411215|a|<d>Idiopathic pulmonary fibrosis</d> <d>IPF</d> is characterized by lung fibroblasts accumulation and extracellular matrix ECM deposition. Recently, long-noncoding RNAs lncRNAs have emerged as critical regulators and prognostic markers in several diseases including <d>IPF</d>. In the present study, we found that the expression of <g>H19</g> was significantly increased in transforming growth factor-b TGF-b-induced fibroblast proliferation and bleomycin-BLM induced <d>lung fibrosis</d> p   <   0.05. We further demonstrated that <g>H19</g> was a direct target of miR-196a and was associated with <g>COL1A1</g> expression by sponging miR-196a. Moreover, downregulation of <g>H19</g> alleviated fibroblast activation and <d>lung fibrosis</d>, and this effect was blocked by a miR-196a inhibitor. In conclusion, our results suggest that lncRNA <g>H19</g> has a promotive effect on BLM-induced <d>IPF</d>, and it functions as a molecular sponge of miR-196a, which provides a novel therapeutic target for <d>IPF</d>.
29440315|a|BACKGROUND: Pulmonary hypertension PH is a common disorder in patients with idiopathic pulmonary fibrosis IPF and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation <i>V</i>/perfusion <i>Q</i> mismatching and oxygen desaturation. Janus kinase type 2 <g>JAK2</g> is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown. OBJECTIVE: The study of <g>JAK2</g> as potential target to treat PH in IPF. METHODS AND RESULTS: <g>JAK2</g> expression was increased in pulmonary arteries PAs from IPF n=10; 1.93-fold; P=0.0011 and IPF+PH n=9; 2.65-fold; P<0.0001 compared with PA from control subjects n=10. PA remodelling was evaluated in human pulmonary artery endothelial cells HPAECs and human pulmonary artery smooth muscle cells HPASMCs from patients with IPF in vitro treated with the <g>JAK2</g> inhibitor JSI-124 or siRNA-<g>JAK2</g> and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-<g>JAK2</g> inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. <g>JAK2</g> inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel BK<sub>Ca</sub>. <g>JAK2</g> inhibition activated BK<sub>Ca</sub>channels and reduced intracellular Ca<sup>2+</sup>. JSI-124 1   mg/kg/day, reduced bleomycin-induced <d>lung fibrosis</d>, PA remodelling, right ventricular hypertrophy, PA hypertension and<i>V</i>/<i>Q</i>mismatching in rats. The animal studies followed the ARRIVE guidelines. CONCLUSIONS: <g>JAK2</g> participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH.
29440315|a|BACKGROUND: Pulmonary <d>hypertension</d> PH is a common disorder in patients with idiopathic pulmonary fibrosis IPF and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation <i>V</i>/perfusion <i>Q</i> mismatching and oxygen desaturation. Janus kinase type 2 <g>JAK2</g> is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown. OBJECTIVE: The study of <g>JAK2</g> as potential target to treat PH in IPF. METHODS AND RESULTS: <g>JAK2</g> expression was increased in pulmonary arteries PAs from IPF n=10; 1.93-fold; P=0.0011 and IPF+PH n=9; 2.65-fold; P<0.0001 compared with PA from control subjects n=10. PA remodelling was evaluated in human pulmonary artery endothelial cells HPAECs and human pulmonary artery smooth muscle cells HPASMCs from patients with IPF in vitro treated with the <g>JAK2</g> inhibitor JSI-124 or siRNA-<g>JAK2</g> and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-<g>JAK2</g> inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. <g>JAK2</g> inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel BK<sub>Ca</sub>. <g>JAK2</g> inhibition activated BK<sub>Ca</sub>channels and reduced intracellular Ca<sup>2+</sup>. JSI-124 1   mg/kg/day, reduced bleomycin-induced <d>lung fibrosis</d>, PA remodelling, right ventricular hypertrophy, PA <d>hypertension</d> and<i>V</i>/<i>Q</i>mismatching in rats. The animal studies followed the ARRIVE guidelines. CONCLUSIONS: <g>JAK2</g> participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH.
