19355895|t|Recent advances in molecular targets and treatment of idiopathic pulmonary fibrosis: focus on TGFbeta signaling and the myofibroblast
Idiopathic Pulmonary Fibrosis (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 (TGFbeta) is a profibrotic factor that increases fibroblast proliferation, stimulates the synthesis and deposition of connective tissue, and inhibits connective tissue breakdown
TGFbeta acts through the promoter of the type 1 collagen gene causing increased collagen synthesis
In addition, TGFbeta 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 TGFbeta on AECs EMT and myofibroblasts in the development of fibrosis
19355895	54	83	idiopathic pulmonary fibrosis	Disease
19355895	94	101	TGFbeta	Gene
19355895	135	164	Idiopathic Pulmonary Fibrosis	Disease
19355895	166	169	IPF	Disease
19355895	342	345	IPF	Disease
19355895	346	354	patients	Species
19355895	423	442	respiratory failure	Disease
19355895	744	752	fibrosis	Disease
19355895	943	974	Transforming growth factor beta	Gene
19355895	976	983	TGFbeta	Gene
19355895	1154	1161	TGFbeta	Gene
19355895	1179	1188	promoter	Entity
19355895	1216	1224	causing	Positive_regulation
19355895	1224	1234	increased	Positive_regulation
19355895	1243	1253	synthesis	Gene_expression
19355895	1267	1274	TGFbeta	Gene
19355895	1452	1460	fibrosis	Disease
19355895	1627	1630	IPF	Disease
19355895	1679	1686	TGFbeta	Gene
19355895	1740	1748	fibrosis	Disease
23499373|t|FAK-related nonkinase is a multifunctional negative regulator of pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	65	83	pulmonary fibrosis	Disease
23499373	85	114	Idiopathic pulmonary fibrosis	Disease
23499373	116	119	IPF	Disease
23499373	138	159	fibrotic lung disease	Disease
23499373	240	279	focal adhesion kinase-related nonkinase	Gene
23499373	281	285	FRNK	Gene
23499373	335	348	lung fibrosis	Disease
23499373	350	355	Loss	Negative_regulation
23499373	358	362	FRNK	Gene
23499373	389	412	increased lung fibrosis	Disease
23499373	432	437	mouse	Species
23499373	449	474	increase in lung fibrosis	Disease
23499373	562	567	loss	Negative_regulation
23499373	570	574	FRNK	Gene
23499373	726	730	FRNK	Gene
23499373	731	741	deficient	Negative_regulation
23499373	741	747	murine	Species
23499373	853	857	FRNK	Gene
23499373	858	869	expression	Gene_expression
23499373	989	993	FRNK	Gene
23499373	1011	1015	FRNK	Gene
23499373	1016	1027	expression	Gene_expression
23499373	1030	1045	down-regulated	Negative_regulation
23499373	1048	1053	human	Species
23499373	1054	1057	IPF	Disease
23499373	1063	1079	down-regulation	Negative_regulation
23499373	1082	1086	FRNK	Gene
23499373	1097	1102	human	Species
23499373	1168	1172	FRNK	Gene
23499373	1173	1183	deficient	Negative_regulation
23499373	1221	1225	FRNK	Gene
23499373	1301	1306	human	Species
23499373	1307	1310	IPF	Disease
23499373	1326	1330	FRNK	Gene
23499373	1375	1388	lung fibrosis	Disease
16908447|t|Tissue inhibitor of metalloproteinase-3 is up-regulated by transforming growth factor-beta1 in vitro and expressed in fibroblastic foci in vivo in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 (ERK)1/2
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	59	91	transforming growth factor-beta1	Gene
16908447	147	176	idiopathic pulmonary fibrosis	Disease
16908447	178	207	Idiopathic pulmonary fibrosis	Disease
16908447	209	212	IPF	Disease
16908447	423	434	expression	Gene_expression
16908447	499	504	human	Species
16908447	587	592	role	Regulation
16908447	638	643	TIMP3	Gene
16908447	644	655	expression	Gene_expression
16908447	656	661	TIMP1	Gene
16908447	663	668	TIMP2	Gene
16908447	674	679	TIMP3	Gene
16908447	692	702	expressed	Gene_expression
16908447	723	761	Transforming growth factor (TGF)-beta1	Gene
16908447	787	795	induced	Positive_regulation
16908447	802	816	up-regulation	Positive_regulation
16908447	819	824	TIMP3	Gene
16908447	907	916	involved	Regulation
16908447	919	928	TGF-beta1	Gene
16908447	929	937	induced	Positive_regulation
16908447	937	942	TIMP3	Gene
16908447	943	954	expression	Gene_expression
16908447	955	964	TGF-beta1	Gene
16908447	965	973	induced	Positive_regulation
16908447	977	993	phosphorylation	Phosphorylation
16908447	996	999	p38	Gene
16908447	1004	1050	extracellular signal-regulated kinase (ERK)1/2	Gene
16908447	1064	1073	blockade	Negative_regulation
16908447	1076	1079	p38	Gene
16908447	1083	1091	SB203580	Chemical
16908447	1254	1263	TGF-beta1	Gene
16908447	1327	1332	TIMP3	Gene
16908447	1338	1349	expression	Gene_expression
16908447	1367	1377	increased	Positive_regulation
16908447	1480	1489	TGF-beta1	Gene
16908447	1490	1498	induced	Positive_regulation
16908447	1498	1503	TIMP3	Gene
20176803|t|Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis
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 IL-1beta, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A
IL-17A and IL-1beta 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	0	9	Bleomycin	Chemical
20176803	14	22	IL-1beta	Gene
20176803	32	50	pulmonary fibrosis	Disease
20176803	54	60	IL-17A	Gene
20176803	72	101	Idiopathic pulmonary fibrosis	Disease
20176803	103	106	IPF	Disease
20176803	125	145	inflammatory disease	Disease
20176803	302	320	pulmonary fibrosis	Disease
20176803	366	372	IL-17A	Gene
20176803	392	401	bleomycin	Chemical
20176803	403	406	BLM	Chemical
20176803	417	436	Schistosoma mansoni	Species
20176803	443	449	IL-17A	Gene
20176803	450	459	produced	Gene_expression
20176803	473	486	gammadelta(+)	Chemical
20176803	515	527	neutrophilia	Disease
20176803	532	550	pulmonary fibrosis	Disease
20176803	594	598	mice	Species
20176803	631	637	IL-17A	Gene
20176803	697	704	il12p40	Gene
20176803	735	739	mice	Species
20176803	744	752	TGF-beta	Gene
20176803	783	789	IL-17A	Gene
20176803	797	805	fibrosis	Disease
20176803	823	828	IL-10	Gene
20176803	848	857	IFN-gamma	Gene
20176803	875	878	BLM	Chemical
20176803	887	893	IL-17A	Gene
20176803	914	922	TGF-beta	Gene
20176803	950	956	IL-17A	Gene
20176803	966	974	fibrosis	Disease
20176803	975	984	required	Positive_regulation
20176803	984	992	TGF-beta	Gene
20176803	1027	1033	IL-17A	Gene
20176803	1038	1046	TGF-beta	Gene
20176803	1069	1077	fibrosis	Disease
20176803	1101	1109	fibrosis	Disease
20176803	1121	1129	IL-1beta	Gene
20176803	1144	1147	BLM	Chemical
20176803	1156	1164	fibrosis	Disease
20176803	1194	1200	IL-17A	Gene
20176803	1202	1208	IL-17A	Gene
20176803	1213	1221	IL-1beta	Gene
20176803	1232	1242	increased	Positive_regulation
20176803	1281	1289	patients	Species
20176803	1295	1298	IPF	Disease
20176803	1353	1359	IL-17A	Gene
20176803	1363	1371	fibrosis	Disease
20176803	1421	1427	IL-17A	Gene
20176803	1457	1469	inflammation	Disease
20176803	1478	1486	fibrosis	Disease
19487460|t|Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis
Diminished cyclooxygenase 2 (COX-2) expression in fibroblasts, with a resultant defect in the production of the antifibrotic mediator prostaglandin E(2), plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (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
19487460	0	10	Defective	Negative_regulation
19487460	33	45	responsible	Regulation
19487460	53	64	diminished	Negative_regulation
19487460	64	75	expression	Gene_expression
19487460	78	94	cyclooxygenase 2	Gene
19487460	98	127	idiopathic pulmonary fibrosis	Disease
19487460	140	156	cyclooxygenase 2	Gene
19487460	158	163	COX-2	Gene
19487460	165	176	expression	Gene_expression
19487460	263	281	prostaglandin E(2)	Chemical
19487460	323	352	idiopathic pulmonary fibrosis	Disease
19487460	427	432	COX-2	Gene
19487460	465	473	patients	Species
19487460	615	632	interleukin-1beta	Gene
19487460	652	657	COX-2	Gene
19487460	716	730	transcription	Transcription
19487460	874	879	COX-2	Gene
19487460	885	899	transcription	Transcription
19487460	982	990	binding	Binding
19487460	997	1002	COX-2	Gene
19487460	1025	1033	reduced	Negative_regulation
19487460	1100	1108	reduced	Negative_regulation
19487460	1145	1155	decreased	Negative_regulation
19487460	1155	1167	recruitment	Binding
19487460	1208	1218	increased	Positive_regulation
19487460	1218	1230	recruitment	Binding
19487460	1278	1283	COX-2	Gene
19487460	1349	1360	inhibitors	Negative_regulation
19487460	1384	1394	increased	Positive_regulation
19487460	1477	1486	restored	Positive_regulation
19487460	1486	1503	cytokine-induced	Positive_regulation
19487460	1503	1508	COX-2	Gene
19487460	1526	1537	expression	Gene_expression
19487460	1668	1673	COX-2	Gene
27582065|t|EZH2 enhances the differentiation of fibroblasts into myofibroblasts in idiopathic pulmonary fibrosis
The accumulation of fibroblasts/myofibroblasts in fibrotic foci is one of the characteristics of idiopathic pulmonary fibrosis (IPF)
Enhancer of zeste homolog 2 (EZH2) 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 EZH2 in the differentiation of fibroblasts into myofibroblasts
We found that EZH2 was upregulated in the lungs of patients with IPF and in mice with bleomycin-induced lung fibrosis
The upregulation of EZH2 occurred in myofibroblasts
The inhibition of EZH2 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 EZH2 induces the differentiation of fibroblasts to myofibroblasts by enhancing Smad2/3 nuclear translocation
27582065	0	4	EZH2	Gene
27582065	72	101	idiopathic pulmonary fibrosis	Disease
27582065	200	229	idiopathic pulmonary fibrosis	Disease
27582065	231	234	IPF	Disease
27582065	237	264	Enhancer of zeste homolog 2	Gene
27582065	266	270	EZH2	Gene
27582065	414	420	lysine	Chemical
27582065	483	487	EZH2	Gene
27582065	561	565	EZH2	Gene
27582065	570	582	upregulated	Positive_regulation
27582065	598	606	patients	Species
27582065	612	615	IPF	Disease
27582065	623	627	mice	Species
27582065	633	642	bleomycin	Chemical
27582065	651	664	lung fibrosis	Disease
27582065	670	683	upregulation	Positive_regulation
27582065	686	690	EZH2	Gene
27582065	723	734	inhibition	Negative_regulation
27582065	737	741	EZH2	Gene
27582065	759	778	3-deazaneplanocin A	Chemical
27582065	780	785	DZNep	Chemical
27582065	811	817	TGF-b1	Gene
27582065	845	850	human	Species
27582065	912	923	expression	Gene_expression
27582065	978	989	fibronectin	Gene
27582065	1010	1015	DZNep	Chemical
27582065	1016	1026	inhibited	Negative_regulation
27582065	1026	1033	Smad2/3	Gene
27582065	1034	1042	nuclear	Entity
27582065	1042	1056	translocation	Localization
27582065	1064	1074	affecting	Regulation
27582065	1074	1081	Smad2/3	Gene
27582065	1082	1098	phosphorylation	Phosphorylation
27582065	1099	1104	DZNep	Chemical
27582065	1126	1135	bleomycin	Chemical
27582065	1144	1162	pulmonary fibrosis	Disease
27582065	1166	1170	mice	Species
27582065	1189	1193	EZH2	Gene
27582065	1258	1268	enhancing	Positive_regulation
27582065	1268	1275	Smad2/3	Gene
24879051|t|y-Herpes virus-68, but not Pseudomonas aeruginosa or influenza A (H1N1), exacerbates established murine lung fibrosis
Patients with idiopathic pulmonary fibrosis (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	27	38	Pseudomonas	Species
24879051	85	117	established murine lung fibrosis	Disease
24879051	97	103	murine	Species
24879051	119	127	Patients	Species
24879051	133	162	idiopathic pulmonary fibrosis	Disease
24879051	164	167	IPF	Disease
24879051	308	314	murine	Species
24879051	360	385	established lung fibrosis	Disease
24879051	414	440	fluorescein isothiocyanate	Chemical
24879051	543	547	mice	Species
24879051	571	580	bleomycin	Chemical
24879051	618	622	mice	Species
24879051	698	720	Pseudomonas aeruginosa	Species
24879051	841	854	P
aeruginosa	Species
24879051	912	921	bleomycin	Chemical
24879051	945	949	mice	Species
24879051	980	993	P
aeruginosa	Species
24879051	1018	1027	bleomycin	Chemical
24879051	1036	1040	mice	Species
24879051	1049	1068	worse lung fibrosis	Disease
24879051	1173	1183	increased	Positive_regulation
24879051	1369	1373	mice	Species
24879051	1374	1384	displayed	Negative_regulation
24879051	1384	1394	increased	Positive_regulation
24879051	1394	1405	expression	Gene_expression
24879051	1425	1435	increased	Positive_regulation
24879051	1435	1440	SMAD3	Gene
24879051	1441	1457	phosphorylation	Phosphorylation
24879051	1504	1530	poly-ADP ribose polymerase	Gene
24879051	1532	1536	PARP	Gene
24879051	1572	1580	fibrosis	Disease
24879051	1706	1721	cytomegalovirus	Disease
16948840|t|Microarray identifies ADAM family members as key responders to TGF-beta1 in alveolar epithelial cells
The molecular mechanisms of Idiopathic Pulmonary Fibrosis (IPF) remain elusive
Transforming Growth Factor beta 1(TGF-beta1) 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 TGF-beta1, IL-4 and IL-13 and Epstein Barr virus
A549 cells were exposed to 10 ng/ml TGF-beta1, 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 TGF-beta1, suggesting a potential role for these molecules in ECM accumulation in IPF
16948840	63	72	TGF-beta1	Gene
16948840	131	160	Idiopathic Pulmonary Fibrosis	Disease
16948840	162	165	IPF	Disease
16948840	217	226	TGF-beta1	Gene
16948840	277	290	lung fibrosis	Disease
16948840	372	383	expression	Gene_expression
16948840	400	408	altered	Regulation
16948840	459	468	TGF-beta1	Gene
16948840	470	474	IL-4	Gene
16948840	479	484	IL-13	Gene
16948840	489	507	Epstein Barr virus	Species
16948840	545	554	TGF-beta1	Gene
16948840	556	560	IL-4	Gene
16948840	565	570	IL-13	Gene
16948840	645	650	Human	Species
16948840	1528	1538	expressed	Gene_expression
16948840	1549	1560	expression	Gene_expression
16948840	1618	1623	IL-13	Gene
16948840	1628	1632	IL-4	Gene
16948840	1688	1699	activation	Positive_regulation
16948840	1727	1733	ADAM19	Gene
16948840	1738	1745	ADAMTS9	Gene
16948840	1816	1827	diminished	Negative_regulation
16948840	1827	1838	production	Gene_expression
16948840	1875	1884	TGF-beta1	Gene
16948840	1957	1960	IPF	Disease
25244495|t|Diagnostic Values For Club Cell Secretory Protein (CC16) in Serum of Patients of Combined Pulmonary Fibrosis and Emphysema
Combined pulmonary fibrosis and emphysema (CPFE) is an under-recognized syndrome for which the diagnostic use of serum biomarkers is an attractive possibility
We hypothesized that CC16 and/or TGF-b1 or combinations with other biomarkers are useful for diagnosing CPFE
Patients with respiratory symptoms and a smoking history, with or without chronic obstructive pulmonary disease, were divided into the following three groups according to findings of high-resolution computed tomography of the chest: controls without either emphysema or fibrosis, patients with emphysema alone, and patients compatible with the diagnosis of CPFE
Serum concentrations of CC16, TGF-b1, SP-D, and KL-6 were measured in patients whose condition was stable for at least 3 months
To investigate changes in biomarkers of lung fibrosis in patients with a life-long smoking history, additional measurements were performed on the patients with idiopathic pulmonary fibrosis (IPF) of smoking history
The mean age of the first three groups was 68.0 years, whereas that of the IPF group was 71.8 years, and the groups contained 36, 115, 27, and 10 individuals, respectively
The serum concentration of CC16 in the four groups was 5.67    0.42, 5.66    0.35, 9.38    1.04 and 22.15    4.64 ng/ml, respectively, indicating that those patients with lung fibrosis had a significantly higher concentration
The combined use of CC16, SP-D, and KL-6 provided supportive diagnosis in conjunction with radiological imaging in diagnosis of CPFE
We conclude that a combination of biomarkers including CC16 could provide useful information to screen and predict the possible diagnosis of CPFE
25244495	51	55	CC16	Gene
25244495	69	77	Patients	Species
25244495	305	309	CC16	Gene
25244495	317	323	TGF-b1	Gene
25244495	394	402	Patients	Species
25244495	674	682	patients	Species
25244495	709	717	patients	Species
25244495	781	785	CC16	Gene
25244495	787	793	TGF-b1	Gene
25244495	795	799	SP-D	Gene
25244495	805	809	KL-6	Gene
25244495	827	835	patients	Species
25244495	943	951	patients	Species
25244495	1032	1040	patients	Species
25244495	1302	1306	CC16	Gene
25244495	1432	1440	patients	Species
25244495	1522	1526	CC16	Gene
25244495	1528	1532	SP-D	Gene
25244495	1538	1542	KL-6	Gene
25244495	1691	1695	CC16	Gene
26523510|t|Anti-pulmonary fibrotic activity of salvianolic acid B was screened by a novel method based on the cyto-biophysical properties
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 transforming growth factor-b1 (TGF-b1), and fibrogenesis was confirmed by conventional immunological assays
Meanwhile, the alterations of cyto-biophysical properties including morphology, roughness and stiffness were measured utilizing atomic force microscopy (AFM)
It was found that fibrogenesis was accompanied with changes of cellular biophysical properties
TGF-b1-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 TGF-b1-stimulated A549 cells was verified respectively by immunological and biophysical markers
The result of Principal Component Analysis showed that stiffness was a leading index among all biophysical markers during fibrogenesis
Salvianolic acid B (SalB), a natural anti-oxidant, was detected by AFM to protect TGF-b1-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	36	54	salvianolic acid B	Chemical
26523510	454	483	transforming growth factor-b1	Gene
26523510	485	491	TGF-b1	Gene
26523510	657	666	stiffness	Disease
26523510	818	824	TGF-b1	Gene
26523510	931	950	N-acetyl-l-cysteine	Chemical
26523510	952	955	NAC	Chemical
26523510	1008	1014	TGF-b1	Gene
26523510	1160	1169	stiffness	Disease
26523510	1241	1259	Salvianolic acid B	Chemical
26523510	1261	1265	SalB	Chemical
26523510	1323	1329	TGF-b1	Gene
26523510	1378	1382	SalB	Chemical
26523510	1430	1433	rat	Species
26523510	1443	1452	bleomycin	Chemical
26523510	1454	1457	BLM	Chemical
26523510	1468	1486	pulmonary fibrosis	Disease
26523510	1512	1516	SalB	Chemical
26523510	1553	1556	BLM	Chemical
26523510	1591	1599	blocked	Negative_regulation
26523510	1608	1622	accumulations	Positive_regulation
26523510	1626	1634	reduced	Negative_regulation
26523510	1634	1639	a-SMA	Gene
26523510	1735	1739	SalB	Chemical
26787543|t|miR-26a suppresses EMT by disrupting the Lin28B/let-7d axis: potential cross-talks among miRNAs in IPF
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and highly lethal fibrotic lung disease with unknown cause or cure
Although some microRNAs (miRNAs), such as miR-26a and let-7d, have been confirmed, the contribution to the pathophysiological processes of IPF, the roles of miRNAs and intrinsic links between them in fibrotic lung diseases are not yet well understood
In this study, we found that Lin28B could induce the process of epithelial-mesenchymal transition (EMT) by inhibiting let-7d, whereas inhibition of Lin28B mitigated TGF-b1-induced fibrogenesis and attenuated EMT in both cultured A549 cells and MLE-12 cells
More importantly, over-expression of miR-26a could simultaneously enhance the expression of let-7d in A549 cells, and further study confirmed that Lin28B was one of the direct targets of miR-26a, which mediates, at least in part, the regulatory effects of miR-26a on the biogenesis of let-7d
Finally, we constructed a regulatory network among miRNAs involved in the progression of IPF
Taken together, our study deciphered the essential role of Lin28B in the pathogenesis of EMT, and unraveled a novel mechanism that miR-26a is a modulator of let-7d
This study also defines the miRNAs network involved in IPF, which may have implications for developing new strategies for pulmonary fibrosis
KEY MESSAGE: Upregulation of Lin28B contributes to idiopathic pulmonary fibrosis
Lin28B causes epithelial-mesenchymal transition (EMT) by inhibition of let-7d
Lin28B is one of the targets of microRNA-26a
miR-26a enhances the expression of let-7d via targeting regulation of Lin28B
A regulatory network among miRNAs involved in the progression of IPF
26787543	0	7	miR-26a	Gene
26787543	41	47	Lin28B	Gene
26787543	48	54	let-7d	Gene
26787543	99	102	IPF	Disease
26787543	104	133	Idiopathic pulmonary fibrosis	Disease
26787543	135	138	IPF	Disease
26787543	185	206	fibrotic lung disease	Disease
26787543	277	284	miR-26a	Gene
26787543	289	295	let-7d	Gene
26787543	374	377	IPF	Disease
26787543	435	457	fibrotic lung diseases	Disease
26787543	516	522	Lin28B	Gene
26787543	605	611	let-7d	Gene
26787543	635	641	Lin28B	Gene
26787543	652	658	TGF-b1	Gene
26787543	731	737	MLE-12	Species
26787543	763	779	over-expression	Positive_regulation
26787543	782	789	miR-26a	Gene
26787543	837	843	let-7d	Gene
26787543	892	898	Lin28B	Gene
26787543	932	939	miR-26a	Gene
26787543	1001	1008	miR-26a	Gene
26787543	1030	1036	let-7d	Gene
26787543	1127	1130	IPF	Disease
26787543	1191	1197	Lin28B	Gene
26787543	1263	1270	miR-26a	Gene
26787543	1289	1295	let-7d	Gene
26787543	1352	1355	IPF	Disease
26787543	1419	1437	pulmonary fibrosis	Disease
26787543	1452	1465	Upregulation	Positive_regulation
26787543	1468	1474	Lin28B	Gene
26787543	1490	1519	idiopathic pulmonary fibrosis	Disease
26787543	1521	1527	Lin28B	Gene
26787543	1592	1598	let-7d	Gene
26787543	1600	1606	Lin28B	Gene
26787543	1646	1653	miR-26a	Gene
26787543	1654	1663	enhances	Positive_regulation
26787543	1681	1687	let-7d	Gene
26787543	1702	1713	regulation	Regulation
26787543	1716	1722	Lin28B	Gene
26787543	1789	1792	IPF	Disease
16738206|t|Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls
The currently accepted approach to treatment of idiopathic pulmonary fibrosis (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	33	62	idiopathic pulmonary fibrosis	Disease
16738206	165	194	idiopathic pulmonary fibrosis	Disease
16738206	196	199	IPF	Disease
16738206	249	269	inflammatory disease	Disease
16738206	587	590	IPF	Disease
16738206	744	747	IPF	Disease
16738206	781	795	animal disease	Disease
16738206	893	931	transforming growth factor (TGF)-beta1	Gene
16738206	977	989	Inflammation	Disease
16738206	1033	1041	fibrosis	Disease
16738206	1105	1113	fibrosis	Disease
16738206	1135	1140	Smad3	Gene
16573560|t|Th1/Th2 cytokine gene polymorphisms in patients with idiopathic pulmonary fibrosis
We investigated 30 patients with idiopathic pulmonary fibrosis (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, P(corr) < 0.0022; vs P < 0.0001, P(corr) < 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	0	3	Th1	Gene
16573560	39	47	patients	Species
16573560	53	82	idiopathic pulmonary fibrosis	Disease
16573560	103	111	patients	Species
16573560	117	146	idiopathic pulmonary fibrosis	Disease
16573560	148	151	IPF	Disease
16573560	219	228	IL-1alpha	Gene
16573560	230	238	IL-1beta	Gene
16573560	247	253	IL-1RA	Gene
16573560	255	259	IL-2	Gene
16573560	261	265	IL-4	Gene
16573560	267	271	IL-6	Gene
16573560	273	278	IL-10	Gene
16573560	287	314	tumor necrosis factor-alpha	Gene
16573560	316	332	interferon-gamma	Gene
16573560	367	375	IL-1beta	Gene
16573560	377	381	IL-2	Gene
16573560	383	387	IL-4	Gene
16573560	393	399	IL-4RA	Gene
16573560	523	527	IL-4	Gene
16573560	612	615	IPF	Disease
16573560	806	809	IPF	Disease
16573560	833	837	IL-4	Gene
26386411|t|VCAM-1 is a TGF-b1 inducible gene upregulated in idiopathic pulmonary fibrosis
UNASSIGNED: Idiopathic pulmonary fibrosis (IPF) is a chronic lethal interstitial lung disease of unknown etiology
We previously reported that high plasma levels of vascular cell adhesion molecule 1 (VCAM-1) predict mortality in IPF subjects
Here we investigated the cellular origin and potential role of VCAM-1 in regulating primary lung fibroblast behavior
VCAM-1 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)
VCAM-1 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 TGF-b1 significantly increased steady-state VCAM1 mRNA and protein levels without affecting VCAM1 mRNA stability
Further, cellular depletion of VCAM-1 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 VCAM-1 is a TGF-b1 responsive mediator that partakes in fibroblast proliferation in subjects with IPF
26386411	0	6	VCAM-1	Gene
26386411	12	18	TGF-b1	Gene
26386411	34	46	upregulated	Positive_regulation
26386411	49	78	idiopathic pulmonary fibrosis	Disease
26386411	92	121	Idiopathic pulmonary fibrosis	Disease
26386411	123	126	IPF	Disease
26386411	148	173	interstitial lung disease	Disease
26386411	245	278	vascular cell adhesion molecule 1	Gene
26386411	280	286	VCAM-1	Gene
26386411	309	312	IPF	Disease
26386411	386	392	VCAM-1	Gene
26386411	441	447	VCAM-1	Gene
26386411	471	481	increased	Positive_regulation
26386411	507	510	IPF	Disease
26386411	691	706	carbon monoxide	Chemical
26386411	708	712	DLCO	Chemical
26386411	715	721	VCAM-1	Gene
26386411	749	759	expressed	Gene_expression
26386411	762	765	IPF	Disease
26386411	835	838	IPF	Disease
26386411	858	863	human	Species
26386411	886	892	TGF-b1	Gene
26386411	907	917	increased	Positive_regulation
26386411	930	935	VCAM1	Gene
26386411	968	978	affecting	Regulation
26386411	978	983	VCAM1	Gene
26386411	1018	1028	depletion	Negative_regulation
26386411	1031	1037	VCAM-1	Gene
26386411	1212	1217	VCAM1	Gene
26386411	1218	1228	depletion	Negative_regulation
26386411	1249	1260	reductions	Negative_regulation
26386411	1327	1336	cyclin D1	Gene
26386411	1376	1382	VCAM-1	Gene
26386411	1388	1394	TGF-b1	Gene
26386411	1474	1477	IPF	Disease
28239659|t|Hsp90 regulation of fibroblast activation in pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 Hsp90 inhibitors as potential therapeutic agents that can suppress fibroblast activation in IPF
Although Hsp90 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 Hsp90 staining in lung biopsies of patients with IPF
Notably, fibroblasts isolated from fibrotic lesions showed heightened Hsp90 ATPase activity compared with normal fibroblasts
17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a small-molecule inhibitor of Hsp90 ATPase activity, attenuated fibroblast activation and also TGF-b-driven effects on fibroblast to myofibroblast transformation
The loss of the Hsp90AB, but not the Hsp90AA 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 pulmonary fibrosis, suggesting that targeting Hsp90 represents an effective strategy for the treatment of fibrotic lung disease
28239659	0	5	Hsp90	Gene
28239659	6	17	regulation	Regulation
28239659	45	63	pulmonary fibrosis	Disease
28239659	65	94	Idiopathic pulmonary fibrosis	Disease
28239659	96	99	IPF	Disease
28239659	113	134	fibrotic lung disease	Disease
28239659	382	385	IPF	Disease
28239659	486	491	Hsp90	Gene
28239659	578	581	IPF	Disease
28239659	592	597	Hsp90	Gene
28239659	628	638	regulates	Regulation
28239659	753	756	IPF	Disease
28239659	773	782	elevated	Positive_regulation
28239659	782	787	Hsp90	Gene
28239659	817	825	patients	Species
28239659	831	834	IPF	Disease
28239659	871	887	fibrotic lesions	Disease
28239659	906	911	Hsp90	Gene
28239659	962	1002	17-N-allylamino-17-demethoxygeldanamycin	Chemical
28239659	1004	1010	17-AAG	Chemical
28239659	1030	1040	inhibitor	Negative_regulation
28239659	1043	1048	Hsp90	Gene
28239659	1108	1113	TGF-b	Gene
28239659	1213	1218	Hsp90	Gene
28239659	1356	1362	17-AAG	Chemical
28239659	1413	1421	fibrosis	Disease
28239659	1427	1432	mouse	Species
28239659	1442	1460	pulmonary fibrosis	Disease
28239659	1488	1493	Hsp90	Gene
28239659	1548	1569	fibrotic lung disease	Disease
24853416|t|Integrated analyses identify the involvement of microRNA-26a in epithelial-mesenchymal transition during idiopathic pulmonary fibrosis
Idiopathic Pulmonary Fibrosis (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	105	134	idiopathic pulmonary fibrosis	Disease
24853416	136	165	Idiopathic Pulmonary Fibrosis	Disease
24853416	167	170	IPF	Disease
24853416	217	238	fibrotic lung disease	Disease
24853416	439	457	pulmonary fibrosis	Disease
24853416	554	557	IPF	Disease
24853416	630	650	EMT in lung fibrosis	Disease
24853416	698	709	regulation	Regulation
24853416	735	745	expressed	Gene_expression
24853416	745	748	IPF	Disease
24853416	798	813	downregulation	Negative_regulation
24853416	816	823	miR-26a	Gene
24853416	827	831	mice	Species
24853416	850	868	pulmonary fibrosis	Disease
24853416	898	905	miR-26a	Gene
24853416	906	916	regulated	Regulation
24853416	916	921	HMGA2	Gene
24853416	1060	1071	inhibition	Negative_regulation
24853416	1074	1081	miR-26a	Gene
24853416	1186	1197	expression	Gene_expression
24853416	1200	1207	miR-26a	Gene
24853416	1219	1225	TGF-b1	Gene
24853416	1231	1234	BLM	Chemical
24853416	1268	1272	mice	Species
24853416	1314	1325	deciphered	Negative_regulation
24853416	1347	1354	miR-26a	Gene
24853416	1385	1403	pulmonary fibrosis	Disease
24853416	1423	1430	miR-26a	Gene
24853416	1473	1476	IPF	Disease
25555634|t|Upregulation of alveolar levels of activin B, but not activin A, in lungs of west highland white terriers with idiopathic pulmonary fibrosis and diffuse alveolar damage
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 idiopathic pulmonary fibrosis (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	0	13	Upregulation	Positive_regulation
25555634	25	32	levels	Gene_expression
25555634	111	140	idiopathic pulmonary fibrosis	Disease
25555634	145	168	diffuse alveolar damage	Disease
25555634	275	287	inflammation	Disease
25555634	292	300	fibrosis	Disease
25555634	372	377	human	Species
25555634	378	407	idiopathic pulmonary fibrosis	Disease
25555634	409	412	IPF	Disease
25555634	464	470	Canine	Species
25555634	476	480	CIPF	Chemical
25555634	498	523	interstitial lung disease	Disease
25555634	714	718	CIPF	Chemical
25555634	740	763	diffuse alveolar damage	Disease
25555634	796	831	acute respiratory distress syndrome	Disease
25555634	833	837	ARDS	Disease
25555634	875	886	expression	Gene_expression
25555634	934	938	CIPF	Chemical
25555634	954	958	CIPF	Chemical
25555634	982	986	dogs	Species
25555634	1010	1014	ARDS	Disease
25555634	1179	1183	CIPF	Chemical
25555634	1260	1270	expressed	Gene_expression
25555634	1332	1336	CIPF	Chemical
25555634	1364	1368	dogs	Species
25555634	1374	1378	ARDS	Disease
25555634	1429	1433	CIPF	Chemical
25555634	1464	1468	dogs	Species
25555634	1613	1617	CIPF	Chemical
25555634	1647	1673	alveolar epithelial damage	Disease
12475802|t|Roles for insulin-like growth factor I and transforming growth factor-beta in fibrotic lung disease
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, insulin-like growth factor (IGF)-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 fibrotic lung diseases 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	10	38	insulin-like growth factor I	Gene
12475802	43	74	transforming growth factor-beta	Gene
12475802	78	99	fibrotic lung disease	Disease
12475802	101	130	Idiopathic pulmonary fibrosis	Disease
12475802	132	135	IPF	Disease
12475802	142	154	lung disease	Disease
12475802	255	267	inflammation	Disease
12475802	362	389	alveolar gas exchange units	Disease
12475802	442	450	patients	Species
12475802	456	459	IPF	Disease
12475802	469	488	respiratory failure	Disease
12475802	507	512	death	Disease
12475802	607	619	inflammation	Disease
12475802	762	770	fibrosis	Disease
12475802	798	810	inflammation	Disease
12475802	828	831	IPF	Disease
12475802	885	900	immune disorder	Disease
12475802	979	1013	insulin-like growth factor (IGF)-I	Gene
12475802	1185	1212	tumor necrosis factor-alpha	Gene
12475802	1217	1234	interleukin-1beta	Gene
12475802	1281	1304	fibrotic lung disorders	Disease
12475802	1315	1318	IPF	Disease
12475802	1320	1324	ARDS	Disease
12475802	1326	1337	sarcoidosis	Disease
12475802	1343	1369	bronchopulmonary dysplasia	Disease
12475802	1410	1427	systemic diseases	Disease
12475802	1436	1456	rheumatoid arthritis	Disease
12475802	1460	1490	progressive systemic sclerosis	Disease
12475802	1492	1503	scleroderma	Disease
12475802	1520	1532	inflammation	Disease
12475802	1638	1660	fibrotic lung diseases	Disease
12475802	1691	1702	production	Gene_expression
12475802	1772	1775	IPF	Disease
12475802	1960	1965	IGF-I	Gene
12475802	2034	2042	patients	Species
12475802	2048	2051	IPF	Disease
27560128|t|Epigenetic Regulation of Caveolin-1 Gene Expression in Lung Fibroblasts
RATIONALE: Fibrotic disorders 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	11	22	Regulation	Regulation
27560128	25	35	Caveolin-1	Gene
27560128	41	52	Expression	Gene_expression
27560128	84	102	Fibrotic disorders	Disease
27560128	183	193	caveolin-1	Gene
27560128	195	198	Cav	Species
27560128	321	324	Cav	Species
27560128	363	374	suppressed	Negative_regulation
27560128	377	406	idiopathic pulmonary fibrosis	Disease
27560128	408	411	IPF	Disease
27560128	535	538	Cav	Species
27560128	541	556	downregulation	Negative_regulation
27560128	559	562	IPF	Disease
27560128	624	627	Cav	Species
27560128	630	641	expression	Gene_expression
27560128	698	709	associated	Binding
27560128	718	721	Cav	Species
27560128	803	806	IPF	Disease
27560128	880	886	murine	Species
27560128	910	919	bleomycin	Chemical
27560128	1003	1006	Cav	Species
27560128	1055	1063	changes	Regulation
27560128	1066	1069	Cav	Species
27560128	1072	1083	expression	Gene_expression
27560128	1131	1134	CpG	Chemical
27560128	1171	1174	Cav	Species
27560128	1229	1232	IPF	Disease
27560128	1243	1252	response	Positive_regulation
27560128	1272	1281	bleomycin	Chemical
27560128	1290	1296	murine	Species
27560128	1297	1308	lung injury	Disease
27560128	1365	1377	association	Binding
27560128	1380	1383	Cav	Species
27560128	1463	1466	Cav	Species
27560128	1469	1484	downregulation	Negative_regulation
27560128	1559	1562	Cav	Species
27560128	1570	1580	silencing	Negative_regulation
27560128	1612	1622	regulated	Regulation
27560128	1652	1660	involve	Regulation
27560128	1824	1831	target	Regulation
27560128	1856	1864	restore	Positive_regulation
27560128	1864	1867	Cav	Species
27560128	1870	1881	expression	Gene_expression
27467922|t|Combined inhibition of TGFb and PDGF signaling attenuates radiation-induced pulmonary fibrosis
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 pulmonary fibrosis
Transforming growth factor b (TGFb) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear
Methods : C57BL/6 mice were treated with 20  Gy to the thorax to induce pulmonary fibrosis
PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFb 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 TGFb 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 TGFb-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFb pathways
Conclusion : Combined small-molecule inhibition of PDGF and TGFb 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 TGFb and PDGF play a key role
Here, we show that a combined inhibition of TGFb and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone
We used the TGFb-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 TGFb 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 TGFb and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of lung cancer
27467922	9	20	inhibition	Negative_regulation
27467922	23	27	TGFb	Gene
27467922	76	94	pulmonary fibrosis	Disease
27467922	174	185	lung cancer	Disease
27467922	267	278	pneumonitis	Disease
27467922	283	301	pulmonary fibrosis	Disease
27467922	303	331	Transforming growth factor b	Gene
27467922	333	337	TGFb	Gene
27467922	490	508	pulmonary fibrosis	Disease
27467922	555	559	mice	Species
27467922	609	627	pulmonary fibrosis	Disease
27467922	643	654	inhibitors	Negative_regulation
27467922	654	660	SU9518	Chemical
27467922	665	672	SU14816	Chemical
27467922	674	682	imatinib	Chemical
27467922	688	692	TGFb	Gene
27467922	712	724	galunisertib	Chemical
27467922	804	812	fibrosis	Disease
27467922	921	932	Osteopontin	Gene
27467922	979	985	SU9518	Chemical
27467922	987	994	SU14816	Chemical
27467922	998	1010	galunisertib	Chemical
27467922	1053	1075	pulmonary inflammation	Disease
27467922	1080	1088	fibrosis	Disease
27467922	1142	1153	lung damage	Disease
27467922	1174	1178	TGFb	Gene
27467922	1179	1190	inhibitors	Negative_regulation
27467922	1226	1231	mouse	Species
27467922	1302	1313	lung damage	Disease
27467922	1327	1332	mouse	Species
27467922	1446	1459	upregulation	Positive_regulation
27467922	1471	1475	TGFb	Gene
27467922	1536	1549	upregulation	Positive_regulation
27467922	1618	1622	TGFb	Gene
27467922	1670	1681	inhibition	Negative_regulation
27467922	1693	1697	TGFb	Gene
27467922	1764	1786	pulmonary inflammation	Disease
27467922	1791	1799	fibrosis	Disease
27467922	1803	1807	mice	Species
27467922	1856	1878	fibrotic lung diseases	Disease
27467922	1882	1888	humans	Species
27467922	1958	1964	cancer	Disease
27467922	2007	2017	toxicities	Disease
27467922	2025	2029	TGFb	Gene
27467922	2086	2097	inhibition	Negative_regulation
27467922	2100	2104	TGFb	Gene
27467922	2175	2186	lung damage	Disease
27467922	2242	2246	TGFb	Gene
27467922	2268	2280	galunisertib	Chemical
27467922	2345	2350	PDGFR	Gene
27467922	2351	2362	inhibitors	Negative_regulation
27467922	2362	2370	imatinib	Chemical
27467922	2375	2381	SU9518	Chemical
27467922	2385	2394	sunitinib	Chemical
27467922	2439	2449	reduction	Negative_regulation
27467922	2452	2456	TGFb	Gene
27467922	2484	2496	attenuation	Negative_regulation
27467922	2499	2503	SPP1	Gene
27467922	2505	2516	Osteopontin	Gene
27467922	2518	2529	expression	Gene_expression
27467922	2661	2667	cancer	Disease
27467922	2713	2720	cancers	Disease
27467922	2724	2748	idiopathic lung fibrosis	Disease
27467922	2750	2753	IPF	Disease
27467922	2823	2834	inhibitors	Negative_regulation
27467922	2837	2841	TGFb	Gene
27467922	2922	2930	toxicity	Disease
27467922	2934	2951	RT of lung cancer	Disease
27350126|t|Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a lethal human disease with short survival time and few treatment options
Herein, we demonstrated that discoidin domain receptor 2 (DDR2), 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 DDR2 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 DDR2 or its kinase inhibitor exhibited therapeutic efficacy against lung fibrosis
Thus, this study not only elucidated novel mechanisms by which DDR2 controls the development of pulmonary fibrosis, but also provided candidate target for the intervention of this stubborn disease
27350126	13	40	Discoidin Domain Receptor 2	Gene
27350126	42	46	DDR2	Gene
27350126	113	131	Pulmonary Fibrosis	Disease
27350126	133	162	Idiopathic pulmonary fibrosis	Disease
27350126	164	167	IPF	Disease
27350126	181	186	human	Species
27350126	276	303	discoidin domain receptor 2	Gene
27350126	305	309	DDR2	Gene
27350126	323	331	tyrosine	Chemical
27350126	445	453	fibrosis	Disease
27350126	518	522	DDR2	Gene
27350126	684	718	vascular endothelial growth factor	Gene
27350126	720	724	VEGF	Gene
27350126	726	737	expression	Gene_expression
27350126	799	803	mice	Species
27350126	818	824	siRNA	Negative_regulation
27350126	832	836	DDR2	Gene
27350126	900	913	lung fibrosis	Disease
27350126	978	982	DDR2	Gene
27350126	1011	1029	pulmonary fibrosis	Disease
27350126	1095	1111	stubborn disease	Disease
25111852|t|Glucagon like peptide-1 attenuates bleomycin-induced pulmonary fibrosis, involving the inactivation of NF-kB in mice
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis in mice
Mice with BLM-induced pulmonary fibrosis 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 Trans(AM) 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 pulmonary fibrosis in mice
Our data found that BLM-induced lung inflammation and pulmonary fibrosis were significantly alleviated by GLP-1 treatment in mice, possibly through inactivation of NF-kB
25111852	0	23	Glucagon like peptide-1	Gene
25111852	35	44	bleomycin	Chemical
25111852	53	71	pulmonary fibrosis	Disease
25111852	87	100	inactivation	Negative_regulation
25111852	112	116	mice	Species
25111852	118	147	Idiopathic pulmonary fibrosis	Disease
25111852	149	152	IPF	Disease
25111852	171	183	lung disease	Disease
25111852	307	325	pulmonary fibrosis	Disease
25111852	330	353	glucagon like peptide-1	Gene
25111852	355	360	GLP-1	Gene
25111852	385	397	inflammation	Disease
25111852	401	414	inactivation	Negative_regulation
25111852	441	455	GLP-1 receptor	Gene
25111852	460	469	detected	Gene_expression
25111852	555	560	GLP-1	Gene
25111852	564	567	BLM	Chemical
25111852	576	594	pulmonary fibrosis	Disease
25111852	598	602	mice	Species
25111852	604	608	Mice	Species
25111852	614	617	BLM	Chemical
25111852	626	644	pulmonary fibrosis	Disease
25111852	674	679	GLP-1	Gene
25111852	710	713	BLM	Chemical
25111852	809	815	TGF-b1	Gene
25111852	839	850	Hematoxylin	Chemical
25111852	851	856	eosin	Chemical
25111852	947	961	hydroxyproline	Chemical
25111852	1050	1055	a-SMA	Gene
25111852	1060	1066	VCAM-1	Gene
25111852	1072	1088	phosphorylation	Phosphorylation
25111852	1097	1100	p65	Gene
25111852	1140	1148	binding	Binding
25111852	1157	1160	p65	Gene
25111852	1192	1195	p65	Gene
25111852	1228	1233	GLP-1	Gene
25111852	1292	1298	TGF-b1	Gene
25111852	1310	1314	mice	Species
25111852	1320	1323	BLM	Chemical
25111852	1358	1372	hydroxyproline	Chemical
25111852	1399	1404	GLP-1	Gene
25111852	1432	1435	BLM	Chemical
25111852	1444	1459	overexpression	Positive_regulation
25111852	1462	1467	a-SMA	Gene
25111852	1472	1478	VCAM-1	Gene
25111852	1495	1500	GLP-1	Gene
25111852	1514	1518	mice	Species
25111852	1520	1525	GLP-1	Gene
25111852	1567	1570	p65	Gene
25111852	1583	1586	p65	Gene
25111852	1597	1600	p65	Gene
25111852	1625	1628	BLM	Chemical
25111852	1637	1655	pulmonary fibrosis	Disease
25111852	1659	1663	mice	Species
25111852	1685	1688	BLM	Chemical
25111852	1697	1714	lung inflammation	Disease
25111852	1719	1737	pulmonary fibrosis	Disease
25111852	1771	1776	GLP-1	Gene
25111852	1790	1794	mice	Species
25111852	1813	1826	inactivation	Negative_regulation
24811261|t|Carbon monoxide-bound hemoglobin-vesicles for the treatment of bleomycin-induced pulmonary fibrosis
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 pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis 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 pulmonary fibrosis via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced pulmonary fibrosis 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	0	15	Carbon monoxide	Chemical
24811261	63	72	bleomycin	Chemical
24811261	81	99	pulmonary fibrosis	Disease
24811261	101	116	Carbon monoxide	Chemical
24811261	282	285	HbV	Species
24811261	312	315	HbV	Species
24811261	351	380	idiopathic pulmonary fibrosis	Disease
24811261	382	385	IPF	Disease
24811261	401	414	lung fibrosis	Disease
24811261	443	455	inflammation	Disease
24811261	478	501	reactive oxygen species	Disease
24811261	487	493	oxygen	Chemical
24811261	503	506	ROS	Disease
24811261	604	618	hydroxyproline	Chemical
24811261	675	684	bleomycin	Chemical
24811261	693	711	pulmonary fibrosis	Disease
24811261	712	716	mice	Species
24811261	727	730	HbV	Species
24811261	845	848	HbV	Species
24811261	879	882	HbV	Species
24811261	886	904	pulmonary fibrosis	Disease
24811261	928	937	decrease	Negative_regulation
24811261	940	943	ROS	Disease
24811261	978	983	NADPH	Chemical
24811261	1155	1158	HbV	Species
24811261	1181	1199	pulmonary fibrosis	Disease
24811261	1266	1275	bleomycin	Chemical
24811261	1284	1302	pulmonary fibrosis	Disease
24811261	1303	1307	mice	Species
24811261	1318	1321	HbV	Species
24811261	1378	1381	IPF	Disease
24811261	1411	1414	ROS	Disease
24811261	1419	1449	inflammation-related disorders	Disease
26474459|t|Protease activated receptor-1 regulates macrophage-mediated cellular senescence: a risk for idiopathic pulmonary fibrosis
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 idiopathic pulmonary fibrosis
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	0	29	Protease activated receptor-1	Gene
26474459	92	121	idiopathic pulmonary fibrosis	Disease
26474459	123	152	Idiopathic pulmonary fibrosis	Disease
26474459	154	157	IPF	Disease
26474459	243	272	Protease-activated receptor-1	Gene
26474459	274	279	PAR-1	Gene
26474459	340	362	fibrotic lung diseases	Disease
26474459	420	425	PAR-1	Gene
26474459	435	464	idiopathic pulmonary fibrosis	Disease
26474459	531	536	PAR-1	Gene
26474459	580	589	bleomycin	Chemical
26474459	629	634	PAR-1	Gene
26474459	777	785	induced	Positive_regulation
26474459	828	838	secretion	Localization
26474459	891	896	TGF-b	Gene
26474459	906	917	inhibitors	Negative_regulation
26474459	1006	1011	PAR-1	Gene
26474459	1053	1058	PAR-1	Gene
26474459	1065	1070	down	Negative_regulation
26474459	1117	1122	PAR-1	Gene
26474459	1138	1143	TGF-b	Gene
26474459	1144	1155	activation	Positive_regulation
26474459	1218	1228	induction	Positive_regulation
26474459	1231	1236	PAR-1	Gene
26474459	1244	1249	TGF-b	Gene
26474459	1250	1261	activation	Positive_regulation
26474459	1277	1280	FXa	Gene
26474459	1326	1331	PAR-1	Gene
26474459	1386	1389	IPF	Disease
26474459	1433	1438	PAR-1	Gene
26474459	1490	1493	IPF	Disease
17363768|t|Control of virus reactivation arrests pulmonary herpesvirus-induced fibrosis in IFN-gamma receptor-deficient mice
RATIONALE: Idiopathic pulmonary fibrosis (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 fibrosis
METHODS: IFN-gamma receptor-deficient (IFN-gammaR(-/-)) mice infected intranasally with murine gamma-herpesvirus 68 (MHV68) develop lung fibrosis 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 fibrosis compared with 40% of the control saline-treated animals
Absence of severe fibrosis was also observed in IFN-gammaR(-/-) mice infected with the defective reactivation mutant MHV68 v-cyclin stop
Decreased fibrosis 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 fibrosis persisted in 60% of the mice
CONCLUSIONS: MHV68-induced fibrosis is a result of viral lytic replication during chronic lung herpesvirus infection in mice
We speculate that antiviral therapy might help to control lung fibrosis in humans with IPF and associated herpesvirus infection
17363768	68	76	fibrosis	Disease
17363768	99	109	deficient	Negative_regulation
17363768	109	113	mice	Species
17363768	126	155	Idiopathic pulmonary fibrosis	Disease
17363768	157	160	IPF	Disease
17363768	187	209	fibrotic lung disorder	Disease
17363768	275	293	Epstein-Barr virus	Species
17363768	337	340	IPF	Disease
17363768	510	528	pulmonary fibrosis	Disease
17363768	569	579	IFN-gammaR	Gene
17363768	586	590	mice	Species
17363768	618	624	murine	Species
17363768	667	675	fibrosis	Disease
17363768	726	743	initial infection	Disease
17363768	791	800	infection	Disease
17363768	854	863	cidofovir	Chemical
17363768	1184	1202	pulmonary fibrosis	Disease
17363768	1278	1286	fibrosis	Disease
17363768	1308	1318	IFN-gammaR	Gene
17363768	1324	1328	mice	Species
17363768	1408	1416	fibrosis	Disease
17363768	1726	1743	but lung fibrosis	Disease
17363768	1768	1772	mice	Species
17363768	1801	1809	fibrosis	Disease
17363768	1869	1890	herpesvirus infection	Disease
17363768	1894	1898	mice	Species
17363768	1963	1971	fibrosis	Disease
17363768	1975	1981	humans	Species
17363768	1987	1990	IPF	Disease
17363768	2006	2027	herpesvirus infection	Disease
25785991|t|Epithelial Cell Mitochondrial Dysfunction and PINK1 Are Induced by Transforming Growth Factor- Beta1 in Pulmonary Fibrosis
BACKGROUND: Epithelial cell death 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 death and fibrosis
METHODS: We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), 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 PINK1 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 PINK1 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, PINK1
PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis
25785991	46	51	PINK1	Gene
25785991	67	100	Transforming Growth Factor- Beta1	Gene
25785991	152	157	death	Disease
25785991	337	342	death	Disease
25785991	347	355	fibrosis	Disease
25785991	388	408	mitochondrial injury	Disease
25785991	435	465	PTEN-induced putative kinase 1	Gene
25785991	467	472	PINK1	Gene
25785991	659	688	transforming growth factor-b1	Gene
25785991	690	696	TGF-b1	Gene
25785991	843	849	murine	Species
25785991	850	859	bleomycin	Chemical
25785991	869	882	lung fibrosis	Disease
25785991	936	946	increased	Positive_regulation
25785991	946	951	PINK1	Gene
25785991	952	963	expression	Gene_expression
25785991	1086	1092	TGF-b1	Gene
25785991	1093	1101	induced	Positive_regulation
25785991	1154	1159	PINK1	Gene
25785991	1160	1171	expression	Gene_expression
25785991	1233	1238	Pink1	Gene
25785991	1242	1246	mice	Species
25785991	1282	1286	mice	Species
25785991	1290	1299	bleomycin	Chemical
25785991	1335	1341	TGF-b1	Gene
25785991	1461	1466	PINK1	Gene
25785991	1468	1473	PINK1	Gene
25785991	1502	1507	death	Disease
27769060|t|MiR-185/AKT and miR-29a/collagen 1a pathways are activated in IPF BAL cells
MicroRNA signatures of BAL cells and alveolar macrophages are currently lacking in IPF
Here we sought to investigate the expression of fibrosis-related microRNAs in the cellular component of the BAL in IPF
We thus focused on microRNAs previously associated with fibrosis (miR-29a, miR-29b, miR-29c, let-7d, and miR-21) and rapid IPF progression (miR-185, miR-210, miR-302c-3p miR-376c and miR-423-5p)
Among the tested microRNAs miR-29a and miR-185 were found significantly downregulated in IPF while miR-302c-3p and miR-376c were not expressed by BAL cells
Importantly, the downregulation of miR-29a inversely correlated with the significantly increased levels of COL1A1 mRNA in IPF 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 AKT1, DNMT1 and HMGA2, no significant correlations were observed in the BAL cells
However, increased levels of total AKT and AKTser473 phosphorylation were observed in the IPF BAL cells
Furthermore, miR-185 inhibition in THP-1 macrophages resulted in significant increase of AKTser473 phosphorylation
Our study highlights the importance of BAL microRNA signatures in IPF and identifies significant differences in miR-185/AKT and miR-29a/collagen axes in the BAL cells of IPF patients
27769060	0	7	MiR-185	Gene
27769060	8	11	AKT	Gene
27769060	16	23	miR-29a	Gene
27769060	49	59	activated	Positive_regulation
27769060	62	65	IPF	Disease
27769060	160	163	IPF	Disease
27769060	213	221	fibrosis	Disease
27769060	280	283	IPF	Disease
27769060	341	349	fibrosis	Disease
27769060	351	358	miR-29a	Gene
27769060	360	367	miR-29b	Gene
27769060	369	376	miR-29c	Gene
27769060	378	384	let-7d	Gene
27769060	390	396	miR-21	Gene
27769060	408	411	IPF	Disease
27769060	425	432	miR-185	Gene
27769060	434	441	miR-210	Gene
27769060	455	463	miR-376c	Gene
27769060	508	515	miR-29a	Gene
27769060	520	527	miR-185	Gene
27769060	570	573	IPF	Disease
27769060	596	604	miR-376c	Gene
27769060	614	624	expressed	Gene_expression
27769060	655	670	downregulation	Negative_regulation
27769060	673	680	miR-29a	Gene
27769060	725	735	increased	Positive_regulation
27769060	735	742	levels	Gene_expression
27769060	745	751	COL1A1	Gene
27769060	760	763	IPF	Disease
27769060	805	819	overexpressed	Positive_regulation
27769060	917	932	downregulation	Negative_regulation
27769060	935	942	miR-185	Gene
27769060	970	975	THP-1	Gene
27769060	1012	1016	TGFb	Gene
27769060	1034	1049	downregulation	Negative_regulation
27769060	1052	1059	miR-185	Gene
27769060	1109	1116	miR-185	Gene
27769060	1160	1167	levels	Transcription
27769060	1176	1183	miR-185	Gene
27769060	1192	1196	AKT1	Gene
27769060	1198	1203	DNMT1	Gene
27769060	1208	1213	HMGA2	Gene
27769060	1284	1294	increased	Positive_regulation
27769060	1294	1301	levels	Gene_expression
27769060	1310	1313	AKT	Gene
27769060	1328	1344	phosphorylation	Phosphorylation
27769060	1365	1368	IPF	Disease
27769060	1393	1400	miR-185	Gene
27769060	1401	1412	inhibition	Negative_regulation
27769060	1415	1420	THP-1	Gene
27769060	1457	1466	increase	Positive_regulation
27769060	1479	1495	phosphorylation	Phosphorylation
27769060	1562	1565	IPF	Disease
27769060	1608	1615	miR-185	Gene
27769060	1616	1619	AKT	Gene
27769060	1624	1631	miR-29a	Gene
27769060	1666	1669	IPF	Disease
27769060	1670	1678	patients	Species
22434388|t|Regulation of TGF-b storage and activation in the human idiopathic pulmonary fibrosis lung
Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown cause
The pathogenesis of the disease is characterized by fibroblast accumulation and excessive transforming growth factor-b (TGF-b) activation
Although TGF-b activation is a complex process involving various protein interactions, little is known of the specific routes of TGF-b storage and activation in human lung
Here, we have systematically analyzed the expression of specific proteins involved in extracellular matrix targeting and activation of TGF-b
Latent TGF-b-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 TGF-b 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 TGF-b signaling activity, respectively, suggesting that LTBP-1-mediated TGF-b 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 TGF-b-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 TGF-b storage protein LTBP-1 and the re-appearance of fibrillin-2, probably modulate TGF-b availability and activation in different pulmonary compartments in the fibrotic lung
22434388	0	11	Regulation	Regulation
22434388	14	19	TGF-b	Gene
22434388	50	55	human	Species
22434388	56	90	idiopathic pulmonary fibrosis lung	Disease
22434388	92	121	Idiopathic pulmonary fibrosis	Disease
22434388	123	126	IPF	Disease
22434388	261	289	transforming growth factor-b	Gene
22434388	291	296	TGF-b	Gene
22434388	319	324	TGF-b	Gene
22434388	325	336	activation	Positive_regulation
22434388	439	444	TGF-b	Gene
22434388	471	476	human	Species
22434388	604	615	activation	Positive_regulation
22434388	618	623	TGF-b	Gene
22434388	632	637	TGF-b	Gene
22434388	655	662	LTBP)-1	Gene
22434388	693	705	upregulated	Positive_regulation
22434388	708	711	IPF	Disease
22434388	712	719	patient	Species
22434388	727	733	LTBP-1	Gene
22434388	734	745	expression	Gene_expression
22434388	760	765	high	Positive_regulation
22434388	840	845	TGF-b	Gene
22434388	976	991	downregulation	Negative_regulation
22434388	994	1000	LTBP-1	Gene
22434388	1043	1048	TGF-b	Gene
22434388	1099	1105	LTBP-1	Gene
22434388	1115	1120	TGF-b	Gene
22434388	1121	1132	activation	Positive_regulation
22434388	1195	1201	LTBP-1	Gene
22434388	1215	1226	colocalize	Binding
22434388	1231	1242	fibronectin	Gene
22434388	1244	1255	fibrillin-1	Gene
22434388	1260	1271	fibrillin-2	Gene
22434388	1288	1291	IPF	Disease
22434388	1298	1309	Fibrillin-2	Gene
22434388	1424	1427	IPF	Disease
22434388	1451	1456	TGF-b	Gene
22434388	1492	1502	expressed	Gene_expression
22434388	1536	1539	IPF	Disease
22434388	1609	1616	levels	Gene_expression
22434388	1623	1628	TGF-b	Gene
22434388	1645	1651	LTBP-1	Gene
22434388	1677	1688	fibrillin-2	Gene
22434388	1699	1708	modulate	Regulation
22434388	1708	1713	TGF-b	Gene
28873461|t|Interleukin-17 induces human alveolar epithelial to mesenchymal cell transition via the TGF-b1 mediated Smad2/3 and ERK1/2 activation
Idiopathic pulmonary fibrosis (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 TGF-b1 were analyzed via quantitative RT-PCR and ELISA
Expressions of Smad2/3, p-Smad2/3, ERK1/2, p-ERK1/2 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 TGF-b1 expression and stimulated Smad2/3 and ERK1/2 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 TGF-b1 mediated Smad2/3 and ERK1/2 activation
28873461	23	28	human	Species
28873461	88	94	TGF-b1	Gene
28873461	95	104	mediated	Positive_regulation
28873461	104	111	Smad2/3	Gene
28873461	116	122	ERK1/2	Gene
28873461	123	134	activation	Positive_regulation
28873461	135	164	Idiopathic pulmonary fibrosis	Disease
28873461	166	169	IPF	Disease
28873461	208	220	lung disease	Disease
28873461	319	337	pulmonary fibrosis	Disease
28873461	339	344	IL-17	Gene
28873461	479	484	IL-17	Gene
28873461	546	551	TGFb1	Gene
28873461	716	721	E-cad	Gene
28873461	726	731	a-SMA	Gene
28873461	812	824	expressions	Transcription
28873461	827	833	TGF-b1	Gene
28873461	883	895	Expressions	Gene_expression
28873461	898	905	Smad2/3	Gene
28873461	909	916	Smad2/3	Gene
28873461	918	924	ERK1/2	Gene
28873461	928	934	ERK1/2	Gene
28873461	941	944	JNK	Gene
28873461	1007	1012	IL-17	Gene
28873461	1123	1128	E-cad	Gene
28873461	1157	1162	a-SMA	Gene
28873461	1189	1194	IL-17	Gene
28873461	1195	1204	enhanced	Positive_regulation
28873461	1204	1210	TGF-b1	Gene
28873461	1211	1222	expression	Gene_expression
28873461	1226	1237	stimulated	Positive_regulation
28873461	1237	1244	Smad2/3	Gene
28873461	1249	1255	ERK1/2	Gene
28873461	1256	1272	phosphorylation	Phosphorylation
28873461	1341	1352	expression	Gene_expression
28873461	1355	1370	phosphorylated	Phosphorylation
28873461	1370	1373	JNK	Gene
28873461	1404	1409	IL-17	Gene
28873461	1421	1429	SB431542	Chemical
28873461	1433	1438	U0126	Chemical
28873461	1548	1553	E-cad	Gene
28873461	1584	1589	a-SMA	Gene
28873461	1639	1644	IL-17	Gene
28873461	1649	1656	induce	Positive_regulation
28873461	1710	1716	TGF-b1	Gene
28873461	1717	1726	mediated	Positive_regulation
28873461	1726	1733	Smad2/3	Gene
28873461	1738	1744	ERK1/2	Gene
28873461	1745	1756	activation	Positive_regulation
29045477|t|Tubastatin ameliorates pulmonary fibrosis by targeting the TGFb-PI3K-Akt pathway
BACKGROUND: Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis, by targeting the TGFb-PI3K-Akt pathway, likely via an HDAC6-independent mechanism
29045477	0	10	Tubastatin	Chemical
29045477	23	41	pulmonary fibrosis	Disease
29045477	69	72	Akt	Gene
29045477	94	123	Idiopathic pulmonary fibrosis	Disease
29045477	125	128	IPF	Disease
29045477	175	196	Histone deacetylase 6	Gene
29045477	198	203	HDAC6	Gene
29045477	271	277	lysine	Chemical
29045477	309	315	TGF-b1	Gene
29045477	386	391	HDAC6	Gene
29045477	395	413	pulmonary fibrosis	Disease
29045477	435	440	HDAC6	Gene
29045477	441	452	expression	Gene_expression
29045477	455	458	IPF	Disease
29045477	582	588	TGF-b1	Gene
29045477	592	597	HDAC6	Gene
29045477	619	629	Tubastatin	Chemical
29045477	631	638	ACY1215	Chemical
29045477	643	649	MC1568	Chemical
29045477	742	746	Mice	Species
29045477	765	774	bleomycin	Chemical
29045477	818	828	Tubastatin	Chemical
29045477	897	908	expression	Gene_expression
29045477	987	992	HDAC6	Gene
29045477	1026	1030	mice	Species
29045477	1049	1058	bleomycin	Chemical
29045477	1114	1119	HDAC6	Gene
29045477	1120	1131	expression	Gene_expression
29045477	1135	1147	deregulated	Regulation
29045477	1150	1153	IPF	Disease
29045477	1171	1176	HDAC6	Gene
29045477	1177	1188	inhibitors	Negative_regulation
29045477	1201	1211	Tubastatin	Chemical
29045477	1226	1236	repressed	Negative_regulation
29045477	1236	1242	TGF-b1	Gene
29045477	1243	1251	induced	Positive_regulation
29045477	1251	1262	expression	Gene_expression
29045477	1336	1346	decreased	Negative_regulation
29045477	1346	1349	Akt	Gene
29045477	1350	1366	phosphorylation	Phosphorylation
29045477	1370	1380	increased	Positive_regulation
29045477	1380	1383	Akt	Gene
29045477	1384	1389	PHLPP	Gene
29045477	1446	1458	association	Binding
29045477	1459	1469	Tubastatin	Chemical
29045477	1470	1480	repressed	Negative_regulation
29045477	1480	1486	TGF-b1	Gene
29045477	1487	1495	induced	Positive_regulation
29045477	1499	1515	phosphorylation	Phosphorylation
29045477	1516	1522	HIF-1a	Gene
29045477	1523	1534	expression	Gene_expression
29045477	1539	1543	VEGF	Gene
29045477	1544	1555	expression	Gene_expression
29045477	1556	1566	Tubastatin	Chemical
29045477	1582	1588	TGF-b1	Gene
29045477	1661	1670	bleomycin	Chemical
29045477	1679	1684	mouse	Species
29045477	1692	1697	HDAC6	Gene
29045477	1698	1709	expression	Gene_expression
29045477	1713	1723	increased	Positive_regulation
29045477	1728	1738	Tubastatin	Chemical
29045477	1739	1749	repressed	Negative_regulation
29045477	1765	1776	expression	Gene_expression
29045477	1789	1794	HDAC6	Gene
29045477	1798	1802	mice	Species
29045477	1804	1813	bleomycin	Chemical
29045477	1838	1849	expression	Gene_expression
29045477	1857	1867	repressed	Negative_regulation
29045477	1882	1886	mice	Species
29045477	1888	1898	Knockdown	Negative_regulation
29045477	1901	1906	HDAC6	Gene
29045477	1919	1925	HDAC10	Gene
29045477	1945	1955	Tubastatin	Chemical
29045477	1972	1980	inhibit	Negative_regulation
29045477	1980	1986	TGF-b1	Gene
29045477	1987	1995	induced	Positive_regulation
29045477	2004	2015	expression	Gene_expression
29045477	2049	2054	HDAC6	Gene
29045477	2055	2066	expression	Gene_expression
29045477	2069	2077	altered	Regulation
29045477	2103	2113	Tubastatin	Chemical
29045477	2114	2124	represses	Negative_regulation
29045477	2124	2130	TGF-b1	Gene
29045477	2131	2139	induced	Positive_regulation
29045477	2148	2159	expression	Gene_expression
29045477	2163	2175	diminishing	Negative_regulation
29045477	2175	2178	Akt	Gene
29045477	2179	2195	phosphorylation	Phosphorylation
29045477	2199	2210	regulating	Regulation
29045477	2237	2243	HIF-1a	Gene
29045477	2244	2248	VEGF	Gene
29045477	2269	2279	Tubastatin	Chemical
29045477	2291	2295	mice	Species
29045477	2318	2327	bleomycin	Chemical
29045477	2336	2344	fibrosis	Disease
29045477	2350	2355	HDAC6	Gene
29045477	2359	2363	mice	Species
29045477	2395	2405	Tubastatin	Chemical
29045477	2418	2436	pulmonary fibrosis	Disease
29045477	2465	2468	Akt	Gene
29045477	2492	2497	HDAC6	Gene
22117501|t|Prognostic factors for idiopathic pulmonary fibrosis: clinical, physiologic, pathologic, and molecular aspects
BACKGROUND: Previous studies identified clinical and physiologic factors of idiopathic pulmonary fibrosis (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	23	52	idiopathic pulmonary fibrosis	Disease
22117501	188	217	idiopathic pulmonary fibrosis	Disease
22117501	219	222	IPF	Disease
22117501	427	442	phosphorylated	Phosphorylation
22117501	442	449	Smad2/3	Gene
22117501	453	460	Smad2/3	Gene
22117501	463	468	tumor	Disease
22117501	489	497	TGF-beta	Gene
22117501	500	520	TGF-beta receptor II	Gene
22117501	522	530	TbetaRII	Gene
22117501	541	554	polymorphism	Positive_regulation
22117501	561	570	TGF-beta1	Gene
22117501	584	595	associated	Binding
22117501	619	622	IPF	Disease
22117501	623	631	patients	Species
22117501	652	655	IPF	Disease
22117501	656	664	patients	Species
22117501	726	733	patient	Species
22117501	842	849	Smad2/3	Gene
22117501	854	862	TbetaRII	Gene
22117501	886	895	TGF-beta1	Gene
22117501	1189	1204	carbon monoxide	Chemical
22117501	1334	1342	fibrosis	Disease
22117501	1344	1355	expression	Gene_expression
22117501	1366	1373	Smad2/3	Gene
22117501	1378	1386	TbetaRII	Gene
22117501	1408	1417	TGF-beta1	Gene
22117501	1652	1662	increased	Positive_regulation
29411215|t|The lncRNA H19 Mediates Pulmonary Fibrosis by Regulating the miR-196a/COL1A1 Axis
Idiopathic pulmonary fibrosis (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 H19 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 H19 was a direct target of miR-196a and was associated with COL1A1 expression by sponging miR-196a
Moreover, downregulation of H19 alleviated fibroblast activation and lung fibrosis, and this effect was blocked by a miR-196a inhibitor
In conclusion, our results suggest that lncRNA H19 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	11	14	H19	Gene
29411215	46	57	Regulating	Regulation
29411215	70	76	COL1A1	Gene
29411215	77	81	Axis	Disease
29411215	83	112	Idiopathic pulmonary fibrosis	Disease
29411215	114	117	IPF	Disease
29411215	341	344	IPF	Disease
29411215	400	403	H19	Gene
29411215	509	518	bleomycin	Chemical
29411215	520	523	BLM	Chemical
29411215	533	546	lung fibrosis	Disease
29411215	592	595	H19	Gene
29411215	609	616	target	Binding
29411215	652	658	COL1A1	Gene
29411215	659	670	expression	Gene_expression
29411215	702	717	downregulation	Negative_regulation
29411215	720	723	H19	Gene
29411215	761	774	lung fibrosis	Disease
29411215	818	828	inhibitor	Negative_regulation
29411215	876	879	H19	Gene
29411215	918	921	IPF	Disease
29411215	1021	1024	IPF	Disease
15563636|t|Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor
Pulmonary fibrosis 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 ALK5, 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	53	66	lung fibrosis	Disease
15563636	98	102	ALK5	Gene
15563636	110	120	inhibitor	Negative_regulation
15563636	121	139	Pulmonary fibrosis	Disease
15563636	236	258	impaired lung function	Disease
15563636	263	282	respiratory failure	Disease
15563636	284	313	Idiopathic pulmonary fibrosis	Disease
15563636	315	318	IPF	Disease
15563636	501	509	fibrosis	Disease
15563636	511	523	Transforming	Disease
15563636	544	552	TGF-beta	Gene
15563636	686	689	IPF	Disease
15563636	691	699	TGF-beta	Gene
15563636	850	859	TGF-beta1	Gene
15563636	868	886	pulmonary fibrosis	Disease
15563636	890	894	rats	Species
15563636	995	1005	inhibitor	Negative_regulation
15563636	1031	1035	ALK5	Gene
15563636	1050	1058	TGF-beta	Gene
15563636	1117	1125	fibrosis	Disease
15563636	1226	1234	fibrosis	Disease
15563636	1293	1301	fibrosis	Disease
15563636	1391	1394	IPF	Disease
15563636	1438	1446	fibrosis	Disease
15563636	1466	1475	blocking	Negative_regulation
15563636	1475	1483	TGF-beta	Gene
15563636	1493	1504	activation	Positive_regulation
27815256|t|Toll-like receptor 4 activation attenuates profibrotic response in control lung fibroblasts but not in fibroblasts from patients with IPF
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a median survival of 3 yr
IPF deteriorates upon viral or bacterial lung infection although pulmonary infection (pneumonia) in healthy lungs rarely induces fibrosis
Bacterial lipopolysaccharide (LPS) activates Toll-like receptor 4 (TLR4), initiating proinflammatory pathways
As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in IPF fibroblasts
Lung tissue sections from patients with IPF were analyzed for TLR4 expression
Isolated normal human lung fibroblasts (NL-FB) and IPF fibroblasts (IPF-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 IPF lungs as well as in primary NL-FB and IPF-FB
As a model for a gram-negative pneumonia in the nonfibrotic lung, NL-FB and IPF-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, IPF-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 IPF fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation
27815256	0	20	Toll-like receptor 4	Gene
27815256	120	128	patients	Species
27815256	134	137	IPF	Disease
27815256	139	168	Idiopathic pulmonary fibrosis	Disease
27815256	170	173	IPF	Disease
27815256	192	204	lung disease	Disease
27815256	237	240	IPF	Disease
27815256	268	292	bacterial lung infection	Disease
27815256	302	321	pulmonary infection	Disease
27815256	323	332	pneumonia	Disease
27815256	366	374	fibrosis	Disease
27815256	411	421	activates	Positive_regulation
27815256	421	441	Toll-like receptor 4	Gene
27815256	443	447	TLR4	Gene
27815256	490	494	TLR4	Gene
27815256	530	538	fibrosis	Disease
27815256	543	554	scleroderma	Disease
27815256	580	585	role	Regulation
27815256	588	592	TLR4	Gene
27815256	596	599	IPF	Disease
27815256	639	647	patients	Species
27815256	653	656	IPF	Disease
27815256	675	679	TLR4	Gene
27815256	680	691	expression	Gene_expression
27815256	708	713	human	Species
27815256	743	746	IPF	Disease
27815256	760	763	IPF	Disease
27815256	792	820	transforming growth factor-b	Gene
27815256	822	827	TGF-b	Gene
27815256	908	912	TLR4	Gene
27815256	916	926	expressed	Gene_expression
27815256	948	951	IPF	Disease
27815256	990	993	IPF	Disease
27815256	1029	1038	pneumonia	Disease
27815256	1074	1077	IPF	Disease
27815256	1107	1112	TGF-b	Gene
27815256	1221	1226	TGF-b	Gene
27815256	1246	1249	IPF	Disease
27815256	1391	1407	prostaglandin E2	Chemical
27815256	1507	1522	downregulation	Negative_regulation
27815256	1525	1530	TGF-b	Gene
27815256	1660	1663	IPF	Disease
27815256	1735	1739	TLR4	Gene
12851645|t|Significant involvement of CCL2 (MCP-1) in inflammatory disorders of the lung
Mounting evidence suggests that CCL2 (MCP-1) and its hematopoietic cell receptor CC chemokine receptor 2 (CCR2) are involved in inflammatory disorders of the lung
In animal models of allergic asthma, idiopathic pulmonary fibrosis (IPF), and bronchiolitis obliterans syndrome (BOS), CCL2 expression and protein production are increased and the disease process is attenuated by CCL2 immunoneutralization
Mechanisms by which CCL2 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 CCL2 has been described with increased cytokine-induced release of CCL2 by monocytes and increased risk of allergic asthma
These studies identify potentially important roles for CCL2 in these lung inflammatory disorders
While CCL2 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 CCL2/CCR2 antagonism will offer breakthrough therapy for patients with allergic asthma, IPF, or BOS, and to confirm the hypothesis that CCL2 polymorphism places patients at greater risk for these disorders
12851645	27	31	CCL2	Gene
12851645	33	38	MCP-1	Gene
12851645	111	115	CCL2	Gene
12851645	117	122	MCP-1	Gene
12851645	160	183	CC chemokine receptor 2	Gene
12851645	185	189	CCR2	Gene
12851645	263	278	allergic asthma	Disease
12851645	280	309	idiopathic pulmonary fibrosis	Disease
12851645	311	314	IPF	Disease
12851645	321	354	bronchiolitis obliterans syndrome	Disease
12851645	356	359	BOS	Disease
12851645	362	366	CCL2	Gene
12851645	367	378	expression	Gene_expression
12851645	405	415	increased	Positive_regulation
12851645	456	460	CCL2	Gene
12851645	503	507	CCL2	Gene
12851645	596	605	histamine	Chemical
12851645	609	620	leukotriene	Chemical
12851645	821	825	CCL2	Gene
12851645	850	860	increased	Positive_regulation
12851645	877	885	release	Localization
12851645	888	892	CCL2	Gene
12851645	928	943	allergic asthma	Disease
12851645	1000	1004	CCL2	Gene
12851645	1049	1053	CCL2	Gene
12851645	1054	1065	inhibition	Negative_regulation
12851645	1068	1076	patients	Species
12851645	1082	1117	acute respiratory distress syndrome	Disease
12851645	1119	1123	ARDS	Disease
12851645	1178	1188	bacteremia	Disease
12851645	1232	1236	CCL2	Gene
12851645	1237	1241	CCR2	Gene
12851645	1289	1297	patients	Species
12851645	1303	1318	allergic asthma	Disease
12851645	1320	1323	IPF	Disease
12851645	1328	1331	BOS	Disease
12851645	1368	1372	CCL2	Gene
12851645	1393	1401	patients	Species
18093617|t|Pirfenidone inhibits the expression of HSP47 in TGF-beta1-stimulated human lung fibroblasts
Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of fibrosis in animal models and patients with idiopathic pulmonary fibrosis (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 HSP47 and collagen type I in cultured normal human lung fibroblasts (NHLF)
Expression levels of HSP47 and collagen type I in NHLF stimulated by transforming growth factor (TGF)-beta1 were evaluated genetically, immunologically and immunocytochemically
Treatment with TGF-beta1 stimulated both mRNA and protein expressions of both HSP47 and collagen type I in NHLF, and pirfenidone significantly inhibited this TGF-beta1-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 HSP47 expression in lung fibroblasts, with a resultant reduction of collagen synthesis in lung fibrosis
18093617	0	11	Pirfenidone	Chemical
18093617	12	21	inhibits	Negative_regulation
18093617	25	36	expression	Gene_expression
18093617	39	44	HSP47	Gene
18093617	48	57	TGF-beta1	Gene
18093617	69	74	human	Species
18093617	93	104	Pirfenidone	Chemical
18093617	106	139	5-methyl-1-phenyl-2-(1H)-pyridone	Chemical
18093617	227	235	fibrosis	Disease
18093617	257	265	patients	Species
18093617	271	300	idiopathic pulmonary fibrosis	Disease
18093617	302	305	IPF	Disease
18093617	308	335	Heat shock protein (HSP) 47	Gene
18093617	491	494	IPF	Disease
18093617	537	545	effects	Regulation
18093617	548	559	pirfenidone	Chemical
18093617	563	574	expression	Gene_expression
18093617	577	582	HSP47	Gene
18093617	622	627	human	Species
18093617	653	664	Expression	Gene_expression
18093617	674	679	HSP47	Gene
18093617	722	760	transforming growth factor (TGF)-beta1	Gene
18093617	846	855	TGF-beta1	Gene
18093617	856	867	stimulated	Positive_regulation
18093617	889	901	expressions	Transcription
18093617	909	914	HSP47	Gene
18093617	948	959	pirfenidone	Chemical
18093617	989	998	TGF-beta1	Gene
18093617	1093	1104	pirfenidone	Chemical
18093617	1145	1156	inhibition	Negative_regulation
18093617	1175	1186	expression	Gene_expression
18093617	1219	1230	inhibition	Negative_regulation
18093617	1233	1238	HSP47	Gene
18093617	1239	1250	expression	Gene_expression
18093617	1288	1298	reduction	Negative_regulation
18093617	1310	1320	synthesis	Gene_expression
18093617	1328	1336	fibrosis	Disease
22240154|t|Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-b1-dependent mechanism
Fibrotic remodelling of lung parenchymal 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 (TGF-b1) 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 TGF-b1
We show that in response to 400 M hydrogen peroxide (H(2)O(2)) 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 TGF-b1
Inhibition of TGF-b1 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, TGF-b1 and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease
22240154	94	100	TGF-b1	Gene
22240154	122	162	Fibrotic remodelling of lung parenchymal	Disease
22240154	261	274	lung diseases	Disease
22240154	283	312	idiopathic pulmonary fibrosis	Disease
22240154	323	360	Chronic Obstructive Pulmonary Disease	Disease
22240154	362	366	COPD	Disease
22240154	375	404	transforming growth factor-b1	Gene
22240154	406	412	TGF-b1	Gene
22240154	570	578	patients	Species
22240154	816	829	augmentation	Positive_regulation
22240154	832	838	TGF-b1	Gene
22240154	874	891	hydrogen peroxide	Chemical
22240154	932	940	alveolar	Disease
22240154	957	962	human	Species
22240154	1049	1059	decreased	Negative_regulation
22240154	1059	1070	expression	Gene_expression
22240154	1093	1103	E-cadherin	Gene
22240154	1108	1112	ZO-1	Gene
22240154	1115	1125	increased	Positive_regulation
22240154	1125	1136	expression	Gene_expression
22240154	1293	1302	promotes	Positive_regulation
22240154	1302	1313	expression	Gene_expression
22240154	1316	1322	TGF-b1	Gene
22240154	1324	1335	Inhibition	Negative_regulation
22240154	1338	1344	TGF-b1	Gene
22240154	1403	1427	phenyl tert-butylnitrone	Chemical
22240154	1438	1460	superoxide dismutase 3	Gene
22240154	1462	1466	SOD3	Gene
22240154	1640	1646	TGF-b1	Gene
22240154	1776	1796	chronic lung disease	Disease
26442443|t|Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo
Idiopathic pulmonary fibrosis (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 (BMPER) as a key regulator of fibroblast activation
BMPER is a secreted glycoprotein that binds directly to BMPs and may regulate TGF-b/BMP signaling, but its role in lung fibrosis is not clear
BMPER is highly expressed in human IPF lung fibroblasts compared to normal lung fibroblasts
Demethylation agent 5'-azacytidine decreased BMPER expression in fibroblasts, and attenuated the invasion and migration of IPF lung fibroblasts
Furthermore, siRNA-mediated reduction of BMPER in the human lung fibroblasts impaired cell migration and invasion
5'-azacytidine treatment additionally regulated BMPER expression and reduced lung fibrosis 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	21	26	BMPER	Gene
26442443	27	38	expression	Gene_expression
26442443	81	89	fibrosis	Disease
26442443	93	97	mice	Species
26442443	107	136	Idiopathic pulmonary fibrosis	Disease
26442443	138	141	IPF	Disease
26442443	160	172	lung disease	Disease
26442443	462	465	IPF	Disease
26442443	486	534	BMP endothelial cell precursor-derived regulator	Gene
26442443	536	541	BMPER	Gene
26442443	588	593	BMPER	Gene
26442443	599	608	secreted	Localization
26442443	626	632	binds	Binding
26442443	657	666	regulate	Regulation
26442443	708	716	fibrosis	Disease
26442443	731	736	BMPER	Gene
26442443	747	757	expressed	Gene_expression
26442443	760	765	human	Species
26442443	766	769	IPF	Disease
26442443	844	858	5'-azacytidine	Chemical
26442443	859	869	decreased	Negative_regulation
26442443	869	874	BMPER	Gene
26442443	875	886	expression	Gene_expression
26442443	947	950	IPF	Disease
26442443	997	1007	reduction	Negative_regulation
26442443	1010	1015	BMPER	Gene
26442443	1023	1028	human	Species
26442443	1084	1098	5'-azacytidine	Chemical
26442443	1122	1132	regulated	Regulation
26442443	1132	1137	BMPER	Gene
26442443	1138	1149	expression	Gene_expression
26442443	1153	1174	reduced lung fibrosis	Disease
26442443	1178	1182	mice	Species
26442443	1310	1313	IPF	Disease
29019702|t|Inhibition of PHGDH Attenuates Bleomycin-induced Pulmonary Fibrosis
Organ fibrosis, including idiopathic pulmonary fibrosis (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 fibrosis 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 (PHGDH, 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 fibrosis in vivo
We found that TGF-b induces mRNA and protein expression of PHGDH in murine fibroblasts
Similarly, intratracheal administration of bleomycin resulted in increased expression of PHGDH in mouse lungs, localized to fibrotic regions
Using a newly developed small molecule inhibitor of PHGDH (NCT-503), we tested whether pharmacologic inhibition of PHGDH 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 PHGDH inhibitor beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung fibrosis
These results indicate that the de novo serine synthesis pathway is necessary for TGF-b-induced collagen synthesis and bleomycin-induced pulmonary fibrosis
PHGDH and other enzymes in the de novo serine synthesis pathway may be a therapeutic target for treatment of fibrotic diseases, including IPF
29019702	0	11	Inhibition	Negative_regulation
29019702	14	19	PHGDH	Gene
29019702	31	40	Bleomycin	Chemical
29019702	49	67	Pulmonary Fibrosis	Disease
29019702	75	83	fibrosis	Disease
29019702	95	124	idiopathic pulmonary fibrosis	Disease
29019702	126	129	IPF	Disease
29019702	310	318	fibrosis	Disease
29019702	358	363	TGF-b	Gene
29019702	462	468	serine	Chemical
29019702	473	480	glycine	Chemical
29019702	502	507	human	Species
29019702	534	564	phosphoglycerate dehydrogenase	Gene
29019702	566	571	PHGDH	Gene
29019702	664	674	synthesis	Gene_expression
29019702	688	693	TGF-b	Gene
29019702	756	762	serine	Chemical
29019702	767	774	glycine	Chemical
29019702	796	809	lung fibrosis	Disease
29019702	833	838	TGF-b	Gene
29019702	839	847	induces	Positive_regulation
29019702	864	875	expression	Transcription
29019702	878	883	PHGDH	Gene
29019702	887	893	murine	Species
29019702	950	959	bleomycin	Chemical
29019702	972	982	increased	Positive_regulation
29019702	982	993	expression	Gene_expression
29019702	996	1001	PHGDH	Gene
29019702	1005	1010	mouse	Species
29019702	1088	1098	inhibitor	Negative_regulation
29019702	1101	1106	PHGDH	Gene
29019702	1150	1161	inhibition	Negative_regulation
29019702	1164	1169	PHGDH	Gene
29019702	1237	1243	murine	Species
29019702	1248	1253	human	Species
29019702	1284	1294	decreased	Negative_regulation
29019702	1294	1299	TGF-b	Gene
29019702	1325	1335	synthesis	Gene_expression
29019702	1336	1340	Mice	Species
29019702	1358	1363	PHGDH	Gene
29019702	1427	1436	bleomycin	Chemical
29019702	1456	1469	lung fibrosis	Disease
29019702	1511	1517	serine	Chemical
29019702	1539	1549	necessary	Positive_regulation
29019702	1553	1558	TGF-b	Gene
29019702	1576	1586	synthesis	Gene_expression
29019702	1590	1599	bleomycin	Chemical
29019702	1608	1626	pulmonary fibrosis	Disease
29019702	1628	1633	PHGDH	Gene
29019702	1667	1673	serine	Chemical
29019702	1737	1754	fibrotic diseases	Disease
29019702	1766	1769	IPF	Disease
29031221|t|Effects of particulate matter from straw burning on lung fibrosis in mice
OBJECTIVE: To investigate the impacts of particulate matter 2.5 (PM2.5) from straw burning on the acute exacerbation of lung fibrosis 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 lung fibrosis 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 lung fibrosis 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	52	65	lung fibrosis	Disease
29031221	69	73	mice	Species
29031221	195	208	lung fibrosis	Disease
29031221	212	216	mice	Species
29031221	247	263	N-acetylcysteine	Chemical
29031221	265	268	NAC	Chemical
29031221	432	436	mice	Species
29031221	476	485	bleomycin	Chemical
29031221	487	490	BLM	Chemical
29031221	500	513	lung fibrosis	Disease
29031221	539	542	BLM	Chemical
29031221	552	555	BLM	Chemical
29031221	622	625	BLM	Chemical
29031221	627	631	mice	Species
29031221	766	770	mice	Species
29031221	779	784	Mouse	Species
29031221	893	914	alveolar lavage fluid	Disease
29031221	916	919	ALF	Disease
29031221	1069	1077	chloride	Chemical
29031221	1094	1103	potassium	Chemical
29031221	1131	1138	sulfate	Chemical
29031221	1140	1147	nitrate	Chemical
29031221	1153	1160	nitrite	Chemical
29031221	1286	1301	alveolar septum	Disease
29031221	1307	1320	lung fibrosis	Disease
29031221	1328	1331	BLM	Chemical
29031221	1356	1359	BLM	Chemical
29031221	1475	1478	BLM	Chemical
29031221	1548	1558	increased	Positive_regulation
29031221	1624	1642	Interleukin (IL)-6	Gene
29031221	1647	1652	TNF-a	Gene
29031221	1653	1660	levels	Gene_expression
29031221	1663	1666	ALF	Disease
29031221	1700	1703	BLM	Chemical
29031221	1728	1731	BLM	Chemical
29031221	1849	1854	TGF-b	Gene
29031221	1865	1868	ALF	Disease
29031221	1927	1930	BLM	Chemical
29031221	1955	1958	BLM	Chemical
29031221	1993	1997	IL-6	Gene
29031221	1999	2004	TNF-a	Gene
29031221	2010	2015	TGF-b	Gene
29031221	2076	2079	BLM	Chemical
29031221	2090	2093	BLM	Chemical
29031221	2111	2125	hydroxyproline	Chemical
29031221	2322	2326	mice	Species
29031221	2362	2366	mice	Species
29031221	2372	2375	BLM	Chemical
29031221	2384	2387	IPF	Disease
29031221	2403	2406	NAC	Chemical
29031221	2439	2442	BLM	Chemical
29031221	2484	2488	mice	Species
29031221	2494	2497	BLM	Chemical
29031221	2506	2509	IPF	Disease
29031221	2550	2567	lung inflammation	Disease
29031221	2572	2580	fibrosis	Disease
29031221	2606	2609	NAC	Chemical
29031221	2624	2629	mouse	Species
26415510|t|BARD1 mediates TGF-b signaling in pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (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 BARD1 expression is upregulated in response to hypoxia and associated with TGF-b signaling, both recognized factors driving lung fibrosis
Differentially spliced BARD1 isoforms, in particular BARD1b, are oncogenic drivers of proliferation in cancers of various origins
We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis
METHODS: We investigated BARD1 expression as a function of TGF-b in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients
RESULTS: FL BARD1 and BARD1b were upregulated in response to TGF-b 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) BARD1 and BARD1b in fibrotic tissues
CONCLUSION: Our data suggest that FL BARD1 and BARD1b might be mediators of pleiotropic effects of TGF-b
In particular BARD1b might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment
26415510	0	5	BARD1	Gene
26415510	15	20	TGF-b	Gene
26415510	34	52	pulmonary fibrosis	Disease
26415510	66	95	Idiopathic pulmonary fibrosis	Disease
26415510	97	100	IPF	Disease
26415510	125	153	fibro-proliferative disorder	Disease
26415510	185	196	lung cancer	Disease
26415510	218	221	IPF	Disease
26415510	364	369	BARD1	Gene
26415510	370	381	expression	Gene_expression
26415510	384	396	upregulated	Positive_regulation
26415510	411	418	hypoxia	Disease
26415510	439	444	TGF-b	Gene
26415510	488	501	lung fibrosis	Disease
26415510	526	531	BARD1	Gene
26415510	606	613	cancers	Disease
26415510	665	670	BARD1	Gene
26415510	704	725	role in lung fibrosis	Disease
26415510	752	757	BARD1	Gene
26415510	758	769	expression	Gene_expression
26415510	786	791	TGF-b	Gene
26415510	814	818	mice	Species
26415510	847	860	lung fibrosis	Disease
26415510	888	906	pulmonary fibrosis	Disease
26415510	907	915	patients	Species
26415510	929	934	BARD1	Gene
26415510	951	963	upregulated	Positive_regulation
26415510	978	983	TGF-b	Gene
26415510	1134	1146	upregulated	Positive_regulation
26415510	1146	1157	expression	Gene_expression
26415510	1177	1182	BARD1	Gene
26415510	1252	1257	BARD1	Gene
26415510	1314	1319	TGF-b	Gene
26415510	1384	1402	pulmonary fibrosis	Disease
25361680|t|Upregulation of activin-B and follistatin in pulmonary fibrosis - a translational study using human biopsies and a specific inhibitor in mouse fibrosis models
BACKGROUND: Activins are members of the TGF-   superfamily of growth factors
First, we identified by expression array screening that activin-B and follistatin are upregulated in human idiopathic pulmonary fibrosis (IPF)
Next, we wanted to clarify their specific role in lung fibrosis formation
METHODS: We used specific antibodies for activin-A and -B subunits and follistatin to measure and localize their levels in idiopathic pulmonary fibrosis and control lung biopsies
To inhibit activin signaling, we used soluble activin type IIB receptor fused to the Fc portion of human IgG1 (sActRIIB-Fc) in two different mouse models of pulmonary fibrosis
RESULTS: Activin-B and follistatin mRNA levels were elevated in the human IPF lung
Immunoreactivity to activin-A, -B and follistatin 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 activin-B and follistatin in IPF is a novel finding
Our results indicate that activin inhibition is not an efficient tool for antifibrotic therapy, but could be useful in reducing alveolar cellular response to injury
Activin-B and follistatin levels may be useful as biomarkers of IPF
25361680	0	13	Upregulation	Positive_regulation
25361680	16	23	activin	Gene
25361680	30	41	follistatin	Gene
25361680	45	63	pulmonary fibrosis	Disease
25361680	94	99	human	Species
25361680	137	142	mouse	Species
25361680	143	151	fibrosis	Disease
25361680	185	193	members	Gene_expression
25361680	294	301	activin	Gene
25361680	308	319	follistatin	Gene
25361680	324	336	upregulated	Positive_regulation
25361680	339	344	human	Species
25361680	345	374	idiopathic pulmonary fibrosis	Disease
25361680	376	379	IPF	Disease
25361680	437	445	fibrosis	Disease
25361680	498	505	activin	Gene
25361680	528	539	follistatin	Gene
25361680	580	609	idiopathic pulmonary fibrosis	Disease
25361680	648	655	activin	Gene
25361680	683	690	activin	Gene
25361680	742	746	IgG1	Gene
25361680	778	783	mouse	Species
25361680	794	812	pulmonary fibrosis	Disease
25361680	823	830	Activin	Gene
25361680	837	848	follistatin	Gene
25361680	866	875	elevated	Positive_regulation
25361680	882	887	human	Species
25361680	888	891	IPF	Disease
25361680	918	925	activin	Gene
25361680	936	947	follistatin	Gene
25361680	948	958	localized	Localization
25361680	979	991	hyperplastic	Disease
25361680	1065	1069	Mice	Species
25361680	1294	1307	upregulation	Positive_regulation
25361680	1310	1317	activin	Gene
25361680	1324	1335	follistatin	Gene
25361680	1339	1342	IPF	Disease
25361680	1389	1396	activin	Gene
25361680	1397	1408	inhibition	Negative_regulation
25361680	1529	1536	Activin	Gene
25361680	1543	1554	follistatin	Gene
25361680	1593	1596	IPF	Disease
21269063|t|Resveratrol inhibits transforming growth factor-b-induced proliferation and differentiation of ex vivo human lung fibroblasts into myofibroblasts through ERK/Akt inhibition and PTEN restoration
The authors investigated the role of resveratrol (RV), a natural poliphenolic molecule with several biological activities, in transforming growth factor-b (TGF-b)-induced proliferation and differentiation of ex vivo human pulmonary fibroblasts into myofibroblasts
The effects of RV treatment were evaluated by analyzing TGF-b-induced a-smooth muscle actin (a-SMA) expression and collagen production, as well as cell proliferation of both normal and idiopathic pulmonary fibrosis (IPF) lung fibroblasts
Results demonstrate that RV inhibits TGF-b-induced cell proliferation of both normal and pathological lung fibroblasts, attenuates a-SMA 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 TGF-b-induced fibrosis
The authors show that RV inhibited TGF-b-induced phosphorylation of both extracellular signal-regulated kinases (ERK1/2) and the serine/threonine kinase, Akt
Moreover, RV treatment blocked the TGF-b-induced decrease in phosphatase and tensin homolog (PTEN) expression levels
21269063	0	11	Resveratrol	Chemical
21269063	103	108	human	Species
21269063	154	157	ERK	Gene
21269063	158	161	Akt	Gene
21269063	162	173	inhibition	Negative_regulation
21269063	177	181	PTEN	Gene
21269063	232	243	resveratrol	Chemical
21269063	351	356	TGF-b	Gene
21269063	411	416	human	Species
21269063	516	521	TGF-b	Gene
21269063	553	558	a-SMA	Gene
21269063	560	571	expression	Gene_expression
21269063	584	595	production	Gene_expression
21269063	645	674	idiopathic pulmonary fibrosis	Disease
21269063	676	679	IPF	Disease
21269063	736	741	TGF-b	Gene
21269063	830	835	a-SMA	Gene
21269063	893	902	inhibits	Negative_regulation
21269063	1078	1083	TGF-b	Gene
21269063	1092	1100	fibrosis	Disease
21269063	1127	1137	inhibited	Negative_regulation
21269063	1137	1142	TGF-b	Gene
21269063	1137	1151	TGF-b-induced	Positive_regulation
21269063	1151	1167	phosphorylation	Phosphorylation
21269063	1215	1221	ERK1/2	Gene
21269063	1231	1237	serine	Chemical
21269063	1238	1247	threonine	Chemical
21269063	1256	1259	Akt	Gene
21269063	1284	1292	blocked	Negative_regulation
21269063	1296	1301	TGF-b	Gene
21269063	1354	1358	PTEN	Gene
21269063	1360	1371	expression	Gene_expression
21502778|t|Effects of doxycycline on production of growth factors and matrix metalloproteinases in pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis 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 pulmonary fibrosis through the inhibition of growth factors and MMP production in AECs
21502778	0	8	Effects	Regulation
21502778	11	22	doxycycline	Chemical
21502778	26	37	production	Gene_expression
21502778	88	106	pulmonary fibrosis	Disease
21502778	120	149	Idiopathic pulmonary fibrosis	Disease
21502778	151	154	IPF	Disease
21502778	188	196	fibrosis	Disease
21502778	418	421	IPF	Disease
21502778	423	448	Doxycycline hydrochloride	Chemical
21502778	450	454	DOXY	Chemical
21502778	490	508	pulmonary fibrosis	Disease
21502778	526	534	patients	Species
21502778	540	543	IPF	Disease
21502778	657	661	DOXY	Chemical
21502778	717	726	Bleomycin	Chemical
21502778	740	746	murine	Species
21502778	783	787	DOXY	Chemical
21502778	855	860	human	Species
21502778	971	975	DOXY	Chemical
21502778	990	1001	expression	Gene_expression
21502778	1050	1060	evaluated	Negative_regulation
21502778	1125	1129	DOXY	Chemical
21502778	1137	1143	TGF-b1	Gene
21502778	1144	1152	induced	Positive_regulation
21502778	1185	1189	DOXY	Chemical
21502778	1190	1198	reduced	Negative_regulation
21502778	1198	1206	fibrosis	Disease
21502778	1222	1233	production	Gene_expression
21502778	1253	1284	connective tissue growth factor	Gene
21502778	1286	1290	CTGF	Gene
21502778	1297	1303	TGF-b1	Gene
21502778	1318	1322	DOXY	Chemical
21502778	1323	1333	inhibited	Negative_regulation
21502778	1342	1353	expression	Transcription
21502778	1356	1361	MMP-2	Gene
21502778	1363	1368	MPP-9	Gene
21502778	1370	1374	CTGF	Gene
21502778	1425	1430	MMP-2	Gene
21502778	1477	1485	induced	Positive_regulation
21502778	1502	1508	TGF-b1	Gene
21502778	1520	1525	Smad2	Gene
21502778	1530	1535	Smad3	Gene
21502778	1536	1552	phosphorylation	Phosphorylation
21502778	1589	1593	DOXY	Chemical
21502778	1660	1664	DOXY	Chemical
21502778	1697	1715	pulmonary fibrosis	Disease
21659414|t|Renin is an angiotensin-independent profibrotic mediator: role in pulmonary fibrosis
The pathogenesis of idiopathic pulmonary fibrosis (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
Renin-stimulated lung fibroblasts displayed an increase in the expression of TGF-b1 (mean    sd 1.8   10(3)    0.2   10(3) versus 1.2   10(3)   0.3   10(3) mRNA copies per 18S ribosomal RNA; p<0.01) and collagen (5.93   10(2)   0.66   10(2) versus 3.28   10(2)    0.5   10(2); 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
Renin 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	0	5	Renin	Gene
21659414	66	84	pulmonary fibrosis	Disease
21659414	106	135	idiopathic pulmonary fibrosis	Disease
21659414	137	140	IPF	Disease
21659414	231	236	renin	Gene
21659414	369	374	renin	Gene
21659414	455	466	expression	Gene_expression
21659414	469	474	renin	Gene
21659414	479	484	renin	Gene
21659414	521	524	IPF	Disease
21659414	555	560	human	Species
21659414	599	604	renin	Gene
21659414	625	630	renin	Gene
21659414	792	802	expressed	Gene_expression
21659414	802	807	renin	Gene
21659414	828	840	upregulated	Positive_regulation
21659414	843	846	IPF	Disease
21659414	935	940	renin	Gene
21659414	953	956	IPF	Disease
21659414	970	975	Renin	Gene
21659414	1017	1026	increase	Positive_regulation
21659414	1033	1044	expression	Gene_expression
21659414	1047	1053	TGF-b1	Gene
21659414	1276	1281	renin	Gene
21659414	1282	1293	expression	Gene_expression
21659414	1323	1332	decrease	Negative_regulation
21659414	1407	1415	losartan	Chemical
21659414	1420	1429	captopril	Chemical
21659414	1455	1460	Renin	Gene
21659414	1466	1476	decreased	Negative_regulation
21659414	1476	1500	matrix metalloprotease-1	Gene
21659414	1501	1512	expression	Gene_expression
21659414	1516	1524	induced	Positive_regulation
21659414	1524	1530	TGF-b1	Gene
21659414	1531	1542	activation	Positive_regulation
21659414	1580	1586	TGF-b1	Gene
21659414	1656	1661	renin	Gene
21659414	1714	1722	fibrosis	Disease
25524739|t|Regulation of myofibroblast differentiation by miR-424 during epithelial-to-mesenchymal transition
UNASSIGNED: Idiopathic pulmonary fibrosis (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, miR-424, increased the expression of a-smooth muscle actin, an indicator of myofibroblast differentiation, but had no effects on the epithelial or mesenchymal cell markers
miR-424 enhanced the activity of the TGF-b signaling pathway, as demonstrated by a luciferase reporter assay
Further experiments showed that miR-424 decreased the protein expression of Smurf2, a negative regulator of TGF-b signaling, indicating that miR-424 exerts a forward regulatory loop in the TGF-b signaling pathway
Our results suggest that miR-424 regulates the myofibroblast differentiation during EMT by potentiating the TGF-b signaling pathway, likely through Smurf2
25524739	47	54	miR-424	Gene
25524739	112	141	Idiopathic pulmonary fibrosis	Disease
25524739	143	146	IPF	Disease
25524739	185	211	interstitial lung diseases	Disease
25524739	386	389	IPF	Disease
25524739	592	595	IPF	Disease
25524739	703	708	human	Species
25524739	834	841	miR-424	Gene
25524739	843	853	increased	Positive_regulation
25524739	857	868	expression	Gene_expression
25524739	1007	1014	miR-424	Gene
25524739	1044	1049	TGF-b	Gene
25524739	1149	1156	miR-424	Gene
25524739	1157	1167	decreased	Negative_regulation
25524739	1179	1190	expression	Gene_expression
25524739	1193	1199	Smurf2	Gene
25524739	1225	1230	TGF-b	Gene
25524739	1258	1265	miR-424	Gene
25524739	1306	1311	TGF-b	Gene
25524739	1356	1363	miR-424	Gene
25524739	1439	1444	TGF-b	Gene
25524739	1479	1485	Smurf2	Gene
19543300|t|MS80, a novel sulfated oligosaccharide, inhibits pulmonary fibrosis by targeting TGF-beta1 both in vitro and in vivo
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 pulmonary fibrosis (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 pulmonary fibrosis in vitro and bleomycin-induced pulmonary fibrosis 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 pulmonary fibrosis 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	49	67	pulmonary fibrosis	Disease
19543300	81	90	TGF-beta1	Gene
19543300	186	195	TGF-beta1	Gene
19543300	268	297	idiopathic pulmonary fibrosis	Disease
19543300	299	302	IPF	Disease
19543300	398	403	bind	Binding
19543300	403	412	TGF-beta1	Gene
19543300	497	506	TGF-beta1	Gene
19543300	725	733	TGF-beta	Gene
19543300	735	738	MTT	Chemical
19543300	940	949	bleomycin	Chemical
19543300	971	974	rat	Species
19543300	1084	1093	TGF-beta1	Gene
19543300	1102	1120	pulmonary fibrosis	Disease
19543300	1134	1143	bleomycin	Chemical
19543300	1152	1170	pulmonary fibrosis	Disease
19543300	1226	1236	inhibited	Negative_regulation
19543300	1247	1256	TGF-beta1	Gene
19543300	1257	1269	interaction	Binding
19543300	1286	1294	binding	Binding
19543300	1307	1316	TGF-beta1	Gene
19543300	1342	1351	TGF-beta1	Gene
19543300	1352	1360	induced	Positive_regulation
19543300	1360	1365	human	Species
19543300	1430	1441	deposition	Gene_expression
19543300	1534	1537	p38	Gene
19543300	1595	1604	bleomycin	Chemical
19543300	1613	1616	rat	Species
19543300	1929	1932	IPF	Disease
26709222|t|Association of HLA and cytokine gene polymorphisms with idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	0	12	Association	Binding
26709222	56	85	idiopathic pulmonary fibrosis	Disease
26709222	87	116	Idiopathic pulmonary fibrosis	Disease
26709222	118	121	IPF	Disease
26709222	158	183	interstitial lung disease	Disease
26709222	280	283	IPF	Disease
26709222	413	416	IPF	Disease
26709222	472	517	HLA-A, -B, -DRB1, tumor necrosis factor alpha	Gene
26709222	519	524	TNF-a	Gene
26709222	526	534	-308 A/G	Mutation
26709222	538	569	transforming growth factor beta	Gene
26709222	579	587	+869 T/C	Mutation
26709222	591	605	interleukin 10	Gene
26709222	607	612	IL-10	Gene
26709222	614	622	-592 C/A	Mutation
26709222	624	632	-819 T/C	Mutation
26709222	638	647	-1082 G/A	Mutation
26709222	680	688	+874 T/A	Mutation
26709222	729	732	IPF	Disease
26709222	934	937	IPF	Disease
26709222	1000	1005	HLA-A	Gene
26709222	1009	1013	DRB1	Gene
26709222	1034	1037	IPF	Disease
26709222	1295	1298	IPF	Disease
26709222	1417	1420	IPF	Disease
26709222	1538	1541	IPF	Disease
18177235|t|Oxidant-antioxidant imbalance as a potential contributor to the progression of human pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	79	84	human	Species
18177235	85	103	pulmonary fibrosis	Disease
18177235	105	134	Idiopathic pulmonary fibrosis	Disease
18177235	136	139	IPF	Disease
18177235	160	193	idiopathic interstitial pneumonia	Disease
18177235	195	198	IPF	Disease
18177235	378	381	IPF	Disease
18177235	410	413	IPF	Disease
18177235	422	438	fibrotic lesions	Disease
18177235	513	526	lung fibrosis	Disease
18177235	534	543	bleomycin	Chemical
18177235	552	560	fibrosis	Disease
18177235	662	683	diffuse lung fibrosis	Disease
18177235	809	822	lung fibrosis	Disease
18177235	848	879	transforming growth factor beta	Gene
18177235	881	889	TGF-beta	Gene
18177235	897	904	patient	Species
18177235	941	954	lung fibrosis	Disease
18177235	1120	1126	oxygen	Chemical
18177235	1145	1156	activation	Positive_regulation
18177235	1198	1206	TGF-beta	Gene
18177235	1356	1364	fibrosis	Disease
18177235	1536	1539	IPF	Disease
23962103|t|Up-regulation of heparan sulfate 6-O-sulfation in idiopathic pulmonary fibrosis
Heparan sulfate proteoglycans (HSPGs) are integral components of the lung
Changes in HSPGs have been documented in idiopathic pulmonary fibrosis (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	50	79	idiopathic pulmonary fibrosis	Disease
23962103	197	226	idiopathic pulmonary fibrosis	Disease
23962103	228	231	IPF	Disease
23962103	300	307	sulfate	Chemical
23962103	398	401	IPF	Disease
23962103	474	477	IPF	Disease
23962103	587	591	HS 6	Chemical
23962103	622	632	increased	Positive_regulation
23962103	635	638	IPF	Disease
23962103	690	705	overexpression	Positive_regulation
23962103	708	712	HS 6	Chemical
23962103	742	750	HS6ST1/2	Gene
23962103	793	799	HS6ST2	Gene
23962103	817	827	expressed	Gene_expression
23962103	904	907	IPF	Disease
23962103	923	929	HS6ST1	Gene
23962103	942	953	expression	Gene_expression
23962103	1007	1010	IPF	Disease
23962103	1017	1027	expressed	Gene_expression
23962103	1027	1033	HS6ST1	Gene
23962103	1039	1054	overexpression	Positive_regulation
23962103	1057	1063	HS6ST1	Gene
23962103	1124	1127	IPF	Disease
23962103	1215	1225	silencing	Negative_regulation
23962103	1228	1234	HS6ST1	Gene
23962103	1282	1290	reduced	Negative_regulation
23962103	1290	1295	Smad2	Gene
23962103	1296	1307	expression	Gene_expression
23962103	1329	1337	reduced	Negative_regulation
23962103	1337	1348	expression	Gene_expression
23962103	1394	1400	TGF-b1	Gene
23962103	1455	1458	IPF	Disease
23962103	1490	1500	silencing	Negative_regulation
23962103	1503	1509	HS6ST1	Gene
23962103	1524	1527	IPF	Disease
23962103	1569	1585	down-regulation	Negative_regulation
23962103	1621	1625	HS 6	Chemical
23962103	1641	1654	up-regulated	Positive_regulation
23962103	1657	1660	IPF	Disease
23962103	1666	1681	overexpression	Positive_regulation
23962103	1684	1690	HS6ST1	Gene
23962103	1695	1701	HS6ST2	Gene
23962103	1707	1722	overexpression	Positive_regulation
23962103	1725	1731	HS6ST1	Gene
23962103	1793	1799	TGF-b1	Gene
7921435|t|Mechanisms of fibrosis in coal workers' pneumoconiosis
Increased production of platelet-derived growth factor, insulin-like growth factor type I, and transforming growth factor beta and relationship to disease severity
To identify the clinical relevance of cytokines involved in the development of lung fibrosis observed in patients with coal workers' pneumoconiosis (CWP), we investigated the BAL fluid contents and AM secretions of three mediators that modulate fibroblast growth: platelet-derived growth factor (PDGF), Type I insulin-like growth factor (IGF-I), and transforming growth factor Type beta (TGF-beta)
Our study population consisted of 25 patients with CWP (16 simple pneumoconiosis, SP, 9 progressive massive fibrosis, PMF, 9 control subjects, and 6 patients with idiopathic pulmonary fibrosis (IPF)
The fibrotic potency of AM supernatants was also tested for their ability to promote the growth of a human lung fibroblast cell line appreciated by [3H]-thymidine incorporation
PDGF and IGF-I concentrations were increased in BAL fluids of patients with PMF compared with SP and control subjects, whereas TGF-beta concentration was significantly higher in BAL fluid of patients with SP compared with PMF and control subjects
PDGF, IGF-I, and TGF-beta concentrations in AM supernatants followed the same profile observed in BAL fluids, suggesting that AM is one of the main cell sources of PDGF, IGF-I, and TGF-beta in the lung of pneumoconiotic patients
After treatment by acidification, which activated the latent form of TGF-beta, AM from patients with SP induced an inhibition of [3H]-thymidine incorporation and fibroblast growth was restored after neutralization of TGF-beta by specific antibodies
In contrast, AM supernatants from patients with PMF and IPF promoted the proliferation of fibroblasts and treatment by acidification did not modify this effect.(ABSTRACT TRUNCATED AT 250 WORDS)
7921435	14	22	fibrosis	Disease
7921435	26	54	coal workers' pneumoconiosis	Disease
7921435	80	182	platelet-derived growth factor, insulin-like growth factor type I, and transforming growth factor beta	Gene
7921435	305	313	fibrosis	Disease
7921435	326	334	patients	Species
7921435	340	368	coal workers' pneumoconiosis	Disease
7921435	370	373	CWP	Disease
7921435	422	433	secretions	Localization
7921435	524	550	Type I insulin-like growth	Disease
7921435	559	564	IGF-I	Gene
7921435	609	617	TGF-beta	Gene
7921435	657	665	patients	Species
7921435	671	674	CWP	Disease
7921435	679	700	simple pneumoconiosis	Disease
7921435	728	736	fibrosis	Disease
7921435	769	777	patients	Species
7921435	783	812	idiopathic pulmonary fibrosis	Disease
7921435	814	817	IPF	Disease
7921435	921	926	human	Species
7921435	968	982	[3H]-thymidine	Chemical
7921435	1007	1012	IGF-I	Gene
7921435	1033	1043	increased	Positive_regulation
7921435	1060	1068	patients	Species
7921435	1125	1133	TGF-beta	Gene
7921435	1189	1197	patients	Species
7921435	1252	1257	IGF-I	Gene
7921435	1263	1271	TGF-beta	Gene
7921435	1416	1421	IGF-I	Gene
7921435	1427	1435	TGF-beta	Gene
7921435	1466	1474	patients	Species
7921435	1516	1526	activated	Positive_regulation
7921435	1545	1553	TGF-beta	Gene
7921435	1563	1571	patients	Species
7921435	1605	1619	[3H]-thymidine	Chemical
7921435	1675	1690	neutralization	Negative_regulation
7921435	1693	1701	TGF-beta	Gene
7921435	1760	1768	patients	Species
7921435	1782	1785	IPF	Disease
25331544|t|Transforming Growth Factor Beta 1 Activation, Storage, and Signaling Pathways in Idiopathic Pulmonary Fibrosis in Dogs
BACKGROUND: The pathogenesis of idiopathic pulmonary fibrosis (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	0	33	Transforming Growth Factor Beta 1	Gene
25331544	81	110	Idiopathic Pulmonary Fibrosis	Disease
25331544	114	118	Dogs	Species
25331544	152	181	idiopathic pulmonary fibrosis	Disease
25331544	183	186	IPF	Disease
25331544	191	195	dogs	Species
25331544	221	226	human	Species
25331544	228	257	transforming growth factor b1	Gene
25331544	259	265	TGF-b1	Gene
25331544	337	343	TGF-b1	Gene
25331544	355	358	IPF	Disease
25331544	492	496	dogs	Species
25331544	713	722	evaluate	Negative_regulation
25331544	722	733	expression	Gene_expression
25331544	753	759	TGF-b1	Gene
25331544	793	799	TGF-b1	Gene
25331544	865	876	expression	Gene_expression
25331544	879	885	TGF-b1	Gene
25331544	956	973	LTBP] 1, 2, and 4	Gene
25331544	1015	1031	thrombospondin-1	Gene
25331544	1056	1062	Smad 7	Gene
25331544	1132	1138	TGF-b1	Gene
25331544	1188	1191	IPF	Disease
25331544	1198	1204	level	Gene_expression
25331544	1207	1213	TGF-b1	Gene
25331544	1244	1252	fibrosis	Disease
25331544	1271	1275	had	Negative_regulation
25331544	1282	1293	expression	Gene_expression
25331544	1359	1369	decreased	Negative_regulation
25331544	1373	1379	LTBP 4	Gene
25331544	1440	1456	thrombospondin-1	Gene
25331544	1498	1503	Smad7	Gene
25331544	1505	1516	LTBP1 and 2	Gene
25331544	1524	1530	TGF-b1	Gene
25331544	1684	1693	enhanced	Positive_regulation
25331544	1693	1699	TGF-b1	Gene
25331544	1722	1725	IPF	Disease
25331544	1727	1733	TGF-b1	Gene
25331544	1850	1856	TGF-b1	Gene
25331544	1939	1942	IPF	Disease
22446029|t|Effect of substrate stiffness on pulmonary fibroblast activation by TGF-b
Peptide crosslinkers containing the sequence C-X-CG (X represents various adhesive peptides) were incorporated into poly(ethylene 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 alpha-smooth muscle actin (a-SMA), a myofibroblast marker, and form an extensive cytoskeleton with focal adhesions
Decreasing substrate stiffness (achieved through hydrolytic degradation) results in down-regulation of a-SMA expression by PFs
Substrate stiffness increases the sensitivity of PFs to exogenously applied transforming growth factor beta (TGF-b1); PFs on the most rigid gels (E=900 kPa) express a-SMA when treated with low concentrations of TGF-b1 (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	68	73	TGF-b	Gene
22446029	191	212	poly(ethylene glycol)	Chemical
22446029	214	217	PEG	Chemical
22446029	598	606	produce	Gene_expression
22446029	606	631	alpha-smooth muscle actin	Gene
22446029	633	638	a-SMA	Gene
22446029	771	793	hydrolytic degradation	Disease
22446029	825	830	a-SMA	Gene
22446029	870	880	increases	Positive_regulation
22446029	926	957	transforming growth factor beta	Gene
22446029	959	965	TGF-b1	Gene
22446029	1015	1020	a-SMA	Gene
22446029	1061	1067	TGF-b1	Gene
22446029	1273	1276	PEG	Chemical
22446029	1329	1332	IPF	Disease
25214520|t|A translational preclinical model of interstitial pulmonary fibrosis and pulmonary hypertension: mechanistic pathways driving disease pathophysiology
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 interstitial pulmonary fibrosis 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	37	68	interstitial pulmonary fibrosis	Disease
25214520	73	95	pulmonary hypertension	Disease
25214520	151	180	Idiopathic pulmonary fibrosis	Disease
25214520	182	185	IPF	Disease
25214520	212	237	interstitial lung disease	Disease
25214520	261	268	patient	Species
25214520	322	344	pulmonary hypertension	Disease
25214520	346	348	PH	Disease
25214520	417	420	IPF	Disease
25214520	425	427	PH	Disease
25214520	670	701	interstitial pulmonary fibrosis	Disease
25214520	717	719	PH	Disease
25214520	786	801	alveolar injury	Disease
25214520	980	984	mPAP	Gene
25214520	1078	1087	elevated	Positive_regulation
25214520	1126	1131	MMP-2	Gene
25214520	1133	1138	MMP-7	Gene
25214520	1144	1150	MMP-12	Gene
25214520	1152	1158	TIMP-1	Gene
25214520	1193	1199	PDGF-b	Gene
25214520	1220	1224	CCL2	Gene
25214520	1229	1235	CXCL12	Gene
25214520	1394	1406	upregulated	Positive_regulation
25214520	1458	1468	increases	Positive_regulation
25214520	1517	1523	TGF-b1	Gene
25214520	1546	1551	TGF-b	Gene
25214520	1571	1576	PAI-1	Gene
25214520	1578	1583	Nox-4	Gene
25214520	1589	1595	HIF-1a	Gene
25214520	1628	1633	ALK-5	Gene
25214520	1634	1639	TGF-b	Gene
25214520	1643	1653	inhibitor	Negative_regulation
25214520	1653	1662	SB-525334	Chemical
25214520	1672	1702	established pulmonary fibrosis	Disease
25214520	1872	1876	mPAP	Gene
19104148|t|Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis
Pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (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 beta-catenin has been implicated in EMT; we found that in primary AECs, alpha3 integrin was required for beta-catenin phosphorylation at tyrosine residue 654 (Y654), formation of the pY654-beta-catenin/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-beta-catenin/pSmad2 complexes and showed accumulation of pY654-beta-catenin in myofibroblasts
These findings demonstrate epithelial integrin-dependent profibrotic crosstalk between beta-catenin and Smad signaling and support the hypothesis that EMT is an important contributor to pathologic fibrosis
19104148	43	55	beta-catenin	Gene
19104148	114	132	pulmonary fibrosis	Disease
19104148	134	152	Pulmonary fibrosis	Disease
19104148	157	197	particular idiopathic pulmonary fibrosis	Disease
19104148	427	446	alveolar epithelial	Disease
19104148	500	508	fibrosis	Disease
19104148	536	545	TGF-beta1	Gene
19104148	596	605	TGF-beta1	Gene
19104148	693	701	fibrosis	Disease
19104148	716	720	mice	Species
19104148	756	761	loss	Negative_regulation
19104148	780	791	expression	Gene_expression
19104148	798	802	mice	Species
19104148	834	843	bleomycin	Chemical
19104148	890	903	accumulation	Localization
19104148	970	978	fibrosis	Disease
19104148	998	1010	beta-catenin	Gene
19104148	1090	1099	required	Positive_regulation
19104148	1103	1115	beta-catenin	Gene
19104148	1116	1132	phosphorylation	Phosphorylation
19104148	1164	1174	formation	Binding
19104148	1187	1199	beta-catenin	Gene
19104148	1301	1310	bleomycin	Chemical
19104148	1361	1369	patients	Species
19104148	1401	1413	beta-catenin	Gene
19104148	1442	1455	accumulation	Positive_regulation
19104148	1464	1476	beta-catenin	Gene
19104148	1583	1595	beta-catenin	Gene
19104148	1693	1701	fibrosis	Disease
19104143|t|Role for alpha3 integrin in EMT and pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive (myo)fibroblast accumulation and collagen deposition
One possible source of (myo)fibroblasts 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	36	54	pulmonary fibrosis	Disease
19104143	56	85	Idiopathic pulmonary fibrosis	Disease
19104143	87	90	IPF	Disease
19104143	325	333	TGF-beta	Gene
19104143	409	418	deletion	Negative_regulation
19104143	453	457	mice	Species
19104143	486	495	bleomycin	Chemical
19104143	504	512	fibrosis	Disease
19104143	608	616	TGF-beta	Gene
19104143	621	633	beta-catenin	Gene
19104143	693	701	tyrosine	Chemical
19104143	693	717	tyrosine-phosphorylated	Phosphorylation
19104143	717	729	beta-catenin	Gene
28922731|t|Shikonin suppresses pulmonary fibroblasts proliferation and activation by regulating Akt and p38 MAPK signaling pathways
Fibroblast is believed to be the primary effector in idiopathic pulmonary fibrosis (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 Akt was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments
The phosphorylation of both p38 MAPK and Akt stimulated by TGF-b was reduced after SHI treatments
Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting Akt activation signaling pathway, and attenuates TGF-b induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of p38 MAPK and Akt
SHI might serve as a therapeutically candidate for IPF patients
28922731	74	85	regulating	Regulation
28922731	85	88	Akt	Gene
28922731	93	96	p38	Gene
28922731	175	204	idiopathic pulmonary fibrosis	Disease
28922731	206	209	IPF	Disease
28922731	214	239	progressive lung disorder	Disease
28922731	594	606	inflammation	Disease
28922731	611	617	cancer	Disease
28922731	651	660	skin scar	Disease
28922731	665	679	renal fibrosis	Disease
28922731	692	697	TGFb1	Gene
28922731	775	778	IPF	Disease
28922731	816	825	carcinoma	Disease
28922731	1046	1055	G1 and G2	Gene
28922731	1079	1087	reduced	Negative_regulation
28922731	1091	1102	production	Gene_expression
28922731	1105	1110	a-SMA	Gene
28922731	1147	1156	response	Positive_regulation
28922731	1159	1164	TGF-b	Gene
28922731	1165	1175	induction	Positive_regulation
28922731	1305	1308	IPF	Disease
28922731	1314	1330	phosphorylation	Phosphorylation
28922731	1333	1336	Akt	Gene
28922731	1341	1356	down-regulated	Negative_regulation
28922731	1357	1360	p53	Gene
28922731	1381	1388	levels	Transcription
28922731	1391	1394	p21	Gene
28922731	1399	1402	p27	Gene
28922731	1403	1412	enhanced	Positive_regulation
28922731	1438	1454	phosphorylation	Phosphorylation
28922731	1462	1465	p38	Gene
28922731	1475	1478	Akt	Gene
28922731	1479	1490	stimulated	Positive_regulation
28922731	1493	1498	TGF-b	Gene
28922731	1503	1511	reduced	Negative_regulation
28922731	1630	1641	inhibiting	Negative_regulation
28922731	1641	1644	Akt	Gene
28922731	1690	1695	TGF-b	Gene
28922731	1696	1704	induced	Positive_regulation
28922731	1731	1742	production	Gene_expression
28922731	1771	1782	modulating	Regulation
28922731	1786	1797	activities	Positive_regulation
28922731	1800	1803	p38	Gene
28922731	1813	1816	Akt	Gene
28922731	1869	1872	IPF	Disease
28922731	1873	1881	patients	Species
16787145|t|Pirfenidone for the treatment of idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	0	11	Pirfenidone	Chemical
16787145	33	62	idiopathic pulmonary fibrosis	Disease
16787145	64	93	Idiopathic pulmonary fibrosis	Disease
16787145	95	98	IPF	Disease
16787145	292	300	fibrosis	Disease
16787145	572	575	IPF	Disease
16787145	662	673	Pirfenidone	Chemical
16787145	725	728	IPF	Disease
16787145	801	804	IPF	Disease
22241478|t|Interactions between b-catenin and transforming growth factor-b signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP)
Interactions between transforming growth factor-b (TGF-b) 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 b-catenin-dependent and transforming growth factor-b1 (TGF-b1) interactions in pulmonary alveolar epithelial cells (AEC) in the context of EMT and pulmonary fibrosis
We previously demonstrated that ICG-001, a small molecule specific inhibitor of the b-catenin/CBP (but not b-catenin/p300) interaction, ameliorates and reverses pulmonary fibrosis and inhibits TGF-b1-mediated a-smooth muscle actin (a-SMA) and collagen induction in AEC
We now demonstrate that TGF-b1 induces LEF/TCF TOPFLASH reporter activation and nuclear b-catenin accumulation, while LiCl augments TGF-b-induced a-SMA expression, further confirming co-operation between b-catenin- and TGF-b-dependent signaling pathways