29440315|a|BACKGROUND: Pulmonary <d>hypertension</d> PH is a common disorder in patients with <d>idiopathic pulmonary fibrosis</d> IPF and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation <i>V</i>/perfusion <i>Q</i> mismatching and oxygen desaturation. Janus kinase type 2 <g>JAK2</g> is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown. OBJECTIVE: The study of <g>JAK2</g> as potential target to treat PH in IPF. METHODS AND RESULTS: <g>JAK2</g> expression was increased in pulmonary arteries PAs from IPF n=10; 1.93-fold; P=0.0011 and IPF+PH n=9; 2.65-fold; P<0.0001 compared with PA from control subjects n=10. PA remodelling was evaluated in human pulmonary artery endothelial cells HPAECs and human pulmonary artery smooth muscle cells HPASMCs from patients with IPF in vitro treated with the <g>JAK2</g> inhibitor JSI-124 or siRNA-<g>JAK2</g> and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-<g>JAK2</g> inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. <g>JAK2</g> inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel BK<sub>Ca</sub>. <g>JAK2</g> inhibition activated BK<sub>Ca</sub>channels and reduced intracellular Ca<sup>2+</sup>. JSI-124 1   mg/kg/day, reduced bleomycin-induced <d>lung fibrosis</d>, PA remodelling, right ventricular hypertrophy, PA <d>hypertension</d> and<i>V</i>/<i>Q</i>mismatching in rats. The animal studies followed the ARRIVE guidelines. CONCLUSIONS: <g>JAK2</g> participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH.
29440315|a|BACKGROUND: Pulmonary <d>hypertension</d> <d>PH</d> is a common disorder in patients with <d>idiopathic pulmonary fibrosis</d> IPF and portends a poor prognosis. Recent studies using vasodilators approved for <d>PH</d> have failed in improving IPF mainly due to ventilation <i>V</i>/perfusion <i>Q</i> mismatching and oxygen desaturation. Janus kinase type 2 <g>JAK2</g> is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in <d>PH</d> associated to <d>PH</d> is unknown. OBJECTIVE: The study of <g>JAK2</g> as potential target to treat <d>PH</d> in IPF. METHODS AND RESULTS: <g>JAK2</g> expression was increased in pulmonary arteries PAs from IPF n=10; 1.93-fold; P=0.0011 and IPF+<d>PH</d> n=9; 2.65-fold; P<0.0001 compared with PA from control subjects n=10. PA remodelling was evaluated in human pulmonary artery endothelial cells HPAECs and human pulmonary artery smooth muscle cells HPASMCs from patients with IPF in vitro treated with the <g>JAK2</g> inhibitor JSI-124 or siRNA-<g>JAK2</g> and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-<g>JAK2</g> inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. <g>JAK2</g> inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel BK<sub>Ca</sub>. <g>JAK2</g> inhibition activated BK<sub>Ca</sub>channels and reduced intracellular Ca<sup>2+</sup>. JSI-124 1   mg/kg/day, reduced bleomycin-induced <d>lung fibrosis</d>, PA remodelling, right ventricular hypertrophy, PA <d>hypertension</d> and<i>V</i>/<i>Q</i>mismatching in rats. The animal studies followed the ARRIVE guidelines. CONCLUSIONS: <g>JAK2</g> participates in PA remodelling and tension and may be an attractive target to treat IPF associated to <d>PH</d>.
29440315|a|BACKGROUND: Pulmonary <d>hypertension</d> <d>PH</d> is a common disorder in patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and portends a poor prognosis. Recent studies using vasodilators approved for <d>PH</d> have failed in improving <d>IPF</d> mainly due to ventilation <i>V</i>/perfusion <i>Q</i> mismatching and oxygen desaturation. Janus kinase type 2 <g>JAK2</g> is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in <d>PH</d> associated to <d>PH</d> is unknown. OBJECTIVE: The study of <g>JAK2</g> as potential target to treat <d>PH</d> in <d>IPF</d>. METHODS AND RESULTS: <g>JAK2</g> expression was increased in pulmonary arteries PAs from <d>IPF</d> n=10; 1.93-fold; P=0.0011 and <d>IPF</d>+<d>PH</d> n=9; 2.65-fold; P<0.0001 compared with PA from control subjects n=10. PA remodelling was evaluated in human pulmonary artery endothelial cells HPAECs and human pulmonary artery smooth muscle cells HPASMCs from patients with <d>IPF</d> in vitro treated with the <g>JAK2</g> inhibitor JSI-124 or siRNA-<g>JAK2</g> and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-<g>JAK2</g> inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. <g>JAK2</g> inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel BK<sub>Ca</sub>. <g>JAK2</g> inhibition activated BK<sub>Ca</sub>channels and reduced intracellular Ca<sup>2+</sup>. JSI-124 1   mg/kg/day, reduced bleomycin-induced <d>lung fibrosis</d>, PA remodelling, right ventricular hypertrophy, PA <d>hypertension</d> and<i>V</i>/<i>Q</i>mismatching in rats. The animal studies followed the ARRIVE guidelines. CONCLUSIONS: <g>JAK2</g> participates in PA remodelling and tension and may be an attractive target to treat <d>IPF</d> associated to <d>PH</d>.