Inhibition and knockdown of Smad3, knockdown of b-catenin and overexpression of ICAT abrogated effects of TGF-b1 on a-SMA transcription/expression, indicating a requirement for b-catenin in these Smad3-dependent effects
Following TGF-b treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and b-catenin, while chromatin immunoprecipitation (ChIP)-re-ChIP identified spatial and temporal regulation of a-SMA via complex formation among Smad3, b-catenin, and CBP
ICG-001 inhibited a-SMA expression/transcription in response to TGF-b as well as a-SMA promoter occupancy by b-catenin and CBP, demonstrating a previously unknown requisite TGF-b1/b-catenin/CBP-mediated pro-EMT signaling pathway
Clinical relevance was shown by b-catenin/Smad3 co-localization and CBP expression in AEC of IPF patients
These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling CBP/catenin-dependent signaling downstream of TGF-b
22241478	0	13	Interactions	Binding
22241478	21	30	b-catenin	Gene
22241478	35	63	transforming growth factor-b	Gene
22241478	179	183	cAMP	Chemical
22241478	218	239	CREB)-binding protein	Gene
22241478	241	244	CBP	Gene
22241478	247	260	Interactions	Binding
22241478	268	296	transforming growth factor-b	Gene
22241478	298	303	TGF-b	Gene
22241478	590	599	b-catenin	Gene
22241478	645	651	TGF-b1	Gene
22241478	669	698	pulmonary alveolar epithelial	Disease
22241478	737	755	pulmonary fibrosis	Disease
22241478	824	834	inhibitor	Negative_regulation
22241478	841	850	b-catenin	Gene
22241478	851	854	CBP	Gene
22241478	864	873	b-catenin	Gene
22241478	874	878	p300	Gene
22241478	880	892	interaction	Binding
22241478	918	936	pulmonary fibrosis	Disease
22241478	941	950	inhibits	Negative_regulation
22241478	950	956	TGF-b1	Gene
22241478	989	994	a-SMA	Gene
22241478	1009	1019	induction	Positive_regulation
22241478	1051	1057	TGF-b1	Gene
22241478	1058	1066	induces	Positive_regulation
22241478	1066	1073	LEF/TCF	Gene
22241478	1092	1103	activation	Positive_regulation
22241478	1115	1124	b-catenin	Gene
22241478	1145	1149	LiCl	Chemical
22241478	1159	1164	TGF-b	Gene
22241478	1173	1178	a-SMA	Gene
22241478	1231	1240	b-catenin	Gene
22241478	1246	1251	TGF-b	Gene
22241478	1282	1293	Inhibition	Negative_regulation
22241478	1297	1307	knockdown	Negative_regulation
22241478	1310	1315	Smad3	Gene
22241478	1317	1327	knockdown	Negative_regulation
22241478	1330	1339	b-catenin	Gene
22241478	1344	1359	overexpression	Positive_regulation
22241478	1362	1366	ICAT	Gene
22241478	1388	1394	TGF-b1	Gene
22241478	1398	1403	a-SMA	Gene
22241478	1404	1429	transcription/expression	Transcription
22241478	1459	1468	b-catenin	Gene
22241478	1478	1483	Smad3	Gene
22241478	1513	1518	TGF-b	Gene
22241478	1604	1609	Smad3	Gene
22241478	1614	1623	b-catenin	Gene
22241478	1708	1719	regulation	Regulation
22241478	1722	1727	a-SMA	Gene
22241478	1756	1761	Smad3	Gene
22241478	1763	1772	b-catenin	Gene
22241478	1778	1781	CBP	Gene
22241478	1791	1801	inhibited	Negative_regulation
22241478	1801	1806	a-SMA	Gene
22241478	1847	1852	TGF-b	Gene
22241478	1864	1869	a-SMA	Gene
22241478	1892	1901	b-catenin	Gene
22241478	1906	1909	CBP	Gene
22241478	1956	1962	TGF-b1	Gene
22241478	1963	1972	b-catenin	Gene
22241478	1973	1976	CBP	Gene
22241478	2045	2054	b-catenin	Gene
22241478	2055	2060	Smad3	Gene
22241478	2061	2077	co-localization	Localization
22241478	2081	2084	CBP	Gene
22241478	2085	2096	expression	Gene_expression
22241478	2106	2109	IPF	Disease
22241478	2110	2118	patients	Species
22241478	2173	2191	pulmonary fibrosis	Disease
22241478	2219	2222	CBP	Gene
22241478	2265	2270	TGF-b	Gene
17975199|t|Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis
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 pulmonary fibrosis (IPF)
OBJECTIVES: To investigate the role of gremlin in the regulation of BMP signaling in pulmonary fibrosis
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: Gremlin 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 pulmonary fibrosis
Rescue of BMP signaling activity may represent a potential beneficial strategy for treating human pulmonary fibrosis
17975199	0	7	Gremlin	Gene
17975199	75	93	pulmonary fibrosis	Disease
17975199	345	348	BMP	Gene
17975199	361	368	gremlin	Gene
17975199	396	425	idiopathic pulmonary fibrosis	Disease
17975199	427	430	IPF	Disease
17975199	464	469	role	Regulation
17975199	472	479	gremlin	Gene
17975199	487	498	regulation	Regulation
17975199	501	504	BMP	Gene
17975199	518	536	pulmonary fibrosis	Disease
17975199	576	584	fibrosis	Disease
17975199	592	597	mouse	Species
17975199	621	626	human	Species
17975199	627	630	IPF	Disease
17975199	632	640	TGF-beta	Gene
17975199	645	648	BMP	Gene
17975199	649	660	expression	Gene_expression
17975199	704	710	murine	Species
17975199	715	720	human	Species
17975199	754	761	gremlin	Gene
17975199	762	772	induction	Positive_regulation
17975199	866	873	gremlin	Gene
17975199	874	885	inhibition	Negative_regulation
17975199	917	922	BMP-7	Gene
17975199	926	930	mice	Species
17975199	987	994	Gremlin	Gene
17975199	1012	1025	up-regulated	Positive_regulation
17975199	1049	1054	mouse	Species
17975199	1093	1098	human	Species
17975199	1099	1102	IPF	Disease
17975199	1116	1132	Down-regulation	Negative_regulation
17975199	1135	1138	BMP	Gene
17975199	1169	1177	reduced	Negative_regulation
17975199	1187	1194	Smad1/5	Gene
17975199	1201	1210	enhanced	Positive_regulation
17975199	1210	1215	Smad2	Gene
17975199	1216	1232	phosphorylation	Phosphorylation
17975199	1293	1298	human	Species
17975199	1341	1358	asbestos-induced	Positive_regulation
17975199	1358	1365	gremlin	Gene
17975199	1366	1377	expression	Gene_expression
17975199	1399	1410	inhibitors	Negative_regulation
17975199	1417	1425	TGF-beta	Gene
17975199	1447	1458	inhibitors	Negative_regulation
17975199	1561	1566	BMP-7	Gene
17975199	1599	1613	hydroxyproline	Chemical
17975199	1647	1651	mice	Species
17975199	1670	1678	TGF-beta	Gene
17975199	1683	1686	BMP	Gene
17975199	1781	1799	pulmonary fibrosis	Disease
17975199	1811	1814	BMP	Gene
17975199	1893	1898	human	Species
17975199	1899	1917	pulmonary fibrosis	Disease
17934117|t|Molecular targets in pulmonary fibrosis: the myofibroblast in focus
Idiopathic pulmonary fibrosis (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	21	39	pulmonary fibrosis	Disease
17934117	69	98	Idiopathic pulmonary fibrosis	Disease
17934117	100	103	IPF	Disease
17934117	126	152	interstitial lung diseases	Disease
17934117	278	281	IPF	Disease
17934117	282	290	patients	Species
17934117	383	386	IPF	Disease
17934117	422	437	corticosteroids	Chemical
17934117	470	480	prednisone	Chemical
17934117	586	589	IPF	Disease
17934117	745	753	fibrosis	Disease
17934117	799	809	synthetic	Gene_expression
17934117	1272	1275	IPF	Disease
24953558|t|miR-92a regulates TGF-b1-induced WISP1 expression in pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 (WISP1) as a highly expressed pro-fibrotic mediator in IPF, but the underlying mechanisms resulting in increased WISP1 expression, remain elusive
Here, we investigated whether WISP1 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 WISP1 3'UTR preferentially bound by the miRNA ribonucleoprotein complex
Both miRNAs were decreased in IPF samples, whereas WISP1 protein was increased
We demonstrated further that transforming growth factor (TGF)-b1-induced WISP1 expression in primary lung fibroblasts in vitro and lung homogenates in vivo
Notably, miR-30a and miR-92a reversed TGF-b1-induced WISP1 mRNA expression in lung fibroblasts
Moreover, miR-92a inhibition increased WISP1 protein expression in lung fibroblasts
An inverse relationship for WISP1 and miR-92a was found in a TGF-b1 dependent lung fibrosis model in vivo
Finally, we found significantly increased WISP1 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 WISP1 expression in pulmonary fibrosis
24953558	8	18	regulates	Regulation
24953558	18	24	TGF-b1	Gene
24953558	25	33	induced	Positive_regulation
24953558	33	38	WISP1	Gene
24953558	39	50	expression	Gene_expression
24953558	53	71	pulmonary fibrosis	Disease
24953558	73	102	Idiopathic pulmonary fibrosis	Disease
24953558	104	107	IPF	Disease
24953558	146	179	idiopathic interstitial pneumonia	Disease
24953558	345	348	IPF	Disease
24953558	393	435	WNT1-inducible signaling pathway protein 1	Gene
24953558	437	442	WISP1	Gene
24953558	456	466	expressed	Gene_expression
24953558	491	494	IPF	Disease
24953558	539	549	increased	Positive_regulation
24953558	549	554	WISP1	Gene
24953558	555	566	expression	Gene_expression
24953558	613	618	WISP1	Gene
24953558	640	651	regulation	Regulation
24953558	725	732	miR-30a	Gene
24953558	778	783	human	Species
24953558	784	789	WISP1	Gene
24953558	811	817	bound	Binding
24953558	887	890	IPF	Disease
24953558	908	913	WISP1	Gene
24953558	926	936	increased	Positive_regulation
24953558	998	1010	-b1-induced	Positive_regulation
24953558	1010	1015	WISP1	Gene
24953558	1016	1027	expression	Gene_expression
24953558	1103	1110	miR-30a	Gene
24953558	1123	1132	reversed	Negative_regulation
24953558	1132	1138	TGF-b1	Gene
24953558	1139	1147	induced	Positive_regulation
24953558	1147	1152	WISP1	Gene
24953558	1158	1169	expression	Gene_expression
24953558	1208	1219	inhibition	Negative_regulation
24953558	1219	1229	increased	Positive_regulation
24953558	1229	1234	WISP1	Gene
24953558	1243	1254	expression	Gene_expression
24953558	1303	1308	WISP1	Gene
24953558	1336	1342	TGF-b1	Gene
24953558	1358	1366	fibrosis	Disease
24953558	1414	1424	increased	Positive_regulation
24953558	1424	1429	WISP1	Gene
24953558	1430	1441	expression	Gene_expression
24953558	1452	1455	IPF	Disease
24953558	1572	1577	role	Positive_regulation
24953558	1592	1597	WISP1	Gene
24953558	1598	1609	expression	Gene_expression
24953558	1612	1630	pulmonary fibrosis	Disease
18245174|t|Transgelin is a direct target of TGF-beta/Smad3-dependent epithelial cell migration in lung fibrosis
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, (myo)fibroblast accumulation, and excessive extracellular matrix deposition
TGF-beta is a potent inducer of lung fibrosis, and it regulates the ATII cell phenotype; however, direct TGF-beta target genes controlling the ATII cell phenotype remain elusive
Here, we identified the transgelin (tagln) gene as a novel immediate target of TGF-beta/Smad3-dependent gene expression in ATII cells using a Smad3 chromatin immunoprecipitation (ChIP) screen
Direct ChIP confirmed the rapid and specific binding of Smad3 to the tagln promoter
Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase (Alk) 5-mediated TGF-beta signaling
TGF-beta 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 TGF-beta-induced migration of lung epithelial A549 cells, as well as primary ATII cells
We thus identified tagln as a novel target of TGF-beta/Smad3-dependent gene expression in ATII cells
Increased ATII cell expression of tagln in experimental and idiopathic pulmonary fibrosis may contribute to TGF-beta-dependent ATII cell injury, repair, and migration in lung fibrosis
18245174	0	10	Transgelin	Gene
18245174	33	41	TGF-beta	Gene
18245174	42	47	Smad3	Gene
18245174	74	100	migration in lung fibrosis	Disease
18245174	175	204	idiopathic pulmonary fibrosis	Disease
18245174	206	209	IPF	Disease
18245174	214	243	progressive and fatal disease	Disease
18245174	261	288	alveolar epithelial type II	Disease
18245174	290	294	ATII	Disease
18245174	301	312	hyperplasia	Disease
18245174	391	399	TGF-beta	Gene
18245174	412	436	inducer of lung fibrosis	Disease
18245174	445	455	regulates	Regulation
18245174	459	463	ATII	Disease
18245174	496	504	TGF-beta	Gene
18245174	534	538	ATII	Disease
18245174	594	604	transgelin	Gene
18245174	606	611	tagln	Gene
18245174	649	657	TGF-beta	Gene
18245174	658	663	Smad3	Gene
18245174	679	690	expression	Gene_expression
18245174	693	697	ATII	Disease
18245174	712	717	Smad3	Gene
18245174	808	816	binding	Binding
18245174	819	824	Smad3	Gene
18245174	832	837	tagln	Gene
18245174	838	847	promoter	Entity
18245174	902	907	tagln	Gene
18245174	957	965	TGF-beta	Gene
18245174	977	985	TGF-beta	Gene
18245174	996	1005	resulted	Positive_regulation
18245174	1014	1028	up-regulation	Positive_regulation
18245174	1031	1036	tagln	Gene
18245174	1046	1052	tagln2	Gene
18245174	1204	1209	tagln	Gene
18245174	1252	1256	ATII	Disease
18245174	1266	1270	mice	Species
18245174	1278	1287	bleomycin	Chemical
18245174	1296	1309	lung fibrosis	Disease
18245174	1353	1356	IPF	Disease
18245174	1357	1365	patients	Species
18245174	1428	1433	tagln	Gene
18245174	1456	1464	TGF-beta	Gene
18245174	1533	1537	ATII	Disease
18245174	1564	1569	tagln	Gene
18245174	1591	1599	TGF-beta	Gene
18245174	1600	1605	Smad3	Gene
18245174	1621	1632	expression	Gene_expression
18245174	1635	1639	ATII	Disease
18245174	1657	1661	ATII	Disease
18245174	1681	1686	tagln	Gene
18245174	1707	1736	idiopathic pulmonary fibrosis	Disease
18245174	1755	1763	TGF-beta	Gene
18245174	1774	1778	ATII	Disease
18245174	1804	1830	migration in lung fibrosis	Disease
28469072|t|Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis
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 lung fibrosis 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 thrombin activity and its downstream signaling pathways
Direct thrombin 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 thrombin 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 thrombin inhibitors that our data suggest could benefit these patients
28469072	56	64	thrombin	Gene
28469072	68	81	lung fibrosis	Disease
28469072	83	104	Fibrotic lung disease	Disease
28469072	119	148	idiopathic pulmonary fibrosis	Disease
28469072	150	153	IPF	Disease
28469072	229	240	lung injury	Disease
28469072	359	372	lung fibrosis	Disease
28469072	462	473	lung injury	Disease
28469072	555	563	fibrosis	Disease
28469072	589	597	fibrosis	Disease
28469072	598	607	produced	Gene_expression
28469072	644	652	thrombin	Gene
28469072	708	716	thrombin	Gene
28469072	717	728	inhibition	Negative_regulation
28469072	733	743	dabigatran	Chemical
28469072	758	768	inhibited	Negative_regulation
28469072	768	797	protease-activated receptor-1	Gene
28469072	799	803	PAR1	Gene
28469072	805	816	activation	Positive_regulation
28469072	826	831	avb6	Entity
28469072	831	841	induction	Positive_regulation
28469072	842	847	TGF-b	Gene
28469072	848	859	activation	Positive_regulation
28469072	883	901	pulmonary fibrosis	Disease
28469072	1059	1069	gadolinium	Chemical
28469072	1163	1168	mouse	Species
28469072	1221	1231	dabigatran	Chemical
28469072	1285	1296	inhibition	Negative_regulation
28469072	1326	1334	thrombin	Gene
28469072	1419	1427	warfarin	Chemical
28469072	1438	1451	downregulate	Negative_regulation
28469072	1455	1459	PAR1	Gene
28469072	1465	1470	TGF-b	Gene
28469072	1509	1517	fibrosis	Disease
28469072	1610	1618	warfarin	Chemical
28469072	1650	1653	IPF	Disease
28469072	1695	1703	thrombin	Gene
28469072	1704	1715	inhibitors	Negative_regulation
28469072	1757	1765	patients	Species
25697336|t|Studies of hepatocyte growth factor in bronchoalveolar lavage fluid in chronic interstitial lung diseases
INTRODUCTION:   Previous studies have suggested that hepatocyte growth factor (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 interstitial lung diseases
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 interstitial lung diseases, they are not enough to prevent lung fibrosis
25697336	11	35	hepatocyte growth factor	Gene
25697336	79	105	interstitial lung diseases	Disease
25697336	160	184	hepatocyte growth factor	Gene
25697336	186	189	HGF	Gene
25697336	191	213	inhibits lung fibrosis	Disease
25697336	300	303	HGF	Gene
25697336	304	315	expression	Gene_expression
25697336	346	354	patients	Species
25697336	369	395	interstitial lung diseases	Disease
25697336	397	405	PATIENTS	Species
25697336	421	424	HGF	Gene
25697336	544	552	patients	Species
25697336	558	579	pulmonary sarcoidosis	Disease
25697336	581	583	PS	Disease
25697336	594	623	idiopathic pulmonary fibrosis	Disease
25697336	625	628	IPF	Disease
25697336	639	673	nonspecific interstitial pneumonia	Disease
25697336	675	679	NSIP	Disease
25697336	690	719	extrinsic allergic alveolitis	Disease
25697336	721	724	EAA	Disease
25697336	734	779	bronchiolitis obliterans organizing pneumonia	Disease
25697336	781	785	BOOP	Disease
25697336	795	825	chronic eosinophilic pneumonia	Disease
25697336	887	890	HGF	Gene
25697336	891	902	expression	Gene_expression
25697336	959	962	HGF	Gene
25697336	1026	1029	IPF	Disease
25697336	1071	1074	IPF	Disease
25697336	1120	1122	PS	Disease
25697336	1236	1239	HGF	Gene
25697336	1484	1487	HGF	Gene
25697336	1581	1584	HGF	Gene
25697336	1607	1610	HGF	Gene
25697336	1658	1666	patients	Species
25697336	1672	1675	IPF	Disease
25697336	1798	1801	HGF	Gene
25697336	1802	1813	expression	Gene_expression
25697336	1817	1829	upregulated	Positive_regulation
25697336	1840	1866	interstitial lung diseases	Disease
25697336	1899	1912	lung fibrosis	Disease
23924348|t|Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor I internalization and inhibiting transforming growth factor-b1 signaling
RATIONALE: Alveolar transforming growth factor (TGF)-b1 signaling and expression of TGF-b1 target genes are increased in patients with idiopathic pulmonary fibrosis (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 TGF-b1 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 TGF-b1 signaling, TGF-b1, 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 TGF-b1 signaling and downstream expression of TGF-b1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis
In vitro, syndecan-2 promoted caveolin-1-dependent internalization of TGF-b1 and TbRI in alveolar epithelial cells, which inhibited TGF-b1 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 caveolin-1-dependent TGF-b1 and TbRI internalization and inhibiting TGF-b1 signaling in alveolar epithelial cells
Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for pulmonary fibrosis
23924348	0	10	Syndecan-2	Gene
23924348	52	62	caveolin-1	Gene
23924348	254	265	expression	Gene_expression
23924348	268	274	TGF-b1	Gene
23924348	292	302	increased	Positive_regulation
23924348	305	313	patients	Species
23924348	319	348	idiopathic pulmonary fibrosis	Disease
23924348	350	353	IPF	Disease
23924348	379	397	pulmonary fibrosis	Disease
23924348	399	415	Internalization	Localization
23924348	419	431	degradation	Protein_catabolism
23924348	434	439	TGF-b	Gene
23924348	454	463	inhibits	Negative_regulation
23924348	463	468	TGF-b	Gene
23924348	514	540	experimental lung fibrosis	Disease
23924348	593	604	lung injury	Disease
23924348	606	611	human	Species
23924348	612	622	syndecan-2	Gene
23924348	666	672	TGF-b1	Gene
23924348	825	833	patients	Species
23924348	839	842	IPF	Disease
23924348	868	883	Transgenic mice	Species
23924348	916	921	human	Species
23924348	922	932	syndecan-2	Gene
23924348	1002	1012	syndecan-2	Gene
23924348	1058	1068	syndecan-2	Gene
23924348	1106	1112	TGF-b1	Gene
23924348	1124	1130	TGF-b1	Gene
23924348	1182	1186	mice	Species
23924348	1217	1222	human	Species
23924348	1223	1233	syndecan-2	Gene
23924348	1263	1272	bleomycin	Chemical
23924348	1281	1292	lung injury	Disease
23924348	1382	1392	syndecan-2	Gene
23924348	1403	1411	patients	Species
23924348	1417	1420	IPF	Disease
23924348	1460	1465	human	Species
23924348	1466	1476	syndecan-2	Gene
23924348	1533	1544	lung injury	Disease
23924348	1559	1565	TGF-b1	Gene
23924348	1591	1602	expression	Gene_expression
23924348	1605	1611	TGF-b1	Gene
23924348	1717	1727	syndecan-2	Gene
23924348	1737	1747	caveolin-1	Gene
23924348	1758	1774	internalization	Localization
23924348	1777	1783	TGF-b1	Gene
23924348	1839	1845	TGF-b1	Gene
23924348	1917	1922	human	Species
23924348	1923	1933	syndecan-2	Gene
23924348	1934	1957	abrogated lung fibrosis	Disease
23924348	1961	1965	mice	Species
23924348	2000	2010	syndecan-2	Gene
23924348	2042	2052	promoting	Positive_regulation
23924348	2052	2062	caveolin-1	Gene
23924348	2073	2079	TGF-b1	Gene
23924348	2109	2120	inhibiting	Negative_regulation
23924348	2120	2126	TGF-b1	Gene
23924348	2189	2200	facilitate	Regulation
23924348	2205	2217	degradation	Protein_catabolism
23924348	2267	2285	pulmonary fibrosis	Disease
25848047|t|Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-b signaling
UNASSIGNED: Idiopathic pulmonary fibrosis (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 (TGF-b) receptor II knockout mice indicating a role for TGF-b signaling in the regulation of peroxisomes
Furthermore, in vitro treatment of IPF fibroblasts with the profibrotic factors TGF-b1 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 TGF-b signaling accompanied by increased ROS production and resulted in the release of cytokines (e.g., IL-6, TGF-b) 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 TGF-b-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	27	56	idiopathic pulmonary fibrosis	Disease
25848047	114	119	TGF-b	Gene
25848047	143	172	Idiopathic pulmonary fibrosis	Disease
25848047	174	177	IPF	Disease
25848047	380	394	liver fibrosis	Disease
25848047	437	440	IPF	Disease
25848047	597	602	human	Species
25848047	615	618	IPF	Disease
25848047	619	627	patients	Species
25848047	643	646	IPF	Disease
25848047	741	747	PEX13p	Gene
25848047	752	770	acyl-CoA oxidase 1	Gene
25848047	894	899	TGF-b	Gene
25848047	922	926	mice	Species
25848047	949	954	TGF-b	Gene
25848047	1034	1037	IPF	Disease
25848047	1079	1085	TGF-b1	Gene
25848047	1089	1116	tumor necrosis factor alpha	Gene
25848047	1118	1123	TNF-a	Gene
25848047	1294	1302	fibrosis	Disease
25848047	1332	1348	down-regulation	Negative_regulation
25848047	1351	1356	PEX13	Gene
25848047	1406	1411	TGF-b	Gene
25848047	1437	1461	increased ROS production	Disease
25848047	1466	1475	resulted	Positive_regulation
25848047	1482	1490	release	Localization
25848047	1510	1514	IL-6	Gene
25848047	1516	1521	TGF-b	Gene
25848047	1537	1548	production	Gene_expression
25848047	1630	1637	WY14643	Chemical
25848047	1639	1645	PPAR-a	Gene
25848047	1694	1702	reduced	Negative_regulation
25848047	1706	1711	TGF-b	Gene
25848047	1774	1777	IPF	Disease
25848047	1921	1924	IPF	Disease
25848047	1929	1937	fibrosis	Disease
25848047	1976	1998	pulmonary inflammation	Disease
25848047	2045	2053	patients	Species
26160872|t|Increased alveolar soluble annexin V promotes lung inflammation and fibrosis
The causes underlying the self-perpetuating nature of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal disease, remain unknown
We hypothesised that alveolar soluble annexin V contributes to lung fibrosis, based on the observation that human IPF bronchoalveolar lavage fluid (BALF) containing high annexin V levels promoted fibroblast involvement in alveolar epithelial wound healing that was reduced when annexin V was depleted from the BALF
Conditioned medium from annexin V-treated alveolar 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 alveolar 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	10	18	alveolar	Disease
26160872	27	36	annexin V	Gene
26160872	46	63	lung inflammation	Disease
26160872	68	76	fibrosis	Disease
26160872	132	161	idiopathic pulmonary fibrosis	Disease
26160872	248	256	alveolar	Disease
26160872	265	274	annexin V	Gene
26160872	295	303	fibrosis	Disease
26160872	335	340	human	Species
26160872	341	367	IPF bronchoalveolar lavage	Disease
26160872	397	406	annexin V	Gene
26160872	449	468	alveolar epithelial	Disease
26160872	505	514	annexin V	Gene
26160872	519	528	depleted	Negative_regulation
26160872	567	576	annexin V	Gene
26160872	585	593	alveolar	Disease
26160872	634	643	annexin V	Gene
26160872	677	682	human	Species
26160872	837	846	annexin V	Gene
26160872	857	862	human	Species
26160872	869	874	ErbB2	Gene
26160872	912	922	activated	Positive_regulation
26160872	925	934	annexin V	Gene
26160872	983	992	annexin V	Gene
26160872	1054	1063	annexin V	Gene
26160872	1067	1072	mouse	Species
26160872	1086	1098	inflammation	Disease
26160872	1100	1108	fibrosis	Disease
26160872	1144	1155	activation	Positive_regulation
26160872	1307	1315	alveolar	Disease
26160872	1316	1325	annexin V	Gene
26160872	1350	1360	increased	Positive_regulation
23817018|t|Simvastatin attenuates TGF-b1-induced epithelial-mesenchymal transition in human alveolar epithelial cells
BACKGROUND: Transforming growth factor-b1 (TGF-b1)-induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) may contribute to idiopathic pulmonary fibrosis (IPF)
TGF-b1-induced EMT in A549 cells (a human AEC cell line) resulted in the adoption of mesenchymal responses that were predominantly mediated via the TGF-b1-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 TGF-b1-induced EMT in A549 cells and its underlying mechanisms remains unknown
METHODS: Cells were incubated with TGF-b1 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 TGF-b1-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 TGF-b1 in A549 cells
CONCLUSION: Sim attenuated TGF-b1-induced EMT in A549 cells and might be a promising therapeutic agent for treating IPF
23817018	0	11	Simvastatin	Chemical
23817018	23	29	TGF-b1	Gene
23817018	75	80	human	Species
23817018	120	149	Transforming growth factor-b1	Gene
23817018	151	157	TGF-b1	Gene
23817018	260	289	idiopathic pulmonary fibrosis	Disease
23817018	291	294	IPF	Disease
23817018	297	303	TGF-b1	Gene
23817018	333	338	human	Species
23817018	445	451	TGF-b1	Gene
23817018	452	457	Smad2	Gene
23817018	479	490	Simvastatin	Chemical
23817018	492	495	Sim	Chemical
23817018	500	530	3-hydroxy-3-methylglutaryl CoA	Chemical
23817018	532	550	HMG-CoA) reductase	Gene
23817018	594	602	inhibit	Negative_regulation
23817018	609	614	human	Species
23817018	690	699	suppress	Negative_regulation
23817018	699	706	Smad2/3	Gene
23817018	707	723	phosphorylation	Phosphorylation
23817018	776	782	TGF-b1	Gene
23817018	891	897	TGF-b1	Gene
23817018	955	965	E-cadherin	Gene
23817018	967	972	E-Cad	Gene
23817018	1028	1031	SMA	Gene
23817018	1034	1042	vimentin	Gene
23817018	1044	1046	Vi	Gene
23817018	1052	1063	fibronectin	Gene
23817018	1065	1067	FN	Gene
23817018	1140	1155	Phosphorylated	Phosphorylation
23817018	1155	1160	Smad2	Gene
23817018	1165	1170	Smad3	Gene
23817018	1182	1213	connective tissue growth factor	Gene
23817018	1215	1219	CTGF	Gene
23817018	1324	1331	levels	Gene_expression
23817018	1334	1373	matrix metalloproteinase (MMP)-2 and -9	Gene
23817018	1465	1471	TGF-b1	Gene
23817018	1492	1497	E-Cad	Gene
23817018	1509	1518	elevated	Positive_regulation
23817018	1532	1537	a-SMA	Gene
23817018	1539	1541	Vi	Gene
23817018	1546	1548	FN	Gene
23817018	1557	1569	suppression	Negative_regulation
23817018	1572	1577	Smad2	Gene
23817018	1582	1587	Smad3	Gene
23817018	1588	1604	phosphorylation	Phosphorylation
23817018	1704	1708	CTGF	Gene
23817018	1709	1720	expression	Gene_expression
23817018	1724	1734	secretion	Localization
23817018	1737	1749	MMP-2 and -9	Gene
23817018	1823	1829	TGF-b1	Gene
23817018	1872	1878	TGF-b1	Gene
23817018	1961	1964	IPF	Disease
22892132|t|Expression of 150-kDa oxygen-regulated protein (ORP150) stimulates bleomycin-induced pulmonary fibrosis and dysfunction in mice
Idiopathic pulmonary fibrosis (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 150-kDa oxygen-regulated protein (ORP150), is essential for the maintenance of cellular viability under stress conditions
In this study, we used heterozygous ORP150-deficient mice (ORP150(+/-) mice) to examine the role of ORP150 in bleomycin-induced pulmonary fibrosis
Treatment of mice with bleomycin induced the expression of ORP150 in the lung
Bleomycin-induced inflammatory responses were slightly exacerbated in ORP150(+/-) 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 ORP150(+/-) mice
Bleomycin-induced increases in pulmonary levels of both active TGF-b1 and myofibroblasts were suppressed in ORP150(+/-) mice
These results suggest that although ORP150 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	14	46	150-kDa oxygen-regulated protein	Gene
22892132	48	54	ORP150	Gene
22892132	67	76	bleomycin	Chemical
22892132	85	119	pulmonary fibrosis and dysfunction	Disease
22892132	123	127	mice	Species
22892132	129	158	Idiopathic pulmonary fibrosis	Disease
22892132	160	163	IPF	Disease
22892132	174	190	pulmonary injury	Disease
22892132	207	229	inflammatory responses	Disease
22892132	231	239	fibrosis	Disease
22892132	436	439	IPF	Disease
22892132	440	448	patients	Species
22892132	476	508	150-kDa oxygen-regulated protein	Gene
22892132	510	516	ORP150	Gene
22892132	635	641	ORP150	Gene
22892132	642	652	deficient	Negative_regulation
22892132	652	656	mice	Species
22892132	658	664	ORP150	Gene
22892132	670	674	mice	Species
22892132	699	705	ORP150	Gene
22892132	709	718	bleomycin	Chemical
22892132	727	745	pulmonary fibrosis	Disease
22892132	760	764	mice	Species
22892132	770	779	bleomycin	Chemical
22892132	780	788	induced	Positive_regulation
22892132	792	803	expression	Gene_expression
22892132	806	812	ORP150	Gene
22892132	826	835	Bleomycin	Chemical
22892132	844	866	inflammatory responses	Disease
22892132	896	902	ORP150	Gene
22892132	908	912	mice	Species
22892132	935	939	mice	Species
22892132	960	969	bleomycin	Chemical
22892132	978	996	pulmonary fibrosis	Disease
22892132	1031	1054	respiratory dysfunction	Disease
22892132	1086	1092	ORP150	Gene
22892132	1098	1102	mice	Species
22892132	1104	1113	Bleomycin	Chemical
22892132	1122	1132	increases	Positive_regulation
22892132	1167	1173	TGF-b1	Gene
22892132	1212	1218	ORP150	Gene
22892132	1224	1228	mice	Species
22892132	1266	1272	ORP150	Gene
22892132	1295	1304	bleomycin	Chemical
22892132	1313	1324	lung injury	Disease
22892132	1355	1364	bleomycin	Chemical
22892132	1373	1391	pulmonary fibrosis	Disease
22892132	1395	1406	increasing	Positive_regulation
22892132	1426	1432	TGF-b1	Gene
23760654|t|Kinase inhibitors fail to induce mesenchymal-epithelial transition in fibroblasts from fibrotic lung tissue
Epithelial-mesenchymal transition (EMT) has been considered to be involved in idiopathic pulmonary fibrosis (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	7	18	inhibitors	Negative_regulation
23760654	187	216	idiopathic pulmonary fibrosis	Disease
23760654	218	221	IPF	Disease
23760654	552	570	pulmonary fibrosis	Disease
23760654	651	659	patients	Species
23760654	665	668	IPF	Disease
23760654	699	727	usual interstitial pneumonia	Disease
23760654	837	845	patients	Species
23760654	851	883	primary spontaneous pneumothorax	Disease
23760654	1022	1029	levels	Gene_expression
23760654	1032	1038	TGF-b1	Gene
23760654	1040	1046	TGF-b1	Gene
23760654	1085	1094	Smad2/3/4	Gene
23760654	1099	1107	Snail1/2	Gene
23760654	1127	1139	upregulated	Positive_regulation
23760654	1168	1179	Inhibitors	Negative_regulation
23760654	1227	1233	TGF-b1	Gene
23760654	1259	1295	p38 mitogen-activated protein kinase	Gene
23760654	1297	1305	p38 MAPK	Gene
23760654	1311	1335	c-Jun NH-terminal kinase	Gene
23760654	1337	1340	JNK	Gene
23760654	1700	1709	reversal	Negative_regulation
24307592|t|The small heat-shock protein aB-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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 Smad4, thereby enhancing the TGF-b1-Smad pathway and the consequent activation of TGF-b1 downstream genes
aB-crystallin over-expression disrupts Smad4 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 Smad4
Consequently, Smad4 mono-ubiquitination and nuclear export are favoured and thus TGF-b1-Smad4 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	64	72	nuclear	Entity
24307592	72	85	localization	Localization
24307592	88	93	Smad4	Gene
24307592	105	123	pulmonary fibrosis	Disease
24307592	125	154	Idiopathic pulmonary fibrosis	Disease
24307592	156	159	IPF	Disease
24307592	304	310	TGF-b1	Gene
24307592	357	360	IPF	Disease
24307592	483	493	expressed	Gene_expression
24307592	828	838	expressed	Gene_expression
24307592	867	870	IPF	Disease
24307592	871	879	patients	Species
24307592	909	927	pulmonary fibrosis	Disease
24307592	971	975	mice	Species
24307592	995	1004	bleomycin	Chemical
24307592	1013	1021	fibrosis	Disease
24307592	1047	1055	fibrosis	Disease
24307592	1089	1093	mice	Species
24307592	1130	1146	over-expression	Positive_regulation
24307592	1149	1154	IL-1b	Gene
24307592	1158	1164	TGF-b1	Gene
24307592	1246	1256	increases	Positive_regulation
24307592	1260	1268	nuclear	Entity
24307592	1268	1281	localization	Localization
24307592	1284	1289	Smad4	Gene
24307592	1299	1309	enhancing	Positive_regulation
24307592	1313	1319	TGF-b1	Gene
24307592	1352	1363	activation	Positive_regulation
24307592	1366	1372	TGF-b1	Gene
24307592	1430	1435	Smad4	Gene
24307592	1459	1471	interacting	Binding
24307592	1618	1623	Smad4	Gene
24307592	1639	1644	Smad4	Gene
24307592	1706	1712	TGF-b1	Gene
24307592	1713	1718	Smad4	Gene
24307592	1744	1754	inhibited	Negative_regulation
24307592	1876	1879	IPF	Disease
24307592	1889	1906	fibrotic diseases	Disease
27869174|t|Developmental Reprogramming in Mesenchymal Stromal Cells of Human Subjects with Idiopathic Pulmonary Fibrosis
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 chronic diseases, 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	60	65	Human	Species
27869174	80	109	Idiopathic Pulmonary Fibrosis	Disease
27869174	279	285	humans	Species
27869174	303	319	chronic diseases	Disease
27869174	329	335	cancer	Disease
27869174	340	348	fibrosis	Disease
27869174	571	576	human	Species
27869174	639	647	patients	Species
27869174	676	705	idiopathic pulmonary fibrosis	Disease
27869174	707	710	IPF	Disease
27869174	860	863	IPF	Disease
27869174	1146	1151	TGF-b	Gene
27869174	1156	1159	SHH	Gene
27869174	1184	1211	fibroblast growth factor-10	Gene
27869174	1213	1219	FGF-10	Gene
27869174	1234	1245	suppressed	Negative_regulation
27869174	1248	1251	IPF	Disease
27869174	1296	1302	TGF-b1	Gene
27869174	1307	1310	SHH	Gene
27869174	1457	1460	IPF	Disease
27869174	1466	1472	FGF-10	Gene
27869174	1473	1484	deficiency	Negative_regulation
21212602|t|Blockade of the Wnt/b-catenin pathway attenuates bleomycin-induced pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis in a bleomycin-induced murine model of pulmonary fibrosis
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, pulmonary fibrosis 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 pulmonary fibrosis 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	0	9	Blockade	Negative_regulation
21212602	49	58	bleomycin	Chemical
21212602	67	85	pulmonary fibrosis	Disease
21212602	87	116	Idiopathic pulmonary fibrosis	Disease
21212602	118	121	IPF	Disease
21212602	140	161	fibrotic lung disease	Disease
21212602	259	262	IPF	Disease
21212602	304	332	transforming growth factor-b	Gene
21212602	334	339	TGF-b	Gene
21212602	359	376	alveolar basement	Disease
21212602	471	482	associated	Binding
21212602	487	497	activated	Positive_regulation
21212602	685	696	activation	Positive_regulation
21212602	736	739	IPF	Disease
21212602	761	772	inhibition	Negative_regulation
21212602	807	835	attenuate pulmonary fibrosis	Disease
21212602	841	850	bleomycin	Chemical
21212602	859	865	murine	Species
21212602	875	893	pulmonary fibrosis	Disease
21212602	895	913	Pulmonary fibrosis	Disease
21212602	936	942	N mice	Species
21212602	976	985	bleomycin	Chemical
21212602	990	998	inhibit	Negative_regulation
21212602	1091	1098	trachea	Disease
21212602	1110	1119	bleomycin	Chemical
21212602	1208	1219	expression	Gene_expression
21212602	1223	1233	increased	Positive_regulation
21212602	1260	1269	bleomycin	Chemical
21212602	1283	1287	mice	Species
21212602	1348	1356	reduced	Negative_regulation
21212602	1366	1377	expression	Gene_expression
21212602	1378	1396	pulmonary fibrosis	Disease
21212602	1410	1420	synthesis	Gene_expression
21212602	1423	1432	bleomycin	Chemical
21212602	1446	1450	mice	Species
21212602	1604	1609	MMP-2	Gene
21212602	1623	1628	TGF-b	Gene
21212602	1669	1678	Blockade	Negative_regulation
21212602	1736	1745	bleomycin	Chemical
21212602	1754	1772	pulmonary fibrosis	Disease
21212602	1780	1786	murine	Species
21212602	1822	1832	targeting	Regulation
21212602	1917	1920	IPF	Disease
21086900|t|Epithelial stem cell exhaustion in the pathogenesis of idiopathic pulmonary fibrosis
New paradigms have been recently proposed in the pathogenesis of idiopathic pulmonary fibrosis (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	55	84	idiopathic pulmonary fibrosis	Disease
21086900	151	180	idiopathic pulmonary fibrosis	Disease
21086900	182	185	IPF	Disease
21086900	207	210	IPF	Disease
21086900	295	315	telomere dysfunction	Disease
21086900	385	392	tobacco	Species
21086900	553	561	scarring	Disease
12570673|t|Re-evaluation of fibrogenic cytokines in lung fibrosis
Idiopathic Pulmonary Fibrosis (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	41	54	lung fibrosis	Disease
12570673	56	85	Idiopathic Pulmonary Fibrosis	Disease
12570673	87	90	IPF	Disease
12570673	105	130	interstitial lung disease	Disease
12570673	158	166	fibrosis	Disease
12570673	963	976	interleukin-8	Gene
12570673	978	982	IL-8	Gene
12570673	985	991	RANTES	Gene
12570673	993	998	IP-10	Gene
12570673	1000	1003	MIG	Gene
12570673	1007	1019	lymphotactin	Gene
12570673	1038	1045	induce	Positive_regulation
12570673	1045	1053	fibrosis	Disease
12570673	1059	1074	over-expressed	Positive_regulation
12570673	1181	1189	IL-1beta	Gene
12570673	1217	1229	inflammation	Disease
12570673	1257	1265	fibrosis	Disease
12570673	1267	1276	TNF-alpha	Gene
12570673	1292	1304	inflammation	Disease
12570673	1314	1322	fibrosis	Disease
12570673	1328	1334	GM-CSF	Gene
12570673	1359	1371	inflammation	Disease
12570673	1376	1384	fibrosis	Disease
12570673	1443	1451	TGF-beta	Gene
12570673	1460	1473	proportionate	Chemical
12570673	1491	1499	fibrosis	Disease
12570673	1517	1525	TGF-beta	Gene
12570673	1546	1558	inflammation	Disease
12570673	1590	1598	fibrosis	Disease
12570673	1662	1670	TGF-beta	Gene
12570673	1672	1676	CTGF	Gene
12570673	1718	1734	over-expression	Positive_regulation
12570673	1737	1741	CTGF	Gene
12570673	1776	1784	fibrosis	Disease
28754682|t|Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis
Autoimmunity 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	0	12	Autoimmunity	Disease
28754682	70	99	Idiopathic Pulmonary Fibrosis	Disease
28754682	101	113	Autoimmunity	Disease
28754682	157	186	idiopathic pulmonary fibrosis	Disease
28754682	188	191	IPF	Disease
28754682	440	450	increased	Positive_regulation
28754682	453	456	IPF	Disease
28754682	577	580	IPF	Disease
28754682	594	603	enhanced	Positive_regulation
28754682	607	618	production	Gene_expression
28754682	716	732	supplementation	Negative_regulation
28754682	735	738	IPF	Disease
28754682	758	767	resulted	Positive_regulation
28754682	777	787	dependent	Positive_regulation
28754682	787	798	production	Gene_expression
28754682	910	913	IPF	Disease
28754682	1092	1095	IPF	Disease
28754682	1357	1360	IPF	Disease
28754682	1766	1769	IPF	Disease
23755232|t|Lung myofibroblasts are characterized by down-regulated cyclooxygenase-2 and its main metabolite, prostaglandin E2
BACKGROUND: Prostaglandin E2 (PGE2), the main metabolite of cyclooxygenase (COX), is a well-known anti-fibrotic agent
Moreover, myofibroblasts expressing a-smooth muscle actin (a-SMA), fibroblast expansion and epithelial-mesenchymal transition (EMT) are critical to the pathogenesis of idiopathic pulmonary fibrosis (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 a-SMA 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 a-SMA 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	41	56	down-regulated	Negative_regulation
23755232	56	72	cyclooxygenase-2	Gene
23755232	98	114	prostaglandin E2	Chemical
23755232	128	144	Prostaglandin E2	Chemical
23755232	146	150	PGE2	Chemical
23755232	162	173	metabolite	Negative_regulation
23755232	260	271	expressing	Gene_expression
23755232	294	299	a-SMA	Gene
23755232	403	432	idiopathic pulmonary fibrosis	Disease
23755232	434	437	IPF	Disease
23755232	485	490	COX-2	Gene
23755232	495	499	PGE2	Chemical
23755232	503	508	human	Species
23755232	621	626	COX-2	Gene
23755232	631	635	PGE2	Chemical
23755232	688	691	IPF	Disease
23755232	692	700	patients	Species
23755232	713	721	patients	Species
23755232	834	840	TGF-b1	Gene
23755232	881	886	COX-2	Gene
23755232	891	896	a-SMA	Gene
23755232	909	913	PGE2	Chemical
23755232	967	972	IL-1b	Gene
23755232	977	981	PGE2	Chemical
23755232	1040	1043	IPF	Disease
23755232	1080	1085	IL-1b	Gene
23755232	1096	1101	COX-2	Gene
23755232	1114	1117	IPF	Disease
23755232	1176	1184	reduced	Negative_regulation
23755232	1184	1189	COX-2	Gene
23755232	1190	1201	expression	Gene_expression
23755232	1216	1221	IL-1b	Gene
23755232	1223	1229	TGF-b1	Gene
23755232	1310	1316	TGF-b1	Gene
23755232	1332	1337	COX-2	Gene
23755232	1425	1428	IPF	Disease
23755232	1465	1471	TGF-b1	Gene
23755232	1499	1504	COX-2	Gene
23755232	1516	1520	PGE2	Chemical
23755232	1535	1540	a-SMA	Gene
23755232	1558	1563	IL-1b	Gene
23755232	1677	1683	TGF-b1	Gene
23755232	1700	1715	down-regulated	Negative_regulation
23755232	1715	1720	COX-2	Gene
23755232	1721	1732	expression	Gene_expression
23755232	1746	1750	PGE2	Chemical
23755232	1751	1761	secretion	Localization
23755232	1776	1781	IL-1b	Gene
23755232	1816	1819	IPF	Disease
23755232	1842	1847	COX-2	Gene
23755232	1937	1942	COX-2	Gene
23755232	1943	1959	down-regulation	Negative_regulation
23755232	1971	1975	PGE2	Chemical
23755232	2014	2017	IPF	Disease
19361498|t|CUX1/Wnt signaling regulates epithelial mesenchymal transition in EBV infected epithelial cells
Idiopathic pulmonary fibrosis (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 CUX1 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 CUX1 signaling
These data present a framework for further description of the link between infectious agents and fibrosis, a significant disease burden
19361498	0	4	CUX1	Gene
19361498	97	126	Idiopathic pulmonary fibrosis	Disease
19361498	128	131	IPF	Disease
19361498	160	185	interstitial lung disease	Disease
19361498	368	376	fibrosis	Disease
19361498	377	385	patients	Species
19361498	545	553	fibrosis	Disease
19361498	674	682	TGFbeta1	Gene
19361498	731	739	TGFbeta1	Gene
19361498	759	770	alteration	Regulation
19361498	773	777	CUX1	Gene
19361498	824	835	expression	Gene_expression
19361498	836	845	inducing	Positive_regulation
19361498	845	856	activation	Positive_regulation
19361498	1014	1022	fibrosis	Disease
19361498	1130	1154	All-Trans Retinoic Acids	Chemical
19361498	1156	1160	ATRA	Chemical
19361498	1278	1282	CUX1	Gene
19361498	1391	1399	fibrosis	Disease
25745043|t|Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	18	28	nintedanib	Chemical
25745043	49	78	idiopathic pulmonary fibrosis	Disease
25745043	80	109	Idiopathic pulmonary fibrosis	Disease
25745043	111	114	IPF	Disease
25745043	179	210	fibrosis of the lung parenchyma	Disease
25745043	215	236	loss of lung function	Disease
25745043	283	286	IPF	Disease
25745043	319	322	IPF	Disease
25745043	371	410	epithelial cell injury and dysregulated	Disease
25745043	836	839	IPF	Disease
25745043	841	851	Nintedanib	Chemical
25745043	879	889	inhibitor	Negative_regulation
25745043	905	913	tyrosine	Chemical
25745043	1042	1052	nintedanib	Chemical
25745043	1089	1097	fibrosis	Disease
25745043	1171	1181	secretion	Localization
25745043	1202	1212	nintedanib	Chemical
25745043	1299	1312	lung fibrosis	Disease
25745043	1381	1391	nintedanib	Chemical
25745043	1395	1403	patients	Species
25745043	1409	1412	IPF	Disease
22802290|t|Idiopathic pulmonary fibrosis: an altered fibroblast proliferation linked to cancer biology
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 cancer
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 cancer
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 cancer-like disease may be helpful in identifying new pathogenic mechanisms that can be borrowed from cancer 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	0	29	Idiopathic pulmonary fibrosis	Disease
22802290	77	83	cancer	Disease
22802290	133	162	idiopathic pulmonary fibrosis	Disease
22802290	164	167	IPF	Disease
22802290	218	251	injury to the alveolar epithelium	Disease
22802290	401	404	IPF	Disease
22802290	534	540	cancer	Disease
22802290	565	586	genetic abnormalities	Disease
22802290	781	784	IPF	Disease
22802290	789	795	cancer	Disease
22802290	797	800	IPF	Disease
22802290	1049	1052	IPF	Disease
22802290	1056	1077	a cancer-like disease	Disease
22802290	1160	1166	cancer	Disease
28449458|t|Lower expression of platelet derived growth factor is associated with better overall survival rate of patients with idiopathic nonspecific interstitial pneumonia
BACKGROUND: Idiopathic nonspecific interstitial pneumonia (INSIP) presents with varying degrees of interstitial inflammation and fibrosis exhibiting a uniform appearance
Lack of knowledge on the underlying mechanisms of INSIP has contributed to few effective treatment strategies
Our study is designed to explore aberrantly expressed cytokines involvement in INSIP development
METHODS: Oligo GEArray was employed to detect the expression of cytokines in INSIP patients, and idiopathic pulmonary fibrosis (IPF) was setup as isotype control
Real-time PCR and immunohistochemistry analysis were used to further confirm the expression of abnormally expressed cytokines
The correlationship between cytokines expression and overall survival rate of patients with IPF and INSIP were analyzed
RESULTS: From microarray detection, transforming growth factor-beta-1 (TGF-b1), fibroblast growth factor 10 (FGF10), and platelet derived growth factor (PDGF) were predominantly up-regulated in patients with INSIP
Real-time PCR and immunohistochemistry also showed these cytokines was abnormally expressed in INSIP
In addition to, the clinical relevance analysis demonstrated relatively lower expression of PDGF patients had longer overall survival rate than those with higher expression of PDGF
CONCLUSIONS: Our study suggests that TGF-b1, FGF10, and PDGF are required for the pathogenesis of INSIP, and may therefore be ideal targets in INSIP treatment
Moreover, INSIP patients with lower expression of PDGF had better survival rate
28449458	102	110	patients	Species
28449458	626	634	patients	Species
28449458	911	919	patients	Species
28449458	990	1023	transforming growth factor-beta-1	Gene
28449458	1025	1031	TGF-b1	Gene
28449458	1034	1061	fibroblast growth factor 10	Gene
28449458	1063	1068	FGF10	Gene
28449458	1132	1145	up-regulated	Positive_regulation
28449458	1148	1156	patients	Species
28449458	1349	1360	expression	Gene_expression
28449458	1368	1376	patients	Species
28449458	1433	1444	expression	Gene_expression
28449458	1490	1496	TGF-b1	Gene
28449458	1498	1503	FGF10	Gene
28449458	1518	1527	required	Localization
28449458	1629	1637	patients	Species
28449458	1649	1660	expression	Gene_expression
26993524|t|Elevated expression of NEU1 sialidase in idiopathic pulmonary fibrosis provokes pulmonary collagen deposition, lymphocytosis, and fibrosis
Idiopathic pulmonary fibrosis (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 (NEU1), an enzyme that removes terminal sialic acid from glycoproteins
We observed increased NEU1 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 NEU1 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, NEU1 overexpression strongly impacted global gene expression, increased T cell adhesion to endothelial monolayers, and disrupted endothelial capillary-like tube formation
NEU1 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 NEU1 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 NEU1 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 fibrosis
26993524	0	9	Elevated	Positive_regulation
26993524	9	20	expression	Gene_expression
26993524	23	27	NEU1	Gene
26993524	41	70	idiopathic pulmonary fibrosis	Disease
26993524	71	80	provokes	Positive_regulation
26993524	111	124	lymphocytosis	Disease
26993524	130	138	fibrosis	Disease
26993524	140	169	Idiopathic pulmonary fibrosis	Disease
26993524	171	174	IPF	Disease
26993524	355	370	neuraminidase 1	Gene
26993524	372	376	NEU1	Gene
26993524	411	422	sialic acid	Chemical
26993524	455	465	increased	Positive_regulation
26993524	465	469	NEU1	Gene
26993524	470	481	expression	Gene_expression
26993524	558	566	patients	Species
26993524	572	575	IPF	Disease
26993524	625	635	adenovirus	Species
26993524	662	666	NEU1	Gene
26993524	687	692	human	Species
26993524	876	880	NEU1	Gene
26993524	881	896	overexpression	Positive_regulation
26993524	1048	1052	NEU1	Gene
26993524	1053	1068	overexpression	Positive_regulation
26993524	1092	1102	increased	Positive_regulation
26993524	1102	1109	levels	Gene_expression
26993524	1189	1201	accelerated	Positive_regulation
26993524	1201	1213	degradation	Protein_catabolism
26993524	1216	1243	matrix metalloproteinase-14	Gene
26993524	1275	1279	NEU1	Gene
26993524	1306	1316	adenovirus	Species
26993524	1521	1524	CD8	Gene
26993524	1544	1547	CD4	Gene
26993524	1610	1619	elevated	Positive_regulation
26993524	1619	1623	NEU1	Gene
26993524	1624	1635	expression	Gene_expression
26993524	1757	1770	accumulation	Positive_regulation
26993524	1825	1833	fibrosis	Disease
8630262|t|TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study
Although it is recognized that three isoforms of transforming growth factor-beta (TGF-beta) exist in mammals, their expression, distribution, and function in injury and repair are not well characterized
Using immunohistochemistry and antibodies to synthetic peptides of TGF-beta 1, TGF-beta 2, and TGF-beta 3, we determined the distribution of TGF-beta isoforms in lung sections with acute and chronic lesions of idiopathic pulmonary fibrosis (IPF), chronic asbestosis and hypersensitivity pneumonitis, as well as non-specific pneumonitis
In lung sections with advanced pulmonary fibrosis and honeycombing, irrespective of the diagnosis, TGF-beta 1 was prominently expressed in epithelial cells and macrophages and was found to be associated with the extracellular matrix
In lungs with early lesions of IPF and only inflammatory changes, TGF-beta 1 was present in alveolar macrophages but TGF-beta 1 was not present in epithelial cells
Small amounts of matrix-associated TGF-beta 1 were present subepithelially in areas of lung sections from patients with IPF with minimal inflammation and no fibrosis
In normal lungs with no evidence of inflammation or fibrosis TGF-beta 1 was not seen in alveolar macrophages, epithelial cells, or extracellularly
TGF-beta 2 and TGF-beta 3 were expressed in alveolar macrophages, epithelial cells, and smooth muscle cells of vessels and bronchi of normal lungs and lungs with both inflammatory and fibrotic changes
Our findings suggest that while TGF-beta 2 and TGF-beta 3 are ubiquitously expressed in the lung, TGF-beta 1 is expressed in epithelial cells of fibrotic lungs where the presence of TGF-beta 1 is not disease-specific but an indication of the chronicity of the injury
8630262	0	10	TGF-beta 1	Gene
8630262	20	30	TGF-beta 2	Gene
8630262	34	44	TGF-beta 3	Gene
8630262	104	122	pulmonary fibrosis	Disease
8630262	425	435	TGF-beta 1	Gene
8630262	437	447	TGF-beta 2	Gene
8630262	453	463	TGF-beta 3	Gene
8630262	568	597	idiopathic pulmonary fibrosis	Disease
8630262	599	602	IPF	Disease
8630262	613	623	asbestosis	Disease
8630262	628	656	hypersensitivity pneumonitis	Disease
8630262	682	693	pneumonitis	Disease
8630262	726	744	pulmonary fibrosis	Disease
8630262	794	804	TGF-beta 1	Gene
8630262	960	963	IPF	Disease
8630262	995	1005	TGF-beta 1	Gene
8630262	1010	1018	present	Gene_expression
8630262	1046	1056	TGF-beta 1	Gene
8630262	1065	1073	present	Gene_expression
8630262	1129	1139	TGF-beta 1	Gene
8630262	1200	1208	patients	Species
8630262	1214	1217	IPF	Disease
8630262	1231	1243	inflammation	Disease
8630262	1251	1259	fibrosis	Disease
8630262	1297	1309	inflammation	Disease
8630262	1313	1321	fibrosis	Disease
8630262	1322	1332	TGF-beta 1	Gene
8630262	1409	1419	TGF-beta 2	Gene
8630262	1424	1434	TGF-beta 3	Gene
8630262	1440	1450	expressed	Gene_expression
8630262	1643	1653	TGF-beta 2	Gene
8630262	1658	1668	TGF-beta 3	Gene
8630262	1686	1696	expressed	Gene_expression
8630262	1709	1719	TGF-beta 1	Gene
8630262	1723	1733	expressed	Gene_expression
8630262	1793	1803	TGF-beta 1	Gene
25162417|t|A critical role for the mTORC2 pathway in lung fibrosis
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 mTORC2, a component of the mTOR pathway, mediates the activation of Akt
In this study we set out to determine if blocking mTORC2 with MLN0128, an active site dual mTOR inhibitor, which blocks both mTORC1 and mTORC2, inhibits lung fibrosis
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 mTORC2 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 mTORC2 in the pathogenesis of lung fibrosis and for the potential of active site mTOR inhibitors in the treatment of IPF and other fibrotic lung diseases
25162417	24	30	mTORC2	Gene
25162417	42	55	lung fibrosis	Disease
25162417	107	110	IPF	Disease
25162417	209	214	TGF-b	Gene
25162417	266	274	secrete	Localization
25162417	407	410	Akt	Gene
25162417	414	424	activated	Positive_regulation
25162417	427	430	IPF	Disease
25162417	477	482	TGF-b	Gene
25162417	534	540	mTORC2	Gene
25162417	561	565	mTOR	Gene
25162417	575	584	mediates	Positive_regulation
25162417	588	599	activation	Positive_regulation
25162417	602	605	Akt	Gene
25162417	657	663	mTORC2	Gene
25162417	669	676	MLN0128	Chemical
25162417	698	702	mTOR	Gene
25162417	703	713	inhibitor	Negative_regulation
25162417	720	727	blocks	Negative_regulation
25162417	732	738	mTORC1	Gene
25162417	743	749	mTORC2	Gene
25162417	751	773	inhibits lung fibrosis	Disease
25162417	801	808	MLN0128	Chemical
25162417	812	817	TGF-b	Gene
25162417	860	863	IPF	Disease
25162417	915	920	TGF-b	Gene
25162417	1011	1018	MLN0128	Chemical
25162417	1026	1032	murine	Species
25162417	1033	1042	bleomycin	Chemical
25162417	1069	1074	TGF-b	Gene
25162417	1087	1093	Rictor	Gene
25162417	1107	1113	mTORC2	Gene
25162417	1117	1120	IPF	Disease
25162417	1152	1155	Akt	Gene
25162417	1156	1167	activation	Positive_regulation
25162417	1177	1184	MLN0128	Chemical
25162417	1270	1276	Rictor	Gene
25162417	1290	1293	Akt	Gene
25162417	1304	1311	MLN0128	Chemical
25162417	1465	1470	TGF-b	Gene
25162417	1482	1485	IPF	Disease
25162417	1513	1521	fibrosis	Disease
25162417	1527	1533	murine	Species
25162417	1534	1543	bleomycin	Chemical
25162417	1618	1623	TGF-b	Gene
25162417	1635	1638	IPF	Disease
25162417	1684	1690	mTORC2	Gene
25162417	1714	1727	lung fibrosis	Disease
25162417	1765	1769	mTOR	Gene
25162417	1770	1781	inhibitors	Negative_regulation
25162417	1801	1804	IPF	Disease
25162417	1815	1837	fibrotic lung diseases	Disease
28292882|t|Cthrc1 lowers pulmonary collagen associated with bleomycin-induced fibrosis and protects lung function
Idiopathic pulmonary fibrosis (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 (Cthrc1) protein inhibits Smad2/3 activation
To test the hypothesis that Cthrc1 limits collagen deposition and the decline of lung function, Cthrc1 knockout (Cthrc1(-/-)) 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 Cthrc1(-/-) compared to WT (53.45      6.15  ng/mL vs
34.48      11.05) after saline injection
Bleomycin injection increased TGF-b in both Cthrc1(-/-) (66.37      8.54  ng/mL) and WT (63.64      8.09  ng/mL)
Hydroxyproline was significantly higher in Cthrc1(-/-) compared to WT after bleomycin-injection (2.676      0.527   g/mg vs
1.889      0.520, P  =  0.028)
Immunohistochemistry of Cthrc1(-/-) 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 Cthrc1(-/-) but there was no effect in WT animals
These data suggest Cthrc1 reduces fibrotic tissue formation in bleomycin-induced lung fibrosis and the effect is potent enough to limit the decline in lung function
We conclude that Cthrc1 plays a protective role, limiting collagen deposition and could form the basis of a novel therapy for pulmonary fibrosis
28292882	0	6	Cthrc1	Gene
28292882	49	58	bleomycin	Chemical
28292882	67	75	fibrosis	Disease
28292882	104	133	Idiopathic pulmonary fibrosis	Disease
28292882	135	138	IPF	Disease
28292882	199	223	decline in lung function	Disease
28292882	247	258	activation	Positive_regulation
28292882	261	268	Smad2/3	Gene
28292882	335	376	Collagen Triple Helix Repeat-Containing-1	Gene
28292882	378	384	Cthrc1	Gene
28292882	394	403	inhibits	Negative_regulation
28292882	403	410	Smad2/3	Gene
28292882	411	422	activation	Positive_regulation
28292882	451	457	Cthrc1	Gene
28292882	519	525	Cthrc1	Gene
28292882	536	542	Cthrc1	Gene
28292882	563	567	mice	Species
28292882	569	571	WT	Disease
28292882	620	629	bleomycin	Chemical
28292882	710	715	TGF-b	Gene
28292882	717	722	IL1-b	Gene
28292882	724	738	hydroxyproline	Chemical
28292882	774	779	TGF-b	Gene
28292882	808	814	Cthrc1	Gene
28292882	832	834	WT	Disease
28292882	905	914	Bleomycin	Chemical
28292882	925	935	increased	Positive_regulation
28292882	935	940	TGF-b	Gene
28292882	949	955	Cthrc1	Gene
28292882	990	992	WT	Disease
28292882	1019	1033	Hydroxyproline	Chemical
28292882	1062	1068	Cthrc1	Gene
28292882	1086	1088	WT	Disease
28292882	1095	1104	bleomycin	Chemical
28292882	1200	1206	Cthrc1	Gene
28292882	1247	1260	localization	Localization
28292882	1264	1275	activation	Positive_regulation
28292882	1347	1349	WT	Disease
28292882	1395	1404	bleomycin	Chemical
28292882	1408	1414	Cthrc1	Gene
28292882	1447	1449	WT	Disease
28292882	1478	1484	Cthrc1	Gene
28292882	1522	1531	bleomycin	Chemical