29440315|a|BACKGROUND: Pulmonary <d>hypertension</d> <d>PH</d> is a common disorder in patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and portends a poor prognosis. Recent studies using vasodilators approved for <d>PH</d> have failed in improving <d>IPF</d> mainly due to ventilation <i>V</i>/perfusion <i>Q</i> mismatching and oxygen desaturation. <g>Janus kinase type 2</g> <g>JAK2</g> is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in <d>PH</d> associated to <d>PH</d> is unknown. OBJECTIVE: The study of <g>JAK2</g> as potential target to treat <d>PH</d> in <d>IPF</d>. METHODS AND RESULTS: <g>JAK2</g> expression was increased in pulmonary arteries PAs from <d>IPF</d> n=10; 1.93-fold; P=0.0011 and <d>IPF</d>+<d>PH</d> n=9; 2.65-fold; P<0.0001 compared with PA from control subjects n=10. <d>PA remodelling</d> was evaluated in human pulmonary artery endothelial cells HPAECs and human pulmonary artery smooth muscle cells HPASMCs from patients with <d>IPF</d> in vitro treated with the <g>JAK2</g> inhibitor JSI-124 or siRNA-<g>JAK2</g> and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-<g>JAK2</g> inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. <g>JAK2</g> inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel BK<sub>Ca</sub>. <g>JAK2</g> inhibition activated BK<sub>Ca</sub>channels and reduced intracellular Ca<sup>2+</sup>. JSI-124 1   mg/kg/day, reduced bleomycin-induced <d>lung fibrosis</d>, <d>PA remodelling</d>, right ventricular hypertrophy, PA <d>hypertension</d> and<i>V</i>/<i>Q</i>mismatching in rats. The animal studies followed the ARRIVE guidelines. CONCLUSIONS: <g>JAK2</g> participates in <d>PA remodelling</d> and tension and may be an attractive target to treat <d>IPF</d> associated to <d>PH</d>.
29440315|a|BACKGROUND: Pulmonary <d>hypertension</d> <d>PH</d> is a common disorder in patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and portends a poor prognosis. Recent studies using vasodilators approved for <d>PH</d> have failed in improving <d>IPF</d> mainly due to ventilation <i>V</i>/perfusion <i>Q</i> mismatching and oxygen desaturation. <g>Janus kinase type 2</g> <g>JAK2</g> is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in <d>PH</d> associated to <d>PH</d> is unknown. OBJECTIVE: The study of <g>JAK2</g> as potential target to treat <d>PH</d> in <d>IPF</d>. METHODS AND RESULTS: <g>JAK2</g> expression was increased in pulmonary arteries PAs from <d>IPF</d> n=10; 1.93-fold; P=0.0011 and <d>IPF</d>+<d>PH</d> n=9; 2.65-fold; P<0.0001 compared with PA from control subjects n=10. <d>PA remodelling</d> was evaluated in human pulmonary artery endothelial cells HPAECs and human pulmonary artery smooth muscle cells HPASMCs from patients with <d>IPF</d> in vitro treated with the <g>JAK2</g> inhibitor JSI-124 or siRNA-<g>JAK2</g> and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-<g>JAK2</g> inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. <g>JAK2</g> inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel BK<sub>Ca</sub>. <g>JAK2</g> inhibition activated BK<sub>Ca</sub>channels and reduced intracellular Ca<sup>2+</sup>. JSI-124 1   mg/kg/day, reduced bleomycin-induced <d>lung fibrosis</d>, <d>PA remodelling</d>, right <d>ventricular hypertrophy</d>, PA <d>hypertension</d> and<i>V</i>/<i>Q</i>mismatching in rats. The animal studies followed the ARRIVE guidelines. CONCLUSIONS: <g>JAK2</g> participates in <d>PA remodelling</d> and tension and may be an attractive target to treat <d>IPF</d> associated to <d>PH</d>.