28292882	1540	1553	lung fibrosis	Disease
28292882	1599	1623	decline in lung function	Disease
28292882	1642	1648	Cthrc1	Gene
28292882	1692	1703	deposition	Negative_regulation
28292882	1751	1769	pulmonary fibrosis	Disease
15117744|t|Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis
Pigment epithelium-derived factor (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 idiopathic pulmonary fibrosis (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	0	33	Pigment epithelium-derived factor	Gene
15117744	37	66	idiopathic pulmonary fibrosis	Disease
15117744	101	134	Pigment epithelium-derived factor	Gene
15117744	136	140	PEDF	Gene
15117744	258	262	PEDF	Gene
15117744	263	274	expression	Gene_expression
15117744	278	288	increased	Positive_regulation
15117744	304	312	patients	Species
15117744	318	347	idiopathic pulmonary fibrosis	Disease
15117744	349	352	IPF	Disease
15117744	440	462	fibrotic lung diseases	Disease
15117744	546	549	IPF	Chemical
15117744	586	590	PEDF	Gene
15117744	595	629	vascular endothelial growth factor	Gene
15117744	696	699	IPF	Disease
15117744	758	762	PEDF	Gene
15117744	767	777	increased	Positive_regulation
15117744	786	820	vascular endothelial growth factor	Gene
15117744	825	835	decreased	Negative_regulation
15117744	836	840	PEDF	Gene
15117744	1099	1109	TGF-beta 1	Gene
15117744	1116	1125	regulate	Regulation
15117744	1125	1129	PEDF	Gene
15117744	1130	1141	expression	Gene_expression
15117744	1171	1176	human	Species
15117744	1210	1214	PEDF	Gene
15117744	1228	1238	TGF-beta 1	Gene
15117744	1289	1293	PEDF	Gene
15117744	1364	1367	IPF	Disease
8520791|t|Cytoskeletal protein modulation in pulmonary alveolar myofibroblasts during idiopathic pulmonary fibrosis
Possible role of transforming growth factor beta and tumor necrosis factor alpha
Pulmonary biopsy specimens from ten cases of idiopathic pulmonary fibrosis (IPF) were examined using routine histological stains, including toluidine blue, and immunohistochemistry by means of specific antibodies against alpha-smooth muscle (alpha-SM) actin, desmin, keratin, TGF beta 1, and TNF alpha
The sections were compared with two cases of normal lung
As shown previously, normal alveolar interstitium did not contain alpha-SM actin positive myofibroblasts nor did the alveolar lining contain any significant number of TGF beta 1 or TNF alpha laden epithelial cells
In IPF, during the inflammatory stage, the alveolar myofibroblasts expressed alpha-SM actin and the regenerating type II alveolar epithelium staining strongly with TGF beta 1 and TNF alpha antibodies
The former cytokine was also detected in the interstitial matrix and fibroblastic cells as well as in the wall of vessels
At this stage, a manifest mast cell infiltration was noted
In very fibrotic and cystic alveolar tissue, i.e., at end stage fibrosis, the number of alpha-SM actin positive myofibroblasts as well as that of TNF alpha laden type II epithelial cells diminished, while TGF beta 1 positive cells persisted
Our findings demonstrate that during IPF alveolar type II epithelium constitutes, if not the site of synthesis, at least the main reservoir for TGF beta 1 and TNF alpha
These cytokines, besides their involvement in fibrogenesis, play probably an important role in the expression of alpha-SM actin by alveolar myofibroblasts
Our study suggests the possibility of an interaction between interstitial cells and alveolar epithelium, during IPF
8520791	35	68	pulmonary alveolar myofibroblasts	Disease
8520791	76	105	idiopathic pulmonary fibrosis	Disease
8520791	160	165	tumor	Disease
8520791	234	263	idiopathic pulmonary fibrosis	Disease
8520791	265	268	IPF	Disease
8520791	329	338	toluidine	Chemical
8520791	448	454	desmin	Gene
8520791	465	475	TGF beta 1	Gene
8520791	481	490	TNF alpha	Gene
8520791	717	727	TGF beta 1	Gene
8520791	731	740	TNF alpha	Gene
8520791	768	771	IPF	Disease
8520791	832	842	expressed	Gene_expression
8520791	929	939	TGF beta 1	Gene
8520791	944	953	TNF alpha	Gene
8520791	1213	1221	fibrosis	Disease
8520791	1295	1304	TNF alpha	Gene
8520791	1354	1364	TGF beta 1	Gene
8520791	1428	1459	IPF alveolar type II epithelium	Disease
8520791	1535	1545	TGF beta 1	Gene
8520791	1550	1559	TNF alpha	Gene
8520791	1660	1671	expression	Gene_expression
8520791	1829	1832	IPF	Disease
20671305|t|Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention
BACKGROUND: Idiopathic pulmonary fibrosis (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-HTR(2A) and 5-HTR(2B) 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-HTR(2A/B) signalling on lung fibrosis in vivo and in vitro
METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of 5-HTR(1A/B) and 5-HTR(2B) 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-HTR(2A) was increased specifically in IPF lungs but not in NSIP lungs
While 5-HTR(2A) protein largely localised to fibroblasts, 5-HTR(2B) localised to the epithelium
To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR(2A/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 b(1)- or WNT3a-induced collagen production
CONCLUSION: The studies revealed an increased expression of 5-HTR(2A) specifically in IPF
Blockade of 5-HTR(2A/B) signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF
20671305	61	90	idiopathic pulmonary fibrosis	Disease
20671305	146	175	Idiopathic pulmonary fibrosis	Disease
20671305	177	180	IPF	Disease
20671305	379	388	Serotonin	Chemical
20671305	390	409	5-hydroxytryptamine	Chemical
20671305	411	415	5-HT	Chemical
20671305	528	531	IPF	Disease
20671305	575	585	determine	Negative_regulation
20671305	589	600	expression	Gene_expression
20671305	603	607	5-HT	Chemical
20671305	621	624	IPF	Disease
20671305	629	655	experimental lung fibrosis	Disease
20671305	742	755	lung fibrosis	Disease
20671305	849	873	5-HTR(1A/B) and 5-HTR(2B	Gene
20671305	919	927	patients	Species
20671305	933	936	IPF	Disease
20671305	962	997	non-specific interstitial pneumonia	Disease
20671305	999	1003	NSIP	Disease
20671305	1082	1092	increased	Positive_regulation
20671305	1108	1111	IPF	Disease
20671305	1129	1133	NSIP	Disease
20671305	1310	1314	mice	Species
20671305	1333	1342	bleomycin	Chemical
20671305	1351	1364	lung fibrosis	Disease
20671305	1409	1418	terguride	Chemical
20671305	1476	1485	bleomycin	Chemical
20671305	1488	1497	Terguride	Chemical
20671305	1506	1510	mice	Species
20671305	1570	1580	decreased	Negative_regulation
20671305	1627	1631	mice	Species
20671305	1673	1682	terguride	Chemical
20671305	1695	1705	inhibitor	Negative_regulation
20671305	1744	1749	WNT3a	Gene
20671305	1767	1778	production	Gene_expression
20671305	1865	1868	IPF	Disease
20671305	1908	1917	terguride	Chemical
20671305	1927	1940	lung fibrosis	Disease
20671305	1990	1993	IPF	Disease
28667660|t|Signaling pathways and their miRNA regulators involved in the etiopathology of idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP)
Idiopathic pulmonary fibrosis (IPF) 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 IPF and HP
Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of ILD
28667660	79	108	idiopathic pulmonary fibrosis	Disease
28667660	110	113	IPF	Disease
28667660	119	147	hypersensitivity pneumonitis	Disease
28667660	149	151	HP	Disease
28667660	154	183	Idiopathic pulmonary fibrosis	Disease
28667660	185	188	IPF	Disease
28667660	194	222	hypersensitivity pneumonitis	Disease
28667660	224	226	HP	Disease
28667660	259	285	interstitial lung diseases	Disease
28667660	287	290	ILD	Disease
28667660	523	535	inflammation	Disease
28667660	537	545	fibrosis	Disease
28667660	595	598	ILD	Disease
28667660	600	605	TNF-a	Gene
28667660	612	617	TGF-b	Gene
28667660	816	819	IPF	Disease
28667660	824	826	HP	Disease
28667660	940	943	ILD	Disease
21498628|t|Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis
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 idiopathic pulmonary fibrosis (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	58	66	patients	Species
21498628	72	101	idiopathic pulmonary fibrosis	Disease
21498628	129	157	transforming growth factor-b	Gene
21498628	159	164	TGF-b	Gene
21498628	192	208	alveolar type II	Disease
21498628	241	245	mice	Species
21498628	271	277	humans	Species
21498628	493	501	patients	Species
21498628	507	536	idiopathic pulmonary fibrosis	Disease
21498628	538	541	IPF	Disease
21498628	555	571	alveolar type II	Disease
21498628	612	617	human	Species
21498628	694	702	patients	Species
21498628	708	711	IPF	Disease
21498628	712	720	express	Transcription
21498628	727	734	levels	Positive_regulation
21498628	811	816	a-SMA	Gene
21498628	823	831	calponin	Chemical
21498628	869	874	human	Species
21498628	875	891	alveolar type II	Disease
21498628	898	907	maintain	Negative_regulation
21498628	966	977	expression	Gene_expression
21498628	980	1000	surfactant protein C	Gene
21498628	1011	1021	E-cadherin	Gene
21498628	1053	1064	fibronectin	Gene
21498628	1070	1075	human	Species
21498628	1140	1149	increase	Positive_regulation
21498628	1149	1160	expression	Gene_expression
21498628	1163	1171	vimentin	Gene
21498628	1173	1183	N-cadherin	Gene
21498628	1189	1194	a-SMA	Gene
21498628	1240	1245	TGF-b	Gene
21498628	1262	1272	inhibitor	Negative_regulation
21498628	1273	1281	SB431542	Chemical
21498628	1304	1315	fibronectin	Gene
21498628	1316	1326	inhibited	Negative_regulation
21498628	1326	1334	vimentin	Gene
21498628	1335	1346	expression	Gene_expression
21498628	1456	1472	alveolar type II	Disease
21498628	1524	1527	IPF	Disease
21498628	1543	1548	TGF-b	Gene
22771387|t|TGF-b1 induces tissue factor expression in human lung fibroblasts in a PI3K/JNK/Akt-dependent and AP-1-dependent manner
The disturbance of hemostatic balance, associated with increased tissue factor (TF) expression and activity, occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF)
However, the molecular mechanisms responsible for the regulation of TF expression under profibrotic conditions have not been assessed
We found that transforming growth factor-b1 (TGF-b1) markedly enhanced TF 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
TGF-b1-induced TF expression correlated with its elevated cell-surface activity, it required de novo gene transcription and protein synthesis, and it was dependent on JNK and Akt activity, because pharmacological inhibition or the knockdown of the previously mentioned kinases prevented TF synthesis
Exposure of HLFs to TGF-b1 activated JNK in a PI3K-dependent manner and induced Akt phosphorylation at threonine 308 and serine 473, but did not change the phosphorylation status of threonine 450
Akt phosphorylation at serine 473 correlated with JNK activity, and co-immunoprecipitation studies revealed a direct interaction between JNK and Akt
Furthermore, TGF-b1-induced TF expression required the recruitment of c-Fos and JunD into a heterodimeric activator protein (AP)-1 complex
Moreover, strong immunoreactivity for phosphorylated Akt and JNK as well as c-Fos and JunD was observed in fibroblasts and myofibroblasts in IPF lungs
In conclusion, PI3K/JNK/Akt and AP-1 synergize to induce TF expression in HLFs after TGF-b1 challenge
Our findings provide new insights into the molecular mechanisms responsible for the regulation of TF 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	0	6	TGF-b1	Gene
22771387	15	28	tissue factor	Gene
22771387	43	48	human	Species
22771387	71	75	PI3K	Gene
22771387	76	79	JNK	Gene
22771387	80	83	Akt	Gene
22771387	98	102	AP-1	Gene
22771387	186	199	tissue factor	Gene
22771387	201	203	TF	Gene
22771387	253	261	patients	Species
22771387	267	296	idiopathic pulmonary fibrosis	Disease
22771387	298	301	IPF	Disease
22771387	358	369	regulation	Regulation
22771387	372	374	TF	Gene
22771387	375	386	expression	Gene_expression
22771387	453	482	transforming growth factor-b1	Gene
22771387	484	490	TGF-b1	Gene
22771387	501	510	enhanced	Positive_regulation
22771387	510	512	TF	Gene
22771387	513	524	expression	Gene_expression
22771387	535	540	human	Species
22771387	624	653	insulin-like growth factor)-1	Gene
22771387	689	693	PDGB	Gene
22771387	716	722	TGF-b1	Gene
22771387	716	731	TGF-b1-induced	Positive_regulation
22771387	731	733	TF	Gene
22771387	734	745	expression	Gene_expression
22771387	870	880	dependent	Positive_regulation
22771387	883	886	JNK	Gene
22771387	891	894	Akt	Gene
22771387	1003	1005	TF	Gene
22771387	1006	1016	synthesis	Gene_expression
22771387	1037	1043	TGF-b1	Gene
22771387	1044	1054	activated	Positive_regulation
22771387	1054	1057	JNK	Gene
22771387	1063	1067	PI3K	Gene
22771387	1089	1097	induced	Positive_regulation
22771387	1097	1100	Akt	Gene
22771387	1101	1117	phosphorylation	Phosphorylation
22771387	1120	1129	threonine	Chemical
22771387	1138	1144	serine	Chemical
22771387	1199	1208	threonine	Chemical
22771387	1214	1217	Akt	Gene
22771387	1218	1234	phosphorylation	Phosphorylation
22771387	1237	1243	serine	Chemical
22771387	1237	1244	serine	Entity
22771387	1264	1267	JNK	Gene
22771387	1331	1343	interaction	Binding
22771387	1351	1354	JNK	Gene
22771387	1359	1362	Akt	Gene
22771387	1377	1383	TGF-b1	Gene
22771387	1377	1392	TGF-b1-induced	Positive_regulation
22771387	1392	1394	TF	Gene
22771387	1395	1406	expression	Gene_expression
22771387	1406	1415	required	Positive_regulation
22771387	1419	1431	recruitment	Binding
22771387	1434	1439	c-Fos	Gene
22771387	1444	1448	JunD	Gene
22771387	1542	1557	phosphorylated	Phosphorylation
22771387	1557	1560	Akt	Gene
22771387	1565	1568	JNK	Gene
22771387	1577	1581	as c	Gene
22771387	1582	1585	Fos	Gene
22771387	1590	1594	JunD	Gene
22771387	1645	1648	IPF	Disease
22771387	1671	1675	PI3K	Gene
22771387	1676	1679	JNK	Gene
22771387	1680	1683	Akt	Gene
22771387	1688	1692	AP-1	Gene
22771387	1706	1713	induce	Positive_regulation
22771387	1713	1715	TF	Gene
22771387	1716	1727	expression	Gene_expression
22771387	1741	1747	TGF-b1	Gene
22771387	1843	1854	regulation	Regulation
22771387	1857	1859	TF	Gene
22771387	1860	1871	expression	Gene_expression
22771387	1918	1955	pulmonary fibrosis and other diseases	Disease
26675886|t|Inhibitory effects of amines from Citrus reticulata on bleomycin-induced pulmonary fibrosis in rats
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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	22	28	amines	Chemical
26675886	55	64	bleomycin	Chemical
26675886	73	91	pulmonary fibrosis	Disease
26675886	95	99	rats	Species
26675886	101	130	Idiopathic pulmonary fibrosis	Disease
26675886	132	135	IPF	Disease
26675886	161	173	lung disease	Disease
26675886	412	418	amines	Chemical
26675886	553	558	human	Species
26675886	616	622	amines	Chemical
26675886	624	661	4-methoxyphenethylamine hydrochloride	Chemical
26675886	663	698	designated as amine hydrochloride 1	Chemical
26675886	781	784	rat	Species
26675886	794	803	bleomycin	Chemical
26675886	812	830	pulmonary fibrosis	Disease
26675886	876	897	amine hydrochloride 1	Chemical
26675886	924	938	hydroxyproline	Chemical
26675886	993	1013	pulmonary alveolitis	Disease
26675886	1018	1026	fibrosis	Disease
26675886	1071	1090	amine hydrochloride	Chemical
26675886	1131	1134	IPF	Disease
26675886	1256	1275	amine hydrochloride	Chemical
26675886	1307	1316	bleomycin	Chemical
26675886	1327	1340	lung fibrosis	Disease
26675886	1344	1348	rats	Species
26675886	1382	1388	amines	Chemical
26675886	1483	1486	IPF	Disease
28360109|t|Focal adhesion kinase signaling determines the fate of lung epithelial cells in response to TGF-b
Alveolar epithelial cell (AEC) injury and apoptosis 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 (TGF-b1)
Rat type II alveolar epithelial cells (RLE-6TN) were treated with or without TGF-b1, 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
TGF-b1 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 TGF-b1 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 TGF-b1 stimulation
TGF-b1-induced EMP is FAK- dependent, whereas TGF-b1-induced apoptosis is favored when FAK signaling is inhibited
28360109	0	21	Focal adhesion kinase	Gene
28360109	92	97	TGF-b	Gene
28360109	130	150	injury and apoptosis	Disease
28360109	190	219	idiopathic pulmonary fibrosis	Disease
28360109	221	224	IPF	Disease
28360109	266	277	lung injury	Disease
28360109	301	304	IPF	Disease
28360109	345	366	focal adhesion kinase	Gene
28360109	368	371	FAK	Gene
28360109	447	476	transforming growth factor-b1	Gene
28360109	478	484	TGF-b1	Gene
28360109	487	490	Rat	Species
28360109	564	570	TGF-b1	Gene
28360109	686	697	inhibitors	Negative_regulation
28360109	776	779	FAK	Gene
28360109	842	853	expression	Gene_expression
28360109	878	881	FAK	Gene
28360109	934	971	terminal deoxynucleotidyl transferase	Gene
28360109	972	976	dUTP	Chemical
28360109	1013	1019	TGF-b1	Gene
28360109	1104	1111	RLE-6TN	Species
28360109	1227	1262	epithelial-myofibroblast plasticity	Disease
28360109	1264	1267	EMP	Disease
28360109	1273	1283	dependent	Positive_regulation
28360109	1286	1291	SMAD3	Gene
28360109	1296	1299	FAK	Gene
28360109	1311	1314	FAK	Gene
28360109	1315	1326	activation	Positive_regulation
28360109	1342	1352	dependent	Regulation
28360109	1355	1359	ALK5	Gene
28360109	1360	1365	SMAD3	Gene
28360109	1394	1400	TGF-b1	Gene
28360109	1414	1417	EMP	Disease
28360109	1496	1505	blockade	Negative_regulation
28360109	1523	1533	inhibited	Negative_regulation
28360109	1533	1536	EMP	Disease
28360109	1589	1600	inhibition	Negative_regulation
28360109	1603	1606	FAK	Gene
28360109	1678	1681	FAK	Gene
28360109	1682	1693	activation	Positive_regulation
28360109	1725	1728	EMP	Disease
28360109	1758	1764	TGF-b1	Gene
28360109	1778	1784	TGF-b1	Gene
28360109	1793	1796	EMP	Disease
28360109	1800	1803	FAK	Gene
28360109	1824	1830	TGF-b1	Gene
28360109	1865	1868	FAK	Gene
28360109	1882	1892	inhibited	Negative_regulation
27494713|t|Amplification of TGFb Induced ITGB6 Gene Transcription May Promote Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (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 TGFb1 can upregulate avb6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated
We confirm that stimulation with exogenous TGFb1 increases expression of the integrin b6 subunit gene (ITGB6) and avb6 integrin cell surface expression in a time- and concentration-dependent manner
TGFb1-induced ITGB6 expression occurs via transcriptional activation of the ITGB6 gene, but does not result from effects on ITGB6 mRNA stability
Basal expression of ITGB6 in, and avb6 integrins on, lung epithelial cells occurs via homeostatic avb6-mediated TGFb1 activation in the absence of exogenous stimulation, and can be amplified by TGFb1 activation
Fundamentally, we show for the first time that TGFb1-induced ITGB6 expression occurs via canonical Smad signalling since dominant negative constructs directed against Smad3 and 4 inhibit ITGB6 transcriptional activity
Furthermore, disruption of a Smad binding site at -798 in the ITGB6 promoter abolishes TGFb1-induced ITGB6 transcriptional activity
Using chromatin immunoprecipitation we demonstrate that TGFb1 stimulation of lung epithelial cells results in direct binding of Smad3, and Smad4, to the ITGB6 gene promoter within this region
Finally, using an adenoviral TGFb1 over-expression model of pulmonary fibrosis we demonstrate that Smad3 is crucial for TGFb1-induced avb6 integrin expression within the alveolar epithelium in vivo
Together, these data confirm that a homeostatic, autocrine loop of avb6 integrin activated TGFb1-induced ITGB6 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 TGFb1 amplifies this pathway both in vitro and in vivo, which may promote fibrosis
27494713	17	21	TGFb	Gene
27494713	30	35	ITGB6	Gene
27494713	41	55	Transcription	Transcription
27494713	67	85	Pulmonary Fibrosis	Disease
27494713	87	116	Idiopathic pulmonary fibrosis	Disease
27494713	118	121	IPF	Disease
27494713	141	160	progressive disease	Disease
27494713	217	230	Upregulation	Positive_regulation
27494713	316	319	IPF	Disease
27494713	345	352	patient	Species
27494713	389	394	TGFb1	Gene
27494713	399	410	upregulate	Positive_regulation
27494713	424	435	expression	Gene_expression
27494713	564	569	TGFb1	Gene
27494713	570	580	increases	Positive_regulation
27494713	580	591	expression	Gene_expression
27494713	624	629	ITGB6	Gene
27494713	662	673	expression	Gene_expression
27494713	720	725	TGFb1	Gene
27494713	726	734	induced	Positive_regulation
27494713	734	739	ITGB6	Gene
27494713	740	751	expression	Gene_expression
27494713	778	789	activation	Positive_regulation
27494713	796	801	ITGB6	Gene
27494713	833	841	effects	Regulation
27494713	844	849	ITGB6	Gene
27494713	872	883	expression	Gene_expression
27494713	886	891	ITGB6	Gene
27494713	969	978	mediated	Positive_regulation
27494713	978	983	TGFb1	Gene
27494713	984	995	activation	Positive_regulation
27494713	1060	1065	TGFb1	Gene
27494713	1066	1077	activation	Positive_regulation
27494713	1125	1130	TGFb1	Gene
27494713	1131	1139	induced	Positive_regulation
27494713	1139	1144	ITGB6	Gene
27494713	1145	1156	expression	Gene_expression
27494713	1245	1256	Smad3 and 4	Gene
27494713	1257	1265	inhibit	Negative_regulation
27494713	1265	1270	ITGB6	Gene
27494713	1310	1321	disruption	Binding
27494713	1359	1364	ITGB6	Gene
27494713	1384	1389	TGFb1	Gene
27494713	1398	1403	ITGB6	Gene
27494713	1486	1491	TGFb1	Gene
27494713	1547	1555	binding	Binding
27494713	1558	1563	Smad3	Gene
27494713	1569	1574	Smad4	Gene
27494713	1583	1588	ITGB6	Gene
27494713	1652	1657	TGFb1	Gene
27494713	1658	1674	over-expression	Gene_expression
27494713	1683	1701	pulmonary fibrosis	Disease
27494713	1722	1727	Smad3	Gene
27494713	1731	1739	crucial	Positive_regulation
27494713	1743	1748	TGFb1	Gene
27494713	1749	1757	induced	Positive_regulation
27494713	1771	1782	expression	Gene_expression
27494713	1903	1913	activated	Positive_regulation
27494713	1913	1918	TGFb1	Gene
27494713	1919	1927	induced	Positive_regulation
27494713	1927	1932	ITGB6	Gene
27494713	1938	1949	expression	Gene_expression
27494713	1949	1959	regulates	Regulation
27494713	1990	2001	expression	Gene_expression
27494713	2071	2082	regulation	Regulation
27494713	2159	2164	TGFb1	Gene
27494713	2233	2241	fibrosis	Disease
18795102|t|Fibrotic myofibroblasts manifest genome-wide derangements of translational control
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 beta 1 integrin 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 fibrotic disease, 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 beta 1 integrin signaling as a fundamental component of IPF pathobiology and indicates that TGF-beta -driven EMT is one source for IPF myofibroblasts
18795102	534	549	beta 1 integrin	Gene
18795102	887	903	fibrotic disease	Disease
18795102	905	934	Idiopathic Pulmonary Fibrosis	Disease
18795102	936	939	IPF	Disease
18795102	1102	1105	IPF	Disease
18795102	1351	1354	IPF	Disease
18795102	1574	1577	IPF	Disease
18795102	1704	1707	IPF	Disease
18795102	1839	1847	TGF-beta	Gene
18795102	1877	1880	IPF	Disease
18795102	2020	2038	fibrotic disorders	Disease
18795102	2047	2050	IPF	Disease
18795102	2131	2146	beta 1 integrin	Gene
18795102	2187	2190	IPF	Disease
18795102	2223	2231	TGF-beta	Gene
18795102	2262	2265	IPF	Disease
20395557|t|Inhibition and role of let-7d in idiopathic pulmonary fibrosis
RATIONALE: Idiopathic pulmonary fibrosis (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 let-7d promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of let-7d in response to transforming growth factor-beta
HMGA2, a let-7d target, was localized by immunohistochemistry
In mice, let-7d was inhibited by intratracheal administration of a let-7d antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry
MEASUREMENTS AND MAIN RESULTS: Eighteen microRNAs including let-7d were significantly decreased in IPF
Transforming growth factor-beta down-regulated let-7d expression, and SMAD3 binding to the let-7d promoter was demonstrated
Inhibition of let-7d caused increases in mesenchymal markers N-cadherin-2, vimentin, and alpha-smooth muscle actin (ACTA2) as well as HMGA2 in multiple epithelial cell lines
let-7d was significantly reduced in IPF lungs and the number of epithelial cells expressing let-7d correlated with pulmonary functions
HMGA2 was increased in alveolar epithelial cells of IPF lungs
let-7d 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 let-7d 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	23	29	let-7d	Gene
20395557	33	62	idiopathic pulmonary fibrosis	Disease
20395557	75	104	Idiopathic pulmonary fibrosis	Disease
20395557	106	109	IPF	Disease
20395557	157	178	fibrotic lung disease	Disease
20395557	344	347	IPF	Disease
20395557	385	388	IPF	Disease
20395557	550	555	SMAD3	Gene
20395557	556	564	binding	Binding
20395557	571	577	let-7d	Gene
20395557	578	587	promoter	Entity
20395557	718	724	let-7d	Gene
20395557	773	778	HMGA2	Gene
20395557	782	788	let-7d	Gene
20395557	801	811	localized	Localization
20395557	839	843	mice	Species
20395557	845	851	let-7d	Gene
20395557	903	909	let-7d	Gene
20395557	1124	1130	let-7d	Gene
20395557	1163	1166	IPF	Disease
20395557	1215	1221	let-7d	Gene
20395557	1238	1243	SMAD3	Gene
20395557	1244	1252	binding	Binding
20395557	1259	1265	let-7d	Gene
20395557	1307	1313	let-7d	Gene
20395557	1321	1331	increases	Positive_regulation
20395557	1368	1376	vimentin	Gene
20395557	1409	1414	ACTA2	Gene
20395557	1427	1432	HMGA2	Gene
20395557	1468	1474	let-7d	Gene
20395557	1504	1507	IPF	Disease
20395557	1560	1566	let-7d	Gene
20395557	1604	1609	HMGA2	Gene
20395557	1614	1624	increased	Positive_regulation
20395557	1656	1659	IPF	Disease
20395557	1667	1673	let-7d	Gene
20395557	1731	1741	increases	Positive_regulation
20395557	1754	1759	ACTA2	Gene
20395557	1772	1783	expression	Gene_expression
20395557	1786	1791	SFTPC	Gene
20395557	1836	1847	expressing	Gene_expression
20395557	1932	1935	IPF	Disease
20395557	1960	1966	let-7d	Gene
20395557	1970	1973	IPF	Disease
20395557	2109	2122	lung fibrosis	Disease
25197006|t|Beyond TGFb - Novel ways to target airway and parenchymal fibrosis
Within the lungs, fibrosis can affect both the parenchyma and the airways
Fibrosis is a hallmark pathological change in the parenchyma in patients with idiopathic pulmonary fibrosis (IPF), whilst in asthma or chronic obstructive pulmonary disease (COPD) fibrosis 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 fibrosis 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 fibrosis through these mediators/pathways in the future
25197006	7	11	TGFb	Gene
25197006	58	66	fibrosis	Disease
25197006	86	94	fibrosis	Disease
25197006	143	151	Fibrosis	Disease
25197006	207	215	patients	Species
25197006	221	250	idiopathic pulmonary fibrosis	Disease
25197006	252	255	IPF	Disease
25197006	268	274	asthma	Disease
25197006	278	315	chronic obstructive pulmonary disease	Disease
25197006	317	321	COPD	Disease
25197006	323	331	fibrosis	Disease
25197006	520	528	fibrosis	Disease
25197006	782	790	fibrosis	Disease
26192087|t|Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase
Excessive production of connective tissue growth factor (CTGF, CCN2) and increased motor ability of the activated fibroblast phenotype contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF)
However, molecules and signal pathways regulating CCN2 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 CCN2 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
CCN2 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 phosphoinositide 3-kinase (PI3K) inhibitor, LY294002 were used to determine rapamycin's mechanism of action
We demonstrated that rapamycin amplified basal or TGF-b1-induced CCN2 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 CCN2 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	0	9	Rapamycin	Chemical
26192087	10	20	increases	Positive_regulation
26192087	20	24	CCN2	Gene
26192087	25	36	expression	Gene_expression
26192087	60	85	phosphoinositide 3-kinase	Gene
26192087	97	108	production	Gene_expression
26192087	111	142	connective tissue growth factor	Gene
26192087	144	148	CTGF	Gene
26192087	150	154	CCN2	Gene
26192087	256	285	idiopathic pulmonary fibrosis	Disease
26192087	287	290	IPF	Disease
26192087	332	343	regulating	Regulation
26192087	343	347	CCN2	Gene
26192087	348	359	expression	Gene_expression
26192087	432	441	rapamycin	Chemical
26192087	468	477	mammalian	Species
26192087	488	497	rapamycin	Chemical
26192087	499	503	mTOR	Gene
26192087	530	534	CCN2	Gene
26192087	535	546	expression	Gene_expression
26192087	618	623	human	Species
26192087	682	690	patients	Species
26192087	696	728	primary spontaneous pneumothorax	Disease
26192087	744	747	IPF	Disease
26192087	812	821	rapamycin	Chemical
26192087	823	828	human	Species
26192087	887	891	CCN2	Gene
26192087	896	942	tissue inhibitor of metalloproteinase (TIMP)-1	Gene
26192087	943	954	expression	Gene_expression
26192087	1105	1115	inhibitor	Negative_regulation
26192087	1116	1124	SB431542	Chemical
26192087	1129	1154	phosphoinositide 3-kinase	Gene
26192087	1156	1160	PI3K	Gene
26192087	1173	1181	LY294002	Chemical
26192087	1205	1214	rapamycin	Chemical
26192087	1259	1268	rapamycin	Chemical
26192087	1288	1294	TGF-b1	Gene
26192087	1303	1307	CCN2	Gene
26192087	1325	1336	expression	Gene_expression
26192087	1394	1398	PI3K	Gene
26192087	1432	1441	rapamycin	Chemical
26192087	1447	1456	enhanced	Positive_regulation
26192087	1456	1462	TIMP-1	Gene
26192087	1463	1474	expression	Gene_expression
26192087	1547	1556	rapamycin	Chemical
26192087	1659	1669	induction	Positive_regulation
26192087	1681	1690	rapamycin	Chemical
26192087	1694	1705	activating	Positive_regulation
26192087	1713	1722	inducing	Positive_regulation
26192087	1722	1726	CCN2	Gene
26192087	1727	1738	expression	Gene_expression
26192087	1859	1868	rapamycin	Chemical
26192087	1877	1885	fibrosis	Disease
15855634|t|Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis
The hallmark of idiopathic pulmonary fibrosis (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	79	111	transforming growth factor-beta1	Gene
15855634	131	160	idiopathic pulmonary fibrosis	Disease
15855634	178	207	idiopathic pulmonary fibrosis	Disease
15855634	209	212	IPF	Disease
15855634	463	501	transforming growth factor (TGF)-beta1	Gene
15855634	531	534	rat	Species
15855634	565	568	rat	Species
15855634	647	655	patients	Species
15855634	661	664	IPF	Disease
15855634	690	704	co-expressing	Gene_expression
15855634	716	752	thyroid transcription factor (TTF)-1	Gene
15855634	859	866	RLE-6TN	Species
15855634	884	893	TGF-beta1	Gene
15855634	1024	1051	tumor necrosis factor-alpha	Gene
15855634	1053	1062	TNF-alpha	Gene
15855634	1077	1080	rat	Species
15855634	1089	1098	TGF-beta1	Gene
15855634	1112	1121	resulted	Positive_regulation
15855634	1124	1134	increased	Positive_regulation
15855634	1134	1145	expression	Gene_expression
15855634	1176	1184	vimentin	Gene
15855634	1261	1271	decreased	Negative_regulation
15855634	1271	1282	expression	Gene_expression
15855634	1285	1290	TTF-1	Gene
15855634	1292	1303	aquaporin-5	Gene
15855634	1305	1309	AQP5	Gene
15855634	1312	1330	zonula occludens-1	Gene
15855634	1332	1336	ZO-1	Gene
15855634	1444	1447	IPF	Disease
15855634	1448	1456	patients	Species
15855634	1530	1539	TGF-beta1	Gene
15855634	1636	1639	IPF	Disease
22284809|t|The profibrotic cytokine transforming growth factor-b1 increases endothelial progenitor cell angiogenic properties
BACKGROUND: Transforming growth factor-b1 (TGF-b1) 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 fibrotic diseases, 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 TGF-b1 modulation of EPC angiogenic properties
METHODS: TGF-b1 plasma levels were determined in 64 patients with IPF and compared with those in controls
The effect of TGF-b1 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 TGF-b1 in ECFCs by using short interfering RNA
RESULTS: Total TGF-b1 plasma levels were significantly increased in patients with IPF as compared with controls (P < 0.0001)
TGF-b1 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 TGF-b1 receptors
CONCLUSIONS: TGF-b1 is proangiogenic in vivo and induces ECFC angiogenic properties in vitro, suggesting that TGF-b1 may play a role during vascular remodeling in fibrotic disease states via EPCs
22284809	25	54	transforming growth factor-b1	Gene
22284809	128	157	Transforming growth factor-b1	Gene
22284809	159	165	TGF-b1	Gene
22284809	341	358	fibrotic diseases	Disease
22284809	368	397	idiopathic pulmonary fibrosis	Disease
22284809	399	402	IPF	Disease
22284809	552	558	TGF-b1	Gene
22284809	609	615	TGF-b1	Gene
22284809	652	660	patients	Species
22284809	666	669	IPF	Disease
22284809	721	727	TGF-b1	Gene
22284809	888	899	expression	Gene_expression
22284809	930	936	TGF-b1	Gene
22284809	993	999	TGF-b1	Gene
22284809	1046	1054	patients	Species
22284809	1060	1063	IPF	Disease
22284809	1104	1110	TGF-b1	Gene
22284809	1148	1159	increasing	Positive_regulation
22284809	1244	1248	mice	Species
22284809	1336	1346	silencing	Negative_regulation
22284809	1361	1367	TGF-b1	Gene
22284809	1392	1398	TGF-b1	Gene
22284809	1489	1495	TGF-b1	Gene
22284809	1542	1558	fibrotic disease	Disease
28771711|t|Tannic acid attenuates TGF-b1-induced epithelial-to-mesenchymal transition by effectively intervening TGF-b signaling in lung epithelial cells
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and an irreversible lung disorder characterized by the accumulation of fibroblasts and myofibroblasts in the extracellular matrix
The transforming growth factor-b1 (TGF-b1)-induced epithelial-to-mesenchymal transition (EMT) is thought to be one of the possible sources for a substantial increase in the number of fibroblasts/myofibroblasts in IPF lungs
Tannic acid (TA), a natural dietary polyphenolic compound has been shown to possess diverse pharmacological effects
However, whether TA can inhibit TGF-b1-mediated EMT in lung epithelial cells remains enigmatic
Both the human adenocarcinomic alveolar epithelial (A549) and normal bronchial epithelial (BEAS-2B) cells were treated with TGF-b1 with or without TA
Results showed that TA addition, markedly inhibited TGF-b1-induced EMT as assessed by reduced expression of N-cadherin, type-1-collagen, fibronectin, and vimentin
Furthermore, TA inhibited TGF-b1-induced cell proliferation through inducing cell cycle arrest at G0/G1 phase
TGF-b1-induced increase in the phosphorylation of Smad (Smad2 and 3), Akt as well as that of mitogen activated protein kinase (ERK1/2, JNK1/2, and p38) mediators was effectively inhibited by TA
On the other hand, TA reduced the TGF-b1-induced increase in TGF-b receptors expression
Using molecular docking approach, FTIR, HPLC and Western blot analyses, we further identified the direct binding of TA to TGF-b1
Finally, we conclude that TA might directly interact with TGF-b1, thereby repressing TGF-b signaling and subsequent EMT process in lung epithelial cells
Further animal studies are needed to clarify its potential therapeutic benefit in pulmonary fibrosis
28771711	0	11	Tannic acid	Chemical
28771711	495	504	increase	Positive_regulation
28771711	562	573	Tannic acid	Chemical
28771711	598	610	polyphenolic	Chemical
28771711	1012	1020	reduced	Negative_regulation
28771711	1020	1031	expression	Gene_expression
28771711	1216	1225	increase	Positive_regulation
28771711	1232	1248	phosphorylation	Phosphorylation
28771711	1379	1389	inhibited	Negative_regulation
28771711	1418	1426	reduced	Negative_regulation
28771711	1445	1454	increase	Positive_regulation
28771711	1473	1484	expression	Gene_expression
28771711	1590	1598	binding	Binding
28771711	1659	1668	interact	Binding
28771711	1689	1700	repressing	Negative_regulation
22173045|t|Predisposition for disrepair in the aged lung
INTRODUCTION: Idiopathic pulmonary fibrosis (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	61	90	Idiopathic pulmonary fibrosis	Disease
22173045	92	95	IPF	Disease
22173045	126	138	lung disease	Disease
22173045	246	249	IPF	Disease
22173045	378	381	IPF	Disease
22173045	502	510	fibrosis	Disease
22173045	639	645	injury	Disease
22173045	670	674	mice	Species
22173045	693	702	bleomycin	Chemical
22173045	779	784	mouse	Species
22173045	809	842	transforming growth factor-beta 1	Gene
22173045	844	850	TGF-b1	Gene
22173045	987	997	inhibitor	Negative_regulation
22173045	1121	1125	mice	Species
22173045	1139	1147	fibrosis	Disease
22173045	1154	1163	bleomycin	Chemical
22173045	1172	1178	injury	Disease
22173045	1214	1218	mice	Species
22173045	1295	1305	increased	Positive_regulation
22173045	1310	1321	expression	Transcription
22173045	1410	1415	MMP-2	Gene
22173045	1420	1425	MMP-9	Gene
22173045	1442	1452	expressed	Transcription
22173045	1459	1466	levels	Positive_regulation
22173045	1490	1496	TGF-b1	Gene
22173045	1541	1551	increased	Positive_regulation
22173045	1551	1556	Smad3	Gene
22173045	1557	1568	expression	Gene_expression
22173045	1660	1668	reduced	Negative_regulation
22173045	1668	1679	expression	Gene_expression
22173045	1703	1708	Thy-1	Gene
22173045	1739	1752	lung fibrosis	Disease
22173045	1789	1794	Thy-1	Gene
22173045	1898	1907	enhanced	Positive_regulation
22173045	1965	1975	increased	Positive_regulation
22173045	1975	1981	TGF-b1	Gene
22173045	1982	1993	expression	Gene_expression
22173045	2028	2033	Thy-1	Gene
22173045	2094	2107	lung fibrosis	Disease
8918367|t|Differential expression of alpha E beta 7 integrins on bronchoalveolar lavage T lymphocyte subsets: regulation by alpha 4 beta 1-integrin crosslinking and TGF-beta
T lymphocytes expressing the alpha E beta 7 integrin are localized and selectively retained in mucosal tissues
To investigate a potential relationship between alpha E beta 7 expression and pulmonary inflammation, the distribution of alpha E beta 7-bearing CD4+ and CD8+ T cells in peripheral blood and bronchoalveolar lavage (BAL) fluids obtained from patients with allergic asthma, sarcoidosis, hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis (IPF) was determined
In contrast to the distribution in peripheral blood, BAL fluid from these patients contained high number of cells expressing alpha E beta 7 with markedly different expression patterns on CD4 or CD8 cells as well as among the various diseases
Despite similar numbers of activated CD4 cells, alpha E beta 7+CD4+ T cells ranged from 15% in asthmatics to 70% in IPF
In contrast, even in normal individuals, 60% to 90% of BAL fluid CD8+ T cells express alpha E beta 7, suggesting differential induction mechanisms on CD4 and CD8 cells
In vitro experiments revealed that a substantial proportion of peripheral blood CD+ T cells express alpha E beta 7 after stimulation with anti-CD3 antibodies, and up to 80% positive cells were found after the addition of TGF-beta
In contrast, less than 10% of CD4 cells express this particular integrin after in vitro stimulation, and the presence of TGF-beta only increased the number to 30%
Supernatants from in vitro-activated BAL cells as well as concentrated BAL fluid from patients with high alpha E beta 7 expression had no further enhancing effect
However, crosslinking of alpha 4 beta 1-, but not beta 2-integrins, significantly increased the number of alpha E beta 7 expressing CD4+ and CD8+ T cells, even in the absence of TGF-beta
These data indicate that in addition to TGF-beta, the interaction of particular T-cell subsets with specific endothelial cell and extracellular matrix proteins may upregulate alpha E beta 7 integrin expression and thereby contribute to the selective accumulation of these cells in inflammatory lung diseases
8918367	13	24	expression	Gene_expression
8918367	100	111	regulation	Regulation
8918367	155	163	TGF-beta	Gene
8918367	179	190	expressing	Gene_expression
8918367	340	351	expression	Gene_expression
8918367	355	377	pulmonary inflammation	Disease
8918367	383	396	distribution	Localization
8918367	422	425	CD4	Gene
8918367	518	526	patients	Species
8918367	532	547	allergic asthma	Disease
8918367	549	560	sarcoidosis	Disease
8918367	562	590	hypersensitivity pneumonitis	Disease
8918367	596	625	idiopathic pulmonary fibrosis	Disease
8918367	627	630	IPF	Disease
8918367	722	730	patients	Species
8918367	762	773	expressing	Gene_expression
8918367	812	823	expression	Gene_expression
8918367	835	838	CD4	Gene
8918367	928	931	CD4	Gene
8918367	954	957	CD4	Gene
8918367	1007	1010	IPF	Disease
8918367	1090	1098	express	Gene_expression
8918367	1162	1165	CD4	Gene
8918367	1273	1281	express	Gene_expression
8918367	1402	1410	TGF-beta	Gene
8918367	1442	1445	CD4	Gene
8918367	1533	1541	TGF-beta	Gene
8918367	1662	1670	patients	Species
8918367	1696	1707	expression	Gene_expression
8918367	1749	1762	crosslinking	Binding
8918367	1790	1796	beta 2	Gene
8918367	1822	1832	increased	Positive_regulation
8918367	1836	1843	number	Gene_expression
8918367	1861	1872	expressing	Gene_expression
8918367	1872	1875	CD4	Gene
8918367	1907	1915	absence	Negative_regulation
8918367	1918	1926	TGF-beta	Gene
8918367	1968	1976	TGF-beta	Gene
8918367	1982	1994	interaction	Binding
8918367	2127	2138	expression	Gene_expression
8918367	2222	2235	lung diseases	Disease
25557625|t|MicroRNA regulatory networks in idiopathic pulmonary fibrosis
UNASSIGNED: Idiopathic pulmonary fibrosis (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	32	61	idiopathic pulmonary fibrosis	Disease
25557625	75	104	Idiopathic pulmonary fibrosis	Disease
25557625	106	109	IPF	Disease
25557625	142	169	fatal scarring lung disease	Disease
25557625	282	287	TGF-b	Gene
25557625	326	329	IPF	Disease
25557625	437	440	IPF	Disease
25557625	537	540	IPF	Disease
25557625	612	617	TGF-b	Gene
26610737|t|Elevated sL1-CAM levels in BALF and serum of IPF patients
BACKGROUND AND OBJECTIVE: IPF 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 IPF 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 IPF patients
METHODS: Forty consecutive Chinese patients (with IPF, 16; LC, 12; and CC, 12), but no apparent lung or other organ's diseases were enrolled
Soluble L1-CAM (sL1-CAM), TGF-b1, PDGF, y-INF levels in BALF and serum sL1-CAM were measured using ELISA
RESULTS: BALF sL1-CAM levels of IPF, 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 sL1-CAM concentration of IPF patients was significantly higher than that in LC and in CC patients
Besides, serum sL1-CAM levels in patients with IPF, 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 sL1-CAM levels in patients with IPF and LC were significantly higher than those in patients with CC (P   <   0.001, respectively)
CONCLUSIONS: The concentrations of sL1-CAM both in BALF and in serum of patients with IPF are markedly increased compared with controls
This indicates that L1-CAM might be involved in the pathogenesis of IPF as well as that of LC
26610737	0	9	Elevated	Positive_regulation
26610737	9	12	sL1	Gene
26610737	45	48	IPF	Disease
26610737	49	57	patients	Species
26610737	85	88	IPF	Disease
26610737	102	124	interstitial pneumonia	Disease
26610737	262	265	IPF	Disease
26610737	270	276	tumour	Disease
26610737	289	295	L1-CAM	Gene
26610737	331	337	tumour	Disease
26610737	354	360	tumour	Disease
26610737	425	431	L1-CAM	Gene
26610737	435	438	IPF	Disease
26610737	439	447	patients	Species
26610737	484	492	patients	Species
26610737	499	502	IPF	Disease
26610737	599	605	L1-CAM	Gene
26610737	607	610	sL1	Gene
26610737	617	623	TGF-b1	Gene
26610737	662	665	sL1	Gene
26610737	711	714	sL1	Gene
26610737	729	732	IPF	Disease
26610737	744	752	patients	Species
26610737	859	862	sL1	Gene
26610737	884	887	IPF	Disease
26610737	888	896	patients	Species
26610737	973	976	sL1	Gene
26610737	991	999	patients	Species
26610737	1005	1008	IPF	Disease
26610737	1130	1133	sL1	Gene
26610737	1148	1156	patients	Species
26610737	1162	1165	IPF	Disease
26610737	1213	1221	patients	Species
26610737	1296	1299	sL1	Gene
26610737	1333	1341	patients	Species
26610737	1347	1350	IPF	Disease
26610737	1364	1374	increased	Positive_regulation
26610737	1418	1424	L1-CAM	Gene
26610737	1466	1469	IPF	Disease
27317687|t|Macrophage Bone Morphogenic Protein Receptor 2 (BMPR2) depletion in Idiopathic Pulmonary Fibrosis (IPF) and Group III Pulmonary Hypertension
UNASSIGNED: Idiopathic Pulmonary Fibrosis (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 BMPR2 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 BMPR2 signaling and elevated TGF-b activity in IPF
In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 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 BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2
We also demonstrate that isolated bone-marrow derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with IHC showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients
In conclusion, our data suggest that depletion of BMPR2 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	11	46	Bone Morphogenic Protein Receptor 2	Gene
27317687	48	53	BMPR2	Gene
27317687	55	65	depletion	Negative_regulation
27317687	68	97	Idiopathic Pulmonary Fibrosis	Disease
27317687	99	102	IPF	Disease
27317687	128	140	Hypertension	Disease
27317687	154	183	Idiopathic Pulmonary Fibrosis	Disease
27317687	185	188	IPF	Disease
27317687	255	277	pulmonary hypertension	Disease
27317687	279	281	PH	Disease
27317687	351	359	patients	Species
27317687	373	386	lung diseases	Disease
27317687	472	488	vascular lesions	Disease
27317687	492	495	IPF	Disease
27317687	528	533	human	Species
27317687	560	568	patients	Species
27317687	574	577	IPF	Disease
27317687	609	611	PH	Disease
27317687	656	664	reduced	Negative_regulation
27317687	664	669	BMPR2	Gene
27317687	670	681	expression	Gene_expression
27317687	684	692	patients	Species
27317687	698	701	IPF	Disease
27317687	705	708	IPF	Disease
27317687	709	711	PH	Disease
27317687	816	821	BMPR2	Gene
27317687	836	845	elevated	Positive_regulation
27317687	845	850	TGF-b	Gene
27317687	863	866	IPF	Disease
27317687	875	884	bleomycin	Chemical
27317687	886	889	BLM	Chemical
27317687	900	913	lung fibrosis	Disease
27317687	918	920	PH	Disease
27317687	937	947	decreased	Negative_regulation
27317687	947	952	BMPR2	Gene
27317687	953	964	expression	Gene_expression
27317687	1037	1039	PH	Disease
27317687	1092	1103	inhibition	Negative_regulation
27317687	1106	1119	interleukin-6	Gene
27317687	1151	1159	fibrosis	Disease
27317687	1164	1166	PH	Disease
27317687	1183	1192	elevated	Positive_regulation
27317687	1192	1199	levels	Gene_expression
27317687	1202	1207	BMPR2	Gene
27317687	1288	1293	BMPR2	Gene
27317687	1366	1369	BLM	Chemical
27317687	1378	1382	mice	Species
27317687	1388	1396	reduced	Negative_regulation
27317687	1396	1401	BMPR2	Gene
27317687	1428	1431	IL6	Gene
27317687	1439	1442	IL6	Gene
27317687	1493	1501	reduced	Negative_regulation
27317687	1501	1506	BMPR2	Gene
27317687	1510	1515	CD206	Gene
27317687	1516	1527	expressing	Gene_expression
27317687	1563	1566	IPF	Disease
27317687	1571	1574	IPF	Disease
27317687	1575	1577	PH	Disease
27317687	1578	1586	patients	Species
27317687	1625	1635	depletion	Negative_regulation
27317687	1638	1643	BMPR2	Gene
27317687	1644	1653	mediated	Positive_regulation
27317687	1677	1685	induced	Positive_regulation
27317687	1688	1692	IL-6	Gene
27317687	1708	1713	STAT3	Gene
27317687	1714	1730	phosphorylation	Phosphorylation
27317687	1791	1808	vascular injuries	Disease
27317687	1812	1815	IPF	Disease
24921217|t|Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis
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 Lrp5 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 Lrp5 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 idiopathic pulmonary fibrosis (IPF)
MEASUREMENTS AND MAIN RESULTS: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, Lrp5 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
Lrp5 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 Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis
Instead, Lrp5 loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes
Consistent with a role of Lrp5 in the activation of TGF-b, Lrp5 null mice were not protected against lung fibrosis induced by TGF-b
CONCLUSIONS: We show that the Wnt coreceptor, Lrp5, 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 Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis
24921217	15	19	Lrp5	Gene
24921217	35	64	idiopathic pulmonary fibrosis	Disease
24921217	81	90	b-catenin	Gene
24921217	124	137	lung fibrosis	Disease
24921217	171	182	expression	Gene_expression
24921217	308	312	Lrp5	Gene
24921217	320	338	pulmonary fibrosis	Disease
24921217	342	346	mice	Species
24921217	388	394	humans	Species
24921217	417	421	mice	Species
24921217	460	465	loss	Negative_regulation
24921217	487	491	Lrp5	Gene
24921217	505	518	lung fibrosis	Disease
24921217	530	539	bleomycin	Chemical
24921217	546	556	adenovirus	Species
24921217	703	711	patients	Species
24921217	717	746	idiopathic pulmonary fibrosis	Disease
24921217	748	751	IPF	Disease
24921217	788	796	patients	Species
24921217	802	805	IPF	Disease
24921217	868	878	elevation	Positive_regulation
24921217	902	912	Lrp5 and 6	Gene
24921217	969	973	LRP5	Gene
24921217	1059	1067	patients	Species
24921217	1073	1076	IPF	Disease
24921217	1078	1082	Lrp5	Gene
24921217	1088	1092	mice	Species
24921217	1116	1125	bleomycin	Chemical
24921217	1134	1152	pulmonary fibrosis	Disease
24921217	1195	1206	inhibition	Negative_regulation
24921217	1209	1218	b-catenin	Gene
24921217	1265	1274	b-catenin	Gene
24921217	1320	1324	Lrp5	Gene
24921217	1363	1367	mice	Species
24921217	1382	1390	fibrosis	Disease
24921217	1401	1405	Lrp5	Gene
24921217	1406	1411	loss	Negative_regulation
24921217	1431	1439	reduced	Negative_regulation
24921217	1439	1444	TGF-b	Gene
24921217	1445	1456	production	Gene_expression
24921217	1523	1527	Lrp5	Gene
24921217	1535	1546	activation	Positive_regulation
24921217	1549	1554	TGF-b	Gene
24921217	1556	1560	Lrp5	Gene
24921217	1566	1570	mice	Species
24921217	1598	1611	lung fibrosis	Disease
24921217	1623	1628	TGF-b	Gene
24921217	1676	1680	Lrp5	Gene
24921217	1695	1718	driver of lung fibrosis	Disease
24921217	1722	1726	mice	Species
24921217	1779	1785	humans	Species
24921217	1791	1794	IPF	Disease
24921217	1810	1815	TGF-b	Gene
24921217	1841	1846	loss	Negative_regulation
24921217	1849	1853	Lrp5	Gene
24921217	1875	1882	patient	Species
24921217	1933	1946	lung fibrosis	Disease
29206498|t|The potential application of strategic released apigenin from polymeric carrier in pulmonary fibrosis
AIM: The capability of reducing fibrotic and inflammatory responses in lung tissues represents a gold standard for evaluating the efficacy of therapeutic interventions for treating idiopathic pulmonary fibrosis (IPF)
A wide variety of therapeutic strategies have been employed in clinic to treat PF, but limited success has been obtained
Apigenin (4, 5, 7-trihydroxyflavone) is a member of flavonoid family that exerts anti-inflammatory and anti-fibrosis effects
In this study, we explore the potential therapeutic effect of apigenin in lung fibrosis
MATERIALS AND METHODS: Apigenin was employed to treat IPF in a bleomycin-induced PF rat model
Apigenin was loaded onto a biodegradable polymer carrier (nanoparticle, NP) to improve its bio-solubility and bio-availability
The properties (e.g
size, apigenin loading and release profile) of the apigenin loaded polymer carrier were well-characterized
In vitro study was performed to assess the impact of apigenin on pulmonary cell viability, growth, as well as inflammatory and pro-fibrosis responses in pulmonary cells
The impact of apigenin on the production of inflammatory cytokines (e.g
TGF-b, TNF-a) and pro-fibrosis factors in bronchoalveolar lavage fluid and pulmonary cells from lung tissues was also investigated
RESULTS: Our results showed, apigenin has anti-fibrosis effect by inhibition fibrosis related cytokines expression
And compared with apigenin in soluble form, the strategic release of apigenin is more effective in inhibiting pulmonary fibrosis and inflammation
CONCLUSION: Our finding suggested that apigenin loaded on polymeric carrier might be an effective treatment for pulmonary fibrosis patients
29206498	48	56	apigenin	Chemical
29206498	443	451	Apigenin	Chemical
29206498	456	478	5, 7-trihydroxyflavone	Chemical
29206498	495	504	flavonoid	Chemical
29206498	631	639	apigenin	Chemical
29206498	681	689	Apigenin	Chemical
29206498	721	730	bleomycin	Chemical
29206498	742	745	rat	Species
29206498	753	761	Apigenin	Chemical
29206498	908	916	apigenin	Chemical
29206498	953	961	apigenin	Chemical
29206498	1063	1071	apigenin	Chemical
29206498	1194	1202	apigenin	Chemical
29206498	1253	1258	TGF-b	Gene
29206498	1260	1265	TNF-a	Gene
29206498	1414	1422	apigenin	Chemical
29206498	1519	1527	apigenin	Chemical
29206498	1570	1578	apigenin	Chemical
29206498	1687	1695	apigenin	Chemical
29206498	1779	1787	patients	Species
27107963|t|Immunomodulation by mesenchymal stem cells in treating human autoimmune disease-associated lung fibrosis
BACKGROUND: Interstitial pneumonia 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	55	60	human	Species
27107963	61	104	autoimmune disease-associated lung fibrosis	Disease
27107963	118	140	Interstitial pneumonia	Disease
27107963	144	170	connective tissue diseases	Disease
27107963	176	178	IP	Disease
27107963	190	202	inflammation	Disease
27107963	207	215	fibrosis	Disease
27107963	238	243	death	Disease
27107963	251	253	IP	Disease
27107963	254	262	patients	Species
27107963	276	298	autoimmune lung injury	Disease
27107963	537	539	IP	Disease
27107963	635	647	autoimmunity	Disease
27107963	807	809	IP	Disease
27107963	810	818	patients	Species
27107963	824	829	human	Species
27107963	867	875	patients	Species
27107963	906	934	usual interstitial pneumonia	Disease
27107963	936	939	UIP	Disease
27107963	1074	1076	IP	Disease
27107963	1220	1223	UIP	Disease
27107963	1360	1362	IP	Disease
27107963	1363	1371	patients	Species
27107963	1436	1439	UIP	Disease
27107963	1500	1513	upregulation	Positive_regulation
27107963	1539	1544	a-SMA	Gene
27107963	1753	1761	patients	Species
27107963	1767	1796	idiopathic pulmonary fibrosis	Disease
27107963	1798	1801	IPF	Disease
27107963	1899	1904	a-SMA	Gene
27107963	1923	1926	UIP	Disease
27107963	1942	1948	TGF-b1	Gene
27107963	1995	1999	IL-6	Gene
27107963	2000	2005	STAT3	Gene
27107963	2027	2032	IP-10	Gene
27107963	2050	2060	secreting	Localization
27107963	2078	2084	TGF-b1	Gene
27107963	2137	2140	BLM	Chemical
27107963	2149	2167	pulmonary fibrosis	Disease
27107963	2171	2175	mice	Species
27107963	2204	2209	TGF-b	Gene
27107963	2255	2259	IL-6	Gene
27107963	2260	2265	STAT3	Gene
27107963	2282	2293	activation	Positive_regulation
27107963	2349	2351	IP	Disease
27107963	2396	2399	UIP	Disease
27107963	2427	2433	TGF-b1	Gene
27107963	2470	2480	regulates	Regulation
27107963	2480	2484	IL-6	Gene
27107963	2485	2490	STAT3	Gene
27107963	2491	2502	activation	Positive_regulation
27107963	2569	2574	IP-10	Gene
27107963	2625	2638	lung fibrosis	Disease
27107963	2642	2654	autoimmunity	Disease
28577568|t|Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy
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 lung fibrosis 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 lung fibrosis 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 lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment
28577568	0	11	Pirfenidone	Chemical
28577568	55	68	lung fibrosis	Disease
28577568	124	135	Pirfenidone	Chemical
28577568	137	140	PFD	Chemical
28577568	182	211	idiopathic pulmonary fibrosis	Disease
28577568	213	216	IPF	Disease
28577568	363	366	IPF	Disease
28577568	475	478	IPF	Disease
28577568	564	575	regulating	Regulation
28577568	598	604	oxygen	Chemical
28577568	628	667	platelet-derived growth factor receptor	Gene
28577568	669	674	PDGFR	Gene
28577568	676	687	activation	Positive_regulation
28577568	717	720	PFD	Chemical
28577568	838	841	PFD	Chemical
28577568	930	958	Transforming growth factor-b	Gene
28577568	960	965	TGF-b	Gene
28577568	978	982	ATG5	Gene
28577568	984	988	ATG7	Gene
28577568	994	999	PARK2	Gene
28577568	1112	1115	PFD	Chemical
28577568	1134	1143	bleomycin	Chemical
28577568	1145	1148	BLM	Chemical
28577568	1158	1171	lung fibrosis	Disease
28577568	1184	1189	PARK2	Gene
28577568	1204	1208	mice	Species
28577568	1233	1236	PFD	Chemical
28577568	1280	1289	enhanced	Positive_regulation
28577568	1289	1294	PARK2	Gene
28577568	1295	1306	expression	Gene_expression
28577568	1403	1408	TGF-b	Gene
28577568	1410	1413	PFD	Chemical
28577568	1469	1474	PARK2	Gene
28577568	1475	1485	knockdown	Negative_regulation
28577568	1488	1497	reducing	Negative_regulation
28577568	1519	1524	PDGFR	Gene
28577568	1546	1549	BLM	Chemical
28577568	1558	1563	PARK2	Gene
28577568	1567	1571	mice	Species
28577568	1585	1614	augmentation of lung fibrosis	Disease
28577568	1664	1667	BLM	Chemical
28577568	1686	1690	mice	Species
28577568	1729	1732	PFD	Chemical
28577568	1774	1777	PFD	Chemical
28577568	1786	1791	PARK2	Gene
28577568	1820	1842	inhibits lung fibrosis	Disease
28577568	1963	1966	PFD	Chemical
28577568	1971	1974	IPF	Disease
28678431|t|Epithelial-to-mesenchymal transition and its role in EGFR-mutant lung adenocarcinoma and idiopathic pulmonary fibrosis
Lung adenocarcinoma cells with activating epidermal growth factor receptor (EGFR) mutations are highly dependent upon EGFR signaling for survival and undergo apoptosis when EGFR signaling is inhibited by tyrosine kinase inhibitor (TKI) treatment
Paradoxically, EGFR-mutant lung adenocarcinomas have subpopulations of cells that can survive independently of activated EGFR
Such EGFR-independent EGFR-mutant cancer cells include cells that have undergone epithelial-to-mesenchymal transition (EMT) or transformed to small cell lung cancer, which almost completely lack EGFR dependency
The presence of such cells suggests that EGFR TKIs cannot eradicate EGFR-mutant lung adenocarcinoma cells
However, little is known about whether and to what extent normal peripheral lung epithelial cells, not lung adenocarcinoma 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	53	57	EGFR	Gene
28678431	65	84	lung adenocarcinoma	Disease
28678431	89	118	idiopathic pulmonary fibrosis	Disease
28678431	120	139	Lung adenocarcinoma	Disease
28678431	162	194	epidermal growth factor receptor	Gene
28678431	196	200	EGFR	Gene
28678431	238	242	EGFR	Gene
28678431	293	297	EGFR	Gene
28678431	311	321	inhibited	Negative_regulation
28678431	324	332	tyrosine	Chemical
28678431	340	350	inhibitor	Negative_regulation
28678431	382	386	EGFR	Gene
28678431	399	414	adenocarcinomas	Disease
28678431	478	488	activated	Positive_regulation
28678431	488	492	EGFR	Gene
28678431	499	503	EGFR	Gene
28678431	516	520	EGFR	Gene
28678431	528	534	cancer	Disease
28678431	636	658	small cell lung cancer	Disease
28678431	689	693	EGFR	Gene
28678431	747	751	EGFR	Gene
28678431	774	778	EGFR	Gene
28678431	786	805	lung adenocarcinoma	Disease
28678431	916	935	lung adenocarcinoma	Disease
28678431	1288	1308	fibrotic destruction	Disease
28678431	1330	1359	idiopathic pulmonary fibrosis	Disease
27367854|t|Resveratrol-Mediated Repression and Reversion of Prostatic Myofibroblast Phenoconversion
BACKGROUND: Resveratrol, a phytoalexin found in berries, peanuts, grapes, and red wine, inhibits oxidation, inflammation, 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	0	11	Resveratrol	Chemical
27367854	102	113	Resveratrol	Chemical
27367854	198	210	inflammation	Disease
27367854	248	258	synthesis	Gene_expression
27367854	306	316	represses	Negative_regulation
27367854	493	503	increased	Positive_regulation
27367854	649	677	urinary obstructive symptoms	Disease
27367854	726	737	Resveratrol	Chemical
27367854	775	779	TGFb	Gene
27367854	788	794	CXCL12	Gene
27367854	1216	1245	idiopathic pulmonary fibrosis	Disease
27367854	1247	1250	IPF	Disease
27367854	1334	1338	TGFb	Gene
27367854	1342	1348	CXCL12	Gene
27367854	1378	1389	Resveratrol	Chemical
27367854	1502	1513	expression	Gene_expression
27367854	1574	1578	EGR1	Gene
27367854	1590	1601	expression	Gene_expression
27367854	1656	1667	Resveratrol	Chemical
27367854	1772	1776	EGR1	Gene
27367854	1782	1796	transcription	Transcription
27367854	1904	1907	IPF	Disease
27367854	1949	1960	Resveratrol	Chemical
27367854	2142	2153	Resveratrol	Chemical
22684844|t|Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis
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 Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130(757F) mice
The extent of fibrosis was attenuated in B lymphocyte-deficient gp130(757F);  MT(-/-) compound mutant mice, but fibrosis still occurred in their Smad3(-/-) counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1a1 gene transcription independently of canonical TGF-b/Smad3 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 Stat3 protected mice from bleomycin-induced lung fibrosis
22684844	24	37	interleukin-6	Gene
22684844	52	56	mice	Species
22684844	69	74	Stat3	Gene
22684844	80	85	Smad3	Gene
22684844	95	108	lung fibrosis	Disease
22684844	110	139	Idiopathic pulmonary fibrosis	Disease
22684844	141	144	IPF	Disease
22684844	273	281	fibrosis	Disease
22684844	323	341	interleukin (IL)-6	Gene
22684844	347	356	elevated	Positive_regulation
22684844	473	481	fibrosis	Disease
22684844	576	585	bleomycin	Chemical
22684844	594	606	inflammation	Disease
22684844	611	619	fibrosis	Disease
22684844	623	627	mice	Species
22684844	662	666	IL-6	Gene
22684844	683	688	gp130	Gene
22684844	757	761	IL-6	Gene
22684844	782	787	Stat3	Gene
22684844	859	867	fibrosis	Disease
22684844	885	890	gp130	Gene
22684844	897	901	mice	Species
22684844	917	925	fibrosis	Disease
22684844	967	972	gp130	Gene
22684844	1005	1009	mice	Species
22684844	1015	1023	fibrosis	Disease
22684844	1048	1053	Smad3	Gene
22684844	1114	1119	Stat3	Gene
22684844	1132	1139	induce	Positive_regulation
22684844	1157	1171	transcription	Transcription
22684844	1198	1203	TGF-b	Gene
22684844	1204	1209	Smad3	Gene
22684844	1295	1300	STAT3	Gene
22684844	1301	1312	activation	Positive_regulation
22684844	1339	1347	patients	Species
22684844	1372	1382	reduction	Negative_regulation
22684844	1385	1390	Stat3	Gene
22684844	1401	1405	mice	Species
22684844	1411	1420	bleomycin	Chemical
22684844	1429	1442	lung fibrosis	Disease
26098610|t|Effects of thymosin b4 and its N-terminal fragment Ac-SDKP on TGF-b-treated human lung fibroblasts and in the mouse model of bleomycin-induced lung fibrosis
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 lung fibrosis
METHODS: We utilized both control and TGF-b-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 TGF-b-induced a-SMA and collagen expression, hallmarks of fibroblast differentiation into myofibroblasts triggered by TGF-b
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	0	8	Effects	Gene_expression
26098610	11	22	thymosin b4	Gene
26098610	31	32	N	Chemical
26098610	51	58	Ac-SDKP	Chemical
26098610	62	67	TGF-b	Gene
26098610	76	81	human	Species
26098610	110	115	mouse	Species
26098610	125	134	bleomycin	Chemical
26098610	143	156	lung fibrosis	Disease
26098610	170	181	Thymosin b4	Gene
26098610	183	186	Tb4	Gene
26098610	196	201	amino	Chemical
26098610	231	268	N-acetyl-seryl-aspartyl-lysyl-proline	Chemical
26098610	270	277	Ac-SDKP	Chemical
26098610	410	413	Tb4	Gene
26098610	449	453	mice	Species
26098610	467	476	bleomycin	Chemical
26098610	549	561	inflammation	Disease
26098610	572	580	fibrosis	Disease
26098610	672	675	Tb4	Gene
26098610	680	687	Ac-SDKP	Chemical
26098610	741	744	Tb4	Gene
26098610	781	790	bleomycin	Chemical
26098610	791	796	mouse	Species
26098610	806	819	lung fibrosis	Disease
26098610	859	864	TGF-b	Gene
26098610	884	889	human	Species
26098610	926	955	idiopathic pulmonary fibrosis	Disease
26098610	957	960	IPF	Disease
26098610	1006	1009	Tb4	Gene
26098610	1027	1030	CD1	Gene
26098610	1031	1035	mice	Species
26098610	1049	1058	bleomycin	Chemical
26098610	1152	1159	Ac-SDKP	Chemical
26098610	1163	1166	IPF	Disease
26098610	1196	1203	Ac-SDKP	Chemical
26098610	1218	1228	inhibited	Negative_regulation
26098610	1228	1233	TGF-b	Gene
26098610	1242	1247	a-SMA	Gene
26098610	1261	1272	expression	Gene_expression
26098610	1346	1351	TGF-b	Gene
26098610	1414	1418	mice	Species
26098610	1432	1441	bleomycin	Chemical
26098610	1453	1456	Tb4	Gene
26098610	1475	1483	fibrosis	Disease
26098610	1565	1568	Tb4	Gene
26098610	1570	1577	Ac-SDKP	Chemical
19597127|t|Transcription factor GATA-6 is expressed in quiescent myofibroblasts in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	0	27	Transcription factor GATA-6	Gene
19597127	31	41	expressed	Gene_expression
19597127	72	101	idiopathic pulmonary fibrosis	Disease
19597127	103	132	Idiopathic pulmonary fibrosis	Disease
19597127	134	137	IPF	Disease
19597127	158	186	usual interstitial pneumonia	Disease
19597127	188	191	UIP	Disease
19597127	267	270	IPF	Disease
19597127	271	274	UIP	Disease
19597127	283	300	fibroblastic foci	Disease
19597127	365	371	GATA-6	Gene
19597127	463	466	IPF	Chemical
19597127	526	532	GATA-6	Gene
19597127	607	610	IPF	Disease
19597127	611	614	UIP	Disease
19597127	626	637	expression	Gene_expression
19597127	649	655	GATA-6	Gene
19597127	771	780	caspase-3	Gene
19597127	799	804	human	Species
19597127	805	808	IPF	Disease
19597127	809	812	UIP	Disease
19597127	844	850	GATA-6	Gene
19597127	851	866	overexpression	Positive_regulation
19597127	956	973	fibroblastic foci	Disease
19597127	977	980	IPF	Disease
19597127	981	984	UIP	Disease
19597127	995	1004	positive	Gene_expression
19597127	1008	1014	GATA-6	Gene
19597127	1020	1029	negative	Gene_expression
19597127	1042	1051	caspase-3	Gene
19597127	1062	1067	human	Species
19597127	1068	1071	IPF	Disease
19597127	1072	1075	UIP	Disease
19597127	1088	1098	expressed	Gene_expression
19597127	1098	1104	GATA-6	Gene
19597127	1205	1215	induction	Positive_regulation
19597127	1218	1224	GATA-6	Gene
19597127	1286	1297	expression	Gene_expression
19597127	1314	1323	decrease	Negative_regulation
19597127	1326	1336	E-cadherin	Gene
19597127	1342	1353	inhibition	Negative_regulation
19597127	1356	1362	GATA-6	Gene
19597127	1363	1374	expression	Gene_expression
19597127	1401	1407	GATA-6	Gene
19597127	1515	1518	IPF	Disease
19597127	1519	1522	UIP	Disease
19597127	1622	1630	express	Gene_expression
19597127	1630	1636	GATA-6	Gene
29046395|t|Epithelial contribution to the pro-fibrotic stiff microenvironment and myofibroblast population in lung fibrosis
The contribution of epithelial-to-mesenchymal transition (EMT) to the pro-fibrotic stiff microenvironment and myofibroblast accumulation in pulmonary fibrosis remains unclear
We examined EMT-competent lung epithelial cells and lung fibroblasts from control (fibrosis-free) donors or patients with idiopathic pulmonary fibrosis (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 FAK(Y397) activity
FAK inhibition was sufficient to decrease fibroblast stiffness and collagen expression, supporting that FAK(Y397) 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 FAK(Y397) may rescue normal mechanobiology in IPF
29046395	104	112	fibrosis	Disease
29046395	254	272	pulmonary fibrosis	Disease
29046395	373	381	fibrosis	Disease
29046395	398	406	patients	Species
29046395	412	441	idiopathic pulmonary fibrosis	Disease
29046395	443	446	IPF	Disease
29046395	460	493	very aggressive fibrotic disorder	Disease
29046395	572	578	TGF-b1	Gene
29046395	631	642	expression	Gene_expression
29046395	759	765	TGF-b1	Gene
29046395	784	787	IPF	Disease
29046395	913	922	enhanced	Positive_regulation
29046395	922	930	FAK(Y397	Gene
29046395	942	945	FAK	Gene
29046395	946	957	inhibition	Negative_regulation
29046395	975	984	decrease	Negative_regulation
29046395	1018	1029	expression	Gene_expression
29046395	1046	1054	FAK(Y397	Gene
29046395	1056	1072	hyperactivation	Positive_regulation
29046395	1116	1119	IPF	Disease
29046395	1207	1210	IPF	Disease
29046395	1597	1608	expression	Gene_expression
29046395	1639	1649	targeting	Gene_expression
29046395	1649	1657	FAK(Y397	Gene
29046395	1695	1698	IPF	Disease
26884454|t|The matricellular protein CCN1 enhances TGF-b1/SMAD3-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury
Matricellular proteins mediate pleiotropic effects during tissue injury and repair
CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair
In this study, we identified CCN1 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 CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci
CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin
RNA interference (RNAi)-mediated knockdown of CCN1 down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts
TGF-b1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)-dependent mechanism
Importantly, endogenous CCN1 potentiates TGF-b1-induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation
In vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury
These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-b1/SMAD3 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 CCN1 enhances TGF-b1/SMAD3-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury
26884454	26	30	CCN1	Gene
26884454	40	46	TGF-b1	Gene
26884454	47	52	SMAD3	Gene
26884454	143	154	lung injury	Disease
26884454	240	244	CCN1	Gene
26884454	314	326	inflammation	Disease
26884454	375	379	CCN1	Gene
26884454	413	426	up-regulated	Positive_regulation
26884454	459	464	human	Species
26884454	499	528	idiopathic pulmonary fibrosis	Disease
26884454	530	533	IPF	Disease
26884454	536	545	Elevated	Positive_regulation
26884454	545	552	levels	Gene_expression
26884454	555	559	CCN1	Gene
26884454	599	602	IPF	Disease
26884454	649	653	CCN1	Gene
26884454	680	690	localized	Localization
26884454	712	716	CCN1	Gene
26884454	717	728	expression	Gene_expression
26884454	739	742	IPF	Disease
26884454	781	792	expression	Gene_expression
26884454	830	847	collagen (Col)1a1	Gene
26884454	849	855	Col1a2	Gene
26884454	861	872	fibronectin	Gene
26884454	966	976	knockdown	Negative_regulation
26884454	979	983	CCN1	Gene
26884454	984	999	down-regulated	Negative_regulation
26884454	1016	1027	expression	Gene_expression
26884454	1057	1060	IPF	Disease
26884454	1074	1080	TGF-b1	Gene
26884454	1123	1131	induces	Positive_regulation
26884454	1148	1159	expression	Gene_expression
26884454	1162	1166	CCN1	Gene
26884454	1173	1214	mothers against decapentaplegic homolog 3	Gene
26884454	1216	1221	SMAD3	Gene
26884454	1268	1272	CCN1	Gene
26884454	1273	1285	potentiates	Positive_regulation
26884454	1285	1291	TGF-b1	Gene
26884454	1300	1305	SMAD3	Gene
26884454	1306	1317	activation	Positive_regulation
26884454	1448	1458	silencing	Negative_regulation
26884454	1461	1465	CCN1	Gene
26884454	1501	1510	bleomycin	Chemical
26884454	1519	1530	lung injury	Disease
26884454	1591	1603	interaction	Binding
26884454	1615	1619	CCN1	Gene
26884454	1656	1662	TGF-b1	Gene
26884454	1663	1668	SMAD3	Gene
26884454	1693	1706	lung fibrosis	Disease
26884454	1851	1855	CCN1	Gene
26884454	1865	1871	TGF-b1	Gene
26884454	1872	1877	SMAD3	Gene
26884454	1968	1979	lung injury	Disease
12610869|t|[Idiopathic pulmonary fibrosis and lung cancer]
It is widely known that patients with idiopathic pulmonary fibrosis (IPF) are frequently associated with lung cancer
Although a complication with lung cancer is an important prognostic factor for IPF, standard treatments for lung cancer 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 lung cancer
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	1	30	Idiopathic pulmonary fibrosis	Disease
12610869	35	46	lung cancer	Disease
12610869	73	81	patients	Species
12610869	87	116	idiopathic pulmonary fibrosis	Disease
12610869	118	121	IPF	Disease
12610869	154	165	lung cancer	Disease
12610869	196	207	lung cancer	Disease
12610869	246	249	IPF	Disease
12610869	275	286	lung cancer	Disease
12610869	314	317	IPF	Disease
12610869	410	413	IPF	Disease
12610869	475	492	fatal lung injury	Disease
12610869	496	502	cancer	Disease
12610869	668	687	IPF and lung cancer	Disease
12610869	764	783	precancerous lesion	Disease
12610869	822	843	genetic abnormalities	Disease
12610869	862	876	carcinogenesis	Disease
12610869	922	943	genetic abnormalities	Disease
12610869	947	950	IPF	Disease
12610869	965	968	p53	Gene
12610869	970	975	K-ras	Gene
12610869	977	981	FHIT	Gene
24279830|t|MicroRNA-326 regulates profibrotic functions of transforming growth factor-b in pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis.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	80	98	pulmonary fibrosis	Disease
24279830	100	129	Idiopathic pulmonary fibrosis	Disease
24279830	131	134	IPF	Disease
24279830	141	155	fatal disorder	Disease
24279830	318	331	lung fibrosis	Disease
24279830	385	390	TGF-b	Gene
24279830	442	451	suppress	Negative_regulation
24279830	451	457	TGF-b1	Gene
24279830	458	468	secretion	Localization
24279830	597	603	TGF-b1	Gene
24279830	604	615	regulation	Regulation
24279830	643	650	miR-326	Gene
24279830	654	672	pulmonary fibrosis	Disease
24279830	686	697	hsa-miR-326	Gene
24279830	698	708	regulates	Regulation
24279830	708	714	TGF-b1	Gene
24279830	715	726	expression	Gene_expression
24279830	735	746	hsa-miR-326	Gene
24279830	782	788	TGF-b1	Gene
24279830	816	821	human	Species
24279830	838	847	increase	Positive_regulation
24279830	850	856	TGF-b1	Gene
24279830	857	868	expression	Gene_expression
24279830	894	903	bleomycin	Chemical
24279830	912	925	lung fibrosis	Disease
24279830	929	933	mice	Species
24279830	962	973	mmu-miR-326	Gene
24279830	990	1001	mmu-miR-326	Gene
24279830	1035	1042	miR-326	Gene
24279830	1068	1076	inhibit	Negative_regulation
24279830	1076	1082	TGF-b1	Gene
24279830	1083	1094	expression	Gene_expression
24279830	1141	1146	human	Species
24279830	1147	1150	IPF	Disease
24279830	1190	1197	miR-326	Gene
24279830	1267	1274	miR-326	Gene
24279830	1287	1292	TGF-b	Gene
24279830	1307	1315	fibrosis	Disease
24279830	1354	1361	miR-326	Gene
24279830	1375	1389	down-regulate	Negative_regulation
24279830	1416	1420	Ets1	Gene
24279830	1422	1427	Smad3	Gene
24279830	1433	1459	matrix metalloproteinase 9	Gene
24279830	1472	1485	up-regulates	Positive_regulation
24279830	1513	1518	Smad7	Gene
24279830	1564	1571	miR-326	Gene
24279830	1592	1603	regulating	Regulation
24279830	1603	1609	TGF-b1	Gene
24279830	1610	1621	expression	Gene_expression
24279830	1729	1742	lung fibrosis	Disease
23583521|t|Role of caveolin-1 in fibrotic diseases
Fibrosis 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, caveolin-1
While caveolin-1 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 caveolin-1 in various cellular processes and highlight different aspects of its antifibrotic activity
We hypothesize that caveolin-1 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 caveolin-1 as a possible novel approach in treatment of fibroproliferative diseases
23583521	8	18	caveolin-1	Gene
23583521	22	39	fibrotic diseases	Disease
23583521	41	49	Fibrosis	Disease
23583521	80	97	numerous diseases	Disease
23583521	118	145	damage of vital body organs	Disease
23583521	166	171	death	Disease
23583521	225	233	fibrosis	Disease
23583521	428	438	caveolin-1	Gene
23583521	446	456	caveolin-1	Gene
23583521	575	583	fibrosis	Disease
23583521	649	659	caveolin-1	Gene
23583521	772	782	caveolin-1	Gene
23583521	832	840	fibrosis	Disease
23583521	848	859	regulating	Regulation
23583521	859	865	TGF-b1	Gene
23583521	1155	1165	caveolin-1	Gene
23583521	1211	1238	fibroproliferative diseases	Disease
27279470|t|Latent cytomegalovirus infection exacerbates experimental pulmonary fibrosis by activating TGF-b1
The aim of the present study was to investigate the hypotheses that cytomegalovirus (CMV) may trigger idiopathic pulmonary fibrosis (IPF) in a susceptible host and/or that the presence of CMV may alter IPF in response to a well-defined trigger of pulmonary fibrosis
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 (SMAD)2 were determined using western blot analysis
MCMV was found to invade the lungs, however, it did not cause pulmonary fibrosis
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 pulmonary fibrosis in the mouse model, possibly through the activation of TGF-b1
27279470	58	76	pulmonary fibrosis	Disease
27279470	80	91	activating	Positive_regulation
27279470	91	97	TGF-b1	Gene
27279470	184	187	CMV	Species
27279470	201	230	idiopathic pulmonary fibrosis	Disease
27279470	232	235	IPF	Disease
27279470	287	290	CMV	Species
27279470	301	304	IPF	Disease
27279470	346	364	pulmonary fibrosis	Disease
27279470	366	410	A mouse model of murine CMV (MCMV) infection	Disease
27279470	368	373	mouse	Species
27279470	383	389	murine	Species
27279470	390	393	CMV	Species
27279470	395	399	MCMV	Species
27279470	436	440	mice	Species
27279470	476	485	bleomycin	Chemical
27279470	499	503	MCMV	Species
27279470	504	513	bleomycin	Chemical
27279470	551	555	mice	Species
27279470	593	611	Pulmonary fibrosis	Disease
27279470	745	757	E  -cadherin	Gene
27279470	759	767	Vimentin	Gene
27279470	772	787	phosphorylated	Phosphorylation
27279470	838	844	SMAD)2	Gene
27279470	890	894	MCMV	Species
27279470	952	970	pulmonary fibrosis	Disease
27279470	991	999	fibrosis	Disease
27279470	1007	1011	mice	Species
27279470	1025	1029	MCMV	Species
27279470	1030	1039	bleomycin	Chemical
27279470	1090	1094	mice	Species
27279470	1118	1126	Vimentin	Gene
27279470	1150	1162	upregulated	Positive_regulation
27279470	1184	1196	E  -cadherin	Gene
27279470	1201	1215	downregulated	Negative_regulation
27279470	1222	1226	MCMV	Species
27279470	1227	1236	bleomycin	Chemical
27279470	1279	1283	MCMV	Species
27279470	1305	1323	pulmonary fibrosis	Disease
27279470	1331	1336	mouse	Species
27279470	1365	1376	activation	Positive_regulation
27279470	1379	1385	TGF-b1	Gene
9163845|t|Significance of elevated procollagen-III-peptide and transforming growth factor-beta levels of bronchoalveolar lavage fluids from idiopathic pulmonary fibrosis patients
Although both procollagen III aminopeptide (P-III-P) and transforming growth factor-beta (TGF-beta) are reported to be present in lung tissue and/or elevated in bronchoalveolar lavage fluid (BALF) from idiopathic pulmonary fibrosis (IPF) patients, we have little knowledge concerning the clinical significance of elevated P-III-P and TGF-beta levels in BALF
Using a radioimmunoassay, we measured P-III-P and TGF-beta in BALF from 48 IPF patients (16F and 32M, 59 +/- 2 years, mean +/- S.E.) who received BAL in our clinic over the past 13 years before glucocorticosteroid treatment
Among them, we could detect a significant amount of P-III-P (2.2 +/- 1.0 U/ml; range 0.03 to 16.5 U/ml) in BALF in 18 of the patients (5F and 13M, 58 +/- 3 years) (group B)
but not (0.03 U/ml or less) in the other 30 patients (11F and 19M, 59 +/- 2 years) (group A)
Lymphocyte (%) and basophil (%) in BALF from group B was much larger than that from group A (33% vs
8%, p < 0.01)
Group B showed a longer duration of onset to BAL (36 months vs
23 months, p < 0.05)
TGF-beta levels were obtained using an ELISA system kit from the same BALF samples
TGF-beta was not detected in 10 patients (100 pg/ml or less) (3F and 7M, 59 +/- 4 years) (group I), while the remaining 38 patients showed a significant amount of TGF-beta (329 +/- 44 pg/ml, range 100 to 1,360 pg/ml)
The latter patients were further divided into two groups; group II 100 to 300 pg/ml (10F and 14M, 56 +/- 3 years) and group III 350 or more (3F and 11M, 63 +/- 2 years)
Group III showed significantly better values in PaO2, Aa-DO2, %VC and %DLco, and smaller percentage of basophils in BALF than did groups I and/or II, whereas survival after BAL in group III was significantly shorter than in group I (31 vs
19 months, p < 0.05)
There was no significant relationship between P-III-P and TGF-beta levels in BALF
These findings suggest that elevated P-III-P level is accompanied by an increase in lymphocyte population in BALF from IPF patients, resulting in a longer duration of the disease, while elevated TGF-beta level reflects alveolar inflammation at an earlier stage of the disease which induces a progression of the disease, resulting in a shorter survival in IPF patients
9163845	16	25	elevated	Positive_regulation
9163845	53	84	transforming growth factor-beta	Gene
9163845	130	159	idiopathic pulmonary fibrosis	Disease
9163845	160	168	patients	Species
9163845	227	258	transforming growth factor-beta	Gene
9163845	260	268	TGF-beta	Gene
9163845	331	359	bronchoalveolar lavage fluid	Disease
9163845	361	365	BALF	Disease
9163845	372	401	idiopathic pulmonary fibrosis	Disease
9163845	403	406	IPF	Disease
9163845	408	416	patients	Species
9163845	467	480	significance	Positive_regulation
9163845	483	492	elevated	Positive_regulation
9163845	504	512	TGF-beta	Gene
9163845	523	527	BALF	Disease
9163845	579	587	TGF-beta	Gene
9163845	591	595	BALF	Disease
9163845	604	607	IPF	Disease
9163845	608	616	patients	Species
9163845	723	742	glucocorticosteroid	Chemical
9163845	806	813	P-III-P	Chemical
9163845	861	865	BALF	Disease
9163845	879	887	patients	Species
9163845	972	980	patients	Species
9163845	1041	1049	basophil	Chemical
9163845	1057	1061	BALF	Disease
9163845	1224	1232	TGF-beta	Gene
9163845	1294	1298	BALF	Disease
9163845	1308	1316	TGF-beta	Gene
9163845	1325	1334	detected	Positive_regulation
9163845	1340	1348	patients	Species
9163845	1431	1439	patients	Species
9163845	1471	1479	TGF-beta	Gene
9163845	1537	1545	patients	Species
9163845	1744	1748	PaO2	Chemical
9163845	1750	1756	Aa-DO2	Chemical
9163845	1812	1816	BALF	Disease
9163845	2016	2024	TGF-beta	Gene
9163845	2035	2039	BALF	Disease
9163845	2150	2154	BALF	Disease
9163845	2160	2163	IPF	Disease
9163845	2164	2172	patients	Species
9163845	2227	2236	elevated	Positive_regulation
9163845	2236	2244	TGF-beta	Gene
9163845	2260	2281	alveolar inflammation	Disease
9163845	2396	2399	IPF	Disease
9163845	2400	2408	patients	Species
18569384|t|The latent form of TGFbeta(1) is induced by TNFalpha through an ERK specific pathway and is activated by asbestos-derived reactive oxygen species in vitro and in vivo
Tumor necrosis factor-alpha (TNFalpha) and transforming growth factor-beta(1) (TGFbeta(1)) are potent peptide growth factors that are likely to play important roles in the development of interstitial pulmonary fibrosis (IPF)
Previously we showed that TNFalpha and TGFbeta(1) 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 TNFalpha receptor knockout mice are resistant to asbestos-induced fibrosis
Importantly, vectors that over-express TNFalpha cause inflammation and fibrogenesis along with increased TGFbeta(1) production in C57Bl/6 mice
Recently we reported that TNFalpha activates the extracellular regulated kinase pathway in fibroblasts leading to a 200-400% increase in TGFbeta(1) mRNA and protein
The mechanism of TNFalpha induction of TGFbeta(1) expression appears to be complex, involving both transcriptional and post-transcriptional mechanisms
In asbestos-exposed animals, this TGFbeta(1) is produced on alveolar surfaces in a latent form (controlled by binding of a latent associated peptide [LAP]) that must be activated for the TGFbeta(1) 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 TGFbeta(1) by oxidation of the LAP
Now, in preliminary findings, we have shown that over-expression of latent TGFbeta(1) prior to asbestos exposure of fibrogenic-resistant TNFalpha 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 TGFbeta(1), 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 TGFbeta(1) 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 TNFalpha controls fibrogenesis by regulating TGFbeta(1) expression and that one mechanism through which ROS induce lung fibrosis is by activating latent TGFbeta(1)
18569384	19	29	TGFbeta(1)	Gene
18569384	44	52	TNFalpha	Gene
18569384	64	67	ERK	Gene
18569384	92	102	activated	Positive_regulation
18569384	131	137	oxygen	Chemical
18569384	168	195	Tumor necrosis factor-alpha	Gene
18569384	197	205	TNFalpha	Gene
18569384	211	245	transforming growth factor-beta(1)	Gene
18569384	247	257	TGFbeta(1)	Gene
18569384	355	386	interstitial pulmonary fibrosis	Disease
18569384	388	391	IPF	Disease
18569384	420	428	TNFalpha	Gene
18569384	433	443	TGFbeta(1)	Gene
18569384	448	461	up-regulated	Positive_regulation
18569384	626	634	TNFalpha	Gene
18569384	653	657	mice	Species
18569384	692	700	fibrosis	Disease
18569384	728	741	over-express	Positive_regulation
18569384	741	749	TNFalpha	Gene
18569384	756	768	inflammation	Disease
18569384	797	807	increased	Positive_regulation
18569384	807	817	TGFbeta(1)	Gene
18569384	818	829	production	Gene_expression
18569384	840	844	mice	Species
18569384	872	880	TNFalpha	Gene
18569384	971	980	increase	Positive_regulation
18569384	983	993	TGFbeta(1)	Gene
18569384	1029	1037	TNFalpha	Gene
18569384	1038	1048	induction	Positive_regulation
18569384	1051	1061	TGFbeta(1)	Gene
18569384	1062	1073	expression	Gene_expression
18569384	1198	1208	TGFbeta(1)	Gene
18569384	1212	1221	produced	Gene_expression
18569384	1333	1343	activated	Positive_regulation
18569384	1351	1361	TGFbeta(1)	Gene
18569384	1365	1370	bind	Binding
18569384	1483	1489	oxygen	Chemical
18569384	1553	1562	activate	Positive_regulation
18569384	1562	1572	TGFbeta(1)	Gene
18569384	1647	1663	over-expression	Gene_expression
18569384	1673	1683	TGFbeta(1)	Gene
18569384	1735	1743	TNFalpha	Gene
18569384	1762	1766	mice	Species
18569384	1776	1792	asbestos lesions	Disease
18569384	1842	1846	mice	Species
18569384	1887	1897	increased	Positive_regulation
18569384	1908	1918	TGFbeta(1)	Gene
18569384	1920	1930	increased	Positive_regulation
18569384	2005	2009	mice	Species
18569384	2077	2087	TGFbeta(1)	Gene
18569384	2091	2101	activated	Positive_regulation
18569384	2123	2129	oxygen	Chemical
18569384	2276	2284	TNFalpha	Gene
18569384	2310	2321	regulating	Regulation
18569384	2321	2331	TGFbeta(1)	Gene
18569384	2332	2343	expression	Gene_expression
18569384	2391	2404	lung fibrosis	Disease
18569384	2411	2422	activating	Positive_regulation
18569384	2429	2439	TGFbeta(1)	Gene
27439438|t|Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice
Idiopathic pulmonary fibrosis (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	0	9	Sunitinib	Chemical
27439438	35	45	Inhibitor	Negative_regulation
27439438	57	66	Bleomycin	Chemical
27439438	75	93	Pulmonary Fibrosis	Disease
27439438	97	101	Mice	Species
27439438	103	132	Idiopathic pulmonary fibrosis	Disease
27439438	134	137	IPF	Disease
27439438	303	324	alveolar architecture	Disease
27439438	326	329	IPF	Disease
27439438	506	513	target	Regulation
27439438	538	541	IPF	Disease
27439438	543	552	Sunitinib	Chemical
27439438	586	594	tyrosine	Chemical
27439438	602	612	inhibitor	Negative_regulation
27439438	684	702	pulmonary fibrosis	Disease
27439438	751	760	sunitinib	Chemical
27439438	769	774	mouse	Species
27439438	784	802	pulmonary fibrosis	Disease
27439438	804	808	Mice	Species
27439438	848	857	bleomycin	Chemical
27439438	859	862	BLM	Chemical
27439438	875	879	mice	Species
27439438	921	930	sunitinib	Chemical
27439438	1133	1136	BLM	Chemical
27439438	1137	1141	mice	Species
27439438	1143	1152	Sunitinib	Chemical
27439438	1168	1186	pulmonary fibrosis	Disease
27439438	1248	1251	BLM	Chemical
27439438	1252	1256	mice	Species
27439438	1333	1342	sunitinib	Chemical
27439438	1376	1381	human	Species
27439438	1425	1430	human	Species
27439438	1449	1458	Sunitinib	Chemical
27439438	1499	1504	TGF-b	Gene
27439438	1589	1598	sunitinib	Chemical
27439438	1599	1607	reduced	Negative_regulation
27439438	1621	1637	phosphorylation	Phosphorylation
27439438	1640	1646	serine	Chemical
27439438	1659	1666	Smad2/3	Gene
27439438	1676	1684	induced	Positive_regulation
27439438	1687	1692	TGF-b	Gene
27439438	1777	1795	pulmonary fibrosis	Disease
27439438	1820	1828	fibrosis	Disease
27439438	1853	1862	sunitinib	Chemical
27439438	1896	1914	pulmonary fibrosis	Disease
28095470|t|Endogenous Semaphorin-7A Impedes Human Lung Fibroblast Differentiation
UNASSIGNED: Semaphorin-7A is a glycosylphosphatidylinositol-anchored protein, initially characterized as an axon guidance protein
Semaphorin-7A 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, semaphorin-7A was shown to be important for TGF-  1-induced pulmonary fibrosis characterized by myofibroblast accumulation and extracellular matrix deposition, but the cell-specific role of semaphorin-7A was not examined in fibroblasts
The purpose of this study is to determine semaphorin-7A expression by fibroblasts and to investigate the function of endogenously expressed semaphorin-7A in primary human lung fibroblasts (HLF)
Herein, we show that non-fibrotic HLF expressed high levels of cell surface semaphorin-7A with little dependence on the percentage of serum or recombinant TGF-  1
Semaphorin-7A siRNA strongly decreased semaphorin-7A mRNA expression and reduced cell surface semaphorin-7A
Reduction of semaphorin-7A induced increased proliferation and migration of non-fibrotic HLF
Also, independent of the presence of TGF-  1, the decline of semaphorin-7A 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 semaphorin-7A in the NIH3T3 fibroblast cell line reduced the production of pro-fibrotic markers
The inverse association between semaphorin-7A and pro-fibrotic fibroblast markers was further analyzed using HLF from idiopathic pulmonary fibrosis (IPF) (n = 6) and non-fibrotic (n = 7) lungs
Using these 13 fibroblast lines, we observed that semaphorin-7A and periostin expression were inversely correlated
In conclusion, our study indicates that endogenous semaphorin-7A in HLF plays a role in maintaining fibroblast homeostasis by preventing up-regulation of pro-fibrotic genes
Therefore, endogenous and exogenous semaphorin-7A may have opposite effects on the fibroblast phenotype
28095470	11	24	Semaphorin-7A	Gene
28095470	33	38	Human	Species
28095470	84	97	Semaphorin-7A	Gene
28095470	103	131	glycosylphosphatidylinositol	Chemical
28095470	203	216	Semaphorin-7A	Gene
28095470	364	369	mouse	Species
28095470	378	391	semaphorin-7A	Gene
28095470	438	456	pulmonary fibrosis	Disease
28095470	568	581	semaphorin-7A	Gene
28095470	657	670	semaphorin-7A	Gene
28095470	671	682	expression	Gene_expression
28095470	745	755	expressed	Gene_expression
28095470	755	768	semaphorin-7A	Gene
28095470	780	785	human	Species
28095470	804	807	HLF	Gene
28095470	844	847	HLF	Gene
28095470	848	858	expressed	Gene_expression
28095470	886	899	semaphorin-7A	Gene
28095470	974	987	Semaphorin-7A	Gene
28095470	1003	1013	decreased	Negative_regulation
28095470	1013	1026	semaphorin-7A	Gene
28095470	1032	1043	expression	Gene_expression
28095470	1068	1081	semaphorin-7A	Gene
28095470	1096	1109	semaphorin-7A	Gene
28095470	1172	1175	HLF	Gene
28095470	1238	1251	semaphorin-7A	Gene
28095470	1281	1291	increased	Positive_regulation
28095470	1313	1324	production	Gene_expression
28095470	1333	1344	expression	Gene_expression
28095470	1347	1356	periostin	Gene
28095470	1358	1369	fibronectin	Gene
28095470	1384	1405	serum response factor	Gene
28095470	1407	1410	SRF	Gene
28095470	1474	1489	overexpression	Positive_regulation
28095470	1492	1505	semaphorin-7A	Gene
28095470	1541	1549	reduced	Negative_regulation
28095470	1621	1634	semaphorin-7A	Gene
28095470	1698	1701	HLF	Gene
28095470	1707	1736	idiopathic pulmonary fibrosis	Disease
28095470	1738	1741	IPF	Disease
28095470	1833	1846	semaphorin-7A	Gene
28095470	1851	1860	periostin	Gene
28095470	1861	1872	expression	Gene_expression
28095470	1950	1963	semaphorin-7A	Gene
28095470	1967	1970	HLF	Gene
28095470	2109	2122	semaphorin-7A	Gene
27002405|t|Protective role of gambogic acid in experimental pulmonary fibrosis in vitro and in vivo
BACKGROUND: Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis 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 pulmonary fibrosis in vivo by modulating VASH-2/VASH-1 and suppressing the TGF-b1/Smad3 pathway
27002405	19	32	gambogic acid	Chemical
27002405	49	67	pulmonary fibrosis	Disease
27002405	102	131	Idiopathic pulmonary fibrosis	Disease
27002405	133	136	IPF	Disease
27002405	211	214	IPF	Disease
27002405	233	246	Gambogic acid	Chemical
27002405	557	563	TGF-b1	Gene
27002405	678	683	human	Species
27002405	760	765	human	Species
27002405	826	835	bleomycin	Chemical
27002405	837	840	BLM	Chemical
27002405	850	868	pulmonary fibrosis	Disease
27002405	907	913	TGF-b1	Gene
27002405	969	979	reduction	Negative_regulation
27002405	993	1002	decrease	Negative_regulation
27002405	1020	1025	Smad3	Gene
27002405	1033	1042	increase	Positive_regulation
27002405	1045	1055	E-cadherin	Gene
27002405	1068	1074	TGF-b1	Gene
27002405	1126	1136	reduction	Negative_regulation
27002405	1153	1162	decrease	Negative_regulation
27002405	1182	1191	increase	Positive_regulation
27002405	1194	1205	VE-cadherin	Gene
27002405	1222	1229	hypoxic	Disease
27002405	1264	1275	Vasohibin-2	Gene
27002405	1277	1283	VASH-2	Gene
27002405	1294	1304	increased	Positive_regulation
27002405	1304	1310	VASH-1	Gene
27002405	1315	1321	TGF-b1	Gene
27002405	1393	1402	decrease	Negative_regulation
27002405	1473	1478	FGF-2	Gene
27002405	1480	1492	expressions	Gene_expression
27002405	1567	1570	BLM	Chemical
27002405	1579	1597	pulmonary fibrosis	Disease
27002405	1601	1605	rats	Species
27002405	1619	1625	VASH-2	Gene
27002405	1661	1667	VASH-1	Gene
27002405	1668	1679	expression	Gene_expression
27002405	1697	1705	fibrosis	Disease
27002405	1723	1734	reductions	Negative_regulation
27002405	1782	1787	a-SMA	Gene
27002405	1798	1803	FGF-2	Gene
27002405	1804	1816	expressions	Gene_expression
27002405	1966	1984	pulmonary fibrosis	Disease
27002405	1996	2007	modulating	Regulation
27002405	2007	2013	VASH-2	Gene
27002405	2014	2020	VASH-1	Gene
27002405	2025	2037	suppressing	Negative_regulation
27002405	2041	2047	TGF-b1	Gene
27002405	2048	2053	Smad3	Gene
28314802|t|An ex vivo model to induce early fibrosis-like changes in human precision-cut lung slices
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 fibrosis-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 fibrosis and could be used to evaluate novel therapies and study early-stage IPF pathomechanisms
28314802	33	41	fibrosis	Disease
28314802	58	63	human	Species
28314802	91	94	IPF	Disease
28314802	120	145	interstitial lung disease	Disease
28314802	147	150	ILD	Disease
28314802	397	400	IPF	Disease
28314802	513	516	IPF	Disease
28314802	573	578	human	Species
28314802	703	706	IPF	Disease
28314802	729	732	IPF	Disease
28314802	833	841	fibrosis	Disease
28314802	858	863	human	Species
28314802	882	890	patients	Species
28314802	899	902	ILD	Disease
28314802	903	906	IPF	Disease
28314802	1193	1204	expression	Gene_expression
28314802	1205	1208	FN1	Gene
28314802	1210	1218	SERPINE1	Gene
28314802	1220	1226	COL1A1	Gene
28314802	1228	1232	CTGF	Gene
28314802	1234	1238	MMP7	Gene
28314802	1243	1248	ACTA2	Gene
28314802	1250	1260	increased	Positive_regulation
28314802	1434	1444	decreases	Negative_regulation
28314802	1447	1452	SFTPC	Gene
28314802	1457	1462	loss	Negative_regulation
28314802	1488	1493	human	Species
28314802	1512	1520	patients	Species
28314802	1529	1532	ILD	Disease
28314802	1533	1536	IPF	Disease
28314802	1615	1623	fibrosis	Disease
28314802	1692	1695	IPF	Disease
28128990|t|Differing Expression of Cytokines and Tumor Markers in Combined Pulmonary Fibrosis and Emphysema Compared to Emphysema and Pulmonary Fibrosis
This study aimed to explore the different pathogeneses of combined pulmonary fibrosis and emphysema (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	38	43	Tumor	Disease
28128990	87	96	Emphysema	Disease
28128990	109	141	Emphysema and Pulmonary Fibrosis	Disease
28128990	201	242	combined pulmonary fibrosis and emphysema	Disease
28128990	244	248	CPFE	Disease
28128990	255	264	emphysema	Disease
28128990	269	287	pulmonary fibrosis	Disease
28128990	303	332	transforming growth factor-b1	Gene
28128990	334	340	TGF-b1	Gene
28128990	343	377	vascular endothelial growth factor	Gene
28128990	379	383	VEGF	Gene
28128990	386	408	Krebs Von Den Lungen-6	Gene
28128990	410	414	KL-6	Gene
28128990	417	443	matrix metalloproteinase-9	Gene
28128990	445	450	MMP-9	Gene
28128990	453	494	tissue inhibitors of metalloproteinases-1	Gene
28128990	496	502	TIMP-1	Gene
28128990	505	519	cytokeratin 19	Gene
28128990	530	539	CYFRA21-1	Chemical
28128990	542	565	squamous cell carcinoma	Disease
28128990	649	653	CPFE	Disease
28128990	654	662	patients	Species
28128990	667	686	pulmonary emphysema	Disease
28128990	687	695	patients	Species
28128990	704	733	idiopathic pulmonary fibrosis	Disease
28128990	735	738	IPF	Disease
28128990	740	748	patients	Species
28128990	784	791	levels	Gene_expression
28128990	794	798	VEGF	Gene
28128990	803	809	TGF-b1	Gene
28128990	813	816	IPF	Disease
28128990	817	825	patients	Species
28128990	866	875	emphysema	Disease
28128990	876	884	patients	Species
28128990	950	954	CPFE	Disease
28128990	955	963	patients	Species
28128990	1011	1015	KL-6	Gene
28128990	1020	1029	CYFRA21-1	Chemical
28128990	1033	1036	IPF	Disease
28128990	1037	1045	patients	Species
28128990	1086	1095	emphysema	Disease
28128990	1100	1104	CPFE	Disease
28128990	1105	1113	patients	Species
28128990	1204	1211	levels	Gene_expression
28128990	1219	1224	MMP-9	Gene
28128990	1226	1232	TIMP-1	Gene
28128990	1234	1239	MMP-9	Gene
28128990	1240	1246	TIMP-1	Gene
28128990	1331	1335	VEGF	Gene
28128990	1337	1343	TGF-b1	Gene
28128990	1345	1349	KL-6	Gene
28128990	1355	1364	CYFRA21-1	Chemical
28128990	1404	1422	pulmonary fibrosis	Disease
28128990	1444	1448	KL-6	Gene
28128990	1453	1462	CYFRA21-1	Chemical
28128990	1466	1470	CPFE	Disease
28128990	1471	1479	patients	Species
28128990	1516	1524	patients	Species
28128990	1533	1542	emphysema	Disease
28128990	1559	1567	fibrosis	Disease
20715983|t|Differential effects of human neutrophil peptide-1 on growth factor and interleukin-8 production by human lung fibroblasts and epithelial cells
alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of lung diseases, 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	24	29	human	Species
20715983	72	85	interleukin-8	Gene
20715983	100	105	human	Species
20715983	276	289	lung diseases	Disease
20715983	301	330	idiopathic pulmonary fibrosis	Disease
20715983	332	335	IPF	Disease
20715983	338	353	cystic fibrosis	Disease
20715983	355	357	CF	Disease
20715983	364	388	diffuse panbronchiolitis	Disease
20715983	390	393	DPB	Chemical
20715983	498	501	IPF	Disease
20715983	528	530	CF	Disease
20715983	535	538	DPB	Chemical
20715983	647	650	IPF	Disease
20715983	652	654	CF	Disease
20715983	660	663	DPB	Chemical
20715983	694	701	induce	Positive_regulation
20715983	701	719	interleukin (IL)-8	Gene
20715983	939	944	human	Species
20715983	945	971	neutrophil peptide (HNP)-1	Gene
20715983	1009	1021	expressions	Gene_expression
20715983	1024	1028	IL-8	Gene
20715983	1142	1147	HNP-1	Gene
20715983	1155	1164	enhanced	Positive_regulation
20715983	1168	1179	expression	Gene_expression
20715983	1182	1186	IL-8	Gene
20715983	1228	1259	transforming growth factor-beta	Gene
20715983	1264	1298	vascular endothelial growth factor	Gene
20715983	1419	1422	IPF	Disease
20715983	1424	1426	CF	Disease
20715983	1432	1435	DPB	Chemical
20715983	1511	1520	produced	Gene_expression
28131417|t|miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-b Receptor II
Idiopathic pulmonary fibrosis (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 (TGF-bRII) mRNA, and this is associated with reduced TGF-bRII expression and suppression of TGF-b-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, TGF-bRII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF
28131417	11	20	Inhibits	Negative_regulation
28131417	64	69	TGF-b	Gene
28131417	83	112	Idiopathic pulmonary fibrosis	Disease
28131417	114	117	IPF	Disease
28131417	124	156	chronic progressive lung disease	Disease
28131417	181	200	respiratory failure	Disease
28131417	205	210	death	Disease
28131417	246	272	pleural pulmonary fibrosis	Disease
28131417	303	306	IPF	Disease
28131417	308	317	Bleomycin	Chemical
28131417	331	335	mice	Species
28131417	356	374	pulmonary fibrosis	Disease
28131417	406	415	bleomycin	Chemical
28131417	479	503	pleural mesothelial cell	Disease
28131417	505	508	PMC	Disease
28131417	528	554	pleural pulmonary fibrosis	Disease
28131417	636	639	IPF	Disease
28131417	690	710	sub-pleural fibrosis	Disease
28131417	761	779	pulmonary fibrosis	Disease
28131417	823	831	reduced	Negative_regulation
28131417	852	861	bleomycin	Chemical
28131417	871	886	downregulation	Negative_regulation
28131417	971	977	binds	Binding
28131417	1087	1095	reduced	Negative_regulation
28131417	1104	1115	expression	Gene_expression
28131417	1134	1139	TGF-b	Gene
28131417	1140	1147	Smad2/3	Gene
28131417	1159	1174	Overexpression	Positive_regulation
28131417	1198	1207	bleomycin	Chemical
28131417	1223	1226	PMC	Disease
28131417	1241	1250	bleomycin	Chemical
28131417	1259	1279	sub-pleural fibrosis	Disease
28131417	1283	1287	mice	Species
28131417	1328	1342	downregulated	Negative_regulation
28131417	1366	1392	pleural pulmonary fibrosis	Disease
28131417	1401	1414	upregulation	Positive_regulation
28131417	1448	1463	overexpression	Positive_regulation
28131417	1538	1541	IPF	Disease
28662409|t|Human placental mesenchymal stem cells of fetal origins-alleviated inflammation and fibrosis by attenuating MyD88 signaling in bleomycin-induced pulmonary fibrosis mice
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 inflammation 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 inflammation 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	0	5	Human	Species
28662409	67	79	inflammation	Disease
28662409	84	92	fibrosis	Disease
28662409	108	113	MyD88	Gene
28662409	127	136	bleomycin	Chemical
28662409	145	163	pulmonary fibrosis	Disease
28662409	164	168	mice	Species
28662409	170	188	Pulmonary fibrosis	Disease
28662409	206	218	lung disease	Disease
28662409	369	381	inflammation	Disease
28662409	386	404	pulmonary fibrosis	Disease
28662409	508	537	idiopathic pulmonary fibrosis	Disease
28662409	539	542	IPF	Disease
28662409	640	643	IPF	Disease
28662409	765	770	MyD88	Gene
28662409	771	781	deficient	Negative_regulation
28662409	781	785	mice	Species
28662409	792	797	human	Species
28662409	874	896	pulmonary inflammation	Disease
28662409	901	909	fibrosis	Disease
28662409	963	968	MyD88	Gene
28662409	969	980	-deficient	Negative_regulation
28662409	980	984	mice	Species
28662409	998	1007	bleomycin	Chemical
28662409	1009	1012	BLM	Chemical
28662409	1042	1047	TGF-b	Gene
28662409	1110	1115	TNF-a	Gene
28662409	1117	1122	IL-1b	Gene
28662409	1212	1215	BLM	Chemical
28662409	1223	1233	increased	Positive_regulation
28662409	1233	1244	expression	Gene_expression
28662409	1265	1270	MyD88	Gene
28662409	1275	1280	TGF-b	Gene
28662409	1323	1334	expression	Gene_expression
28662409	1338	1349	inhibition	Negative_regulation
28662409	1352	1357	MyD88	Gene
28662409	1404	1409	TGF-b	Gene
28662409	1454	1457	BLM	Chemical
28662409	1498	1504	TGF-b1	Gene
28662409	1536	1543	effect	Regulation
28662409	1546	1551	MyD88	Gene
28662409	1595	1598	BLM	Chemical
28662409	1673	1676	BLM	Chemical
28662409	1685	1703	pulmonary fibrosis	Disease
28662409	1707	1711	mice	Species
28662409	1734	1748	hydroxyproline	Chemical
28662409	1750	1753	HYP	Chemical
28662409	1767	1772	MyD88	Gene
28662409	1777	1782	TGF-b	Gene
28662409	1890	1895	MyD88	Gene
28662409	1896	1901	TGF-b	Gene
28662409	2047	2065	pulmonary fibrosis	Disease
17178917|t|Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder characterized by activation of fibroblasts and overproduction of extracellular matrix (ECM)
Caveolin-1 (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	0	10	Caveolin-1	Gene
17178917	36	49	lung fibrosis	Disease
17178917	53	82	idiopathic pulmonary fibrosis	Disease
17178917	84	113	Idiopathic pulmonary fibrosis	Disease
17178917	115	118	IPF	Disease
17178917	137	153	chronic disorder	Disease
17178917	247	264	Caveolin-1 (cav-1	Gene
17178917	259	262	cav	Species
17178917	416	426	reduction	Negative_regulation
17178917	429	432	cav	Species
17178917	435	446	expression	Gene_expression
17178917	504	507	IPF	Disease
17178917	508	516	patients	Species
17178917	567	570	cav	Species
17178917	594	603	bleomycin	Chemical
17178917	605	608	BLM	Chemical
17178917	618	636	pulmonary fibrosis	Disease
17178917	677	691	hydroxyproline	Chemical
17178917	823	833	decreased	Negative_regulation
17178917	833	836	cav	Species
17178917	839	850	expression	Gene_expression
17178917	853	858	human	Species
17178917	882	885	cav	Species
17178917	978	989	regulation	Regulation
17178917	1002	1003	N	Chemical
17178917	1057	1067	activated	Positive_regulation
17178917	1087	1090	IPF	Disease
17178917	1154	1165	suppressed	Negative_regulation
17178917	1171	1174	cav	Species
17178917	1285	1288	cav	Species
17178917	1323	1328	role	Regulation
17178917	1332	1335	cav	Species
17178917	1345	1356	regulation	Regulation
17178917	1400	1408	patients	Species
17178917	1414	1432	pulmonary fibrosis	Disease
21044893|t|TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P
The pleiotropic growth factor TGFb(1) promotes many of the pathogenic mechanisms observed in lung fibrosis 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 fibrosis through an inhibition of pulmonary fibrocyte and pro-fibrotic alternative (M2) macrophage accumulation
It is unknown if SAP has effects downstream of TGFb(1), a major mediator of pulmonary fibrosis
Using the lung specific TGFb(1) transgenic mouse model, we determined that SAP inhibits all of the pathologies driven by TGFb(1) including apoptosis, airway inflammation, pulmonary fibrocyte accumulation and collagen deposition, without affecting levels of TGFb(1)
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 TGFb(1)-induced lung disease are via modulating monocyte responses
21044893	0	8	TGF-beta	Gene
21044893	21	29	fibrosis	Disease
21044893	116	122	TGFb(1	Gene
21044893	184	192	fibrosis	Disease
21044893	425	434	bleomycin	Chemical
21044893	448	456	fibrosis	Disease
21044893	608	615	TGFb(1)	Gene
21044893	637	655	pulmonary fibrosis	Disease
21044893	681	688	TGFb(1)	Gene
21044893	700	705	mouse	Species
21044893	778	785	TGFb(1)	Gene
21044893	807	826	airway inflammation	Disease
21044893	894	904	affecting	Regulation
21044893	914	921	TGFb(1)	Gene
21044893	1001	1011	clodronate	Chemical
21044893	1231	1241	increased	Positive_regulation
21044893	1251	1255	IP10	Gene
21044893	1256	1262	CXCL10	Gene
21044893	1263	1274	expression	Gene_expression
21044893	1279	1285	SMAD 3	Gene
21044893	1345	1353	reduced	Negative_regulation
21044893	1375	1378	IPF	Disease
21044893	1379	1387	patients	Species
21044893	1518	1526	patients	Species
21044893	1599	1606	TGFb(1)	Gene
21044893	1615	1627	lung disease	Disease
28751023|t|Lysocardiolipin acyltransferase regulates TGF-b mediated lung fibroblast differentiation
Lysocardiolipin acyltransferase (LYCAT), a cardiolipin remodeling enzyme, plays a key role in mitochondrial function and vascular development
We previously reported that reduced LYCAT mRNA levels in peripheral blood mononuclear cells correlated with poor pulmonary function outcomes and decreased survival in IPF patients
Further LYCAT overexpression reduced lung fibrosis, and LYCAT knockdown accentuated experimental pulmonary fibrosis
NADPH Oxidase 4 (NOX4) expression and oxidative stress are known to contribute to lung fibroblast differentiation and progression of fibrosis
In this study, we investigated the role of LYCAT in TGF-b mediated differentiation of human lung fibroblasts to myofibroblasts, and whether this occurred through mitochondrial superoxide and NOX4 mediated hydrogen peroxide (H2O2) generation
Our data indicated that LYCAT expression was up-regulated in primary lung fibroblasts isolated from IPF patients and bleomycin-challenged mice, compared to controls
In vitro, siRNA-mediated SMAD3 depletion inhibited TGF-b stimulated LYCAT expression in human lung fibroblasts
ChIP immunoprecipitation assay revealed TGF-b stimulated SMAD2/3 binding to the endogenous LYCAT promoter, and mutation of the SMAD2/3 binding sites (-179/-183 and -540/-544) reduced TGF-b-stimulated LYCAT promoter activity
Overexpression of LYCAT attenuated TGF-b-induced mitochondrial and intracellular oxidative stress, NOX4 expression and differentiation of human lung fibroblasts
Further, pretreatment with Mito-TEMPO, a mitochondrial superoxide scavenger, blocked TGF-b-induced mitochondrial superoxide, NOX4 expression and differentiation of human lung fibroblasts
Treatment of human lung fibroblast with NOX1/NOX4 inhibitor, GKT137831, also attenuated TGF-b induced fibroblast differentiation and mitochondrial oxidative stress
Collectively, these results suggest that LYCAT is a negative regulator of TGF-b-induced lung fibroblast differentiation by modulation of mitochondrial superoxide and NOX4 dependent H2O2 generation, and this may serve as a potential therapeutic target for human lung fibrosis
28751023	0	31	Lysocardiolipin acyltransferase	Gene
28751023	42	47	TGF-b	Gene
28751023	90	121	Lysocardiolipin acyltransferase	Gene
28751023	123	128	LYCAT	Gene
28751023	133	144	cardiolipin	Chemical
28751023	261	269	reduced	Negative_regulation
28751023	269	274	LYCAT	Gene
28751023	404	412	patients	Species
28751023	422	427	LYCAT	Gene
28751023	428	443	overexpression	Positive_regulation
28751023	470	475	LYCAT	Gene
28751023	476	486	knockdown	Negative_regulation
28751023	531	546	NADPH Oxidase 4	Gene
28751023	548	552	NOX4	Gene
28751023	554	565	expression	Gene_expression
28751023	717	722	LYCAT	Gene
28751023	726	731	TGF-b	Gene
28751023	760	765	human	Species
28751023	850	860	superoxide	Chemical
28751023	865	869	NOX4	Gene
28751023	879	896	hydrogen peroxide	Chemical
28751023	898	902	H2O2	Chemical
28751023	940	945	LYCAT	Gene
28751023	946	957	expression	Gene_expression
28751023	961	974	up-regulated	Positive_regulation
28751023	1020	1028	patients	Species
28751023	1033	1042	bleomycin	Chemical
28751023	1054	1058	mice	Species
28751023	1107	1112	SMAD3	Gene
28751023	1113	1123	depletion	Negative_regulation
28751023	1123	1133	inhibited	Negative_regulation
28751023	1133	1138	TGF-b	Gene
28751023	1139	1150	stimulated	Positive_regulation
28751023	1150	1155	LYCAT	Gene
28751023	1156	1167	expression	Gene_expression
28751023	1170	1175	human	Species
28751023	1225	1234	revealed	Negative_regulation
28751023	1234	1239	TGF-b	Gene
28751023	1240	1251	stimulated	Positive_regulation
28751023	1251	1258	SMAD2/3	Gene
28751023	1259	1267	binding	Binding
28751023	1285	1290	LYCAT	Gene
28751023	1305	1314	mutation	Positive_regulation
28751023	1321	1326	SMAD2	Gene
28751023	1344	1354	-179/-183	Entity
28751023	1377	1382	TGF-b	Gene
28751023	1394	1399	LYCAT	Gene
28751023	1419	1434	Overexpression	Positive_regulation
28751023	1437	1442	LYCAT	Gene
28751023	1454	1459	TGF-b	Gene
28751023	1518	1522	NOX4	Gene
28751023	1523	1534	expression	Gene_expression
28751023	1557	1562	human	Species
28751023	1613	1618	TEMPO	Chemical
28751023	1636	1646	superoxide	Chemical
28751023	1658	1666	blocked	Negative_regulation
28751023	1666	1671	TGF-b	Gene
28751023	1694	1704	superoxide	Chemical
28751023	1706	1710	NOX4	Gene
28751023	1711	1722	expression	Gene_expression
28751023	1745	1750	human	Species
28751023	1782	1787	human	Species
28751023	1809	1813	NOX1	Gene
28751023	1814	1818	NOX4	Gene
28751023	1819	1829	inhibitor	Negative_regulation
28751023	1830	1839	GKT137831	Chemical
28751023	1857	1862	TGF-b	Gene
28751023	1975	1980	LYCAT	Gene
28751023	2008	2013	TGF-b	Gene
28751023	2085	2095	superoxide	Chemical
28751023	2100	2104	NOX4	Gene
28751023	2115	2119	H2O2	Chemical
28751023	2189	2194	human	Species
11350829|t|Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression
Idiopathic pulmonary fibrosis (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	17	46	idiopathic pulmonary fibrosis	Disease
11350829	109	119	inhibitor	Negative_regulation
11350829	141	152	expression	Gene_expression
11350829	153	182	Idiopathic pulmonary fibrosis	Disease
11350829	184	187	IPF	Disease
11350829	194	215	chronic lung disorder	Disease
11350829	353	363	synthesis	Gene_expression
11350829	442	450	formazan	Chemical
11350829	532	548	propidium iodide	Chemical
11350829	767	829	tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4	Gene
11350829	830	841	expression	Gene_expression
11350829	920	923	IPF	Disease
11350829	982	985	IPF	Disease
11350829	1161	1164	IPF	Disease
11350829	1337	1340	IPF	Disease
11350829	1413	1416	IPF	Disease
11350829	1454	1463	increase	Positive_regulation
11350829	1491	1500	TGF-beta1	Gene
11350829	1536	1547	expression	Gene_expression
11350829	1587	1598	expression	Gene_expression
11350829	1665	1668	IPF	Disease
26264443|t|Phosphatase and tensin homolog deleted on chromosome 10 contributes to phenotype transformation of fibroblasts in idiopathic pulmonary fibrosis via multiple pathways
Idiopathic pulmonary fibrosis (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	114	143	idiopathic pulmonary fibrosis	Disease
26264443	167	196	Idiopathic pulmonary fibrosis	Disease
26264443	198	201	IPF	Disease
26264443	208	237	progressive and fatal disease	Disease
26264443	258	277	cancer-like disease	Disease
26264443	342	346	PTEN	Gene
26264443	348	353	tumor	Disease
26264443	408	411	IPF	Disease
26264443	434	438	PTEN	Gene
26264443	582	586	PTEN	Gene
26264443	587	598	expression	Gene_expression
26264443	611	619	reduced	Negative_regulation
26264443	663	666	IPF	Disease
26264443	690	695	loss	Negative_regulation
26264443	698	702	PTEN	Gene
26264443	855	859	PTEN	Gene
26264443	860	871	deficiency	Negative_regulation
26264443	871	883	upregulated	Positive_regulation
26264443	883	904	hyaluronan synthase 2	Gene
26264443	905	916	expression	Gene_expression
26264443	993	997	PTEN	Gene
26264443	1006	1035	transforming growth factor b1	Gene
26264443	1037	1043	TGF-b1	Gene
26264443	1057	1061	PTEN	Gene
26264443	1075	1082	hypoxia	Disease
26264443	1126	1130	PTEN	Gene
26264443	1214	1217	IPF	Disease
12598227|t|Release of biologically active TGF-beta1 by alveolar epithelial cells results in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive fatal fibrotic lung disease
Transforming growth factor (TGF)-beta1 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 TGF-beta1 by alveolar epithelial cells (AECs), the AECs of explanted normal rat lungs were transfected with the TGF-beta1 gene using the retrovirus pMX-L-s223,225-TGF-beta1
In situ hybridization using a digoxigenin-labeled cDNA of the puromycin resistance gene contained in the pMX demonstrated that pMX-L-s233,225-TGF-beta1 was selectively transfected into AECs of the explants
Conditioned media overlying explants obtained 7 days after being treated with pMX-L-s223,225-TGF-beta1 contained 14.5 +/- 3.15 pg/ml of active TGF-beta1
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-TGF-beta1
The findings in the current study suggest that IPF may be a disorder of epithelial cells and not inflammatory cells
12598227	0	8	Release	Localization
12598227	31	40	TGF-beta1	Gene