29440315|a|BACKGROUND: Pulmonary <d>hyper<d>tension</d></d> <d>PH</d> is a common disorder in patients with <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> and portends a poor prognosis. Recent studies using vasodilators approved for <d>PH</d> have failed in improving <d>IPF</d> mainly due to ventilation <i>V</i>/perfusion <i>Q</i> mismatching and oxygen desaturation. <g>Janus kinase type 2</g> <g>JAK2</g> is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in <d>PH</d> associated to <d>PH</d> is unknown. OBJECTIVE: The study of <g>JAK2</g> as potential target to treat <d>PH</d> in <d>IPF</d>. METHODS AND RESULTS: <g>JAK2</g> expression was increased in pulmonary arteries PAs from <d>IPF</d> n=10; 1.93-fold; P=0.0011 and <d>IPF</d>+<d>PH</d> n=9; 2.65-fold; P<0.0001 compared with PA from control subjects n=10. <d>PA remodelling</d> was evaluated in human pulmonary artery endothelial cells HPAECs and human pulmonary artery smooth muscle cells HPASMCs from patients with <d>IPF</d> in vitro treated with the <g>JAK2</g> inhibitor JSI-124 or siRNA-<g>JAK2</g> and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-<g>JAK2</g> inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. <g>JAK2</g> inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel BK<sub>Ca</sub>. <g>JAK2</g> inhibition activated BK<sub>Ca</sub>channels and reduced intracellular Ca<sup>2+</sup>. JSI-124 1   mg/kg/day, reduced bleomycin-induced <d>lung fibrosis</d>, <d>PA remodelling</d>, right <d>ventricular hypertrophy</d>, PA <d>hyper<d>tension</d></d> and<i>V</i>/<i>Q</i>mismatching in rats. The animal studies followed the ARRIVE guidelines. CONCLUSIONS: <g>JAK2</g> participates in <d>PA remodelling</d> and <d>tension</d> and may be an attractive target to treat <d>IPF</d> associated to <d>PH</d>.
29459894|a|At present, the etiology of <d>idiopathic pulmonary fibrosis</d> IPF remains elusive. Over the past two decades, however, researchers have identified and described the underlying processes that result in metabolic dysregulation, metabolic reprogramming, and mitochondrial dysfunction observed in the cells of IPF lungs. Metabolic changes and mitochondrial dysfunction in IPF include decreased efficiency of electron transport chain function with increasing production of reactive oxygen species, decreased mitochondrial biogenesis, and impaired mitochondrial macroautophagy, a key pathway for the removal of dysfunctional mitochondria. Metabolic changes in IPF have potential impact on lung cell function, differentiation, and activation of fibrotic responses. These alterations result in activation of TGF-b and predispose to the development of pulmonary fibrosis. IPF is a disease of the aged, and many of these same bioenergetic changes are present to a lesser extent with normal aging, raising the possibility that these anticipated alterations in metabolic processes play important roles in creating susceptibility to the development of IPF. This review explores what is known regarding the cellular metabolic and mitochondrial changes that are found in IPF, and examines this body of literature to identify future research direction and potential points of intervention in the pathogenesis of IPF.
29459894|a|At present, the etiology of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> remains elusive. Over the past two decades, however, researchers have identified and described the underlying processes that result in metabolic dysregulation, metabolic reprogramming, and mitochondrial dysfunction observed in the cells of <d>IPF</d> lungs. Metabolic changes and mitochondrial dysfunction in <d>IPF</d> include decreased efficiency of electron transport chain function with increasing production of reactive oxygen species, decreased mitochondrial biogenesis, and impaired mitochondrial macroautophagy, a key pathway for the removal of dysfunctional mitochondria. Metabolic changes in <d>IPF</d> have potential impact on lung cell function, differentiation, and activation of fibrotic responses. These alterations result in activation of TGF-b and predispose to the development of pulmonary fibrosis. <d>IPF</d> is a disease of the aged, and many of these same bioenergetic changes are present to a lesser extent with normal aging, raising the possibility that these anticipated alterations in metabolic processes play important roles in creating susceptibility to the development of <d>IPF</d>. This review explores what is known regarding the cellular metabolic and mitochondrial changes that are found in <d>IPF</d>, and examines this body of literature to identify future research direction and potential points of intervention in the pathogenesis of <d>IPF</d>.