12598227	81	99	pulmonary fibrosis	Disease
12598227	101	130	Idiopathic pulmonary fibrosis	Disease
12598227	132	135	IPF	Disease
12598227	160	181	fibrotic lung disease	Disease
12598227	183	221	Transforming growth factor (TGF)-beta1	Gene
12598227	324	327	IPF	Disease
12598227	363	374	expression	Gene_expression
12598227	397	406	TGF-beta1	Gene
12598227	473	476	rat	Species
12598227	488	500	transfected	Positive_regulation
12598227	509	518	TGF-beta1	Gene
12598227	560	569	TGF-beta1	Gene
12598227	601	612	digoxigenin	Chemical
12598227	633	642	puromycin	Chemical
12598227	713	722	TGF-beta1	Gene
12598227	871	880	TGF-beta1	Gene
12598227	921	930	TGF-beta1	Gene
12598227	1072	1075	IPF	Disease
12598227	1094	1117	type II AEC hyperplasia	Disease
12598227	1336	1346	increased	Positive_regulation
12598227	1386	1395	TGF-beta1	Gene
12598227	1444	1447	IPF	Disease
28613983|t|Azithromycin attenuates myofibroblast differentiation and lung fibrosis development through proteasomal degradation of NOX4
Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (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 fibrosis 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 fibrosis 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 fibrosis 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 fibrosis development
AZM may be a candidate for the treatment of the fibrotic lung disease IPF
28613983	0	12	Azithromycin	Chemical
28613983	63	71	fibrosis	Disease
28613983	92	115	proteasomal degradation	Disease
28613983	104	116	degradation	Protein_catabolism
28613983	119	123	NOX4	Gene
28613983	198	206	fibrosis	Disease
28613983	226	255	idiopathic pulmonary fibrosis	Disease
28613983	257	260	IPF	Disease
28613983	276	280	TGFB	Gene
28613983	282	310	transforming growth factor b	Gene
28613983	392	396	NOX4	Gene
28613983	398	413	NADPH oxidase 4	Gene
28613983	440	444	TGFB	Gene
28613983	470	482	Azithromycin	Chemical
28613983	484	487	AZM	Chemical
28613983	524	533	macrolide	Chemical
28613983	592	604	proteostasis	Disease
28613983	634	637	AZM	Chemical
28613983	642	651	regulate	Regulation
28613983	651	655	NOX4	Gene
28613983	677	689	proteostasis	Disease
28613983	730	734	TGFB	Gene
28613983	751	759	fibrosis	Disease
28613983	773	778	Human	Species
28613983	823	827	TGFB	Gene
28613983	883	887	NOX4	Gene
28613983	888	899	regulation	Regulation
28613983	903	915	proteostasis	Disease
28613983	1071	1074	AZM	Chemical
28613983	1097	1106	bleomycin	Chemical
28613983	1108	1111	BLM	Chemical
28613983	1126	1134	fibrosis	Disease
28613983	1135	1140	mouse	Species
28613983	1149	1153	TGFB	Gene
28613983	1154	1162	induced	Positive_regulation
28613983	1162	1166	NOX4	Gene
28613983	1214	1224	inhibited	Negative_regulation
28613983	1227	1230	AZM	Chemical
28613983	1248	1251	AZM	Chemical
28613983	1261	1265	NOX4	Gene
28613983	1307	1312	MG132	Chemical
28613983	1338	1341	AZM	Chemical
28613983	1408	1411	AZM	Chemical
28613983	1444	1448	NOX4	Gene
28613983	1453	1463	increased	Positive_regulation
28613983	1471	1478	levels	Gene_expression
28613983	1481	1486	STUB1	Gene
28613983	1488	1493	STIP1	Gene
28613983	1580	1583	AZM	Chemical
28613983	1634	1637	AZM	Chemical
28613983	1654	1662	fibrosis	Disease
28613983	1686	1689	BLM	Chemical
28613983	1709	1717	reduced	Negative_regulation
28613983	1717	1721	NOX4	Gene
28613983	1800	1803	AZM	Chemical
28613983	1804	1815	suppresses	Negative_regulation
28613983	1815	1819	NOX4	Gene
28613983	1833	1856	proteasomal degradation	Disease
28613983	1885	1889	TGFB	Gene
28613983	1937	1945	fibrosis	Disease
28613983	1959	1962	AZM	Chemical
28613983	2007	2028	fibrotic lung disease	Disease
28613983	2029	2032	IPF	Disease
12837171|t|[Potential role of cytokines in idiopathic pulmonary fibrosis]
OBJECTIVE: To investigate the expression of platelet-derived growth factor(PDGF) and transforming growth factor-beta (TGF-beta) in transbronchial lung biopsy (TBLB) from patients with idiopathic pulmonary fibrosis(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	32	61	idiopathic pulmonary fibrosis	Disease
12837171	94	105	expression	Gene_expression
12837171	149	180	transforming growth factor-beta	Gene
12837171	182	190	TGF-beta	Gene
12837171	234	242	patients	Species
12837171	248	277	idiopathic pulmonary fibrosis	Disease
12837171	278	281	IPF	Disease
12837171	348	351	IPF	Disease
12837171	421	432	expression	Gene_expression
12837171	441	449	TGF-beta	Gene
12837171	463	471	patients	Species
12837171	477	480	IPF	Disease
12837171	494	497	IPF	Disease
12837171	498	506	patients	Species
12837171	508	516	TGF-beta	Gene
12837171	643	654	expression	Gene_expression
12837171	884	895	expression	Gene_expression
12837171	949	957	TGF-beta	Gene
12837171	965	974	interact	Binding
12837171	1041	1059	pulmonary fibrosis	Disease
17198680|t|Overproduction of collagen and diminished SOCS1 expression are causally linked in fibroblasts from idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 SOCS1 than fibroblasts from normal lung
By using mouse fibroblasts, we demonstrated the causal relationship between them: the deficiency of SOCS1 in fibroblasts resulted in increased collagen production, whereas overexpression of SOCS1 suppressed collagen production
IFN-gamma suppressed spontaneous collagen production even in SOCS1-deficient fibroblasts, indicating that IFN-gamma inhibition is SOCS1-independent
In contrast, IFN-gamma suppressed the increase of collagen production induced by IL-4 in wild type fibroblasts but not SOCS1-deficient fibroblasts, suggesting IFN-gamma acted exclusively via SOCS1 in this case
Following IFN-gamma stimulation, the amount of SOCS1 mRNA expressed by IPF fibroblasts was comparable to that of normal fibroblasts
Thus, the extent of SOCS1 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 SOCS1, and IPF fibroblasts are more susceptible to IFN-gamma because of decreased expression of SOCS1
17198680	0	15	Overproduction	Gene_expression
17198680	31	42	diminished	Negative_regulation
17198680	42	47	SOCS1	Gene
17198680	48	59	expression	Gene_expression
17198680	99	128	idiopathic pulmonary fibrosis	Disease
17198680	130	159	Idiopathic pulmonary fibrosis	Disease
17198680	161	164	IPF	Disease
17198680	209	227	pulmonary disorder	Disease
17198680	279	287	fibrosis	Disease
17198680	403	406	IPF	Disease
17198680	495	504	produced	Gene_expression
17198680	552	563	expression	Gene_expression
17198680	573	578	SOCS1	Gene
17198680	623	628	mouse	Species
17198680	700	711	deficiency	Negative_regulation
17198680	714	719	SOCS1	Gene
17198680	747	757	increased	Positive_regulation
17198680	766	777	production	Gene_expression
17198680	786	801	overexpression	Positive_regulation
17198680	804	809	SOCS1	Gene
17198680	830	841	production	Gene_expression
17198680	842	851	IFN-gamma	Gene
17198680	884	895	production	Gene_expression
17198680	903	908	SOCS1	Gene
17198680	909	919	deficient	Negative_regulation
17198680	948	957	IFN-gamma	Gene
17198680	958	969	inhibition	Negative_regulation
17198680	972	977	SOCS1	Gene
17198680	1004	1013	IFN-gamma	Gene
17198680	1014	1025	suppressed	Negative_regulation
17198680	1029	1038	increase	Positive_regulation
17198680	1050	1061	production	Gene_expression
17198680	1061	1069	induced	Positive_regulation
17198680	1072	1076	IL-4	Gene
17198680	1110	1115	SOCS1	Gene
17198680	1116	1126	deficient	Negative_regulation
17198680	1150	1159	IFN-gamma	Gene
17198680	1182	1187	SOCS1	Gene
17198680	1212	1221	IFN-gamma	Gene
17198680	1249	1254	SOCS1	Gene
17198680	1260	1270	expressed	Gene_expression
17198680	1355	1360	SOCS1	Gene
17198680	1391	1400	IFN-gamma	Gene
17198680	1466	1475	IFN-gamma	Gene
17198680	1476	1486	inhibited	Negative_regulation
17198680	1495	1506	production	Gene_expression
17198680	1612	1623	production	Gene_expression
17198680	1695	1706	diminished	Negative_regulation
17198680	1706	1717	expression	Gene_expression
17198680	1720	1725	SOCS1	Gene
17198680	1756	1768	susceptible	Positive_regulation
17198680	1771	1780	IFN-gamma	Gene
17198680	1792	1802	decreased	Negative_regulation
17198680	1802	1813	expression	Gene_expression
17198680	1816	1821	SOCS1	Gene
16837501|t|Thalidomide reduces IL-18, IL-8 and TNF-alpha release from alveolar macrophages in interstitial lung disease
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 (TNF)-alpha
The mechanisms that underlie the properties of thalidomide are still unclear in interstitial lung disease
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, TNF-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12p70, IL-12p40 and IL-18 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 TNF-alpha, IL-12p40 and IL-18 release
At the highest thalidomide concentration (0.1 mM), LPS-stimulated IL-8 production was also suppressed
In IPF patients, although spontaneous production of TNF-alpha, IL-12p40, IL-18 and IL-8 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	0	11	Thalidomide	Chemical
16837501	12	20	reduces	Negative_regulation
16837501	20	25	IL-18	Gene
16837501	27	31	IL-8	Gene
16837501	36	45	TNF-alpha	Gene
16837501	46	54	release	Localization
16837501	83	108	interstitial lung disease	Disease
16837501	110	121	Thalidomide	Chemical
16837501	155	167	inflammation	Disease
16837501	225	236	thalidomide	Chemical
16837501	250	261	sarcoidosis	Disease
16837501	267	279	lupus pernio	Disease
16837501	304	315	inhibition	Negative_regulation
16837501	318	324	tumour	Disease
16837501	325	333	necrosis	Disease
16837501	342	352	TNF)-alpha	Gene
16837501	401	412	thalidomide	Chemical
16837501	434	459	interstitial lung disease	Disease
16837501	519	527	effects	Regulation
16837501	530	541	thalidomide	Chemical
16837501	593	604	production	Gene_expression
16837501	640	649	TNF-alpha	Gene
16837501	651	673	interleukin (IL)-1beta	Gene
16837501	675	679	IL-6	Gene
16837501	681	685	IL-8	Gene
16837501	687	692	IL-10	Gene
16837501	717	722	IL-18	Gene
16837501	778	786	patients	Species
16837501	792	803	sarcoidosis	Disease
16837501	813	841	hypersensitivity pneumonitis	Disease
16837501	843	845	HP	Disease
16837501	858	887	idiopathic pulmonary fibrosis	Disease
16837501	889	892	IPF	Disease
16837501	906	917	sarcoidosis	Disease
16837501	922	924	HP	Disease
16837501	925	933	patients	Species
16837501	935	946	thalidomide	Chemical
16837501	947	955	induced	Positive_regulation
16837501	981	993	suppression	Negative_regulation
16837501	1031	1040	TNF-alpha	Gene
16837501	1055	1060	IL-18	Gene
16837501	1085	1096	thalidomide	Chemical
16837501	1136	1140	IL-8	Gene
16837501	1176	1179	IPF	Disease
16837501	1180	1188	patients	Species
16837501	1211	1222	production	Gene_expression
16837501	1225	1234	TNF-alpha	Gene
16837501	1246	1251	IL-18	Gene
16837501	1256	1260	IL-8	Gene
16837501	1279	1290	sarcoidosis	Disease
16837501	1295	1297	HP	Disease
16837501	1298	1306	patients	Species
16837501	1362	1371	elevated	Positive_regulation
16837501	1403	1414	thalidomide	Chemical
16837501	1431	1442	thalidomide	Chemical
16837501	1501	1512	sarcoidosis	Disease
16837501	1514	1542	hypersensitivity pneumonitis	Disease
16837501	1547	1576	idiopathic pulmonary fibrosis	Disease
16837501	1580	1589	reducing	Negative_regulation
16837501	1589	1595	tumour	Disease
16837501	1596	1604	necrosis	Disease
16837501	1619	1636	interleukin-12p40	Gene
16837501	1638	1652	interleukin-18	Gene
16837501	1657	1670	interleukin-8	Gene
16837501	1671	1682	production	Gene_expression
11776068|t|The potential role of PDGF, IGF-1, TGF-beta expression in idiopathic pulmonary fibrosis
OBJECTIVE: To identify the role of cytokines involved in the development of lung fibrosis 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 (IGF-1), and transforming growth factor beta (TGF-beta) 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, IGF-1, TGF-beta were localized in alveolar macrophages
Evaluation of open lung biopsies from patients with IPF showed that IGF-1 was prominently present in pulmonary vessel walls in fibrotic lesions
PDGF and TGF-beta 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 TGF-beta 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, IGF-1 and TGF-beta; (2) IGF-1 could be responsible for angiogenesis in IPF; (3) PDGF, TGF-beta are associated with fibroplasia and the deposition of extracellular matrix, as well as vessel remodeling and epithelial cell repopularization
11776068	14	19	role	Regulation
11776068	28	33	IGF-1	Gene
11776068	35	43	TGF-beta	Gene
11776068	44	55	expression	Gene_expression
11776068	58	87	idiopathic pulmonary fibrosis	Disease
11776068	165	178	lung fibrosis	Disease
11776068	182	190	patients	Species
11776068	196	225	idiopathic-pulmonary fibrosis	Disease
11776068	227	230	IPF	Disease
11776068	260	271	expression	Gene_expression
11776068	352	357	IGF-1	Gene
11776068	364	395	transforming growth factor beta	Gene
11776068	397	405	TGF-beta	Gene
11776068	473	481	patients	Species
11776068	487	490	IPF	Disease
11776068	619	625	PDGF-A	Gene
11776068	627	633	PDGF-B	Gene
11776068	635	640	IGF-1	Gene
11776068	642	650	TGF-beta	Gene
11776068	729	737	patients	Species
11776068	743	746	IPF	Disease
11776068	759	764	IGF-1	Gene
11776068	818	834	fibrotic lesions	Disease
11776068	845	853	TGF-beta	Gene
11776068	868	878	localized	Localization
11776068	1107	1113	PDGF-A	Gene
11776068	1118	1126	TGF-beta	Gene
11776068	1153	1162	detected	Gene_expression
11776068	1295	1307	inflammation	Disease
11776068	1344	1354	releasing	Localization
11776068	1360	1365	IGF-1	Gene
11776068	1370	1378	TGF-beta	Gene
11776068	1384	1389	IGF-1	Gene
11776068	1431	1434	IPF	Disease
11776068	1446	1454	TGF-beta	Gene
11776068	1459	1470	associated	Binding
11776068	1475	1486	fibroplasia	Disease
24140943|t|Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice
Our objective was to investigate the pathogenesis pathways of idiopathic pulmonary fibrosis (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	25	54	idiopathic pulmonary fibrosis	Disease
24140943	58	67	bleomycin	Chemical
24140943	76	87	lung injury	Disease
24140943	97	101	mice	Species
24140943	165	194	idiopathic pulmonary fibrosis	Disease
24140943	196	199	IPF	Disease
24140943	202	211	Bleomycin	Chemical
24140943	213	216	BLM	Chemical
24140943	243	269	experimental lung fibrosis	Disease
24140943	330	335	Smad3	Gene
24140943	340	345	IL-31	Gene
24140943	355	367	expressions	Gene_expression
24140943	370	376	TGF-b1	Gene
24140943	378	383	Smad3	Gene
24140943	385	390	IL-31	Gene
24140943	395	400	STAT1	Gene
24140943	493	515	injury or inflammation	Disease
24140943	569	581	inflammation	Disease
24140943	601	619	pulmonary fibrosis	Disease
24140943	630	641	expression	Gene_expression
24140943	644	650	TGF-b1	Gene
24140943	655	660	Smad3	Gene
24140943	661	671	increased	Positive_regulation
24140943	672	682	Activated	Positive_regulation
24140943	682	687	Smad3	Gene
24140943	688	694	bound	Binding
24140943	701	706	IL-31	Gene
24140943	777	787	inhibitor	Negative_regulation
24140943	790	796	TGF-b1	Gene
24140943	820	825	IL-31	Gene
24140943	858	863	IL-31	Gene
24140943	869	879	decreased	Negative_regulation
24140943	883	888	STAT1	Gene
24140943	889	900	expression	Gene_expression
24140943	968	973	mouse	Species
24140943	985	994	involves	Regulation
24140943	998	1003	TGF-b	Gene
24140943	1005	1010	IL-31	Gene
18395486|t|Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGFbeta1, IL-13 and CCL2
One of the hallmarks of idiopathic pulmonary fibrosis with a usual interstitial pneumonia histological pathology (IPF/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 IPF/UIP fibroblasts
IPF/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, IPF/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 IPF/UIP, where these three mediators feedback on each other, promoting the fibrotic response
18395486	24	27	IPF	Disease
18395486	28	31	UIP	Disease
18395486	63	71	TGFbeta1	Gene
18395486	73	78	IL-13	Gene
18395486	83	87	CCL2	Gene
18395486	113	142	idiopathic pulmonary fibrosis	Disease
18395486	156	178	interstitial pneumonia	Disease
18395486	203	206	IPF	Disease
18395486	207	210	UIP	Disease
18395486	325	331	murine	Species
18395486	342	355	lung fibrosis	Disease
18395486	405	410	IL-13	Gene
18395486	419	423	CCL2	Gene
18395486	446	454	TGFbeta1	Gene
18395486	545	550	human	Species
18395486	582	587	human	Species
18395486	588	591	IPF	Disease
18395486	592	595	UIP	Disease
18395486	609	612	IPF	Disease
18395486	613	616	UIP	Disease
18395486	791	799	TGFbeta1	Gene
18395486	838	843	IL-13	Gene
18395486	847	851	CCL2	Gene
18395486	862	865	IPF	Disease
18395486	866	869	UIP	Disease
18395486	901	909	TGFbeta1	Gene
18395486	911	916	IL-13	Gene
18395486	921	925	CCL2	Gene
18395486	942	950	TGFbeta1	Gene
18395486	952	956	CCL2	Gene
18395486	961	966	IL-13	Gene
18395486	971	983	upregulated	Positive_regulation
18395486	1004	1009	IL-13	Gene
18395486	1019	1030	expression	Gene_expression
18395486	1200	1204	CCL2	Gene
18395486	1213	1222	bleomycin	Chemical
18395486	1231	1249	pulmonary fibrosis	Disease
18395486	1264	1272	reduced	Negative_regulation
18395486	1310	1314	CCR2	Gene
18395486	1315	1326	expression	Gene_expression
18395486	1339	1348	bleomycin	Chemical
18395486	1356	1360	CTGF	Gene
18395486	1378	1386	induced	Positive_regulation
18395486	1519	1527	TGFbeta1	Gene
18395486	1529	1534	IL-13	Gene
18395486	1539	1543	CCL2	Gene
18395486	1547	1550	IPF	Disease
18395486	1551	1554	UIP	Disease
19381013|t|VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats
Idiopathic pulmonary fibrosis (IPF) can lead to the development of secondary pulmonary hypertension (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 VEGF 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 VEGF 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 VEGF 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 VEGF ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, VEGF-based therapies should be used with caution
19381013	0	4	VEGF	Gene
19381013	27	39	hypertension	Disease
19381013	105	113	fibrosis	Disease
19381013	117	121	rats	Species
19381013	123	152	Idiopathic pulmonary fibrosis	Disease
19381013	154	157	IPF	Disease
19381013	190	222	secondary pulmonary hypertension	Disease
19381013	340	343	rat	Species
19381013	353	356	IPF	Disease
19381013	432	436	VEGF	Gene
19381013	528	537	TGF-beta1	Gene
19381013	629	666	increased pulmonary arterial pressure	Disease
19381013	668	671	PAP	Disease
19381013	722	732	decreased	Negative_regulation
19381013	742	746	VEGF	Gene
19381013	802	805	PAP	Chemical
19381013	891	894	IPF	Disease
19381013	895	899	rats	Species
19381013	928	932	VEGF	Gene
19381013	1016	1019	PAP	Disease
19381013	1059	1061	PF	Disease
19381013	1097	1115	pulmonary fibrosis	Disease
19381013	1117	1119	PF	Disease
19381013	1290	1294	VEGF	Gene
19381013	1381	1385	VEGF	Gene
20081107|t|Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension
Idiopathic pulmonary arterial hypertension (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 b(558) 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	78	120	idiopathic pulmonary arterial hypertension	Disease
20081107	125	157	secondary pulmonary hypertension	Disease
20081107	159	201	Idiopathic pulmonary arterial hypertension	Disease
20081107	257	288	pulmonary arteriolar remodeling	Disease
20081107	405	427	pulmonary hypertension	Disease
20081107	429	431	PH	Disease
20081107	615	617	PH	Disease
20081107	631	660	idiopathic pulmonary fibrosis	Disease
20081107	662	665	IPF	Disease
20081107	861	874	pathogenesis	Gene_expression
20081107	956	960	cAMP	Chemical
20081107	1001	1009	estrogen	Chemical
20081107	1020	1032	nitric oxide	Chemical
20081107	1096	1107	expression	Gene_expression
20081107	1111	1125	downregulated	Negative_regulation
20081107	1176	1181	Women	Species
20081107	1202	1213	expression	Gene_expression
20081107	1223	1242	estrogen receptor 1	Gene
20081107	1255	1260	women	Species
20081107	1312	1323	expression	Gene_expression
20081107	1390	1392	PH	Disease
20081107	1393	1403	secondary	Binding
20081107	1406	1409	IPF	Disease
20081107	1413	1430	disintegrin-like	Binding
20081107	1526	1531	L1CAM	Gene
20081107	1533	1545	cytochrome b	Gene
20081107	1612	1617	A-myb	Gene
20081107	1754	1768	tropomodulin 3	Gene
20081107	1792	1795	PAH	Chemical
20081107	1800	1802	PH	Disease
20081107	1816	1819	IPF	Disease
24515257|t|Transforming growth factor-b1 downregulates vascular endothelial growth factor-D expression in human lung fibroblasts via the Jun NH2-terminal kinase signaling pathway
Vascular endothelial growth factor (VEGF)-D, a member of the VEGF family, induces both angiogenesis and lymphangiogenesis by activating VEGF receptor-2 (VEGFR-2) and VEGFR-3 on the surface of endothelial cells
Transforming growth factor (TGF)-b1 has been shown to stimulate VEGF-A expression in human lung fibroblast via the Smad3 signaling pathway and to induce VEGF-C in human proximal tubular epithelial cells
However, the effects of TGF-b1 on VEGF-D regulation are unknown
To investigate the regulation of VEGF-D, human lung fibroblasts were studied under pro-fibrotic conditions in vitro and in idiopathic pulmonary fibrosis (IPF) lung tissue
We demonstrate that TGF-b1 downregulates VEGF-D expression in a dose- and time-dependent manner in human lung fibroblasts
This TGF-b1 effect can be abolished by inhibitors of TGF-b type I receptor kinase and Jun NH2-terminal kinase (JNK), but not by Smad3 knockdown
In addition, VEGF-D knockdown in human lung fibroblasts induces G1/S transition and promotes cell proliferation
Importantly, VEGF-D protein expression is decreased in lung homogenates from IPF patients compared with control lung
In IPF lung sections, fibroblastic foci show very weak VEGF-D immunoreactivity, whereas VEGF-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 TGF-b1 in lung fibroblasts, through which they may mediate tissue remodeling in IPF
24515257	44	78	vascular endothelial growth factor	Gene
24515257	95	100	human	Species
24515257	126	149	Jun NH2-terminal kinase	Gene
24515257	169	203	Vascular endothelial growth factor	Gene
24515257	205	209	VEGF	Gene
24515257	230	234	VEGF	Gene
24515257	294	305	activating	Positive_regulation
24515257	305	320	VEGF receptor-2	Gene
24515257	322	329	VEGFR-2	Gene
24515257	335	342	VEGFR-3	Gene
24515257	380	415	Transforming growth factor (TGF)-b1	Gene
24515257	434	444	stimulate	Positive_regulation
24515257	444	450	VEGF-A	Gene
24515257	451	462	expression	Gene_expression
24515257	465	470	human	Species
24515257	495	500	Smad3	Gene
24515257	526	533	induce	Positive_regulation
24515257	533	539	VEGF-C	Gene
24515257	543	548	human	Species
24515257	597	605	effects	Regulation
24515257	608	614	TGF-b1	Gene
24515257	618	624	VEGF-D	Gene
24515257	625	636	regulation	Regulation
24515257	668	679	regulation	Regulation
24515257	682	688	VEGF-D	Gene
24515257	772	801	idiopathic pulmonary fibrosis	Disease
24515257	803	806	IPF	Disease
24515257	841	847	TGF-b1	Gene
24515257	848	862	downregulates	Negative_regulation
24515257	862	868	VEGF-D	Gene
24515257	869	880	expression	Gene_expression
24515257	920	925	human	Species
24515257	949	955	TGF-b1	Gene
24515257	970	980	abolished	Binding
24515257	983	994	inhibitors	Negative_regulation
24515257	1030	1053	Jun NH2-terminal kinase	Gene
24515257	1055	1058	JNK	Gene
24515257	1072	1077	Smad3	Gene
24515257	1102	1108	VEGF-D	Gene
24515257	1109	1119	knockdown	Negative_regulation
24515257	1122	1127	human	Species
24515257	1145	1153	induces	Positive_regulation
24515257	1215	1221	VEGF-D	Gene
24515257	1230	1241	expression	Gene_expression
24515257	1244	1254	decreased	Negative_regulation
24515257	1279	1282	IPF	Disease
24515257	1283	1291	patients	Species
24515257	1323	1326	IPF	Disease
24515257	1375	1381	VEGF-D	Gene
24515257	1408	1414	VEGF-D	Gene
24515257	1429	1439	expressed	Gene_expression
24515257	1589	1595	TGF-b1	Gene
24515257	1669	1672	IPF	Disease
24886817|t|Corilagin attenuates aerosol bleomycin-induced experimental lung injury
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 lung injury 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	0	9	Corilagin	Chemical
24886817	29	38	bleomycin	Chemical
24886817	60	71	lung injury	Disease
24886817	73	102	Idiopathic pulmonary fibrosis	Disease
24886817	104	107	IPF	Disease
24886817	182	191	Corilagin	Chemical
24886817	197	203	tannin	Chemical
24886817	305	308	IPF	Disease
24886817	346	355	corilagin	Chemical
24886817	359	370	lung injury	Disease
24886817	381	390	bleomycin	Chemical
24886817	422	440	pulmonary fibrosis	Disease
24886817	442	451	Corilagin	Chemical
24886817	462	471	bleomycin	Chemical
24886817	485	493	fibrosis	Disease
24886817	551	565	hydroxyproline	Chemical
24886817	590	599	Corilagin	Chemical
24886817	777	786	Bleomycin	Chemical
24886817	796	804	induced	Positive_regulation
24886817	804	815	expression	Gene_expression
24886817	818	821	MDA	Chemical
24886817	823	827	IKKa	Gene
24886817	844	848	IKKa	Gene
24886817	852	856	IKKa	Gene
24886817	870	875	TNF-a	Gene
24886817	880	885	IL-1b	Gene
24886817	918	922	mice	Species
24886817	988	997	corilagin	Chemical
24886817	1071	1080	corilagin	Chemical
24886817	1090	1096	TGF-b1	Gene
24886817	1112	1117	a-SMA	Gene
24886817	1199	1208	corilagin	Chemical
24886817	1220	1229	bleomycin	Chemical
24886817	1238	1255	epithelial injury	Disease
24886817	1260	1268	fibrosis	Disease
24886817	1273	1286	inactivation	Negative_regulation
24886817	1354	1360	TGF-b1	Gene
24886817	1372	1381	Corilagin	Chemical
24886817	1429	1447	pulmonary fibrosis	Disease
23565148|t|Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease
The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (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	0	9	Bleomycin	Chemical
23565148	57	86	idiopathic pulmonary fibrosis	Disease
23565148	143	152	bleomycin	Chemical
23565148	161	174	lung fibrosis	Disease
23565148	218	247	idiopathic pulmonary fibrosis	Disease
23565148	249	252	IPF	Disease
23565148	524	533	bleomycin	Chemical
23565148	542	546	mice	Species
23565148	551	559	patients	Species
23565148	565	568	IPF	Disease
23565148	718	727	bleomycin	Chemical
23565148	792	795	IPF	Disease
23565148	796	804	patients	Species
23565148	1091	1094	IPF	Disease
23565148	1095	1103	patients	Species
23565148	1163	1167	TGFb	Gene
23565148	1255	1260	ALK-5	Gene
23565148	1261	1271	inhibitor	Negative_regulation
23565148	1271	1279	SB525334	Chemical
23565148	1327	1335	fibrosis	Disease
23565148	1408	1417	bleomycin	Chemical
23565148	1454	1457	IPF	Disease
23565148	1558	1567	bleomycin	Chemical
23565148	1673	1676	IPF	Disease
23565148	1714	1722	patients	Species
12882453|t|Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10
Modulation of cytokine expression represents a potentially useful approach for the treatment of idiopathic pulmonary fibrosis (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 idiopathic pulmonary fibrosis 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	21	50	idiopathic pulmonary fibrosis	Disease
12882453	81	89	TGF-beta	Gene
12882453	94	99	IL-10	Gene
12882453	197	226	idiopathic pulmonary fibrosis	Disease
12882453	228	231	IPF	Disease
12882453	480	488	patients	Species
12882453	494	497	IPF	Disease
12882453	832	842	increased	Positive_regulation
12882453	864	872	patients	Species
12882453	878	881	IPF	Disease
12882453	1043	1069	keratinocyte growth factor	Gene
12882453	1071	1074	KGF	Gene
12882453	1081	1091	expressed	Gene_expression
12882453	1124	1132	patients	Species
12882453	1138	1141	IPF	Disease
12882453	1216	1219	IPF	Disease
12882453	1304	1309	IL-10	Gene
12882453	1323	1326	KGF	Gene
12882453	1480	1488	TGF-beta	Gene
12882453	1567	1596	idiopathic pulmonary fibrosis	Disease
12882453	1646	1677	transforming growth factor-beta	Gene
12882453	1682	1696	interleukin-10	Gene
27658114|t|Therapeutic targets in fibrotic pathways
The pathogenetic heterogeneity of pulmonary fibrosis 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 pulmonary fibrosis, 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 pulmonary fibrosis in the continuing search for therapy
27658114	76	94	pulmonary fibrosis	Disease
27658114	264	269	TGF-b	Gene
27658114	359	387	decreased pulmonary function	Disease
27658114	425	437	introducing	Gene_expression
27658114	482	487	FIEL1	Gene
27658114	505	515	regulator	Regulation
27658114	518	523	TGF-b	Gene
27658114	556	568	degradation	Protein_catabolism
27658114	571	576	PIAS4	Gene
27658114	578	583	FIEL1	Gene
27658114	596	605	bleomycin	Chemical
27658114	614	620	murine	Species
27658114	621	639	pulmonary fibrosis	Disease
27658114	748	753	FIEL1	Gene
27658114	769	778	inhibits	Negative_regulation
27658114	782	794	degradation	Protein_catabolism
27658114	797	802	PIAS4	Gene
27658114	820	828	fibrosis	Disease
27658114	832	838	murine	Species
27658114	950	968	pulmonary fibrosis	Disease
27476938|t|Protective Effect of Ginsenoside Rg1 on Bleomycin-Induced Pulmonary Fibrosis in Rats: Involvement of Caveolin-1 and TGF-b1 Signal Pathway
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and high mortality rate
Panax Notoginseng Saponins (PNS), extracted from Panax Notoginseng as a traditional Asian medicine, displayed a significant anti-fibrosis effect in liver and lung
However, whether Ginsenoside Rg1 (Rg1), an important and active ingredient of PNS, exerts anti-fibrotic activity on IPF still remain unclear
In this study, we investigated the effect of Rg1 on bleomycin-induced pulmonary fibrosis in rats
Bleomycin (5   mg/kg body weight) was intratracheally administrated to male rats
Rg1 (18, 36 and 72   mg/kg) was orally administered on the next day after bleomycin
Lungs were harvested at day 7 and 28 for the further experiments
Histological analysis revealed that bleomycin successfully induced pulmonary fibrosis, and that Rg1 restored the histological alteration of bleomycin-induced pulmonary fibrosis (PF), significantly decreased lung coefficient, scores of alveolitis, scores of PF as well as contents of alpha smooth muscle actin (a-SMA) and hydroxyproline (Hyp) in a dose-dependent manner in PF rats
Moreover, Rg1 increased the expression levels of Caveolin-1 (Cav-1) mRNA and protein, lowered the expression of transforming growth factor-b1 (TGF-b1) mRNA and protein in the lung tissues of PF rats
These data suggest that Rg1 exhibits protective effect against bleomycin-induced PF in rats, which is potentially associated with the down-regulation of TGF-b1 and up-regulation of Cav-1
27476938	21	36	Ginsenoside Rg1	Chemical
27476938	40	49	Bleomycin	Chemical
27476938	80	84	Rats	Species
27476938	101	111	Caveolin-1	Gene
27476938	116	122	TGF-b1	Gene
27476938	245	262	Panax Notoginseng	Species
27476938	263	271	Saponins	Chemical
27476938	294	311	Panax Notoginseng	Species
27476938	426	441	Ginsenoside Rg1	Chemical
27476938	443	446	Rg1	Chemical
27476938	596	599	Rg1	Chemical
27476938	603	612	bleomycin	Chemical
27476938	643	647	rats	Species
27476938	649	658	Bleomycin	Chemical
27476938	725	729	rats	Species
27476938	731	734	Rg1	Chemical
27476938	805	814	bleomycin	Chemical
27476938	918	927	bleomycin	Chemical
27476938	978	981	Rg1	Chemical
27476938	1022	1031	bleomycin	Chemical
27476938	1165	1190	alpha smooth muscle actin	Gene
27476938	1192	1197	a-SMA	Gene
27476938	1203	1217	hydroxyproline	Chemical
27476938	1219	1222	Hyp	Chemical
27476938	1257	1261	rats	Species
27476938	1273	1276	Rg1	Chemical
27476938	1277	1287	increased	Positive_regulation
27476938	1291	1302	expression	Gene_expression
27476938	1312	1322	Caveolin-1	Gene
27476938	1324	1327	Cav	Species
27476938	1361	1372	expression	Transcription
27476938	1406	1412	TGF-b1	Gene
27476938	1457	1461	rats	Species
27476938	1487	1490	Rg1	Chemical
27476938	1526	1535	bleomycin	Chemical
27476938	1550	1554	rats	Species
27476938	1597	1613	down-regulation	Negative_regulation
27476938	1616	1622	TGF-b1	Gene
27476938	1627	1641	up-regulation	Positive_regulation
27476938	1644	1647	Cav	Species
20388759|t|Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis
BACKGROUND AND AIM: There is a growing body of evidence demonstrating that plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis
In fact, PAI-1 knockout mice are protected from bleomycin-induced pulmonary fibrosis
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 pulmonary fibrosis
METHODS: Lung biopsies from patients with idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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 pulmonary fibrosis
The inhibition of EMT may be, at least in part, involved in this effect
20388759	0	12	Suppression	Negative_regulation
20388759	15	48	plasminogen activator inhibitor-1	Gene
20388759	80	98	pulmonary fibrosis	Disease
20388759	175	208	plasminogen activator inhibitor-1	Gene
20388759	210	215	PAI-1	Gene
20388759	251	269	pulmonary fibrosis	Disease
20388759	280	285	PAI-1	Gene
20388759	295	299	mice	Species
20388759	319	328	bleomycin	Chemical
20388759	337	355	pulmonary fibrosis	Disease
20388759	470	480	targeting	Positive_regulation
20388759	480	485	PAI-1	Gene
20388759	487	498	PAI-1-siRNA	Gene
20388759	526	535	bleomycin	Chemical
20388759	544	562	pulmonary fibrosis	Disease
20388759	592	600	patients	Species
20388759	606	635	idiopathic pulmonary fibrosis	Disease
20388759	637	640	IPF	Disease
20388759	659	664	PAI-1	Gene
20388759	709	714	PAI-1	Gene
20388759	857	868	PAI-1-siRNA	Gene
20388759	874	879	mouse	Species
20388759	889	898	bleomycin	Chemical
20388759	907	925	pulmonary fibrosis	Disease
20388759	941	952	PAI-1-siRNA	Gene
20388759	1030	1035	mouse	Species
20388759	1078	1083	PAI-1	Gene
20388759	1109	1128	hyperplastic type 2	Disease
20388759	1173	1181	patients	Species
20388759	1187	1190	IPF	Disease
20388759	1230	1235	PAI-1	Gene
20388759	1325	1341	fibrotic lesions	Disease
20388759	1374	1379	PAI-1	Gene
20388759	1454	1463	bleomycin	Chemical
20388759	1472	1476	mice	Species
20388759	1477	1485	reduced	Negative_regulation
20388759	1489	1494	PAI-1	Gene
20388759	1530	1543	accumulation	Positive_regulation
20388759	1617	1624	TGFbeta	Gene
20388759	1657	1670	transfection	Positive_regulation
20388759	1675	1680	PAI-1	Gene
20388759	1712	1724	suppression	Gene_expression
20388759	1727	1732	PAI-1	Gene
20388759	1785	1790	PAI-1	Gene
20388759	1843	1861	pulmonary fibrosis	Disease
20388759	1867	1878	inhibition	Negative_regulation
28148565|t|Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors
Pirfenidone is an antifibrotic drug, recently approved for the treatment of patients with idiopathic pulmonary fibrosis (IPF)
Although pirfenidone exhibits anti-inflammatory, antioxidant, and antifibrotic properties, the molecular mechanism underlying its protective effects remains unknown
Here, we link pirfenidone action with the regulation of the profibrotic hedgehog (Hh) signaling pathway
We demonstrate that pirfenidone selectively destabilizes the glioma-associated oncogene homolog (GLI)2 protein, the primary activator of Hh-mediated gene transcription
Consequently, pirfenidone decreases overall Hh pathway activity in patients with IPF and in patient-derived primary lung fibroblasts and leads to diminished levels of Hh target genes, such as GLI1, Hh receptor Patched-1, a-smooth muscle actin, and fibronectin, and to reduced cell migration and proliferation
Interestingly, Hh-triggered TGF-b1 expression potentiated Hh responsiveness of primary lung fibroblasts by elevating the available pool of glioma-associated oncogene homolog (GLI)1/GLI2, thus creating a vicious cycle of amplifying fibrotic processes
Because GLI transcription factors are not only crucial for Hh-mediated changes but are also required as mediators of TGF-b signaling, our findings suggest that pirfenidone exerts its clinically beneficial effects through dual Hh/TGF-b inhibition by targeting the GLI2 protein.-Didiasova, M., Singh, R., Wilhelm, J., Kwapiszewska, G., Wujak, L., Zakrzewicz, D., Schaefer, L., Markart, P., Seeger, W., Lauth, M., Wygrecka, M
Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors
28148565	0	11	Pirfenidone	Chemical
28148565	48	59	inhibition	Negative_regulation
28148565	89	100	Pirfenidone	Chemical
28148565	225	236	pirfenidone	Chemical
28148565	396	407	pirfenidone	Chemical
28148565	507	518	pirfenidone	Chemical
28148565	670	681	pirfenidone	Chemical
28148565	682	692	decreases	Negative_regulation
28148565	802	813	diminished	Negative_regulation
28148565	813	820	levels	Positive_regulation
28148565	1001	1012	expression	Gene_expression
28148565	1264	1272	crucial	Localization
28148565	1309	1318	required	Localization
28148565	1377	1388	pirfenidone	Chemical
28148565	1452	1463	inhibition	Negative_regulation
28148565	1641	1652	Pirfenidone	Chemical
28148565	1689	1700	inhibition	Negative_regulation
23442250|t|Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression
Idiopathic pulmonary fibrosis (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	70	79	bleomycin	Chemical
23442250	88	118	pulmonary fibrosis progression	Disease
23442250	120	149	Idiopathic pulmonary fibrosis	Disease
23442250	151	154	IPF	Disease
23442250	210	216	oxygen	Chemical
23442250	240	250	superoxide	Chemical
23442250	266	273	O2(  -)	Chemical
23442250	321	324	IPF	Disease
23442250	358	391	serum albumin (HSA)-thioredoxin 1	Gene
23442250	393	396	Trx	Gene
23442250	418	421	Trx	Gene
23442250	516	519	Trx	Gene
23442250	626	629	Trx	Gene
23442250	636	639	IPF	Disease
23442250	656	665	bleomycin	Chemical
23442250	667	670	BLM	Chemical
23442250	680	698	pulmonary fibrosis	Disease
23442250	731	734	Trx	Gene
23442250	738	741	Trx	Gene
23442250	749	753	mice	Species
23442250	902	905	Trx	Gene
23442250	915	918	Trx	Gene
23442250	944	952	fibrosis	Disease
23442250	1013	1027	hydroxyproline	Chemical
23442250	1040	1043	Trx	Gene
23442250	1295	1304	phosphate	Chemical
23442250	1358	1365	O2(  -)	Chemical
23442250	1392	1395	Trx	Gene
23442250	1432	1435	Trx	Gene
23442250	1481	1489	fibrosis	Disease
23442250	1522	1525	Trx	Gene
23442250	1573	1576	IPF	Disease
27071460|t|Profibrotic role of WNT10A via TGF-b signaling in idiopathic pulmonary fibrosis
BACKGROUND: WNT/b-catenin signaling plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the role of WNT10A via transforming growth factor (TGF)-b signaling remains unclear
METHODS: We evaluated the expression of WNT10A and TGF-b in bleomycin (BLM)-treated mice and the interactions between TGF-b or BLM and WNT10A in vitro
Additionally, we investigated IPF patients who underwent video-assisted thoracoscopic surgery to determine whether the WNT10A expression is related to the survival
RESULTS: Increased WNT10A and TGF-b expressions were noted in the BLM-treated mice
Real-time PCR and luciferase reporter assays demonstrated the levels of WNT10A and collagen in the fibroblasts cells to increase after TGF-b administration
Conversely, WNT10A 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 WNT10A-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 WNT10A 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: WNT10A plays an important role in the pathogenesis of IPF via TGF-b activation and it may also be a sensitive predictor for the onset of an AE-IPF
27071460	20	26	WNT10A	Gene
27071460	31	36	TGF-b	Gene
27071460	50	79	idiopathic pulmonary fibrosis	Disease
27071460	164	193	idiopathic pulmonary fibrosis	Disease
27071460	195	198	IPF	Disease
27071460	222	228	WNT10A	Gene
27071460	321	332	expression	Gene_expression
27071460	335	341	WNT10A	Gene
27071460	346	351	TGF-b	Gene
27071460	355	364	bleomycin	Chemical
27071460	366	369	BLM	Chemical
27071460	379	383	mice	Species
27071460	413	418	TGF-b	Gene
27071460	422	425	BLM	Chemical
27071460	430	436	WNT10A	Gene
27071460	477	480	IPF	Disease
27071460	481	489	patients	Species
27071460	566	572	WNT10A	Gene
27071460	573	584	expression	Gene_expression
27071460	621	631	Increased	Positive_regulation
27071460	631	637	WNT10A	Gene
27071460	642	647	TGF-b	Gene
27071460	648	660	expressions	Gene_expression
27071460	678	681	BLM	Chemical
27071460	690	694	mice	Species
27071460	768	774	WNT10A	Gene
27071460	831	836	TGF-b	Gene
27071460	865	871	WNT10A	Gene
27071460	888	898	inhibited	Negative_regulation
27071460	902	912	synthesis	Gene_expression
27071460	1052	1055	IPF	Disease
27071460	1056	1064	patients	Species
27071460	1072	1078	WNT10A	Gene
27071460	1206	1221	overexpression	Positive_regulation
27071460	1224	1230	WNT10A	Gene
27071460	1300	1303	IPF	Disease
27071460	1308	1311	IPF	Disease
27071460	1382	1388	WNT10A	Gene
27071460	1436	1439	IPF	Disease
27071460	1444	1449	TGF-b	Gene
27071460	1525	1528	IPF	Disease
25373521|t|Mesenchymal Stem Cells Correct Inappropriate Epithelial-mesenchyme Relation in Pulmonary Fibrosis Using Stanniocalcin-1
Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (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 (Stanniocalcin-1) 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	79	97	Pulmonary Fibrosis	Disease
25373521	104	119	Stanniocalcin-1	Gene
25373521	219	248	idiopathic pulmonary fibrosis	Disease
25373521	250	253	IPF	Disease
25373521	288	294	TGF-b1	Gene
25373521	295	305	secretion	Localization
25373521	513	521	fibrosis	Disease
25373521	583	586	IPF	Disease
25373521	711	715	STC1	Gene
25373521	717	732	Stanniocalcin-1	Gene
25373521	734	744	secretion	Localization
25373521	749	758	bleomycin	Chemical
25373521	767	770	IPF	Disease
25373521	804	808	STC1	Gene
25373521	864	868	STC1	Gene
25373521	943	951	fibrosis	Disease
25373521	958	966	secrete	Localization
25373521	983	987	STC1	Gene
25373521	1003	1009	TGF-b1	Gene
25373521	1077	1081	STC1	Gene
25373521	1090	1099	reducing	Negative_regulation
25373521	1117	1138	endoplasmic reticulum	Disease
25373521	1140	1142	ER	Disease
25373521	1156	1162	TGF-b1	Gene
25373521	1163	1174	production	Gene_expression
25373521	1187	1191	STC1	Gene
25373521	1221	1230	blocking	Negative_regulation
25373521	1230	1250	uncoupling protein 2	Gene
25373521	1252	1256	UCP2	Gene
25373521	1266	1276	secretion	Localization
25373521	1279	1288	affected	Regulation
25373521	1295	1298	PI3	Gene
25373521	1299	1302	AKT	Gene
25373521	1303	1309	mTORC1	Gene
25373521	1310	1321	inhibitors	Negative_regulation
25373521	1348	1352	STC1	Gene
25373521	1434	1438	STC1	Gene
25373521	1470	1474	STC1	Gene
25373521	1524	1527	IPF	Disease
17504233|t|Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in myofibroblasts and macrophages
Angiotensin II (ANGII) has been identified as a proapoptotic and profibrotic factor in experimental lung fibrosis models, and patients with the ID/DD polymorphism of ANG converting enzyme (ACE), which confers higher levels of ACE, are predisposed to lung fibrosis (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 ANGII 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 TGF-beta1 mRNA, and released more AGT protein, ANGII and active TGF-beta1 protein into serum-free conditioned media (both p<0.01)
Incubation of HIPF fibrotic isolates with the ANGII receptor antagonist saralasin reduced both TGF-beta1 mRNA and active protein, suggesting that the constitutive expression of AGT drives the higher expression of TGF-beta1 by the HIPF cells
Consistent with this premise, treatment of either the primary NLFs or the WI38 cell line with 10(-7) M ANGII increased both TGF-beta1 mRNA and soluble active TGF-beta1 protein
Moreover, induction of the myofibroblast transition in the IMR90 cell line with 2 ng/ml TGF-beta1 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 TGF-beta1 mRNA or TGF-beta 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/TGF-beta1 "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 lung fibrosis 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	12	20	TGF-beta	Gene
17504233	36	41	human	Species
17504233	42	71	idiopathic pulmonary fibrosis	Disease
17504233	129	143	Angiotensin II	Gene
17504233	145	150	ANGII	Gene
17504233	229	242	lung fibrosis	Disease
17504233	255	263	patients	Species
17504233	295	316	ANG converting enzyme	Gene
17504233	318	321	ACE	Gene
17504233	355	358	ACE	Gene
17504233	379	392	lung fibrosis	Disease
17504233	399	405	Pathol	Chemical
17504233	476	481	human	Species
17504233	516	524	patients	Species
17504233	530	559	Idiopathic Pulmonary Fibrosis	Disease
17504233	561	564	IPF	Disease
17504233	566	577	synthesize	Gene_expression
17504233	581	586	ANGII	Gene
17504233	597	612	angiotensinogen	Gene
17504233	614	617	AGT	Gene
17504233	709	712	AGT	Gene
17504233	814	822	patients	Species
17504233	828	831	IPF	Disease
17504233	881	886	human	Species
17504233	914	918	WI38	Species
17504233	919	924	human	Species
17504233	998	1006	patients	Species
17504233	1012	1015	IPF	Disease
17504233	1102	1114	synthesized	Gene_expression
17504233	1119	1122	AGT	Gene
17504233	1127	1136	TGF-beta1	Gene
17504233	1147	1156	released	Localization
17504233	1161	1164	AGT	Gene
17504233	1174	1179	ANGII	Gene
17504233	1184	1191	active	Positive_regulation
17504233	1191	1200	TGF-beta1	Gene
17504233	1304	1309	ANGII	Gene
17504233	1340	1348	reduced	Negative_regulation
17504233	1353	1362	TGF-beta1	Gene
17504233	1435	1438	AGT	Gene
17504233	1439	1446	drives	Positive_regulation
17504233	1457	1468	expression	Gene_expression
17504233	1471	1480	TGF-beta1	Gene
17504233	1574	1578	WI38	Species
17504233	1603	1608	ANGII	Gene
17504233	1609	1619	increased	Positive_regulation
17504233	1624	1633	TGF-beta1	Gene
17504233	1658	1667	TGF-beta1	Gene
17504233	1765	1774	TGF-beta1	Gene
17504233	1775	1785	increased	Positive_regulation
17504233	1798	1801	AGT	Gene
17504233	1851	1859	induced	Positive_regulation
17504233	1859	1870	expression	Gene_expression
17504233	1876	1879	AGT	Gene
17504233	1981	1990	TGF-beta1	Gene
17504233	1999	2007	TGF-beta	Gene
17504233	2109	2117	reduced	Negative_regulation
17504233	2117	2120	AGT	Gene
17504233	2121	2132	expression	Gene_expression
17504233	2155	2158	IPF	Disease
17504233	2159	2166	patient	Species
17504233	2192	2195	AGT	Gene
17504233	2359	2368	TGF-beta1	Gene
17504233	2389	2394	human	Species
17504233	2491	2494	IPF	Disease
17504233	2543	2546	ACE	Gene
17504233	2547	2558	inhibitors	Negative_regulation
17504233	2609	2622	lung fibrosis	Disease
17504233	2714	2719	human	Species
17504233	2720	2723	IPF	Disease
17504233	2809	2812	IPF	Disease
26542979|t|microRNA-1343 attenuates pathways of fibrosis by targeting the TGF-b receptors
UNASSIGNED: Irreversible respiratory obstruction resulting from progressive airway damage, inflammation and fibrosis is a feature of several chronic respiratory diseases, including cystic fibrosis, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease
The cytokine transforming growth factor beta (TGF-b) has a pivotal role in promoting lung fibrosis 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	37	45	fibrosis	Disease
26542979	49	59	targeting	Binding
26542979	63	68	TGF-b	Gene
26542979	105	128	respiratory obstruction	Disease
26542979	171	183	inflammation	Disease
26542979	188	196	fibrosis	Disease
26542979	229	249	respiratory diseases	Disease
26542979	261	276	cystic fibrosis	Disease
26542979	278	307	idiopathic pulmonary fibrosis	Disease
26542979	312	349	chronic obstructive pulmonary disease	Disease
26542979	364	395	transforming growth factor beta	Gene
26542979	397	402	TGF-b	Gene
26542979	441	449	fibrosis	Disease
26542979	471	490	respiratory disease	Disease
26542979	558	566	miR-1343	Gene
26542979	580	591	expression	Gene_expression
26542979	599	604	TGF-b	Gene
26542979	634	644	targeting	Binding
26542979	665	670	TGF-b	Gene
26542979	704	712	miR-1343	Gene
26542979	727	737	decreases	Negative_regulation
26542979	757	762	TGF-b	Gene
26542979	1014	1022	miR-1343	Gene
26542979	1046	1051	human	Species
26542979	1150	1158	miR-1343	Gene
26542979	1203	1224	fibrotic lung disease	Disease
23459460|t|miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1
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 lung diseases, 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	15	27	upregulated	Positive_regulation
23459460	140	150	caveolin-1	Gene
23459460	355	368	lung diseases	Disease
23459460	385	400	idiopathic form	Disease
23459460	402	405	IPF	Disease
23459460	467	470	IPF	Disease
23459460	471	479	patients	Species
23459460	826	837	expression	Gene_expression
23459460	865	870	mouse	Species
23459460	930	943	lung fibrosis	Disease
23459460	950	959	bleomycin	Chemical
23459460	1060	1069	bleomycin	Chemical
23459460	1162	1165	IPF	Disease
23459460	1166	1174	patients	Species
23459460	1179	1182	IPF	Disease
23459460	1258	1268	increased	Positive_regulation
23459460	1299	1304	mouse	Species
23459460	1371	1374	IPF	Disease
23459460	1487	1498	expression	Gene_expression
23459460	1502	1510	induced	Positive_regulation
23459460	1515	1519	TGFb	Gene
23459460	1542	1553	expression	Gene_expression
23459460	1799	1803	TGFb	Gene
23459460	1848	1852	CAV1	Gene
23459460	1877	1895	pulmonary fibrosis	Disease
23459460	1918	1929	expression	Gene_expression
23459460	1994	1999	mouse	Species
23459460	2009	2024	kidney fibrosis	Disease
23459460	2068	2072	CCl4	Gene
23459460	2081	2086	mouse	Species
23459460	2097	2111	liver fibrosis	Disease
23459460	2283	2291	fibrosis	Disease
23459460	2326	2353	fibroproliferative diseases	Disease
25199049|t|Increased expression of protease nexin-1 in fibroblasts during idiopathic pulmonary fibrosis regulates thrombin activity and fibronectin expression
Idiopathic pulmonary fibrosis (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, thrombin 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 thrombin 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 fibronectin expression, whereas PN-1 silencing induced in fibrotic fibroblasts led to decreased fibronectin expression
Overexpression of PN-1 lacking either its antiprotease activity or its binding capacity to glycosaminoglycans had no effect on fibronectin 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	0	10	Increased	Positive_regulation
25199049	10	21	expression	Gene_expression
25199049	24	40	protease nexin-1	Gene
25199049	63	92	idiopathic pulmonary fibrosis	Disease
25199049	93	103	regulates	Regulation
25199049	103	111	thrombin	Gene
25199049	125	136	fibronectin	Gene
25199049	137	148	expression	Gene_expression
25199049	149	178	Idiopathic pulmonary fibrosis	Disease
25199049	180	183	IPF	Disease
25199049	198	218	diffuse lung disease	Disease
25199049	292	308	Protease nexin-1	Gene
25199049	310	314	PN-1	Gene
25199049	335	344	produced	Gene_expression
25199049	392	396	PN-1	Gene
25199049	481	492	inhibiting	Negative_regulation
25199049	507	515	thrombin	Gene
25199049	542	546	PN-1	Gene
25199049	622	625	IPF	Disease
25199049	669	673	PN-1	Gene
25199049	764	772	patients	Species
25199049	778	781	IPF	Disease
25199049	799	803	PN-1	Gene
25199049	951	954	IPF	Disease
25199049	972	1005	plasminogen activator inhibitor-1	Gene
25199049	1007	1012	PAI-1	Gene
25199049	1022	1036	overexpressed	Positive_regulation
25199049	1068	1073	PAI-1	Gene
25199049	1086	1090	PN-1	Gene
25199049	1102	1111	secreted	Localization
25199049	1111	1115	PN-1	Gene
25199049	1121	1124	IPF	Disease
25199049	1166	1174	inhibit	Negative_regulation
25199049	1186	1194	thrombin	Gene
25199049	1272	1275	IPF	Disease
25199049	1375	1390	overexpression	Positive_regulation
25199049	1393	1397	PN-1	Gene
25199049	1398	1406	induced	Positive_regulation
25199049	1452	1462	increased	Positive_regulation
25199049	1462	1473	fibronectin	Gene
25199049	1474	1485	expression	Gene_expression
25199049	1494	1498	PN-1	Gene
25199049	1499	1509	silencing	Negative_regulation
25199049	1548	1558	decreased	Negative_regulation
25199049	1558	1569	fibronectin	Gene
25199049	1570	1581	expression	Gene_expression
25199049	1600	1604	PN-1	Gene
25199049	1709	1720	fibronectin	Gene
25199049	1721	1732	expression	Gene_expression
25199049	1781	1785	PN-1	Gene
25199049	1860	1863	IPF	Disease
25199049	1984	1988	PN-1	Gene
25199049	2049	2052	IPF	Disease
21864521|t|Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF)
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal pulmonary fibrotic disease and useful biomarkers are required to diagnose and predict disease activity
CCN2 (connective tissue growth factor; CTGF) 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 CCN2 levels
We examined the utility of plasma CCN2 levels as a surrogate marker in IPF
METHODS: Plasma CCN2 levels were calculated in 33 patients with IPF, 14 patients with non-IPF 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 CCN2
We evaluated the utility of plasma CCN2 levels by comparison with clinical parameters
RESULTS: Plasma CCN2 levels were significantly higher in patients with IPF than in those with non-IPF IIPs and healthy volunteers
Importantly, plasma CCN2 levels showed significantly negative correlation with 6-month change of forced vital capacity (FVC) in patients with IPF
CONCLUSIONS: Plasma CCN2 is a potential biomarker for IPF
21864521	7	11	CCN2	Gene
21864521	46	50	CTGF	Gene
21864521	80	109	idiopathic pulmonary fibrosis	Disease
21864521	111	114	IPF	Disease
21864521	129	158	Idiopathic pulmonary fibrosis	Disease
21864521	160	163	IPF	Disease
21864521	195	227	fatal pulmonary fibrotic disease	Disease
21864521	305	309	CCN2	Gene
21864521	344	348	CTGF	Gene
21864521	422	450	transforming growth factor-b	Gene
21864521	452	457	TGF-b	Gene
21864521	525	542	fibrotic diseases	Disease
21864521	620	624	CCN2	Gene
21864521	667	671	CCN2	Gene
21864521	704	707	IPF	Disease
21864521	725	729	CCN2	Gene
21864521	759	767	patients	Species
21864521	773	776	IPF	Disease
21864521	781	789	patients	Species
21864521	799	802	IPF	Disease
21864521	803	837	idiopathic interstitial pneumonias	Disease
21864521	839	843	IIPs	Disease
21864521	992	997	human	Species
21864521	998	1002	CCN2	Gene
21864521	1039	1043	CCN2	Gene
21864521	1107	1111	CCN2	Gene
21864521	1148	1156	patients	Species
21864521	1162	1165	IPF	Disease
21864521	1189	1192	IPF	Disease
21864521	1193	1197	IIPs	Disease
21864521	1242	1246	CCN2	Gene
21864521	1350	1358	patients	Species
21864521	1364	1367	IPF	Disease
21864521	1389	1393	CCN2	Gene
21864521	1423	1426	IPF	Disease
21882188|t|Cysteine-rich protein 1 is regulated by transforming growth factor-b1 and expressed in lung fibrosis
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 fibrosis (IPF)
Cysteine-rich protein 1 (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	0	23	Cysteine-rich protein 1	Gene
21882188	40	69	transforming growth factor-b1	Gene
21882188	92	100	fibrosis	Disease
21882188	102	130	Transforming growth factor-b	Gene
21882188	132	137	TGF-b	Gene
21882188	265	279	Dysregulation	Regulation
21882188	282	287	TGF-b	Gene
21882188	307	325	fibrotic disorders	Disease
21882188	390	419	idiopathic pulmonary fibrosis	Disease
21882188	421	424	IPF	Disease
21882188	427	450	Cysteine-rich protein 1	Gene
21882188	452	456	CRP1	Gene
21882188	561	567	TGF-b1	Gene
21882188	568	578	increases	Positive_regulation
21882188	582	593	expression	Gene_expression
21882188	596	600	CRP1	Gene
21882188	618	622	CRP1	Gene
21882188	630	639	increase	Positive_regulation
21882188	694	703	increase	Positive_regulation
21882188	706	710	CRP1	Gene
21882188	750	759	increase	Positive_regulation
21882188	762	766	CRP1	Gene
21882188	828	834	TGF-b1	Gene
21882188	835	845	regulates	Regulation
21882188	849	860	expression	Gene_expression
21882188	863	867	CRP1	Gene
21882188	902	905	p38	Gene
21882188	1067	1071	CRP1	Gene
21882188	1072	1082	silencing	Negative_regulation
21882188	1104	1108	CRP1	Gene
21882188	1173	1182	localize	Localization
21882188	1182	1186	CRP1	Gene
21882188	1211	1214	IPF	Disease
21882188	1235	1239	CRP1	Gene
21882188	1262	1272	expressed	Gene_expression
21882188	1275	1278	IPF	Disease
21882188	1337	1341	CRP1	Gene
21882188	1353	1359	TGF-b1	Gene
21882188	1360	1370	regulated	Regulation
21882188	1386	1396	expressed	Gene_expression
21882188	1399	1415	fibrotic lesions	Disease
21882188	1427	1436	relevant	Positive_regulation
21882188	1443	1454	IPF disease	Disease
28213468|t|Microencapsulation of lefty-secreting engineered cells for pulmonary fibrosis therapy in mice
UNASSIGNED: Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis
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 pulmonary fibrosis in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses
28213468	59	77	pulmonary fibrosis	Disease
28213468	89	93	mice	Species
28213468	107	136	Idiopathic pulmonary fibrosis	Disease
28213468	138	141	IPF	Disease
28213468	273	295	pulmonary architecture	Disease
28213468	300	321	impaired gas exchange	Disease
28213468	369	372	IPF	Disease
28213468	435	442	Lefty A	Gene
28213468	596	610	renal fibrosis	Disease
28213468	670	677	Lefty A	Gene
28213468	692	701	bleomycin	Chemical
28213468	703	706	BLM	Chemical
28213468	716	734	pulmonary fibrosis	Disease
28213468	836	843	Lefty A	Gene
28213468	978	982	mice	Species
28213468	1043	1046	BLM	Chemical
28213468	1057	1075	pulmonary fibrosis	Disease
28213468	1093	1101	fibrosis	Disease
28213468	1173	1184	expression	Gene_expression
28213468	1209	1216	Lefty A	Gene
28213468	1293	1300	Lefty A	Gene
28213468	1315	1323	reduced	Negative_regulation
28213468	1327	1338	expression	Gene_expression
28213468	1341	1372	connective tissue growth factor	Gene
28213468	1374	1378	CTGF	Gene
28213468	1471	1480	bleomycin	Chemical
28213468	1486	1496	increased	Positive_regulation
28213468	1500	1511	expression	Gene_expression
28213468	1514	1546	matrix metalloproteinase (MMP)-9	Gene
28213468	1599	1606	Lefty A	Gene
28213468	1611	1639	attenuate pulmonary fibrosis	Disease
28213468	1688	1693	human	Species
28213468	1694	1720	pulmonary fibrotic disease	Disease
21224216|t|Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-b-induced senescence of human bronchial epithelial cells
Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis
Recent studies suggest that epithelial senescence is a risk factor for development of IPF, 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 IPF 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 IPF 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 IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6
21224216	42	45	IPF	Disease
21224216	73	78	SIRT6	Gene
21224216	82	87	TGF-b	Gene
21224216	110	115	human	Species
21224216	259	288	idiopathic pulmonary fibrosis	Disease
21224216	290	293	IPF	Disease
21224216	316	319	IPF	Disease
21224216	420	423	IPF	Disease
21224216	556	561	SIRT6	Gene
21224216	712	717	SIRT6	Gene
21224216	718	729	expression	Gene_expression
21224216	732	735	IPF	Disease
21224216	826	829	p21	Gene
21224216	996	1001	human	Species
21224216	1041	1049	changes	Regulation
21224216	1052	1057	SIRT6	Gene
21224216	1059	1062	p21	Gene
21224216	1068	1087	interleukin (IL)-1b	Gene
21224216	1088	1099	expression	Gene_expression
21224216	1099	1106	levels	Positive_regulation
21224216	1142	1153	expression	Gene_expression
21224216	1195	1198	IPF	Disease
21224216	1216	1225	increase	Positive_regulation
21224216	1254	1259	SIRT6	Gene
21224216	1260	1271	expression	Gene_expression
21224216	1369	1374	TGF-b	Gene
21224216	1413	1424	increasing	Positive_regulation
21224216	1424	1427	p21	Gene
21224216	1428	1439	expression	Gene_expression
21224216	1453	1458	TGF-b	Gene
21224216	1464	1472	induced	Positive_regulation
21224216	1472	1477	SIRT6	Gene
21224216	1542	1557	overexpression	Positive_regulation
21224216	1560	1565	SIRT6	Gene
21224216	1588	1593	TGF-b	Gene
21224216	1629	1641	degradation	Protein_catabolism
21224216	1644	1647	p21	Gene
21224216	1649	1654	TGF-b	Gene
21224216	1678	1687	secreted	Localization
21224216	1708	1713	IL-1b	Gene
21224216	1870	1873	IPF	Disease
21224216	1940	1953	interactions	Binding
21224216	1982	1987	SIRT6	Gene
27013092|t|Effect of Renshen Pingfei Decoction, a traditional Chinese prescription, on IPF induced by Bleomycin in rats and regulation of TGF-b1/Smad3
AIM OF THE STUDY: Idiopathic pulmonary fibrosis (IPF), 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 IPF 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 IPF 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 IPF 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 IPF model rats
The protective role might mediated by down-regulating TGF-b1/Smad3 signaling pathway
27013092	76	79	IPF	Disease
27013092	80	88	induced	Positive_regulation
27013092	91	100	Bleomycin	Chemical
27013092	104	108	rats	Species
27013092	113	124	regulation	Regulation
27013092	127	133	TGF-b1	Gene
27013092	134	139	Smad3	Gene
27013092	159	188	Idiopathic pulmonary fibrosis	Disease
27013092	190	193	IPF	Disease
27013092	266	281	ancient disease	Disease
27013092	461	465	rats	Species
27013092	475	478	IPF	Disease
27013092	501	512	regulation	Regulation
27013092	515	521	TGF-b1	Gene
27013092	522	527	Smad3	Gene
27013092	740	743	IPF	Disease
27013092	769	773	rats	Species
27013092	798	807	Bleomycin	Chemical
27013092	809	812	BLM	Chemical
27013092	929	933	rats	Species
27013092	1092	1098	TGF-b1	Gene
27013092	1103	1108	Smad3	Gene
27013092	1126	1138	expressions	Gene_expression
27013092	1341	1344	IPF	Disease
27013092	1351	1355	rats	Species
27013092	1435	1444	reducing	Negative_regulation
27013092	1457	1463	TGF-b1	Gene
27013092	1468	1472	NFkB	Gene
27013092	1491	1502	decreasing	Negative_regulation
27013092	1510	1513	MDA	Chemical
27013092	1550	1566	down-regulating	Negative_regulation
27013092	1566	1572	TGF-b1	Gene
27013092	1577	1582	Smad3	Gene
27013092	1600	1612	expressions	Gene_expression
27013092	1671	1682	lung injury	Disease
27013092	1687	1695	fibrosis	Disease
27013092	1732	1735	IPF	Disease
27013092	1742	1746	rats	Species
27013092	1786	1802	down-regulating	Negative_regulation
27013092	1802	1808	TGF-b1	Gene
27013092	1809	1814	Smad3	Gene
28493530|t|M2 macrophages induce EMT through the TGF-b/Smad2 signaling pathway
IPF is characterized by fibroblast accumulation, collagen deposition and ECM remodeling, with myofibroblasts believed to be the effector cell type
Myofibroblasts develop due to EMT of lung alveolar epithelial cells, which can be induced by TGF-b
M2 macrophages, a macrophage subpopulation, secrete large amounts of TGF-b
To clarify the relationship between IPF, EMT, TGF-b 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 EMT, such as elevated protein levels of a-SMA in lung tissue and decreased levels of E-cadherin and CK-18
Additionally, increased TGF-b levels and TGF-b/Smad2 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
TGF-b 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 TGF-b receptor inhibitor, LY2109761 was used, the EMT induced by M2 macrophages was blocked
In conclusion, we demonstrated that M2 macrophages induce EMT through the TGF-b/Smad2 signaling pathway
28493530	15	22	induce	Positive_regulation
28493530	22	25	EMT	Gene
28493530	38	43	TGF-b	Gene
28493530	44	49	Smad2	Gene
28493530	69	72	IPF	Disease
28493530	247	250	EMT	Gene
28493530	310	315	TGF-b	Gene
28493530	361	369	secrete	Localization
28493530	386	391	TGF-b	Gene
28493530	429	432	IPF	Disease
28493530	434	437	EMT	Gene
28493530	439	444	TGF-b	Gene
28493530	467	476	bleomycin	Chemical
28493530	485	503	pulmonary fibrosis	Disease
28493530	504	509	mouse	Species
28493530	547	551	mice	Species
28493530	570	579	bleomycin	Chemical
28493530	615	633	pulmonary fibrosis	Disease
28493530	728	731	EMT	Gene
28493530	741	750	elevated	Positive_regulation
28493530	768	773	a-SMA	Gene
28493530	793	803	decreased	Negative_regulation
28493530	803	810	levels	Gene_expression
28493530	813	823	E-cadherin	Gene
28493530	849	859	increased	Positive_regulation
28493530	859	864	TGF-b	Gene
28493530	876	881	TGF-b	Gene
28493530	882	887	Smad2	Gene
28493530	898	909	activation	Positive_regulation
28493530	1048	1061	up-regulated	Positive_regulation
28493530	1061	1066	CD206	Gene
28493530	1143	1147	IL-4	Gene
28493530	1210	1215	TGF-b	Gene
28493530	1390	1395	a-SMA	Gene
28493530	1411	1421	E-cadherin	Gene
28493530	1432	1442	decreased	Negative_regulation
28493530	1450	1455	TGF-b	Gene
28493530	1465	1475	inhibitor	Negative_regulation
28493530	1476	1485	LY2109761	Chemical
28493530	1500	1503	EMT	Gene
28493530	1594	1601	induce	Positive_regulation
28493530	1601	1604	EMT	Gene
28493530	1617	1622	TGF-b	Gene
28493530	1623	1628	Smad2	Gene
19411308|t|Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-beta1 in vitro
Idiopathic pulmonary fibrosis (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 (TGF)-beta1, 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 TGF-beta1 in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts
Here we demonstrate that PMC activated by TGF-beta1 undergo epithelial-mesenchymal transition (EMT) and respond with haptotactic migration to a gradient of TGF-beta1 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 TGF-beta1, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in IPF
19411308	101	110	TGF-beta1	Gene
19411308	121	150	Idiopathic pulmonary fibrosis	Disease
19411308	152	155	IPF	Disease
19411308	226	259	subpleural foci of myofibroblasts	Disease
19411308	293	301	fibrosis	Disease
19411308	315	335	pulmonary parenchyma	Disease
19411308	337	362	Pleural mesothelial cells	Disease
19411308	364	367	PMC	Disease
19411308	536	539	PMC	Disease
19411308	563	593	pulmonary parenchymal fibrosis	Disease
19411308	620	658	Transforming growth factor (TGF)-beta1	Gene
19411308	820	828	patients	Species
19411308	834	837	IPF	Disease
19411308	854	863	TGF-beta1	Gene
19411308	937	940	PMC	Disease
19411308	985	988	PMC	Disease
19411308	1002	1011	TGF-beta1	Gene
19411308	1116	1125	TGF-beta1	Gene
19411308	1153	1156	PMC	Disease
19411308	1191	1197	smad-2	Gene
19411308	1220	1223	PMC	Disease
19411308	1238	1251	upregulation	Positive_regulation
19411308	1293	1322	fibroblast specific protein-1	Gene
19411308	1324	1329	FSP-1	Gene
19411308	1352	1363	expression	Gene_expression
19411308	1364	1377	Cytokeratin-8	Gene
19411308	1382	1392	E-cadherin	Gene
19411308	1393	1404	expression	Gene_expression
19411308	1404	1414	decreased	Negative_regulation
19411308	1476	1479	PMC	Disease
19411308	1481	1491	Knockdown	Negative_regulation
19411308	1494	1500	smad-2	Gene
19411308	1584	1587	PMC	Disease
19411308	1638	1641	PMC	Disease
19411308	1671	1674	PMC	Disease
19411308	1703	1712	TGF-beta1	Gene
19411308	1724	1730	smad-2	Gene
19411308	1746	1749	PMC	Disease
19411308	1796	1799	IPF	Disease
26895395|t|Exercise Reduces Lung Fibrosis Involving Serotonin/Akt Signaling
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), Fibrosis (Fi), and Fibrosis + 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	9	17	Reduces	Negative_regulation
26895395	22	30	Fibrosis	Disease
26895395	41	50	Serotonin	Chemical
26895395	75	104	Idiopathic pulmonary fibrosis	Disease
26895395	106	109	IPF	Disease
26895395	134	156	interstitial pneumonia	Disease
26895395	182	191	serotonin	Chemical
26895395	193	212	5-hydroxytryptamine	Chemical
26895395	214	218	5-HT	Chemical
26895395	273	289	aerobic training	Disease
26895395	291	293	AT	Disease
26895395	336	347	lung injury	Disease
26895395	381	383	AT	Disease
26895395	395	404	bleomycin	Chemical
26895395	413	426	lung fibrosis	Disease
26895395	453	457	5-HT	Chemical
26895395	511	515	mice	Species
26895395	565	573	Fibrosis	Disease
26895395	575	577	Fi	Disease
26895395	584	592	Fibrosis	Disease
26895395	605	607	Fi	Disease
26895395	622	631	Bleomycin	Chemical
26895395	685	687	AT	Disease
26895395	832	851	interleukin (IL)-1b	Gene
26895395	853	857	IL-6	Gene
26895395	859	864	CXCL1	Gene
26895395	869	874	IL-10	Gene
26895395	876	881	tumor	Disease
26895395	882	890	necrosis	Disease
26895395	986	990	5-HT	Chemical
26895395	1029	1040	expression	Gene_expression
26895395	1068	1084	phosphorylation	Phosphorylation
26895395	1109	1111	AT	Disease
26895395	1120	1129	bleomycin	Chemical
26895395	1266	1274	reduced	Negative_regulation
26895395	1288	1293	IL-1b	Gene
26895395	1306	1310	IL-6	Gene
26895395	1323	1328	CXCL1	Gene
26895395	1345	1350	tumor	Disease
26895395	1351	1359	necrosis	Disease
26895395	1481	1486	IL-10	Gene
26895395	1511	1520	bleomycin	Chemical
26895395	1531	1535	5-HT	Chemical
26895395	1587	1598	Reductions	Negative_regulation
26895395	1655	1666	expression	Gene_expression
26895395	1686	1702	phosphorylation	Phosphorylation
26895395	1745	1747	AT	Disease
26895395	1778	1795	lung inflammation	Disease
26895395	1800	1808	fibrosis	Disease
26895395	1823	1832	bleomycin	Chemical
26895395	1841	1854	lung fibrosis	Disease
26895395	1881	1885	5-HT	Chemical
17498688|t|p63 - Key molecule in the early phase of epithelial abnormality in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 p63, jagged 1 (jag1) and the genes of structure proteins
Western blotting and RT-PCR analysis revealed that DeltaNp63alpha was the dominant isoform of p63 in our experimental model
Immunohistochemical analysis demonstrated the expression of p63 and jag1 in lung tissues of IPF
Inhibition of p63 with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14
Interestingly, the up-regulation of p63 was totally suppressed by N-acetyl-l-cysteine (NAC), but not by dexamethasone or pirfenidone
Thus, the p63-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	0	3	p63	Gene
17498688	41	63	epithelial abnormality	Disease
17498688	67	96	idiopathic pulmonary fibrosis	Disease
17498688	98	127	Idiopathic pulmonary fibrosis	Disease
17498688	153	165	lung disease	Disease
17498688	179	190	lung cancer	Disease
17498688	222	246	epithelial abnormalities	Disease
17498688	275	294	squamous metaplasia	Disease
17498688	302	334	transforming growth factor beta1	Gene
17498688	336	345	TGF beta1	Gene
17498688	413	424	expression	Gene_expression
17498688	427	435	squamous	Disease
17498688	482	498	keratin 6 and 14	Gene
17498688	543	554	expression	Gene_expression
17498688	567	576	TGF beta1	Gene
17498688	626	639	up-regulated	Positive_regulation
17498688	655	658	p63	Gene
17498688	660	668	jagged 1	Gene
17498688	670	674	jag1	Gene
17498688	764	778	DeltaNp63alpha	Chemical
17498688	807	810	p63	Gene
17498688	884	895	expression	Gene_expression
17498688	898	901	p63	Gene
17498688	906	910	jag1	Gene
17498688	935	946	Inhibition	Negative_regulation
17498688	949	952	p63	Gene
17498688	964	971	caused	Positive_regulation
17498688	975	991	down-regulation	Negative_regulation
17498688	994	998	jag1	Gene
17498688	999	1010	expression	Gene_expression
17498688	1037	1053	keratin 6 and 14	Gene
17498688	1074	1088	up-regulation	Positive_regulation
17498688	1091	1094	p63	Gene
17498688	1107	1118	suppressed	Negative_regulation
17498688	1121	1140	N-acetyl-l-cysteine	Chemical
17498688	1159	1172	dexamethasone	Chemical
17498688	1176	1187	pirfenidone	Chemical
17498688	1199	1202	p63	Gene
17498688	1203	1207	jag1	Gene
17498688	1223	1236	up-regulated	Positive_regulation
17498688	1257	1281	epithelial abnormalities	Disease
17498688	1331	1340	TGF beta1	Gene
26883801|t|Chop Deficiency Protects Mice Against Bleomycin-induced Pulmonary Fibrosis by Attenuating M2 Macrophage Production
C/EBP homologous protein (Chop) has been shown to have altered expression in patients with idiopathic pulmonary fibrosis (IPF), but its exact role in IPF pathoaetiology has not been fully addressed
Studies conducted in patients with IPF and Chop(-/-) mice have dissected the role of Chop and endoplasmic reticulum (ER) stress in pulmonary fibrosis pathogenesis
The effect of Chop 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 Chop expression and ER stress
In particular, Chop deficiency protected mice against BLM-induced lung injury and fibrosis
Loss of Chop significantly attenuated transforming growth factor b (TGF-b) production and reduced M2 macrophage infiltration in the lung following BLM induction
Mechanistic studies showed that Chop deficiency repressed the M2 program in macrophages, which then attenuated TGF-b secretion
Specifically, loss of Chop promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which Chop 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 Chop and ER stress are implicated in IPF pathoaetiology, involving at least the induction and differentiation of M2 macrophages
26883801	0	4	Chop	Gene
26883801	25	29	Mice	Species
26883801	38	47	Bleomycin	Chemical
26883801	56	74	Pulmonary Fibrosis	Disease
26883801	116	140	C/EBP homologous protein	Gene
26883801	142	146	Chop	Gene
26883801	179	190	expression	Gene_expression
26883801	193	201	patients	Species
26883801	207	236	idiopathic pulmonary fibrosis	Disease
26883801	238	241	IPF	Disease
26883801	266	269	IPF	Disease
26883801	336	344	patients	Species
26883801	350	353	IPF	Disease
26883801	358	362	Chop	Gene
26883801	368	372	mice	Species
26883801	400	404	Chop	Gene
26883801	446	464	pulmonary fibrosis	Disease
26883801	493	497	Chop	Gene
26883801	498	509	deficiency	Negative_regulation
26883801	625	633	Patients	Species
26883801	639	642	IPF	Disease
26883801	647	651	mice	Species
26883801	657	666	bleomycin	Chemical
26883801	668	671	BLM	Chemical
26883801	681	699	pulmonary fibrosis	Disease
26883801	705	714	affected	Regulation
26883801	729	733	Chop	Gene
26883801	734	745	expression	Gene_expression
26883801	775	779	Chop	Gene
26883801	801	805	mice	Species
26883801	814	817	BLM	Chemical
26883801	826	837	lung injury	Disease
26883801	842	850	fibrosis	Disease
26883801	860	864	Chop	Gene
26883801	890	918	transforming growth factor b	Gene
26883801	920	925	TGF-b	Gene
26883801	999	1002	BLM	Chemical
26883801	1046	1050	Chop	Gene
26883801	1051	1062	deficiency	Negative_regulation
26883801	1114	1125	attenuated	Negative_regulation
26883801	1125	1130	TGF-b	Gene
26883801	1131	1141	secretion	Localization
26883801	1164	1168	Chop	Gene
26883801	1291	1295	Chop	Gene
26883801	1526	1530	Chop	Gene
26883801	1563	1566	IPF	Disease
27513632|t|miR  -221 targets HMGA2 to inhibit bleomycin  -induced pulmonary fibrosis by regulating TGF  -b1/Smad3-induced EMT
MicroRNA  (miR)-221 plays an essential role in the epithelial-mesenchymal transition (EMT)
High mobility group AT-hook 2  (HMGA2), is a key regulator of EMT
However, the role of miR  -221 in pulmonary fibrosis, and the association between miR  -221 and HMGA2 remain largely unknown
For this purpose, we examined the expression of miR  -221 and HMGA2 in human idiopathic pulmonary fibrosis  (IPF) tissues and pulmonary cells, namely the adenocarcinoma  A549 and human bronchial epithelium  (HBE) cell lines, and found that the expression of miR  -221 was inhibited in both tissues and cells whereas high mRNA and protein expression of HMGA2 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 miR  -221 mimics, and found that the expression of phosphorylated-Smad3 in miR  -221  -overexpressing cells was significantly downregulated, compared with that in the TGF  -b1-treated cells without transfection
Furthermore, the overexpression of miR  -221 decreased the expression of HMGA2, suppressed the EMT, and inhibited the proliferation of A549 and HBE cells
HMGA2 was directly targeted by miR  -221 which was confirmed by the dual-luciferase reporter gene assay
Finally, a mouse model of bleomycin  (BLM)  -induced pulmonary fibrosis was used to confirm the effect of miR  -221 on EMT
Hematoxylin and eosin staining showed that BLM induced thicker alveolar walls and more collagen deposition, whereas miR  -221 treatment reduced lung fibrosis and the tissues exhibited thinner alveolar walls and normal lung alveoli
Furthermore, the EMT process was suppressed following miR  -221 injection
Taken together, these findings sugest that miR  -221 targets HMGA2 to inhibit BLM  -induced pulmonary fibrosis through the TGF  -b1/Smad3 signaling pathway
27513632	0	9	miR  -221	Gene
27513632	18	23	HMGA2	Gene
27513632	35	44	bleomycin	Chemical
27513632	55	73	pulmonary fibrosis	Disease
27513632	88	96	TGF  -b1	Gene
27513632	97	102	Smad3	Gene
27513632	116	135	MicroRNA  (miR)-221	Gene
27513632	208	237	High mobility group AT-hook 2	Gene
27513632	240	245	HMGA2	Gene
27513632	257	267	regulator	Regulation
27513632	296	305	miR  -221	Gene
27513632	309	327	pulmonary fibrosis	Disease
27513632	337	349	association	Binding
27513632	357	366	miR  -221	Gene
27513632	371	376	HMGA2	Gene
27513632	435	446	expression	Gene_expression
27513632	449	458	miR  -221	Gene
27513632	463	468	HMGA2	Gene
27513632	472	477	human	Species
27513632	478	507	idiopathic pulmonary fibrosis	Disease
27513632	510	513	IPF	Disease
27513632	555	575	adenocarcinoma  A549	Disease
27513632	580	585	human	Species
27513632	659	668	miR  -221	Gene
27513632	739	750	expression	Transcription
27513632	753	758	HMGA2	Gene
27513632	787	818	transforming growth factor  -b1	Gene
27513632	821	829	TGF  -b1	Gene
27513632	869	881	upregulated	Positive_regulation
27513632	881	892	expression	Gene_expression
27513632	927	939	N  -cadherin	Gene
27513632	941	949	vimentin	Gene
27513632	1065	1075	E-cadherin	Gene
27513632	1135	1144	miR  -221	Gene
27513632	1172	1183	expression	Gene_expression
27513632	1186	1201	phosphorylated	Phosphorylation
27513632	1201	1206	Smad3	Gene
27513632	1210	1219	miR  -221	Gene
27513632	1261	1275	downregulated	Negative_regulation
27513632	1302	1310	TGF  -b1	Gene
27513632	1364	1379	overexpression	Positive_regulation
27513632	1382	1391	miR  -221	Gene
27513632	1406	1417	expression	Gene_expression
27513632	1420	1425	HMGA2	Gene
27513632	1502	1507	HMGA2	Gene
27513632	1533	1542	miR  -221	Gene
27513632	1618	1623	mouse	Species
27513632	1633	1642	bleomycin	Chemical
27513632	1645	1648	BLM	Chemical
27513632	1660	1678	pulmonary fibrosis	Disease
27513632	1713	1722	miR  -221	Gene
27513632	1731	1742	Hematoxylin	Chemical
27513632	1747	1752	eosin	Chemical
27513632	1774	1777	BLM	Chemical
27513632	1778	1786	induced	Positive_regulation
27513632	1786	1808	thicker alveolar walls	Disease
27513632	1847	1856	miR  -221	Gene
27513632	1880	1888	fibrosis	Disease
27513632	2017	2026	miR  -221	Gene
27513632	2081	2090	miR  -221	Gene
27513632	2099	2104	HMGA2	Gene
27513632	2116	2119	BLM	Chemical
27513632	2130	2148	pulmonary fibrosis	Disease
27513632	2161	2169	TGF  -b1	Gene
27513632	2170	2175	Smad3	Gene
7767546|t|Increased interleukin-1 receptor antagonist in idiopathic pulmonary fibrosis
A compartmental analysis
Idiopathic pulmonary fibrosis (IPF) is a poorly understood interstitial disease that usually proves refractory to therapy and results in irreversible tissue scarring and pulmonary dysfunction
Previous investigations have suggested a number of possible mediators of inflammation and fibrosis that typify IPF
We report increases in lung interleukin-1 receptor antagonist protein (IRAP) content in patients with IPF, as compared with normal control subjects
Importantly, this increase in IRAP was not accompanied by concomitant increases in interleukin-1 beta (IL-1 beta), resulting in a local environment that may be profibrotic
Tissue homogenates and bronchoalveolar lavage fluid from patients with IPF both demonstrate elevated IRAP content compared with that in normal subjects
Immunohistochemical staining and in situ hybridization localize IRAP to hyperplastic type II pneumocytes, macrophages, and local stromal cells
Finally, in vitro studies utilizing fibroblasts isolated from patients with IPF demonstrated no difference in constitutive IRAP production compared with that in normal subjects, but they revealed an exaggerated response to stimulation with transforming growth factor-beta (TGF-beta)
These findings suggest that the fibrotic tissue changes of IPF and possibly other chronic interstitial lung diseases may result in part from the local effects of IRAP, and they also demonstrate that pulmonary nonimmune cells may influence local tissue changes through the elaboration of IRAP
7767546	0	10	Increased	Positive_regulation
7767546	47	76	idiopathic pulmonary fibrosis	Disease
7767546	104	133	Idiopathic pulmonary fibrosis	Disease
7767546	135	138	IPF	Disease
7767546	163	183	interstitial disease	Disease
7767546	274	295	pulmonary dysfunction	Disease
7767546	370	382	inflammation	Disease
7767546	387	395	fibrosis	Disease
7767546	408	411	IPF	Disease
7767546	423	433	increases	Positive_regulation
7767546	441	482	interleukin-1 receptor antagonist protein	Gene
7767546	484	488	IRAP	Gene
7767546	501	509	patients	Species
7767546	515	518	IPF	Disease
7767546	592	596	IRAP	Gene
7767546	645	663	interleukin-1 beta	Gene
7767546	665	674	IL-1 beta	Gene
7767546	792	800	patients	Species
7767546	806	809	IPF	Disease
7767546	827	836	elevated	Positive_regulation
7767546	836	840	IRAP	Gene
7767546	943	952	localize	Localization
7767546	952	956	IRAP	Gene
7767546	1094	1102	patients	Species
7767546	1108	1111	IPF	Disease
7767546	1155	1159	IRAP	Gene
7767546	1375	1378	IPF	Disease
7767546	1406	1432	interstitial lung diseases	Disease
7767546	1478	1482	IRAP	Gene
7767546	1603	1607	IRAP	Gene
27836973|t|Transforming Growth Factor (TGF)-b Promotes de Novo Serine Synthesis for Collagen Production
TGF-b promotes excessive collagen deposition in fibrotic diseases 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 TGF-b induces expression of glycolytic genes and increases glycolytic flux
TGF-b 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 TGF-b-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of fibrotic diseases including IPF
27836973	47	58	Novo Serine	Chemical
27836973	82	93	Production	Gene_expression
27836973	94	99	TGF-b	Gene
27836973	100	109	promotes	Positive_regulation
27836973	142	159	fibrotic diseases	Disease
27836973	168	197	idiopathic pulmonary fibrosis	Disease
27836973	199	202	IPF	Disease
27836973	209	219	amino acid	Chemical
27836973	276	283	glycine	Chemical
27836973	314	319	TGF-b	Gene
27836973	328	339	expression	Gene_expression
27836973	390	395	TGF-b	Gene
27836973	401	409	induces	Positive_regulation
27836973	413	424	expression	Gene_expression
27836973	454	460	serine	Chemical
27836973	480	496	phosphoglycerate	Chemical
27836973	512	517	PHGDH	Gene
27836973	520	552	phosphoserine aminotransferase 1	Gene
27836973	554	559	PSAT1	Gene
27836973	566	579	phosphoserine	Chemical
27836973	593	597	PSPH	Gene
27836973	612	619	glycine	Chemical
27836973	631	664	serine hydroxymethyltransferase 2	Gene
27836973	666	671	SHMT2	Gene
27836973	711	723	attenuation	Negative_regulation
27836973	726	731	PHGDH	Gene
27836973	735	740	SHMT2	Gene
27836973	759	770	inhibition	Negative_regulation
27836973	773	778	PHGDH	Gene
27836973	809	818	required	Positive_regulation
27836973	831	841	synthesis	Gene_expression
27836973	899	905	carbon	Chemical
27836973	911	918	glucose	Chemical
27836973	958	964	humans	Species
27836973	970	973	IPF	Disease
27836973	987	997	increased	Positive_regulation
27836973	997	1008	expression	Gene_expression
27836973	1011	1016	PHGDH	Gene
27836973	1021	1026	SHMT2	Gene
27836973	1068	1074	serine	Chemical
27836973	1096	1106	necessary	Positive_regulation
27836973	1110	1115	TGF-b	Gene
27836973	1133	1144	production	Gene_expression
27836973	1219	1236	fibrotic diseases	Disease
27836973	1247	1250	IPF	Disease
22815997|t|Autophagy in idiopathic pulmonary fibrosis
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 idiopathic pulmonary fibrosis
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-b(1) 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-b(1) inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-b(1)
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-b(1) may represent a mechanism for the promotion of fibrogenesis in IPF
22815997	13	42	idiopathic pulmonary fibrosis	Disease
22815997	211	216	human	Species
22815997	236	242	cancer	Disease
22815997	247	279	chronic obstructive lung disease	Disease
22815997	330	359	idiopathic pulmonary fibrosis	Disease
22815997	370	375	Human	Species
22815997	394	402	patients	Species
22815997	408	411	IPF	Disease
22815997	578	585	TGF-b(1	Gene
22815997	601	606	human	Species
22815997	728	737	bleomycin	Chemical
22815997	746	754	fibrosis	Disease
22815997	755	760	mouse	Species
22815997	795	798	IPF	Disease
22815997	799	807	patients	Species
22815997	877	880	LC3	Gene
22815997	882	885	p62	Gene
22815997	894	905	expression	Gene_expression
22815997	960	967	TGF-b(1	Gene
22815997	1033	1044	activation	Positive_regulation
22815997	1047	1053	mTORC1	Gene
22815997	1055	1066	expression	Gene_expression
22815997	1069	1074	TIGAR	Gene
22815997	1083	1093	increased	Positive_regulation
22815997	1108	1116	TGF-b(1)	Gene
22815997	1125	1134	bleomycin	Chemical
22815997	1144	1162	pulmonary fibrosis	Disease
22815997	1164	1173	rapamycin	Chemical
22815997	1205	1214	rapamycin	Chemical
22815997	1220	1230	decreases	Negative_regulation
22815997	1230	1241	expression	Gene_expression
22815997	1271	1282	fibronectin	Gene
22815997	1308	1319	Inhibition	Negative_regulation
22815997	1351	1354	LC3	Gene
22815997	1359	1367	beclin-1	Gene
22815997	1391	1398	effect	Regulation
22815997	1412	1423	expression	Gene_expression
22815997	1453	1464	fibronectin	Gene
22815997	1506	1524	pulmonary fibrosis	Disease
22815997	1611	1619	TGF-b(1)	Gene
22815997	1683	1686	IPF	Disease
9512902|t|Molecular pathogenesis of interstitial pneumonitis with TNF-alpha transgenic mice
Tumour necrosis factor alpha (TNF-alpha) transgenic mice, which overexpress TNF-alpha in the lungs, develop interstitial pneumonitis resembling idiopathic pulmonary fibrosis (IPF) in humans
Transgenic mice were used to study molecular pathogenesis of interstitial pneumonitis with regard to sequential histological changes and cytokine network induced by TNF-alpha
The authors divided the histological process of interstitial pneumonitis into three stages: early stage with lymphocytic infiltration in alveolar septa, middle stage with recruitment of macrophages, and late stage with hyperplasia of epithelial cells and mild fibrosis
As for cytokine network, prolonged overexpression of TNF-alpha along with increasing interleukin 6 (IL-6) were associated with the progression of interstitial pneumonitis
Increasing IL-1 was found only in the early stage, the beginning of lymphocyte proliferation
The mRNA level of an anti-inflammatory cytokine, IL-10, was constantly enhanced in the lungs of transgenic mice
However, transforming growth factor beta 1 (TGF-beta 1) protein decreased, which is closely associated with prolonged TNF-alpha synthesis, resulting in development of chronic inflammation and less severe fibrosis in the lungs of this animal model, analogous to inflammatory stage of human IPF
TNF-alpha transgenic mice enabled the analysis of the sequential process of interstitial pneumonitis as a model of IPF pathogenesis in humans, the results of which will give rise to new therapeutic measures for human IPF
9512902	26	50	interstitial pneumonitis	Disease
9512902	56	65	TNF-alpha	Gene
9512902	66	81	transgenic mice	Species
9512902	83	98	Tumour necrosis	Disease
9512902	113	122	TNF-alpha	Gene
9512902	124	139	transgenic mice	Species
9512902	147	159	overexpress	Gene_expression
9512902	159	168	TNF-alpha	Gene
9512902	191	215	interstitial pneumonitis	Disease
9512902	227	256	idiopathic pulmonary fibrosis	Disease
9512902	258	261	IPF	Disease
9512902	266	272	humans	Species
9512902	274	289	Transgenic mice	Species
9512902	335	359	interstitial pneumonitis	Disease
9512902	439	448	TNF-alpha	Gene
9512902	498	522	interstitial pneumonitis	Disease
9512902	710	718	fibrosis	Disease
9512902	755	770	overexpression	Positive_regulation
9512902	773	782	TNF-alpha	Gene
9512902	794	805	increasing	Positive_regulation
9512902	805	818	interleukin 6	Gene
9512902	820	824	IL-6	Gene
9512902	866	890	interstitial pneumonitis	Disease
9512902	892	903	Increasing	Positive_regulation
9512902	903	907	IL-1	Gene
9512902	1035	1040	IL-10	Gene
9512902	1082	1097	transgenic mice	Species
9512902	1108	1141	transforming growth factor beta 1	Gene
9512902	1143	1153	TGF-beta 1	Gene
9512902	1217	1226	TNF-alpha	Gene
9512902	1227	1237	synthesis	Gene_expression
9512902	1266	1286	chronic inflammation	Disease
9512902	1303	1311	fibrosis	Disease
9512902	1382	1387	human	Species
9512902	1388	1391	IPF	Disease
9512902	1393	1402	TNF-alpha	Gene
9512902	1403	1418	transgenic mice	Species
9512902	1469	1493	interstitial pneumonitis	Disease
9512902	1508	1511	IPF	Disease
9512902	1528	1534	humans	Species
9512902	1604	1609	human	Species
9512902	1610	1613	IPF	Disease
23418199|t|Overexpression of Sulf2 in idiopathic pulmonary fibrosis
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 Sulf2 in a murine model of pulmonary fibrosis
In this study, we focused on the role of Sulf2 in modulating TGF-b1 function and the development of pulmonary fibrosis
We found that Sulf2 mRNA was overexpressed in lung samples from human patients with idiopathic pulmonary fibrosis (IPF), and Sulf2 protein was specifically localized to the hyperplastic type II alveolar epithelial cells (AECs)
In vitro, TGF-b1 induced the expression of Sulf2 with accompanied HS 6-O-desulfation in A549 cells, adenocarcinoma cells derived from the type II alveolar epithelium
Using small interference RNA to block Sulf2 expression, we observed a biphasic TGF-b1 response with early enhanced Smad activation, but eventually reduced TGF-b1 target gene expression in Sulf2 knockdown A549 cells compared with the control cells
To study the role of Sulf2 in normal type II AECs, we isolated primary type II cells from wild-type and Sulf2 knockout mice
We observed enhanced Smad activation as well as enhanced TGF-b1 target gene expression in Sulf2 knockout type II AECs compared with wild-type type II AECs
In conclusion, Sulf2 is overexpressed in IPF and may play a role in regulating TGF-b1 signaling in type II AECs
23418199	0	15	Overexpression	Positive_regulation
23418199	18	23	Sulf2	Gene
23418199	27	56	idiopathic pulmonary fibrosis	Disease
23418199	97	104	sulfate	Chemical
23418199	131	136	Sulf1	Gene
23418199	143	172	transforming growth factor-b1	Gene
23418199	174	180	TGF-b1	Gene
23418199	208	213	human	Species
23418199	281	287	TGF-b1	Gene
23418199	297	303	TGF-b1	Gene
23418199	304	312	induces	Positive_regulation
23418199	316	327	expression	Gene_expression
23418199	330	335	Sulf1	Gene
23418199	375	380	Sulf2	Gene
23418199	386	392	murine	Species
23418199	402	420	pulmonary fibrosis	Disease
23418199	463	468	Sulf2	Gene
23418199	483	489	TGF-b1	Gene
23418199	522	540	pulmonary fibrosis	Disease
23418199	556	561	Sulf2	Gene
23418199	571	585	overexpressed	Positive_regulation
23418199	606	611	human	Species
23418199	612	620	patients	Species
23418199	626	655	idiopathic pulmonary fibrosis	Disease
23418199	657	660	IPF	Disease
23418199	667	672	Sulf2	Gene
23418199	698	708	localized	Localization
23418199	780	786	TGF-b1	Gene
23418199	813	818	Sulf2	Gene
23418199	836	840	HS 6	Chemical
23418199	870	884	adenocarcinoma	Disease
23418199	908	935	type II alveolar epithelium	Disease
23418199	969	975	block	Negative_regulation
23418199	975	980	Sulf2	Gene
23418199	981	992	expression	Gene_expression
23418199	1016	1022	TGF-b1	Gene
23418199	1043	1052	enhanced	Positive_regulation
23418199	1057	1068	activation	Positive_regulation
23418199	1084	1092	reduced	Negative_regulation
23418199	1092	1098	TGF-b1	Gene
23418199	1111	1122	expression	Gene_expression
23418199	1125	1130	Sulf2	Gene
23418199	1131	1141	knockdown	Negative_regulation
23418199	1206	1211	Sulf2	Gene
23418199	1289	1294	Sulf2	Gene
23418199	1304	1308	mice	Species
23418199	1322	1331	enhanced	Positive_regulation
23418199	1336	1347	activation	Positive_regulation
23418199	1358	1367	enhanced	Positive_regulation
23418199	1367	1373	TGF-b1	Gene
23418199	1386	1397	expression	Gene_expression
23418199	1400	1405	Sulf2	Gene
23418199	1481	1486	Sulf2	Gene
23418199	1490	1504	overexpressed	Positive_regulation
23418199	1507	1510	IPF	Disease
23418199	1534	1545	regulating	Regulation
23418199	1545	1551	TGF-b1	Gene
24265486|t|Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis
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 idiopathic pulmonary fibrosis (IPF); however, the contribution of Wilms' tumor 1 (Wt1)-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 Wt1-knockdown PMCs (sh Wt1) were generated with Wt1 shRNA, and morphologic and functional assays were performed in vitro
Loss of Wt1 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 Wt1-EGFP transgenic mice
Lineage-tracing experiments to map the fate of Wt1(+) 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 Wt1 is necessary for the morphologic integrity of pleural membrane and that loss of Wt1 contributes to IPF via MMT of PMCs into a myofibroblast phenotype
24265486	0	14	Wilms' tumor 1	Gene
24265486	16	19	Wt1	Gene
24265486	105	134	idiopathic pulmonary fibrosis	Disease
24265486	366	395	idiopathic pulmonary fibrosis	Disease
24265486	397	400	IPF	Disease
24265486	432	446	Wilms' tumor 1	Gene
24265486	448	451	Wt1	Gene
24265486	558	561	IPF	Disease
24265486	654	657	Wt1	Gene
24265486	677	680	Wt1	Gene
24265486	702	705	Wt1	Gene
24265486	784	787	Wt1	Gene
24265486	891	899	reduced	Negative_regulation
24265486	899	910	expression	Gene_expression
24265486	913	923	E-cadherin	Gene
24265486	931	940	increase	Positive_regulation
24265486	990	995	a-SMA	Gene
24265486	1253	1256	Wt1	Gene
24265486	1262	1277	transgenic mice	Species
24265486	1326	1329	Wt1	Gene
24265486	1341	1346	mouse	Species
24265486	1367	1373	TGF-b1	Gene
24265486	1472	1475	Wt1	Gene
24265486	1548	1553	loss	Negative_regulation
24265486	1556	1559	Wt1	Gene
24265486	1575	1578	IPF	Disease
27867035|t|Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis
UNASSIGNED: Idiopathic pulmonary fibrosis (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	119	127	Fibrosis	Disease
27867035	141	170	Idiopathic pulmonary fibrosis	Disease
27867035	172	175	IPF	Disease
27867035	202	227	interstitial lung disease	Disease
27867035	289	292	IPF	Disease
27867035	652	660	fibrosis	Disease
27867035	710	714	mice	Species
27867035	831	839	fibrosis	Disease
27867035	951	959	fibrosis	Disease
27867035	1033	1041	fibrosis	Disease
27867035	1066	1071	human	Species
27867035	1097	1102	human	Species
27867035	1170	1173	IPF	Disease
27867035	1235	1243	patients	Species
25575513|t|Matrix metalloproteinase (MMP)-19 deficient fibroblasts display a profibrotic phenotype
UNASSIGNED: Idiopathic pulmonary fibrosis (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	0	33	Matrix metalloproteinase (MMP)-19	Gene
25575513	34	44	deficient	Negative_regulation
25575513	101	130	Idiopathic pulmonary fibrosis	Disease
25575513	132	135	IPF	Disease
25575513	173	198	interstitial lung disease	Disease
25575513	479	503	abnormal lung remodeling	Disease
25575513	533	538	Mmp19	Gene
25575513	542	546	mice	Species
25575513	570	579	bleomycin	Chemical
25575513	593	601	fibrosis	Disease
25575513	674	679	MMP19	Gene
25575513	680	691	deficiency	Negative_regulation
25575513	763	768	Mmp19	Gene
25575513	999	1003	mice	Species
25575513	1005	1010	Mmp19	Gene
25575513	1038	1048	increased	Positive_regulation
25575513	1095	1106	production	Gene_expression
25575513	1128	1133	TGF-b	Gene
25575513	1149	1159	increased	Positive_regulation
25575513	1185	1196	expression	Gene_expression
25575513	1217	1222	Mmp19	Gene
25575513	1223	1233	deficient	Negative_regulation
25575513	1469	1475	MMP-19	Gene
21135509|t|Epithelium-specific deletion of TGF-b receptor type II protects mice from bleomycin-induced pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments
Although the etiology of IPF is unknown, dysregulated TGF-b 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 TGF-b signaling via TGF-b 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 TGF-b signaling in vitro and in a bleomycin-induced, TGF-b-mediated mouse model of pulmonary fibrosis
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 TGF-b
However, TbRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced pulmonary fibrosis
To our knowledge, these findings are the first to demonstrate a specific role for TGF-b signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis
21135509	32	37	TGF-b	Gene
21135509	64	68	mice	Species
21135509	74	83	bleomycin	Chemical
21135509	92	110	pulmonary fibrosis	Disease
21135509	112	141	Idiopathic pulmonary fibrosis	Disease
21135509	143	146	IPF	Disease
21135509	161	198	fibroproliferative pulmonary disorder	Disease
21135509	269	272	IPF	Disease
21135509	285	298	dysregulated	Regulation
21135509	298	303	TGF-b	Gene
21135509	495	500	TGF-b	Gene
21135509	515	532	TGF-b receptor II	Gene
21135509	534	539	TbRII	Gene
21135509	565	573	fibrosis	Disease
21135509	588	592	mice	Species
21135509	602	607	TbRII	Gene
21135509	625	637	inactivated	Negative_regulation
21135509	640	645	mouse	Species
21135509	669	673	mice	Species
21135509	723	727	mice	Species
21135509	766	771	TbRII	Gene
21135509	772	785	inactivation	Negative_regulation
21135509	870	875	TGF-b	Gene
21135509	904	913	bleomycin	Chemical
21135509	923	928	TGF-b	Gene
21135509	938	943	mouse	Species
21135509	953	971	pulmonary fibrosis	Disease
21135509	1110	1114	mice	Species
21135509	1125	1134	emphysema	Disease
21135509	1176	1181	TbRII	Gene
21135509	1207	1215	Absence	Negative_regulation
21135509	1218	1223	TbRII	Gene
21135509	1224	1234	increased	Positive_regulation
21135509	1234	1250	phosphorylation	Phosphorylation
21135509	1253	1258	Smad2	Gene
21135509	1295	1301	block	Negative_regulation
21135509	1302	1318	phosphorylation	Phosphorylation
21135509	1321	1326	Smad3	Gene
21135509	1365	1370	TGF-b	Gene
21135509	1397	1401	mice	Species
21135509	1449	1458	bleomycin	Chemical
21135509	1467	1485	pulmonary fibrosis	Disease
21135509	1569	1574	TGF-b	Gene
21135509	1631	1649	pulmonary fibrosis	Disease
16607487|t|[Pulmonary fibrosis--a therapeutic dilemma?]
The idiopathic interstitial pneumonias, 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	61	84	interstitial pneumonias	Disease
16607487	101	130	idiopathic pulmonary fibrosis	Disease
16607487	132	135	IPF	Disease
16607487	159	173	lung disorders	Disease
16607487	234	237	IPF	Disease
16607487	252	260	Thoracic	Disease
16607487	365	380	corticosteroids	Chemical
16607487	385	397	azathioprine	Chemical
16607487	401	417	cyclophosphamide	Chemical
16607487	561	564	IPF	Disease
16607487	650	653	IPF	Disease
16607487	708	711	IPF	Disease
16607487	861	864	IPF	Disease
16607487	973	987	acetylcysteine	Chemical
16607487	998	1004	oxygen	Chemical
16607487	1067	1070	Th1	Gene
16607487	1114	1125	pirfenidone	Chemical
16607487	1185	1192	FG 3019	Chemical
16607487	1240	1257	imatinib mesylate	Chemical
16607487	1304	1312	bosentan	Chemical
16607487	1339	1347	zileutin	Chemical
16607487	1388	1397	blockade	Negative_regulation
16607487	1400	1427	tumor necrosis factor-alpha	Gene
16607487	1439	1463	alveolar anticoagulation	Disease
16607487	1543	1546	IPF	Disease
25959210|t|Bleomycin in the setting of lung fibrosis induction: From biological mechanisms to counteractions
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 lung fibrosis 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 lung fibrosis in different animal models and to summarize modalities and timing of in vivo drug administration
Understanding the mechanisms of BLM-induced lung fibrosis and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena
25959210	0	9	Bleomycin	Chemical
25959210	28	41	lung fibrosis	Disease
25959210	111	120	Bleomycin	Chemical
25959210	122	125	BLM	Chemical
25959210	170	179	neoplasms	Disease
25959210	181	184	BLM	Chemical
25959210	217	230	lung toxicity	Disease
25959210	282	308	loss of pulmonary function	Disease
25959210	329	334	death	Disease
25959210	448	451	BLM	Chemical
25959210	502	515	lung fibrosis	Disease
25959210	613	621	patients	Species
25959210	713	735	epithelial cell injury	Disease
25959210	741	761	reactive hyperplasia	Disease
25959210	954	957	BLM	Chemical
25959210	1151	1169	pulmonary fibrosis	Disease
25959210	1288	1321	transforming growth factor beta 1	Gene
25959210	1323	1350	tumor necrosis factor alpha	Gene
25959210	1500	1503	BLM	Chemical
25959210	1512	1525	lung fibrosis	Disease
25959210	1656	1659	BLM	Chemical
25959210	1668	1681	lung fibrosis	Disease
25959210	1731	1739	fibrosis	Disease
20676040|t|Signaling pathways in the epithelial origins of pulmonary fibrosis
Pulmonary fibrosis complicates a number of disease processes and leads to substantial morbidity and mortality
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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	48	66	pulmonary fibrosis	Disease
20676040	68	86	Pulmonary fibrosis	Disease
20676040	179	208	Idiopathic pulmonary fibrosis	Disease
20676040	210	213	IPF	Disease
20676040	374	382	patients	Species
20676040	434	437	IPF	Chemical
20676040	581	586	mouse	Species
20676040	597	610	lung fibrosis	Disease
20676040	656	669	lung fibrosis	Disease
20676040	773	791	pulmonary fibrosis	Disease
20676040	919	935	fibrotic lesions	Disease
20676040	943	975	transforming growth factor-alpha	Gene
20676040	996	1009	lung fibrosis	Disease
25505594|t|Assessment of the effect of potential antifibrotic compounds on total and aVb6 integrin-mediated TGF-b activation
Transforming growth factor-b (TGF-b) plays an important role in the development of tissue fibrosis, and molecules inhibiting this pathway are attractive therapeutic targets for fibrotic diseases such as idiopathic pulmonary fibrosis (IPF)
Activation of TGF-b is the rate-limiting step in TGF-b bioavailability, and activation by the aVb6 integrin is important in fibrosis 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	103	114	activation	Positive_regulation
25505594	205	213	fibrosis	Disease
25505594	292	309	fibrotic diseases	Disease
25505594	318	347	idiopathic pulmonary fibrosis	Disease
25505594	349	352	IPF	Disease
25505594	355	366	Activation	Positive_regulation
25505594	479	487	fibrosis	Disease
25505594	520	531	Activation	Positive_regulation
25505594	548	557	requires	Positive_regulation
25505594	597	605	release	Localization
25505594	865	869	mink	Species
25505594	991	1001	inhibitor	Negative_regulation
25505594	1002	1015	Dexamethasone	Chemical
25505594	1017	1028	Pirfenidone	Chemical
25505594	1030	1046	N-acetylcysteine	Chemical
25505594	1048	1051	NAC	Chemical
25505594	1058	1066	BIBF1120	Chemical
25505594	1192	1203	expressing	Gene_expression
25505594	1272	1287	phosphorylated	Phosphorylation
25505594	1355	1366	inhibitors	Negative_regulation
25505594	1418	1429	Pirfenidone	Chemical
25505594	1431	1439	BIBF1120	Chemical
25505594	1445	1448	NAC	Chemical
25505594	1483	1496	Dexamethasone	Chemical
20495078|t|FGF-1 reverts epithelial-mesenchymal transition induced by TGF-{beta}1 through MAPK/ERK kinase pathway
Idiopathic pulmonary fibrosis (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 (FGF-1) inhibits several profibrogenic effects of TGF-beta1
In this study, we examined the effects of FGF-1 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 FGF-1 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
FGF-1 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 FGF-1 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 FGF-1 and suggest therapeutic approaches to target this process in IPF
20495078	0	5	FGF-1	Gene
20495078	59	70	TGF-{beta}1	Gene
20495078	104	133	Idiopathic pulmonary fibrosis	Disease
20495078	135	138	IPF	Disease
20495078	161	180	lethal lung disease	Disease
20495078	453	462	TGF-beta1	Gene
20495078	614	640	fibroblast growth factor-1	Gene
20495078	642	647	FGF-1	Gene
20495078	691	700	TGF-beta1	Gene
20495078	744	749	FGF-1	Gene
20495078	753	762	TGF-beta1	Gene
20495078	794	799	human	Species
20495078	804	807	rat	Species
20495078	866	875	TGF-beta1	Gene
20495078	915	924	TGF-beta1	Gene
20495078	945	950	FGF-1	Gene
20495078	994	1003	TGF-beta1	Gene
20495078	1097	1107	reduction	Negative_regulation
20495078	1110	1120	E-cadherin	Gene
20495078	1125	1137	cytokeratins	Chemical
20495078	1153	1163	induction	Positive_regulation
20495078	1262	1267	FGF-1	Gene
20495078	1469	1478	TGF-beta1	Gene
20495078	1532	1537	FGF-1	Gene
20495078	1578	1588	resulting	Positive_regulation
20495078	1591	1596	ERK-1	Gene
20495078	1597	1613	phosphorylation	Phosphorylation
20495078	1617	1622	Smad2	Gene
20495078	1623	1641	dephosphorylation	Phosphorylation
20495078	1671	1680	TGF-beta1	Gene
20495078	1708	1713	FGF-1	Gene
20495078	1775	1778	IPF	Disease
26138704|t|The anti-fibrotic effect of inhibition of TGFb-ALK5 signalling in experimental pulmonary fibrosis in mice is attenuated in the presence of concurrent y-herpesvirus infection
UNASSIGNED: TGFb-ALK5 pro-fibrotic signalling and herpesvirus infections have been implicated in the pathogenesis and exacerbation of pulmonary fibrosis
In this study we addressed the role of TGFb-ALK5 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 pulmonary fibrosis
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 pulmonary fibrosis (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 TGFb-ALK5 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 TGFb-ALK5 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 TGFb-ALK5 signalling axis in experimental lung fibrosis, with different outcomes in response to ALK5 inhibition depending on the presence of viral infection
These findings raise important considerations for the targeting of TGFb signalling responses in the context of pulmonary fibrosis
26138704	28	39	inhibition	Negative_regulation
26138704	42	46	TGFb	Gene
26138704	47	51	ALK5	Gene
26138704	79	97	pulmonary fibrosis	Disease
26138704	101	105	mice	Species
26138704	187	191	TGFb	Gene
26138704	192	196	ALK5	Gene
26138704	225	247	herpesvirus infections	Disease
26138704	309	327	pulmonary fibrosis	Disease
26138704	360	365	role	Regulation
26138704	368	372	TGFb	Gene
26138704	373	377	ALK5	Gene
26138704	415	423	fibrosis	Disease
26138704	437	442	mouse	Species
26138704	452	458	murine	Species
26138704	477	480	MHV	Species
26138704	529	538	bleomycin	Chemical
26138704	547	565	pulmonary fibrosis	Disease
26138704	711	714	MHV	Species
26138704	736	744	enhance	Positive_regulation
26138704	758	769	deposition	Negative_regulation
26138704	831	843	inflammatory	Disease
26138704	1032	1040	fibrosis	Disease
26138704	1106	1135	idiopathic pulmonary fibrosis	Disease
26138704	1163	1169	murine	Species
26138704	1225	1255	inflammatory cell infiltration	Disease
26138704	1260	1270	increased	Positive_regulation
26138704	1280	1284	CCL2	Gene
26138704	1286	1290	TNFa	Gene
26138704	1292	1297	IL-1b	Gene
26138704	1302	1307	IL-10	Gene
26138704	1309	1318	Blockade	Negative_regulation
26138704	1321	1325	TGFb	Gene
26138704	1326	1330	ALK5	Gene
26138704	1342	1353	attenuated	Negative_regulation
26138704	1367	1380	accumulation	Positive_regulation
26138704	1383	1392	bleomycin	Chemical
26138704	1407	1411	mice	Species
26138704	1486	1501	viral infection	Disease
26138704	1516	1527	inhibition	Negative_regulation
26138704	1530	1534	TGFb	Gene
26138704	1535	1539	ALK5	Gene
26138704	1614	1626	inflammatory	Disease
26138704	1647	1657	increased	Positive_regulation
26138704	1657	1664	levels	Gene_expression
26138704	1751	1755	TGFb	Gene
26138704	1756	1760	ALK5	Gene
26138704	1780	1806	experimental lung fibrosis	Disease
26138704	1847	1851	ALK5	Gene
26138704	1852	1863	inhibition	Negative_regulation
26138704	1892	1907	viral infection	Disease
26138704	1976	1980	TGFb	Gene
26138704	2020	2038	pulmonary fibrosis	Disease
25451236|t|Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis
Idiopathic pulmonary fibrosis (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 fibrosis as compared to young mice
Most interestingly, we show that fewer (myo)fibroblasts underwent apoptosis and more (myo)fibroblasts 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 fibrosis in part by protecting fibroblasts from apoptosis
25451236	0	33	Plasminogen activator inhibitor 1	Gene
25451236	109	117	fibrosis	Disease
25451236	119	148	Idiopathic pulmonary fibrosis	Disease
25451236	150	153	IPF	Disease
25451236	166	179	lung disorder	Disease
25451236	263	266	IPF	Disease
25451236	342	345	IPF	Disease
25451236	419	422	IPF	Disease
25451236	513	546	plasminogen activator inhibitor 1	Gene
25451236	548	553	PAI-1	Gene
25451236	657	667	increased	Positive_regulation
25451236	679	684	mouse	Species
25451236	728	737	bleomycin	Chemical
25451236	753	757	mice	Species
25451236	780	785	PAI-1	Gene
25451236	805	813	fibrosis	Disease
25451236	835	839	mice	Species
25451236	948	958	increased	Positive_regulation
25451236	967	972	PAI-1	Gene
25451236	1018	1022	mice	Species
25451236	1029	1038	bleomycin	Chemical
25451236	1131	1135	mice	Species
25451236	1154	1190	H2O2 and tumor necrosis factor alpha	Gene
25451236	1249	1255	TGF-b1	Gene
25451236	1301	1305	mice	Species
25451236	1307	1318	Inhibition	Negative_regulation
25451236	1321	1326	PAI-1	Gene
25451236	1343	1348	PAI-1	Gene
25451236	1349	1359	inhibitor	Negative_regulation
25451236	1433	1439	TGF-b1	Gene
25451236	1514	1519	PAI-1	Gene
25451236	1523	1528	human	Species
25451236	1551	1556	PAI-1	Gene
25451236	1651	1657	TGF-b1	Gene
25451236	1694	1704	increased	Positive_regulation
25451236	1704	1709	PAI-1	Gene
25451236	1710	1721	expression	Gene_expression
25451236	1752	1780	sensitivity to lung fibrosis	Disease
26545872|t|Antifibrotic properties of receptor for advanced glycation end products in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	75	104	idiopathic pulmonary fibrosis	Disease
26545872	106	135	Idiopathic pulmonary fibrosis	Disease
26545872	137	140	IPF	Disease
26545872	159	192	chronic interstitial lung disease	Disease
26545872	313	317	RAGE	Gene
26545872	342	345	IPF	Disease
26545872	415	419	RAGE	Gene
26545872	425	429	mice	Species
26545872	478	482	RAGE	Gene
26545872	497	506	bleomycin	Chemical
26545872	515	533	pulmonary fibrosis	Disease
26545872	556	560	mice	Species
26545872	572	576	RAGE	Gene
26545872	582	586	mice	Species
26545872	635	648	lung fibrosis	Disease
26545872	734	738	RAGE	Gene
26545872	827	832	a-SMA	Gene
26545872	895	923	transforming growth factor-b	Gene
26545872	925	930	TGF-b	Gene
26545872	1045	1049	RAGE	Gene
26545872	1058	1063	TGF-b	Gene
26545872	1072	1083	activation	Positive_regulation
26545872	1086	1091	Smad2	Gene
26545872	1093	1096	ERK	Gene
26545872	1231	1235	RAGE	Gene
26545872	1265	1283	pulmonary fibrosis	Disease
26545872	1330	1348	pulmonary fibrosis	Disease
26545872	1353	1357	RAGE	Gene
26545872	1358	1369	regulation	Regulation
22189082|t|Participation of miR-200 in pulmonary fibrosis
Excessive extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis and from patients with IPF
Indeed, the introduction of miR-200c diminishes experimental pulmonary fibrosis 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	28	46	pulmonary fibrosis	Disease
22189082	149	166	fibrotic diseases	Disease
22189082	176	205	idiopathic pulmonary fibrosis	Disease
22189082	207	210	IPF	Disease
22189082	387	395	fibrosis	Disease
22189082	522	544	fibrotic lung diseases	Disease
22189082	606	614	miR-200a	Gene
22189082	616	624	miR-200b	Gene
22189082	630	638	miR-200c	Gene
22189082	657	672	down-regulated	Negative_regulation
22189082	688	692	mice	Species
22189082	716	724	fibrosis	Disease
22189082	736	744	miR-200a	Gene
22189082	749	757	miR-200c	Gene
22189082	763	771	reduced	Negative_regulation
22189082	787	795	patients	Species
22189082	801	804	IPF	Disease
22189082	885	889	mice	Species
22189082	908	926	pulmonary fibrosis	Disease
22189082	1184	1188	mice	Species
22189082	1207	1225	pulmonary fibrosis	Disease
22189082	1235	1243	patients	Species
22189082	1249	1252	IPF	Disease
22189082	1266	1279	introduction	Gene_expression
22189082	1282	1290	miR-200c	Gene
22189082	1315	1333	pulmonary fibrosis	Disease
22189082	1337	1341	mice	Species
22189082	1403	1425	fibrotic lung diseases	Disease
22189082	1540	1567	pulmonary fibrotic diseases	Disease
28254114|t|Genetic polymorphism in matrix metalloproteinase-9 and transforming growth factor-b1 and susceptibility to combined pulmonary fibrosis and emphysema in  a Chinese population
In this study, we aimed to explore the association of genetic polymorphism in matrix metalloproteinase-9 (MMP-9) and transforming growth factor-b1 (TGF-b1) and the susceptibility to combined pulmonary fibrosis 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	24	50	matrix metalloproteinase-9	Gene
28254114	55	84	transforming growth factor-b1	Gene
28254114	107	134	combined pulmonary fibrosis	Disease
28254114	139	148	emphysema	Disease
28254114	253	279	matrix metalloproteinase-9	Gene
28254114	281	286	MMP-9	Gene
28254114	292	321	transforming growth factor-b1	Gene
28254114	323	329	TGF-b1	Gene
28254114	357	384	combined pulmonary fibrosis	Disease
28254114	389	398	emphysema	Disease
28254114	444	449	MMP-9	Gene
28254114	450	457	C-1562T	Mutation
28254114	462	468	TGF-b1	Gene
28254114	469	474	T869C	Mutation
28254114	486	494	patients	Species
28254114	499	518	pulmonary emphysema	Disease
28254114	519	527	patients	Species
28254114	536	565	idiopathic pulmonary fibrosis	Disease
28254114	567	570	IPF	Disease
28254114	572	580	patients	Species
28254114	626	631	MMP-9	Gene
28254114	682	684	CC	Chemical
28254114	701	710	emphysema	Disease
28254114	735	738	IPF	Disease
28254114	790	800	increased	Positive_regulation
28254114	856	865	emphysema	Disease
28254114	887	890	IPF	Disease
28254114	953	959	TGF-b1	Gene
28254114	1045	1054	emphysema	Disease
28254114	1100	1103	IPF	Disease
28254114	1123	1133	increases	Positive_regulation
28254114	1194	1203	emphysema	Disease
28254114	1224	1227	IPF	Disease
28254114	1284	1289	MMP-9	Gene
28254114	1291	1298	C-1562T	Mutation
28254114	1316	1322	TGF-b1	Gene
28254114	1324	1329	T869C	Mutation
28254114	1351	1370	pulmonary emphysema	Disease
28254114	1388	1393	MMP-9	Gene
28254114	1395	1402	C-1562T	Mutation
28254114	1425	1433	patients	Species
28254114	1439	1457	pulmonary fibrosis	Disease
28254114	1469	1478	emphysema	Disease
20160152|t|Proteasomal regulation of pulmonary fibrosis
It is estimated that, combined, 400,000 people are diagnosed with idiopathic pulmonary fibrosis (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	26	44	pulmonary fibrosis	Disease
20160152	86	92	people	Species
20160152	112	141	idiopathic pulmonary fibrosis	Disease
20160152	143	146	IPF	Disease
20160152	151	168	acute lung injury	Disease
20160152	169	204	acute respiratory distress syndrome	Disease
20160152	519	536	acute lung injury	Disease
20160152	567	575	fibrosis	Disease
20160152	579	582	IPF	Disease
20160152	668	706	transforming growth factor (TGF)-beta1	Gene
20160152	764	774	modulates	Regulation
20160152	774	783	TGF-beta1	Gene
20160152	784	795	expression	Gene_expression
20160152	912	920	fibrosis	Disease
20160152	952	961	regulate	Regulation
20160152	961	970	TGF-beta1	Gene
20160152	971	982	expression	Gene_expression
20160152	1065	1100	acute respiratory distress syndrome	Disease
20160152	1104	1107	IPF	Disease
23288928|t|Inhibition of HSP27 blocks fibrosis development and EMT features by promoting Snail degradation
Idiopathic pulmonary fibrosis (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 HSP27 in fibrogenesis and EMT
In vitro, we have up- and down-modulated HSP27 expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF-b1
In vivo, we inhibited HSP27 with the antisense oligonucleotide OGX-427 (in phase II clinical trials as anticancer agent) in our rat subpleural/pulmonary fibrosis models
We demonstrate that HSP27 is strongly expressed during the fibrotic process in patients with IPF and in different in vivo models