29459894|a|At present, the etiology of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> remains elusive. Over the past two decades, however, researchers have identified and described the underlying processes that result in <d>metabolic dysregulation</d>, metabolic reprogramming, and mitochondrial dysfunction observed in the cells of <d>IPF</d> lungs. Metabolic changes and mitochondrial dysfunction in <d>IPF</d> include decreased efficiency of electron transport chain function with increasing production of reactive oxygen species, decreased mitochondrial biogenesis, and impaired mitochondrial macroautophagy, a key pathway for the removal of dysfunctional mitochondria. Metabolic changes in <d>IPF</d> have potential impact on lung cell function, differentiation, and activation of fibrotic responses. These alterations result in activation of TGF-b and predispose to the development of pulmonary fibrosis. <d>IPF</d> is a disease of the aged, and many of these same bioenergetic changes are present to a lesser extent with normal aging, raising the possibility that these anticipated alterations in metabolic processes play important roles in creating susceptibility to the development of <d>IPF</d>. This review explores what is known regarding the cellular metabolic and mitochondrial changes that are found in <d>IPF</d>, and examines this body of literature to identify future research direction and potential points of intervention in the pathogenesis of <d>IPF</d>.
29459894|a|At present, the etiology of <d>idiopathic pulmonary fibrosis</d> <d>IPF</d> remains elusive. Over the past two decades, however, researchers have identified and described the underlying processes that result in <d>metabolic dysregulation</d>, metabolic reprogramming, and mitochondrial dysfunction observed in the cells of <d>IPF</d> lungs. Metabolic changes and mitochondrial dysfunction in <d>IPF</d> include decreased efficiency of electron transport chain function with increasing production of reactive oxygen species, decreased mitochondrial biogenesis, and impaired mitochondrial macroautophagy, a key pathway for the <d>removal of dysfunctional mitochondria</d>. Metabolic changes in <d>IPF</d> have potential impact on lung cell function, differentiation, and activation of fibrotic responses. These alterations result in activation of TGF-b and predispose to the development of pulmonary fibrosis. <d>IPF</d> is a disease of the aged, and many of these same bioenergetic changes are present to a lesser extent with normal aging, raising the possibility that these anticipated alterations in metabolic processes play important roles in creating susceptibility to the development of <d>IPF</d>. This review explores what is known regarding the cellular metabolic and mitochondrial changes that are found in <d>IPF</d>, and examines this body of literature to identify future research direction and potential points of intervention in the pathogenesis of <d>IPF</d>.
29459894|a|At present, the etiology of <d>idiopathic <d>pulmonary fibrosis</d></d> <d>IPF</d> remains elusive. Over the past two decades, however, researchers have identified and described the underlying processes that result in <d>metabolic dysregulation</d>, metabolic reprogramming, and mitochondrial dysfunction observed in the cells of <d>IPF</d> lungs. Metabolic changes and mitochondrial dysfunction in <d>IPF</d> include decreased efficiency of electron transport chain function with increasing production of reactive oxygen species, decreased mitochondrial biogenesis, and impaired mitochondrial macroautophagy, a key pathway for the <d>removal of dysfunctional mitochondria</d>. Metabolic changes in <d>IPF</d> have potential impact on lung cell function, differentiation, and activation of fibrotic responses. These alterations result in activation of <g>TGF-b</g> and predispose to the development of <d>pulmonary fibrosis</d>. <d>IPF</d> is a disease of the aged, and many of these same bioenergetic changes are present to a lesser extent with normal aging, raising the possibility that these anticipated alterations in metabolic processes play important roles in creating susceptibility to the development of <d>IPF</d>. This review explores what is known regarding the cellular metabolic and mitochondrial changes that are found in <d>IPF</d>, and examines this body of literature to identify future research direction and potential points of intervention in the pathogenesis of <d>IPF</d>.