We showed that HSP27 binds to and stabilizes Snail and consequently induces EMT
Conversely, HSP27 knockdown leads to Snail proteasomal degradation, thus inhibiting TGF-b1-induced EMT
Inhibition of HSP27 with OGX-427 efficiently blocks EMT and fibrosis development
Controls in vivo were an empty adenovirus that did not induce fibrosis and a control antisense oligonucleotide
The present work opens the possibility of a new therapeutic use for HSP27 inhibitors against IPF, for which there is no conclusively effective treatment
23288928	0	11	Inhibition	Negative_regulation
23288928	14	19	HSP27	Gene
23288928	27	35	fibrosis	Disease
23288928	78	83	Snail	Gene
23288928	97	126	Idiopathic pulmonary fibrosis	Disease
23288928	128	131	IPF	Disease
23288928	384	389	Snail	Gene
23288928	475	480	HSP27	Gene
23288928	547	552	HSP27	Gene
23288928	553	564	expression	Gene_expression
23288928	668	674	TGF-b1	Gene
23288928	688	698	inhibited	Negative_regulation
23288928	698	703	HSP27	Gene
23288928	739	746	OGX-427	Chemical
23288928	804	807	rat	Species
23288928	819	837	pulmonary fibrosis	Disease
23288928	866	871	HSP27	Gene
23288928	884	894	expressed	Gene_expression
23288928	925	933	patients	Species
23288928	939	942	IPF	Disease
23288928	991	996	HSP27	Gene
23288928	997	1003	binds	Binding
23288928	1010	1021	stabilizes	Negative_regulation
23288928	1021	1026	Snail	Gene
23288928	1044	1052	induces	Positive_regulation
23288928	1069	1074	HSP27	Gene
23288928	1075	1085	knockdown	Negative_regulation
23288928	1094	1099	Snail	Gene
23288928	1141	1147	TGF-b1	Gene
23288928	1161	1172	Inhibition	Negative_regulation
23288928	1175	1180	HSP27	Gene
23288928	1186	1193	OGX-427	Chemical
23288928	1221	1229	fibrosis	Disease
23288928	1274	1284	adenovirus	Species
23288928	1305	1313	fibrosis	Disease
23288928	1423	1428	HSP27	Gene
23288928	1429	1440	inhibitors	Negative_regulation
23288928	1448	1451	IPF	Disease
23523906|t|Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-kB dependant TGF-b activation: a biphasic experimental study
Idiopathic pulmonary fibrosis (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 fibrosis, 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	0	9	Berberine	Chemical
23523906	21	30	bleomycin	Chemical
23523906	39	57	pulmonary toxicity	Disease
23523906	62	70	fibrosis	Disease
23523906	75	87	suppressing	Negative_regulation
23523906	87	92	NF-kB	Gene
23523906	103	108	TGF-b	Gene
23523906	109	120	activation	Positive_regulation
23523906	152	181	Idiopathic pulmonary fibrosis	Disease
23523906	183	186	IPF	Disease
23523906	229	242	lung disorder	Disease
23523906	310	313	IPF	Disease
23523906	479	482	IPF	Disease
23523906	484	493	Berberine	Chemical
23523906	584	601	multiple diseases	Disease
23523906	676	685	berberine	Chemical
23523906	694	703	bleomycin	Chemical
23523906	712	723	lung injury	Disease
23523906	728	736	fibrosis	Disease
23523906	769	780	wistar rats	Species
23523906	848	857	bleomycin	Chemical
23523906	868	877	Berberine	Chemical
23523906	958	967	Berberine	Chemical
23523906	1013	1022	bleomycin	Chemical
23523906	1111	1120	Berberine	Chemical
23523906	1197	1211	hydroxyproline	Chemical
23523906	1245	1254	bleomycin	Chemical
23523906	1291	1300	histamine	Chemical
23523906	1338	1347	berberine	Chemical
23523906	1349	1358	Berberine	Chemical
23523906	1359	1368	enhanced	Positive_regulation
23523906	1400	1413	upregulating	Positive_regulation
23523906	1452	1486	nuclear factor E2-related factor 2	Gene
23523906	1488	1492	Nrf2	Gene
23523906	1495	1504	Berberine	Chemical
23523906	1505	1515	inhibited	Negative_regulation
23523906	1519	1528	bleomycin	Chemical
23523906	1538	1549	activation	Positive_regulation
23523906	1574	1596	nuclear factor kappa B	Gene
23523906	1598	1603	NF-kB	Gene
23523906	1609	1620	suppressed	Negative_regulation
23523906	1635	1642	target	Regulation
23523906	1642	1652	inducible	Positive_regulation
23523906	1642	1673	inducible nitric oxide synthase	Gene
23523906	1694	1703	berberine	Chemical
23523906	1721	1733	attenuation	Binding
23523906	1736	1763	tumor necrosis factor alpha	Gene
23523906	1765	1770	TNF-a	Gene
23523906	1838	1844	TGF-b1	Gene
23523906	1908	1917	berberine	Chemical
23523906	1926	1935	bleomycin	Chemical
23523906	1983	1987	Nrf2	Gene
23523906	2004	2009	NF-kB	Gene
23523906	2037	2043	TGF-b1	Gene
25684348|t|Transforming growth factor-b inhibits IQ motif containing guanosine triphosphatase activating protein  1 expression in lung fibroblasts via the nuclear factor-kB signaling pathway
UNASSIGNED: IQ motif containing guanosine triphosphatase activating protein  1 (IQGAP1) is associated with idiopathic pulmonary fibrogenesis (IPF); however, characterization of the expression of IQGAP1 in lung fibroblasts has remained elusive
The present study therefore evaluated IQGAP1 expression in mouse and human lung fibroblasts under fibrotic conditions via western blot analysis
It was revealed that IQGAP1 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 IQGAP1 in WI  -38  cells human lung fibroblasts
Furthermore, inhibition of nuclear factor (NF)  -kB activation restored the TGF  -b  -induced inhibition of IQGAP1 expression in WI  -38  cells
In lysophosphatidic acid (LPA)  -challenged WI  -38  cells, the expression of IQGAP1 was also decreased, while neutralized anti  -TGF  -b antibody treatment restored the LPA  -induced inhibition of IQGAP1 expression
These data indicated that TGF  -b inhibited IQGAP1 expression in lung fibroblasts via the NF  -kB signaling pathway, presenting a potential novel therapeutic target for the treatment of IPF
25684348	29	38	inhibits	Negative_regulation
25684348	58	67	guanosine	Chemical
25684348	83	94	activating	Positive_regulation
25684348	105	116	expression	Gene_expression
25684348	213	222	guanosine	Chemical
25684348	261	267	IQGAP1	Gene
25684348	288	321	idiopathic pulmonary fibrogenesis	Disease
25684348	323	326	IPF	Disease
25684348	362	373	expression	Gene_expression
25684348	376	382	IQGAP1	Gene
25684348	463	469	IQGAP1	Gene
25684348	470	481	expression	Gene_expression
25684348	484	489	mouse	Species
25684348	494	499	human	Species
25684348	591	597	IQGAP1	Gene
25684348	598	609	expression	Gene_expression
25684348	635	645	decreased	Negative_regulation
25684348	679	688	bleomycin	Chemical
25684348	702	706	mice	Species
25684348	732	736	mice	Species
25684348	770	777	TGF  -b	Gene
25684348	815	825	decreased	Negative_regulation
25684348	825	836	expression	Gene_expression
25684348	839	845	IQGAP1	Gene
25684348	849	856	WI  -38	Species
25684348	864	869	human	Species
25684348	951	960	restored	Positive_regulation
25684348	964	971	TGF  -b	Gene
25684348	982	993	inhibition	Negative_regulation
25684348	996	1002	IQGAP1	Gene
25684348	1003	1014	expression	Gene_expression
25684348	1017	1024	WI  -38	Species
25684348	1036	1057	lysophosphatidic acid	Chemical
25684348	1059	1062	LPA	Chemical
25684348	1077	1084	WI  -38	Species
25684348	1097	1108	expression	Gene_expression
25684348	1111	1117	IQGAP1	Gene
25684348	1127	1137	decreased	Negative_regulation
25684348	1163	1170	TGF  -b	Gene
25684348	1203	1206	LPA	Chemical
25684348	1217	1228	inhibition	Negative_regulation
25684348	1231	1237	IQGAP1	Gene
25684348	1238	1249	expression	Gene_expression
25684348	1276	1283	TGF  -b	Gene
25684348	1284	1294	inhibited	Negative_regulation
25684348	1294	1300	IQGAP1	Gene
25684348	1301	1312	expression	Gene_expression
25684348	1436	1439	IPF	Disease
27080864|t|Role of CD248 as a potential severity marker in idiopathic pulmonary fibrosis
BACKGROUND: CD248 or Endosialin is a transmembrane molecule expressed in stromal cells binding to extracellular matrix (ECM) components
It has been previously implicated in kidney fibrosis, rheumatoid arthritis as well as in tumour-stromal interactions
This study investigates the role of CD248 in the pathogenesis of fibrotic diseases in Idiopathic Pulmonary Fibrosis (IPF)
METHODS: CD248 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 CD248 silencing was evaluated on fibroblast proliferation and myofibroblast differentiation
RESULTS: IHC revealed strong CD248 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 CD248 staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO (r2   >   0        35, p   <   0        01)
CD248 protein levels were significantly greater in IPF-derived lung fibroblasts vs normal lung fibroblasts (p   <   0        01) and CD248 silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation
CONCLUSION: We conclude that CD248 overexpression is possibly involved in the pathogenesis of IPF and it has potential as a disease severity marker
Given that CD248 ligands are collagen type I, IV and fibronectin, we hypothesise that CD248 signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in IPF
27080864	8	13	CD248	Gene
27080864	48	77	idiopathic pulmonary fibrosis	Disease
27080864	91	96	CD248	Gene
27080864	100	110	Endosialin	Gene
27080864	139	149	expressed	Gene_expression
27080864	260	268	fibrosis	Disease
27080864	270	290	rheumatoid arthritis	Disease
27080864	305	311	tumour	Disease
27080864	370	375	CD248	Gene
27080864	399	416	fibrotic diseases	Disease
27080864	420	449	Idiopathic Pulmonary Fibrosis	Disease
27080864	451	454	IPF	Disease
27080864	466	471	CD248	Gene
27080864	550	553	IPF	Disease
27080864	554	562	patients	Species
27080864	650	658	Effects	Regulation
27080864	661	666	CD248	Gene
27080864	783	788	CD248	Gene
27080864	789	800	expression	Gene_expression
27080864	992	997	CD248	Gene
27080864	1147	1152	CD248	Gene
27080864	1198	1201	IPF	Disease
27080864	1280	1285	CD248	Gene
27080864	1286	1296	silencing	Negative_regulation
27080864	1438	1443	CD248	Gene
27080864	1444	1459	overexpression	Positive_regulation
27080864	1503	1506	IPF	Disease
27080864	1569	1574	CD248	Gene
27080864	1611	1622	fibronectin	Gene
27080864	1644	1649	CD248	Gene
27080864	1756	1759	IPF	Disease
25845491|t|Immunoglobulin A in serum: an old acquaintance as a new prognostic biomarker in idiopathic pulmonary fibrosis
UNASSIGNED: Immunoglobulin (Ig)A 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 idiopathic pulmonary fibrosis (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	80	109	idiopathic pulmonary fibrosis	Disease
25845491	250	261	production	Gene_expression
25845491	271	281	regulated	Regulation
25845491	379	397	pulmonary fibrosis	Disease
25845491	399	404	TGF-b	Gene
25845491	424	432	patients	Species
25845491	438	467	idiopathic pulmonary fibrosis	Disease
25845491	469	472	IPF	Disease
25845491	590	598	patients	Species
25845491	604	607	IPF	Disease
25845491	659	667	patients	Species
25845491	683	686	IPF	Disease
25845491	712	715	IPF	Disease
25845491	886	894	patients	Species
25845491	945	953	patients	Species
25845491	1132	1135	IPF	Disease
12947024|t|Defect of hepatocyte growth factor secretion by fibroblasts in idiopathic pulmonary fibrosis
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 idiopathic pulmonary fibrosis (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	0	7	Defect	Negative_regulation
12947024	10	34	hepatocyte growth factor	Gene
12947024	35	45	secretion	Localization
12947024	63	92	idiopathic pulmonary fibrosis	Disease
12947024	94	118	Hepatocyte growth factor	Gene
12947024	120	123	HGF	Gene
12947024	189	207	pulmonary fibrosis	Disease
12947024	255	258	HGF	Gene
12947024	273	278	human	Species
12947024	301	309	patients	Species
12947024	315	344	idiopathic pulmonary fibrosis	Disease
12947024	346	349	IPF	Disease
12947024	399	402	HGF	Gene
12947024	403	413	secretion	Localization
12947024	416	419	IPF	Disease
12947024	436	446	decreased	Negative_regulation
12947024	504	507	HGF	Gene
12947024	512	521	secreted	Localization
12947024	564	567	IPF	Disease
12947024	593	596	HGF	Gene
12947024	623	631	reduced	Negative_regulation
12947024	634	637	IPF	Disease
12947024	651	664	Prostaglandin	Chemical
12947024	686	689	IPF	Disease
12947024	780	784	PGE2	Chemical
12947024	797	817	dibutyryl cyclic AMP	Chemical
12947024	828	831	HGF	Gene
12947024	832	842	secretion	Localization
12947024	845	848	IPF	Disease
12947024	914	918	PGE2	Chemical
12947024	934	946	indomethacin	Chemical
12947024	947	955	reduced	Negative_regulation
12947024	955	958	HGF	Gene
12947024	959	969	secretion	Localization
12947024	1003	1010	effect	Regulation
12947024	1013	1016	IPF	Disease
12947024	1030	1033	HGF	Gene
12947024	1034	1044	secretion	Localization
12947024	1085	1095	inhibited	Negative_regulation
12947024	1098	1136	transforming growth factor (TGF)-beta1	Gene
12947024	1141	1152	stimulated	Positive_regulation
12947024	1160	1168	TGF-beta	Gene
12947024	1216	1219	IPF	Disease
12947024	1259	1266	defect	Negative_regulation
12947024	1269	1272	HGF	Gene
12947024	1273	1284	production	Gene_expression
12947024	1287	1290	IPF	Disease
12947024	1339	1343	PGE2	Chemical
26248335|t|Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-b Induced Myofibroblast Differentiation via Prostaglandin E2
INTRODUCTION: Idiopathic pulmonary fibrosis (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	7	12	Human	Species
26248335	114	127	Prostaglandin	Chemical
26248335	146	175	Idiopathic pulmonary fibrosis	Disease
26248335	177	180	IPF	Disease
26248335	277	285	fibrosis	Disease
26248335	486	494	fibrosis	Disease
26248335	567	570	IPF	Disease
26248335	933	938	human	Species
26248335	1188	1198	expressed	Gene_expression
26248335	1481	1486	TGF-b	Gene
26248335	1574	1579	TGF-b	Gene
26248335	1603	1624	prostaglandin (PG) E2	Chemical
26248335	1843	1848	TGF-b	Gene
26248335	2017	2021	PGE2	Chemical
26248335	2213	2221	fibrosis	Disease
29409529|t|The JAK2 pathway is activated in idiopathic pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (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 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown
The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease
METHODS AND RESULTS: JAK2/p-JAK2 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 JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions
Dual p-JAK2/p-STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 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-JAK2/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 JAK2 and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis
CONCLUSIONS: JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease
29409529	4	8	JAK2	Gene
29409529	33	62	idiopathic pulmonary fibrosis	Disease
29409529	76	105	Idiopathic pulmonary fibrosis	Disease
29409529	107	110	IPF	Disease
29409529	154	171	fibrotic disorder	Disease
29409529	205	255	signal transducer and activator of transcription 3	Gene
29409529	257	262	STAT3	Gene
29409529	275	285	activated	Positive_regulation
29409529	364	377	lung fibrosis	Disease
29409529	381	384	IPF	Disease
29409529	395	406	activation	Positive_regulation
29409529	409	423	Janus kinase 2	Gene
29409529	425	429	JAK2	Gene
29409529	454	477	proliferative disorders	Disease
29409529	483	488	role	Gene_expression
29409529	491	494	IPF	Disease
29409529	544	548	JAK2	Gene
29409529	549	560	activation	Positive_regulation
29409529	563	566	IPF	Disease
29409529	593	597	JAK2	Gene
29409529	598	603	STAT3	Gene
29409529	604	615	inhibition	Negative_regulation
29409529	690	694	JAK2	Gene
29409529	697	701	JAK2	Gene
29409529	706	711	STAT3	Gene
29409529	719	730	expression	Gene_expression
29409529	734	744	evaluated	Regulation
29409529	834	839	human	Species
29409529	926	929	IPF	Disease
29409529	930	938	patients	Species
29409529	1066	1076	activated	Positive_regulation
29409529	1076	1080	JAK2	Gene
29409529	1085	1090	STAT3	Gene
29409529	1179	1183	JAK2	Gene
29409529	1186	1191	STAT3	Gene
29409529	1192	1203	inhibition	Negative_regulation
29409529	1208	1215	JSI-124	Chemical
29409529	1232	1236	JAK2	Gene
29409529	1241	1246	STAT3	Gene
29409529	1253	1264	suppressed	Negative_regulation
29409529	1375	1379	JAK2	Gene
29409529	1383	1388	STAT3	Gene
29409529	1389	1400	inhibitors	Negative_regulation
29409529	1510	1521	preventing	Negative_regulation
29409529	1521	1531	increases	Positive_regulation
29409529	1560	1565	Bcl-2	Gene
29409529	1566	1577	expression	Gene_expression
29409529	1618	1622	rats	Species
29409529	1636	1643	JSI-124	Chemical
29409529	1652	1662	inhibitor	Negative_regulation
29409529	1667	1671	JAK2	Gene
29409529	1674	1679	STAT3	Gene
29409529	1708	1717	bleomycin	Chemical
29409529	1726	1739	lung fibrosis	Disease
29409529	1765	1776	deposition	Gene_expression
29409529	1792	1802	inhibited	Negative_regulation
29409529	1811	1815	JAK2	Gene
29409529	1820	1825	STAT3	Gene
29409529	1826	1837	activation	Positive_regulation
29409529	1860	1868	fibrosis	Disease
29409529	1926	1930	JAK2	Gene
29409529	1935	1940	STAT3	Gene
29409529	1945	1955	activated	Positive_regulation
29409529	1958	1961	IPF	Disease
28060543|t|Inhibition of the KCa3.1 Channel Alleviates Established Pulmonary Fibrosis in a Large Animal Model
UNASSIGNED: Idiopathic pulmonary fibrosis is a chronic progressive disease of increasing prevalence marked by poor prognosis and limited treatment options
Ca2+-activated KCa3.1 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 KCa3.1 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 KCa3.1 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	0	11	Inhibition	Negative_regulation
28060543	18	24	KCa3.1	Gene
28060543	112	141	Idiopathic pulmonary fibrosis	Disease
28060543	256	260	Ca2+	Chemical
28060543	256	271	Ca2+-activated	Positive_regulation
28060543	271	277	KCa3.1	Gene
28060543	278	287	potassium	Chemical
28060543	480	483	IPF	Disease
28060543	515	518	IPF	Disease
28060543	559	567	prevent	Negative_regulation
28060543	576	580	bFGF	Gene
28060543	660	669	blockade	Negative_regulation
28060543	676	682	KCa3.1	Gene
28060543	818	826	fibrosis	Disease
28060543	848	853	sheep	Species
28060543	865	883	pulmonary fibrosis	Disease
28060543	965	970	sheep	Species
28060543	1031	1039	fibrosis	Disease
28060543	1058	1067	bleomycin	Chemical
28060543	1188	1197	bleomycin	Chemical
28060543	1340	1350	reduction	Negative_regulation
28060543	1384	1395	expression	Gene_expression
28060543	1471	1482	inhibiting	Negative_regulation
28060543	1486	1492	KCa3.1	Gene
28060543	1556	1565	bleomycin	Chemical
28060543	1576	1584	fibrosis	Disease
28060543	1632	1637	sheep	Species
28060543	1705	1710	human	Species
28060543	1711	1714	IPF	Disease
28060543	1753	1764	inhibiting	Negative_regulation
28060543	1764	1770	Kca3.1	Gene
28060543	1827	1830	IPF	Disease
24088250|t|Possible involvement of pirfenidone metabolites in the antifibrotic action of a therapy for idiopathic pulmonary fibrosis
Pirfenidone (PFD) is the first and only clinically used antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (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	24	35	pirfenidone	Chemical
24088250	92	121	idiopathic pulmonary fibrosis	Disease
24088250	123	134	Pirfenidone	Chemical
24088250	136	139	PFD	Chemical
24088250	218	247	idiopathic pulmonary fibrosis	Disease
24088250	249	252	IPF	Disease
24088250	323	326	PFD	Chemical
24088250	328	348	5-hydroxypirfenidone	Chemical
24088250	350	356	PFD-OH	Chemical
24088250	362	382	5-carboxypirfenidone	Chemical
24088250	384	387	PFD	Chemical
24088250	388	392	COOH	Chemical
24088250	398	403	WI-38	Species
24088250	474	477	PFD	Chemical
24088250	478	480	OH	Chemical
24088250	485	488	PFD	Chemical
24088250	489	493	COOH	Chemical
24088250	497	526	transforming growth factor-b1	Gene
24088250	528	534	TGF-b1	Gene
24088250	553	563	synthesis	Gene_expression
24088250	566	571	WI-38	Species
24088250	620	634	hydroxyproline	Chemical
24088250	679	682	PFD	Chemical
24088250	683	685	OH	Chemical
24088250	690	693	PFD	Chemical
24088250	694	698	COOH	Chemical
24088250	762	768	TGF-b1	Gene
24088250	777	791	hydroxyproline	Chemical
24088250	803	808	WI-38	Species
24088250	844	847	PFD	Chemical
24088250	848	850	OH	Chemical
24088250	855	858	PFD	Chemical
24088250	859	863	COOH	Chemical
24088250	900	908	inhibit	Negative_regulation
24088250	917	927	synthesis	Gene_expression
24088250	990	993	PFD	Chemical
24088250	1059	1062	IPF	Disease
24613900|t|Effect of pirfenidone on proliferation, TGF-b-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts
Pirfenidone is an orally active small molecule that has been shown to inhibit the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis
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, TGF-b-induced differentiation and fibrogenic activity of primary human lung fibroblasts (HLFs)
Pirfenidone reduced fibroblast proliferation and attenuated TGF-b-induced a-smooth muscle actin (SMA) and pro-collagen (Col)-I mRNA and protein levels
Importantly, pirfenidone inhibited TGF-b-induced phosphorylation of Smad3, p38, and Akt, key factors in the TGF-b pathway
Together, these results demonstrate that pirfenidone modulates HLF proliferation and TGF-b-mediated differentiation into myofibroblasts by attenuating key TGF-b-induced signaling pathways
24613900	10	21	pirfenidone	Chemical
24613900	40	45	TGF-b	Gene
24613900	119	124	human	Species
24613900	143	154	Pirfenidone	Chemical
24613900	240	248	fibrosis	Disease
24613900	273	281	patients	Species
24613900	287	316	idiopathic pulmonary fibrosis	Disease
24613900	327	338	pirfenidone	Chemical
24613900	551	562	pirfenidone	Chemical
24613900	581	586	TGF-b	Gene
24613900	646	651	human	Species
24613900	677	688	Pirfenidone	Chemical
24613900	726	737	attenuated	Negative_regulation
24613900	737	742	TGF-b	Gene
24613900	774	777	SMA	Gene
24613900	842	853	pirfenidone	Chemical
24613900	854	864	inhibited	Negative_regulation
24613900	864	869	TGF-b	Gene
24613900	864	878	TGF-b-induced	Entity
24613900	878	894	phosphorylation	Phosphorylation
24613900	897	902	Smad3	Gene
24613900	904	907	p38	Gene
24613900	913	916	Akt	Gene
24613900	937	942	TGF-b	Gene
24613900	993	1004	pirfenidone	Chemical
24613900	1037	1042	TGF-b	Gene
24613900	1107	1112	TGF-b	Gene
28810065|t|Olodaterol shows anti-fibrotic efficacy in in vitro and in vivo models of pulmonary fibrosis
BACKGROUND AND PURPOSE: Idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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	0	10	Olodaterol	Chemical
28810065	74	92	pulmonary fibrosis	Disease
28810065	118	147	Idiopathic pulmonary fibrosis	Disease
28810065	149	152	IPF	Disease
28810065	165	184	respiratory disease	Disease
28810065	307	324	b2 -adrenoceptors	Gene
28810065	326	332	b2 -AR	Gene
28810065	588	598	olodaterol	Chemical
28810065	610	615	human	Species
28810065	634	637	HLF	Gene
28810065	646	652	murine	Species
28810065	663	681	pulmonary fibrosis	Disease
28810065	734	744	olodaterol	Chemical
28810065	845	848	HLF	Gene
28810065	873	881	patients	Species
28810065	887	890	IPF	Disease
28810065	892	898	IPF-LF	Disease
28810065	939	949	olodaterol	Chemical
28810065	1055	1061	murine	Species
28810065	1072	1085	lung fibrosis	Disease
28810065	1104	1113	bleomycin	Chemical
28810065	1121	1136	overexpression	Positive_regulation
28810065	1139	1145	TGF-b1	Gene
28810065	1168	1171	HLF	Gene
28810065	1176	1182	IPF-LF	Disease
28810065	1184	1194	olodaterol	Chemical
28810065	1195	1206	attenuated	Negative_regulation
28810065	1206	1211	TGF-b	Gene
28810065	1220	1231	expression	Gene_expression
28810065	1257	1268	fibronectin	Gene
28810065	1273	1285	endothelin-1	Gene
28810065	1287	1291	ET-1	Gene
28810065	1308	1316	induced	Positive_regulation
28810065	1347	1352	TGF-b	Gene
28810065	1353	1357	ET-1	Gene
28810065	1387	1397	olodaterol	Chemical
28810065	1427	1436	bleomycin	Chemical
28810065	1470	1500	reduced bronchoalveolar lavage	Disease
28810065	1570	1619	MMP-9 and tissue inhibitor of metalloproteinase-1	Gene
28810065	1587	1597	inhibitor	Negative_regulation
28810065	1709	1714	TGF-b	Gene
28810065	1737	1747	olodaterol	Chemical
28810065	1761	1769	reduced	Negative_regulation
28810065	1773	1779	Col3A1	Gene
28810065	1785	1796	expression	Gene_expression
28810065	1826	1836	Olodaterol	Chemical
28810065	1880	1883	HLF	Gene
28810065	1901	1904	IPF	Disease
28810065	1905	1913	patients	Species
28810065	1921	1927	murine	Species
28810065	1938	1951	lung fibrosis	Disease
25829947|t|Human lung myofibroblast TGFb1-dependent Smad2/3 signalling is Ca(2+)-dependent and regulated by KCa3.1 K(+) channels
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a common and invariably lethal interstitial lung disease with poorly effective therapy
Blockade of the K(+) channel KCa3.1 reduces constitutive a-SMA and Smad2/3 nuclear translocation in IPF-derived human lung myofibroblasts (HLMFs), and inhibits several transforming growth factor beta 1 (TGFb1)-dependent cell processes
We hypothesized that KCa3.1-dependent cell processes also regulate the TGFb1-dependent Smad2/3 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 KCa3.1 blockers (TRAM-34 200 nM and ICA-17043 [Senicapoc] 100 nM) were used to determine their effects on TGFb1-dependent signalling
Expression of phosphorylated and total Smad2/3 following TGFb1 stimulation was determined by Western blot and Smad2/3 nuclear translocation by immunofluorescence
RESULTS: KCa3.1 block attenuated TGFb1-dependent Smad2/3 phosphorylation and nuclear translocation, and this was mimicked by lowering the extracellular Ca(2+) concentration
KCa3.1 block also inhibited Smad2/3-dependent gene transcription (aSMA, collagen type I), inhibited KCa3.1 mRNA expression, and attenuated TGFb1-dependent aSMA protein expression
CONCLUSIONS: KCa3.1 activity regulates TGFb1-dependent effects in NFC- and IPF-derived primary HLMFs through the regulation of the TGFb1/Smad signalling pathway, with promotion of downstream gene transcription and protein expression
KCa3.1 blockers may offer a novel approach to treating IPF
25829947	0	5	Human	Species
25829947	25	30	TGFb1	Gene
25829947	41	48	Smad2/3	Gene
25829947	63	69	Ca(2+)	Chemical
25829947	84	94	regulated	Regulation
25829947	97	103	KCa3.1	Gene
25829947	104	108	K(+)	Chemical
25829947	131	160	Idiopathic pulmonary fibrosis	Disease
25829947	162	165	IPF	Disease
25829947	201	226	interstitial lung disease	Disease
25829947	258	267	Blockade	Negative_regulation
25829947	274	278	K(+)	Chemical
25829947	287	293	KCa3.1	Gene
25829947	315	320	a-SMA	Gene
25829947	325	332	Smad2/3	Gene
25829947	358	361	IPF	Disease
25829947	370	375	human	Species
25829947	426	459	transforming growth factor beta 1	Gene
25829947	461	466	TGFb1	Gene
25829947	515	521	KCa3.1	Gene
25829947	552	561	regulate	Regulation
25829947	565	570	TGFb1	Gene
25829947	581	588	Smad2/3	Gene
25829947	670	673	IPF	Disease
25829947	810	816	KCa3.1	Gene
25829947	827	834	TRAM-34	Chemical
25829947	846	855	ICA-17043	Chemical
25829947	916	921	TGFb1	Gene
25829947	944	955	Expression	Gene_expression
25829947	958	973	phosphorylated	Phosphorylation
25829947	983	990	Smad2/3	Gene
25829947	1001	1006	TGFb1	Gene
25829947	1007	1019	stimulation	Positive_regulation
25829947	1054	1061	Smad2/3	Gene
25829947	1116	1122	KCa3.1	Gene
25829947	1123	1129	block	Negative_regulation
25829947	1129	1140	attenuated	Negative_regulation
25829947	1140	1145	TGFb1	Gene
25829947	1146	1156	dependent	Positive_regulation
25829947	1156	1163	Smad2/3	Gene
25829947	1164	1180	phosphorylation	Phosphorylation
25829947	1184	1192	nuclear	Entity
25829947	1192	1206	translocation	Localization
25829947	1259	1265	Ca(2+)	Chemical
25829947	1281	1287	KCa3.1	Gene
25829947	1288	1294	block	Negative_regulation
25829947	1309	1316	Smad2/3	Gene
25829947	1371	1381	inhibited	Negative_regulation
25829947	1381	1387	KCa3.1	Gene
25829947	1393	1404	expression	Gene_expression
25829947	1409	1420	attenuated	Positive_regulation
25829947	1420	1425	TGFb1	Gene
25829947	1449	1460	expression	Gene_expression
25829947	1474	1480	KCa3.1	Gene
25829947	1500	1505	TGFb1	Gene
25829947	1536	1539	IPF	Disease
25829947	1574	1585	regulation	Regulation
25829947	1592	1597	TGFb1	Gene
25829947	1695	1701	KCa3.1	Gene
25829947	1750	1753	IPF	Disease
28455433|t|AKT2 Regulates Pulmonary Inflammation and Fibrosis via Modulating Macrophage Activation
Idiopathic pulmonary fibrosis (IPF) is a highly lethal pathological process that is characterized by inflammation, fibroblast accumulation, and excessive collagen deposition
Although AKT2-mediated signaling pathways modulate inflammatory responses, their role in IPF has not been defined
We report that AKT2 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 AKT2 and FoxO3a was remarkably upregulated
Collectively, these results indicate that AKT2 modulates pulmonary fibrosis through inducing TGF-b1 and IL-13 production by macrophages, and inhibition of AKT2 may be a potential strategy for treating IPF
28455433	0	4	AKT2	Gene
28455433	15	37	Pulmonary Inflammation	Disease
28455433	42	50	Fibrosis	Disease
28455433	89	118	Idiopathic pulmonary fibrosis	Disease
28455433	120	123	IPF	Disease
28455433	190	202	inflammation	Disease
28455433	273	277	AKT2	Gene
28455433	345	350	role	Regulation
28455433	353	356	IPF	Disease
28455433	394	398	AKT2	Gene
28455433	399	410	deficiency	Negative_regulation
28455433	411	415	Akt2	Gene
28455433	438	447	bleomycin	Chemical
28455433	456	474	pulmonary fibrosis	Disease
28455433	479	491	inflammation	Disease
28455433	557	562	IL-13	Gene
28455433	566	570	Akt2	Gene
28455433	574	578	mice	Species
28455433	585	611	restore pulmonary fibrosis	Disease
28455433	628	633	IL-33	Gene
28455433	645	649	Akt2	Gene
28455433	675	685	decreased	Negative_regulation
28455433	685	696	production	Gene_expression
28455433	699	704	IL-13	Gene
28455433	709	715	TGF-b1	Gene
28455433	720	731	attenuated	Negative_regulation
28455433	731	747	phosphorylation	Phosphorylation
28455433	750	756	FoxO3a	Gene
28455433	771	775	Akt2	Gene
28455433	809	820	expression	Gene_expression
28455433	823	828	IL-13	Gene
28455433	833	843	increased	Positive_regulation
28455433	881	887	FoxO3a	Gene
28455433	894	900	FoxO3a	Gene
28455433	957	975	pulmonary fibrosis	Disease
28455433	976	984	patients	Species
28455433	1004	1020	phosphorylation	Phosphorylation
28455433	1023	1027	AKT2	Gene
28455433	1032	1038	FoxO3a	Gene
28455433	1054	1066	upregulated	Positive_regulation
28455433	1109	1113	AKT2	Gene
28455433	1124	1142	pulmonary fibrosis	Disease
28455433	1151	1160	inducing	Positive_regulation
28455433	1160	1166	TGF-b1	Gene
28455433	1171	1176	IL-13	Gene
28455433	1177	1188	production	Gene_expression
28455433	1208	1219	inhibition	Negative_regulation
28455433	1222	1226	AKT2	Gene
28455433	1268	1271	IPF	Disease
16948989|t|[Quantifying plasma levels of transforming growth factor beta1 in idiopathic pulmonary fibrosis]
OBJECTIVE: Transforming growth factor ss1 (TGF-ss1) is one of the key profibrotic mediators in the pathogenesis of idiopathic pulmonary fibrosis (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	30	62	transforming growth factor beta1	Gene
16948989	66	95	idiopathic pulmonary fibrosis	Disease
16948989	213	242	idiopathic pulmonary fibrosis	Disease
16948989	244	247	IPF	Disease
16948989	349	357	patients	Species
16948989	363	366	IPF	Disease
16948989	368	376	PATIENTS	Species
16948989	429	432	IPF	Disease
16948989	433	441	patients	Species
16948989	607	610	IPF	Disease
16948989	611	619	patients	Species
16948989	822	825	IPF	Disease
16948989	826	834	patients	Species
16948989	1107	1115	changes	Regulation
16948989	1173	1182	TGF-beta1	Gene
16948989	1200	1208	patients	Species
16948989	1214	1217	IPF	Disease
9817168|t|Transforming growth factor-beta1 in sarcoidosis
Transforming growth factor-beta (TGF-beta) is a cytokine that promotes extracellular matrix accumulation and inhibits matrix degradation
Although the natural course of sarcoidosis is usually favourable, granuloma healing in the lung may result in pulmonary fibrosis and respiratory impairment in some patients
In this study TGF-beta1 was evaluated in bronchoalveolar lavage (BAL) fluid and culture supernatants of alveolar macrophages (AM) from 73 patients with biopsy-proven sarcoidosis
Disease activity was defined when patients recently developed or increased symptoms (cough, dyspnoea, systemic symptoms) and/or demonstrated increasing opacities on chest radiography
Pulmonary function tests were performed in all patients including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and the diffusing capacity of the lung for carbon monoxide (DL,CO)
Fourteen patients with idiopathic pulmonary fibrosis (IPF) and 14 healthy subjects were investigated as a control group
Immunohistochemistry was used to evaluate the cell distribution of TGF-beta1 on lung specimens
TGF-beta1 levels in BAL and in AM supernatants were not different between sarcoidosis and healthy subjects, whereas they were markedly increased in IPF
However, the TGF-beta1 level was significantly increased in BAL fluid but not in AM supernatants from sarcoidosis with altered lung function, compared with patients with normal lung function
The TGF-beta1 level in BAL was increased in active sarcoidosis but this increased level was mainly related to the higher level observed in patients with altered lung function
TGF-beta1 levels in BAL correlated significantly with the lymphocyte percentage
TGF-beta1 staining assessed by immunohistochemistry was intense in epithelioid histiocytes comprising non-necrotizing granuloma and in bronchiolar epithelial cells, in hyperplastic type II pneumocytes and occasionally in AM
This study supports the hypothesis that overproduction of transforming growth factor-beta1 is associated with functional impairment in patients with pulmonary sarcoidosis
9817168	0	32	Transforming growth factor-beta1	Gene
9817168	36	47	sarcoidosis	Disease
9817168	49	80	Transforming growth factor-beta	Gene
9817168	82	90	TGF-beta	Gene
9817168	218	229	sarcoidosis	Disease
9817168	253	262	granuloma	Disease
9817168	297	315	pulmonary fibrosis	Disease
9817168	320	342	respiratory impairment	Disease
9817168	351	359	patients	Species
9817168	375	384	TGF-beta1	Gene
9817168	499	507	patients	Species
9817168	527	538	sarcoidosis	Disease
9817168	574	582	patients	Species
9817168	771	779	patients	Species
9817168	935	950	carbon monoxide	Chemical
9817168	969	977	patients	Species
9817168	983	1012	idiopathic pulmonary fibrosis	Disease
9817168	1014	1017	IPF	Disease
9817168	1148	1157	TGF-beta1	Gene
9817168	1177	1186	TGF-beta1	Gene
9817168	1251	1262	sarcoidosis	Disease
9817168	1312	1322	increased	Positive_regulation
9817168	1325	1328	IPF	Disease
9817168	1343	1352	TGF-beta1	Gene
9817168	1377	1387	increased	Positive_regulation
9817168	1432	1443	sarcoidosis	Disease
9817168	1486	1494	patients	Species
9817168	1526	1535	TGF-beta1	Gene
9817168	1553	1563	increased	Positive_regulation
9817168	1573	1584	sarcoidosis	Disease
9817168	1661	1669	patients	Species
9817168	1698	1707	TGF-beta1	Gene
9817168	1779	1788	TGF-beta1	Gene
9817168	1881	1906	non-necrotizing granuloma	Disease
9817168	1947	1979	hyperplastic type II pneumocytes	Disease
9817168	2044	2059	overproduction	Gene_expression
9817168	2062	2094	transforming growth factor-beta1	Gene
9817168	2139	2147	patients	Species
9817168	2153	2174	pulmonary sarcoidosis	Disease
24625972|t|BAX inhibitor-1-associated V-ATPase glycosylation enhances collagen degradation in pulmonary fibrosis
Endoplasmic reticulum (ER) stress is considered one of the pathological mechanisms of idiopathic pulmonary fibrosis (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 pulmonary fibrosis in a mouse model by enhancing collagen degradation, most likely by enhanced activation of the lysosomal V-ATPase through glycosylation
We also found a correlation between post-translational glycosylation of the V-ATPase and its associated chaperone, calnexin, in BI-1-overexpressing cells
BI-1-induced degradation of collagen through lysosomal V-ATPase 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 V-ATPase glycosylation in IPF
24625972	0	15	BAX inhibitor-1	Gene
24625972	27	35	V-ATPase	Gene
24625972	50	59	enhances	Positive_regulation
24625972	68	80	degradation	Protein_catabolism
24625972	83	101	pulmonary fibrosis	Disease
24625972	189	218	idiopathic pulmonary fibrosis	Disease
24625972	220	223	IPF	Disease
24625972	281	296	Bax inhibitor-1	Gene
24625972	298	302	BI-1	Gene
24625972	305	315	regulates	Regulation
24625972	324	337	accumulation	Positive_regulation
24625972	364	372	fibrosis	Disease
24625972	405	413	fibrosis	Disease
24625972	431	435	BI-1	Gene
24625972	556	565	bleomycin	Chemical
24625972	574	592	pulmonary fibrosis	Disease
24625972	598	603	mouse	Species
24625972	613	623	enhancing	Positive_regulation
24625972	632	644	degradation	Protein_catabolism
24625972	669	680	activation	Positive_regulation
24625972	697	705	V-ATPase	Gene
24625972	805	813	V-ATPase	Gene
24625972	844	852	calnexin	Gene
24625972	857	861	BI-1	Gene
24625972	884	888	BI-1	Gene
24625972	897	909	degradation	Protein_catabolism
24625972	939	947	V-ATPase	Gene
24625972	985	993	calnexin	Gene
24625972	1014	1023	bleomycin	Chemical
24625972	1032	1040	fibrosis	Disease
24625972	1041	1046	mouse	Species
24625972	1101	1105	BI-1	Gene
24625972	1109	1112	IPF	Disease
24625972	1165	1173	V-ATPase	Gene
24625972	1191	1194	IPF	Disease
26216407|t|The anti-fibrotic effects of microRNA-153 by targeting TGFBR-2 in pulmonary fibrosis
UNASSIGNED: Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis
26216407	45	55	targeting	Regulation
26216407	55	62	TGFBR-2	Gene
26216407	66	84	pulmonary fibrosis	Disease
26216407	98	127	Idiopathic pulmonary fibrosis	Disease
26216407	129	132	IPF	Disease
26216407	151	185	interstitial fibrotic lung disease	Disease
26216407	280	308	transforming growth factor-b	Gene
26216407	310	315	TGF-b	Gene
26216407	346	354	fibrosis	Disease
26216407	449	454	TGF-b	Gene
26216407	591	598	miR-153	Gene
26216407	599	610	expression	Gene_expression
26216407	614	627	dysregulated	Regulation
26216407	643	647	mice	Species
26216407	653	684	experimental pulmonary fibrosis	Disease
26216407	689	695	TGF-b1	Gene
26216407	696	706	decreased	Negative_regulation
26216407	706	713	miR-153	Gene
26216407	714	725	expression	Gene_expression
26216407	761	771	increased	Positive_regulation
26216407	771	778	miR-153	Gene
26216407	824	831	miR-153	Gene
26216407	872	878	TGF-b1	Gene
26216407	884	891	miR-153	Gene
26216407	970	976	TGFBR2	Gene
26216407	994	1000	serine	Chemical
26216407	1001	1010	threonine	Chemical
26216407	1031	1036	TGF-b	Gene
26216407	1065	1072	target	Binding
26216407	1075	1082	miR-153	Gene
26216407	1121	1132	regulation	Regulation
26216407	1139	1150	expression	Gene_expression
26216407	1153	1159	TGFBR2	Gene
26216407	1161	1177	phosphorylation	Phosphorylation
26216407	1180	1187	SMAD2/3	Gene
26216407	1211	1218	miR-153	Gene
26216407	1244	1251	miR-153	Gene
26216407	1261	1267	TGF-b1	Gene
26216407	1296	1304	effects	Regulation
26216407	1387	1405	pulmonary fibrosis	Disease
8678788|t|Cytokines in human lung fibrosis
Fibrosis is a pathological process characterized by the replacement of normal tissue by mesenchymal cells and the extracellular matrix produced by these cells
The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in the area of derangement
The same sequence of events occurs in wound healing with normal granulation tissue and scar formation, but, while normal scar formation is very localized and transient, in contrast, in fibrosis, the repair process is exaggerated and usually widespread and can be chronic
Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair
The evaluation of three human fibrotic lung diseases, two diffuse [idiopathic pulmonary fibrosis (IPF), and the adult respiratory distress syndrome (ARDS)], and one focal (tumor stroma in lung cancer), has shown that several cytokines participate to the local injury and inflammatory reaction [interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha)], while other cytokines are involved in tissue repair and fibrosis [platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)]
A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches
8678788	13	18	human	Species
8678788	19	32	lung fibrosis	Disease
8678788	34	42	Fibrosis	Disease
8678788	228	236	fibrosis	Disease
8678788	298	310	inflammation	Disease
8678788	639	647	fibrosis	Disease
8678788	917	922	human	Species
8678788	923	945	fibrotic lung diseases	Disease
8678788	960	989	idiopathic pulmonary fibrosis	Disease
8678788	991	994	IPF	Disease
8678788	1005	1040	adult respiratory distress syndrome	Disease
8678788	1042	1046	ARDS	Disease
8678788	1065	1070	tumor	Disease
8678788	1081	1092	lung cancer	Disease
8678788	1147	1159	local injury	Disease
8678788	1187	1200	interleukin-1	Gene
8678788	1202	1206	IL-1	Gene
8678788	1209	1222	interleukin-8	Gene
8678788	1224	1228	IL-8	Gene
8678788	1231	1261	monocyte chemotactic protein-1	Gene
8678788	1263	1268	MCP-1	Gene
8678788	1271	1298	tumor necrosis factor-alpha	Gene
8678788	1300	1309	TNF-alpha	Gene
8678788	1369	1377	fibrosis	Disease
8678788	1418	1446	insulin-like growth factor-1	Gene
8678788	1448	1453	IGF-1	Gene
8678788	1504	1534	basic-fibroblast growth factor	Gene
8678788	1536	1541	b-FGF	Gene
8678788	1616	1632	in lung fibrosis	Disease
28726637|t|MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation
Aberrant proliferation and activation of lung fibroblasts contribute to the initiation and progression of idiopathic pulmonary fibrosis (IPF)
However, the mechanisms responsible for the proliferation and activation of fibroblasts are not fully understood
The objective of this study was to investigate the role of miR-101 in the proliferation and activation of lung fibroblasts
miR-101 expression was determined in lung tissues from patients with IPF and mice with bleomycin-induced pulmonary fibrosis
The regulation of miR-101 and cellular signaling was investigated in pulmonary fibroblasts in vitro The role of miR-101 in pulmonary fibrosis in vivo was studied using adenovirus-mediated gene transfer in mice
The expression of miR-101 was down-regulated in fibrotic lungs from patients with IPF and bleomycin-treated mice
The down-regulation of miR-101 occurred via the E26 transformation-specific (ETS) transcription factor
miR-101 suppressed the WNT5a-induced proliferation of lung fibroblasts by inhibiting NFATc2 signaling via targeting Frizzled receptor 4/6 and the TGF-b-induced activation of lung fibroblasts by inhibition of SMAD2/3 signaling via targeting the TGF-b receptor 1
Adenovirus-mediated miR-101 gene transfer in the mouse lung attenuated bleomycin-induced lung fibrosis and improved lung function
Our data suggest that miR-101 is an anti-fibrotic microRNA and a potential therapeutic target for pulmonary fibrosis
28726637	414	421	miR-101	Gene
28726637	479	486	miR-101	Gene
28726637	534	542	patients	Species
28726637	556	560	mice	Species
28726637	566	575	bleomycin	Chemical
28726637	622	629	miR-101	Gene
28726637	716	723	miR-101	Gene
28726637	772	782	adenovirus	Species
28726637	809	813	mice	Species
28726637	833	840	miR-101	Gene
28726637	883	891	patients	Species
28726637	905	914	bleomycin	Chemical
28726637	923	927	mice	Species
28726637	952	959	miR-101	Gene
28726637	1033	1040	miR-101	Gene
28726637	1056	1061	WNT5a	Gene
28726637	1118	1124	NFATc2	Gene
28726637	1179	1184	TGF-b	Gene
28726637	1241	1248	SMAD2/3	Gene
28726637	1263	1273	targeting	Regulation
28726637	1277	1282	TGF-b	Gene
28726637	1295	1305	Adenovirus	Species
28726637	1315	1322	miR-101	Gene
28726637	1344	1349	mouse	Species
28726637	1366	1375	bleomycin	Chemical
28726637	1448	1455	miR-101	Gene
22365247|t|Idiopathic pulmonary fibrosis: pathobiology of novel approaches to treatment
Idiopathic pulmonary fibrosis (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	0	29	Idiopathic pulmonary fibrosis	Disease
22365247	78	107	Idiopathic pulmonary fibrosis	Disease
22365247	109	112	IPF	Disease
22365247	269	272	IPF	Disease
22365247	303	306	IPF	Disease
22365247	426	429	IPF	Disease
22365247	518	536	pulmonary fibrosis	Disease
12540741|t|Novel pharmacological approaches to manage interstitial lung fibrosis in the twenty-first century
Pharmacological agents currently in use to treat interstitial lung fibrosis 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	43	69	interstitial lung fibrosis	Disease
12540741	148	174	interstitial lung fibrosis	Disease
12540741	214	220	humans	Species
12540741	323	336	accumulation	Positive_regulation
12540741	363	388	hallmark of lung fibrosis	Disease
12540741	455	461	NAD(+)	Chemical
12540741	466	469	ATP	Chemical
12540741	471	480	blocking	Negative_regulation
12540741	594	597	NOS	Gene
12540741	645	653	cysteine	Chemical
12540741	776	779	IPF	Disease
12540741	783	789	humans	Species
27853171|t|De-ubiquitinating enzyme, USP11, promotes transforming growth factor b-1 signaling through stabilization of transforming growth factor b receptor II
The transforming growth factor b-1 (TGFb-1) signaling pathway plays a central role in the pathogenesis of pulmonary fibrosis
Two TGFb-1 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, USP11, promotes TGFb-1 signaling through de-ubiquitination and stabilization of TbRII
We elucidate the role that mitoxantrone (MTX), an USP11 inhibitor, has in the attenuation of TGFb-1 signaling
Inhibition or downregulation of USP11 results in increases in TbRII ubiquitination and reduction of TbRII stability
Subsequently, TGFb-1 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 USP11 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 USP11 and TbRII were detected in lung tissues from bleomycin-challenged mice and IPF patients
Therefore, USP11 may contribute to the pathogenesis of pulmonary fibrosis by stabilization of TbRII and promotion of TGFb-1 signaling
This study provides mechanistic evidence for development of USP11 inhibitors as potential antifibrotic drugs for pulmonary fibrosis
27853171	26	31	USP11	Gene
27853171	42	72	transforming growth factor b-1	Gene
27853171	91	105	stabilization	Binding
27853171	154	184	transforming growth factor b-1	Gene
27853171	186	192	TGFb-1	Gene
27853171	256	274	pulmonary fibrosis	Disease
27853171	280	286	TGFb-1	Gene
27853171	461	472	regulation	Regulation
27853171	552	557	USP11	Gene
27853171	568	574	TGFb-1	Gene
27853171	666	678	mitoxantrone	Chemical
27853171	680	683	MTX	Chemical
27853171	689	694	USP11	Gene
27853171	695	705	inhibitor	Negative_regulation
27853171	732	738	TGFb-1	Gene
27853171	750	761	Inhibition	Negative_regulation
27853171	782	787	USP11	Gene
27853171	881	887	TGFb-1	Gene
27853171	937	947	decreases	Negative_regulation
27853171	950	966	phosphorylation	Phosphorylation
27853171	969	976	SMAD2/3	Gene
27853171	1003	1014	fibronectin	Gene
27853171	1024	1043	smooth muscle actin	Disease
27853171	1045	1048	SMA	Disease
27853171	1051	1066	Overexpression	Positive_regulation
27853171	1069	1074	USP11	Gene
27853171	1124	1138	stabilization	Localization
27853171	1147	1157	elevating	Positive_regulation
27853171	1157	1173	phosphorylation	Phosphorylation
27853171	1176	1183	SMAD2/3	Gene
27853171	1201	1212	expression	Gene_expression
27853171	1222	1225	SMA	Disease
27853171	1236	1245	elevated	Positive_regulation
27853171	1245	1256	expression	Gene_expression
27853171	1259	1264	USP11	Gene
27853171	1310	1319	bleomycin	Chemical
27853171	1331	1335	mice	Species
27853171	1340	1343	IPF	Disease
27853171	1344	1352	patients	Species
27853171	1365	1370	USP11	Gene
27853171	1409	1427	pulmonary fibrosis	Disease
27853171	1431	1445	stabilization	Positive_regulation
27853171	1471	1477	TGFb-1	Gene
27853171	1549	1554	USP11	Gene
27853171	1602	1620	pulmonary fibrosis	Disease
20061390|t|SPARC suppresses apoptosis of idiopathic pulmonary fibrosis fibroblasts through constitutive activation of beta-catenin
Idiopathic pulmonary fibrosis (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 SPARC, plasminogen activator inhibitor-1 (PAI-1), and active beta-catenin compared with control cells
Control of basal PAI-1 expression in IPF fibroblasts was regulated by SPARC-mediated activation of Akt, leading to inhibition of glycogen synthase kinase-3beta and activation of beta-catenin
Additionally, IPF fibroblasts (but not control fibroblasts) were resistant to plasminogen-induced apoptosis and were sensitized to plasminogen-mediated apoptosis by inhibition of SPARC or beta-catenin
These findings uncover a newly discovered regulatory pathway in IPF fibroblasts that is characterized by elevated SPARC, giving rise to activated beta-catenin, 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	0	5	SPARC	Gene
20061390	30	59	idiopathic pulmonary fibrosis	Disease
20061390	93	104	activation	Positive_regulation
20061390	107	119	beta-catenin	Gene
20061390	121	150	Idiopathic pulmonary fibrosis	Disease
20061390	152	155	IPF	Disease
20061390	504	507	IPF	Disease
20061390	508	516	patients	Species
20061390	547	555	patients	Species
20061390	561	564	IPF	Disease
20061390	678	681	IPF	Disease
20061390	697	700	IPF	Disease
20061390	728	738	expressed	Gene_expression
20061390	738	748	increased	Positive_regulation
20061390	764	769	SPARC	Gene
20061390	771	804	plasminogen activator inhibitor-1	Gene
20061390	806	811	PAI-1	Gene
20061390	825	837	beta-catenin	Gene
20061390	884	889	PAI-1	Gene
20061390	904	907	IPF	Disease
20061390	924	934	regulated	Regulation
20061390	937	942	SPARC	Gene
20061390	952	963	activation	Positive_regulation
20061390	966	969	Akt	Gene
20061390	971	979	leading	Positive_regulation
20061390	982	993	inhibition	Negative_regulation
20061390	996	1026	glycogen synthase kinase-3beta	Gene
20061390	1031	1042	activation	Positive_regulation
20061390	1045	1057	beta-catenin	Gene
20061390	1073	1076	IPF	Disease
20061390	1224	1235	inhibition	Negative_regulation
20061390	1238	1243	SPARC	Gene
20061390	1247	1259	beta-catenin	Gene
20061390	1325	1328	IPF	Disease
20061390	1366	1375	elevated	Positive_regulation
20061390	1375	1380	SPARC	Gene
20061390	1397	1407	activated	Positive_regulation
20061390	1407	1419	beta-catenin	Gene
20061390	1427	1437	regulates	Regulation
20061390	1437	1448	expression	Gene_expression
20061390	1477	1482	PAI-1	Gene
20061390	1601	1604	IPF	Disease
24376648|t|Cartilage oligomeric matrix protein in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	0	35	Cartilage oligomeric matrix protein	Gene
24376648	39	68	idiopathic pulmonary fibrosis	Disease
24376648	70	99	Idiopathic pulmonary fibrosis	Disease
24376648	101	104	IPF	Disease
24376648	193	196	IPF	Disease
24376648	264	275	hyperplasia	Disease
24376648	361	372	expression	Gene_expression
24376648	402	437	cartilage oligomeric matrix protein	Gene
24376648	439	443	COMP	Gene
24376648	579	582	IPF	Disease
24376648	687	690	IPF	Disease
24376648	820	824	COMP	Gene
24376648	829	839	expressed	Gene_expression
24376648	868	871	IPF	Disease
24376648	882	895	co-localized	Localization
24376648	927	938	expressing	Gene_expression
24376648	967	972	human	Species
24376648	995	1001	TGF-b1	Gene
24376648	1013	1022	increase	Positive_regulation
24376648	1025	1029	COMP	Gene
24376648	1047	1058	expression	Gene_expression
24376648	1069	1073	COMP	Gene
24376648	1084	1089	human	Species
24376648	1189	1195	TGF-b1	Gene
24376648	1199	1205	COL1A1	Gene
24376648	1210	1214	PAI1	Gene
24376648	1216	1220	COMP	Gene
24376648	1307	1310	IPF	Disease
24376648	1311	1319	patients	Species
24376648	1360	1364	COMP	Gene
24376648	1386	1394	patients	Species
24376648	1441	1445	COMP	Gene
24376648	1453	1463	increased	Positive_regulation
24376648	1636	1640	COMP	Gene
24376648	1681	1687	TGF-b1	Gene
24376648	1700	1708	patients	Species
24376648	1714	1717	IPF	Disease
24376648	1763	1770	affect	Regulation
24376648	1770	1774	COMP	Gene
24376648	1775	1786	expression	Gene_expression
24376648	1818	1826	rigidity	Disease
24376648	1851	1854	IPF	Disease
24376648	1895	1901	TGF-b1	Gene
24344132|t|Aortic carboxypeptidase-like protein (ACLP) enhances lung myofibroblast differentiation through transforming growth factor b receptor-dependent and -independent pathways
Idiopathic pulmonary fibrosis (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
Aortic carboxypeptidase-like protein (ACLP) 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, ACLP knockout mice are significantly protected from bleomycin-induced fibrosis
The goal of this study was to identify the mechanisms of ACLP action on fibroblast differentiation
As primary lung fibroblasts differentiated into myofibroblasts, ACLP expression preceded SMA and collagen expression
Recombinant ACLP induced SMA and collagen expression in mouse and human lung fibroblasts
Knockdown of ACLP slowed the fibroblast-to-myofibroblast transition and partially reverted differentiated myofibroblasts by reducing SMA expression
We hypothesized that ACLP stimulates myofibroblast formation partly through activating TGFb signaling
Treatment of fibroblasts with recombinant ACLP induced phosphorylation and nuclear translocation of Smad3
This phosphorylation and induction of SMA was dependent on TGFb receptor binding and kinase activity
ACLP-induced collagen expression was independent of interaction with the TGFb receptor
These findings indicate that ACLP stimulates the fibroblast-to-myofibroblast transition by promoting SMA expression via TGFb signaling and promoting collagen expression through a TGFb receptor-independent pathway
24344132	0	36	Aortic carboxypeptidase-like protein	Gene
24344132	38	42	ACLP	Gene
24344132	171	200	Idiopathic pulmonary fibrosis	Disease
24344132	202	205	IPF	Disease
24344132	224	242	fatal lung disease	Disease
24344132	468	472	TGFb	Gene
24344132	480	489	promotes	Positive_regulation
24344132	498	509	expression	Gene_expression
24344132	536	557	smooth muscle a-actin	Gene
24344132	559	562	SMA	Gene
24344132	589	625	Aortic carboxypeptidase-like protein	Gene
24344132	627	631	ACLP	Gene
24344132	668	677	secreted	Localization
24344132	718	728	expressed	Gene_expression
24344132	740	745	human	Species
24344132	765	769	mice	Species
24344132	775	784	bleomycin	Chemical
24344132	793	801	fibrosis	Disease
24344132	816	820	ACLP	Gene
24344132	830	834	mice	Species
24344132	868	877	bleomycin	Chemical
24344132	886	894	fibrosis	Disease
24344132	953	957	ACLP	Gene
24344132	1060	1064	ACLP	Gene
24344132	1065	1076	expression	Gene_expression
24344132	1076	1085	preceded	Positive_regulation
24344132	1085	1088	SMA	Gene
24344132	1102	1113	expression	Gene_expression
24344132	1126	1130	ACLP	Gene
24344132	1131	1139	induced	Positive_regulation
24344132	1139	1142	SMA	Gene
24344132	1156	1167	expression	Gene_expression
24344132	1170	1175	mouse	Species
24344132	1180	1185	human	Species
24344132	1217	1221	ACLP	Gene
24344132	1337	1340	SMA	Gene
24344132	1341	1352	expression	Gene_expression
24344132	1374	1378	ACLP	Gene
24344132	1429	1440	activating	Positive_regulation
24344132	1440	1444	TGFb	Gene
24344132	1498	1502	ACLP	Gene
24344132	1503	1511	induced	Positive_regulation
24344132	1511	1527	phosphorylation	Phosphorylation
24344132	1531	1539	nuclear	Entity
24344132	1539	1553	translocation	Localization
24344132	1556	1561	Smad3	Gene
24344132	1568	1584	phosphorylation	Phosphorylation
24344132	1588	1598	induction	Positive_regulation
24344132	1601	1604	SMA	Gene
24344132	1622	1626	TGFb	Gene
24344132	1636	1644	binding	Binding
24344132	1665	1669	ACLP	Gene
24344132	1665	1678	ACLP-induced	Positive_regulation
24344132	1687	1698	expression	Gene_expression
24344132	1717	1729	interaction	Binding
24344132	1738	1742	TGFb	Gene
24344132	1782	1786	ACLP	Gene
24344132	1854	1857	SMA	Gene
24344132	1873	1877	TGFb	Gene
24344132	1892	1902	promoting	Positive_regulation
24344132	1911	1922	expression	Gene_expression
24344132	1932	1936	TGFb	Gene
23911740|t|IL-4 polymorphisms, HRCT score and lung tissue markers in idiopathic pulmonary fibrosis
AIMS: We studied the influence of IL-4 gene polymorphisms on the IPF phenotype, i.e., extent of radiological changes (HRCT interstitial (IS) and alveolar (AS) score) and histopathological markers from lung biopsies
PATIENTS AND METHODS: 46 IPF 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 IL-4 and IL-4 R alpha gene polymorphisms were characterized
RESULTS: We found a correlation between eosinophils in lung biopsies and AS
The Ashcroft score was higher in IL-4 HA 2 GCC and MF were more frequent in IL-4 HA 2 TCC carriers
A relationship was found between IL-4 (-1098) A2 T and PAR-2 expression and IL-4 (-590) A1 T, IL-4 HA1TTT and CD124 expression
AS was lower in IL-4 (-590) A1 C, in IL-4 HA1 TCC and in IL-4RA (+1902) A1 A carriers
CONCLUSIONS: We suggest that the polymorphisms of IL-4 genes might influence the phenotype of IPF reflected by histopathological changes in lung biopsies and HRCT score
23911740	0	4	IL-4	Gene
23911740	58	87	idiopathic pulmonary fibrosis	Disease
23911740	110	120	influence	Regulation
23911740	123	127	IL-4	Gene
23911740	154	157	IPF	Disease
23911740	244	246	AS	Disease
23911740	305	313	PATIENTS	Species
23911740	330	333	IPF	Disease
23911740	334	342	patients	Species
23911740	392	400	patients	Species
23911740	463	465	AS	Disease
23911740	517	535	myofibroblast foci	Disease
23911740	537	539	MF	Disease
23911740	555	567	inflammation	Disease
23911740	572	580	fibrosis	Disease
23911740	629	639	granulomas	Disease
23911740	703	708	PAR-2	Gene
23911740	710	715	CD124	Gene
23911740	717	725	TGF beta	Gene
23911740	727	731	YY-1	Gene
23911740	736	740	TSLP	Gene
23911740	756	760	IL-4	Gene
23911740	765	777	IL-4 R alpha	Gene
23911740	890	892	AS	Disease
23911740	927	931	IL-4	Gene
23911740	945	947	MF	Disease
23911740	970	974	IL-4	Gene
23911740	1027	1031	IL-4	Gene
23911740	1040	1044	A2 T	Mutation
23911740	1049	1054	PAR-2	Gene
23911740	1055	1066	expression	Gene_expression
23911740	1070	1074	IL-4	Gene
23911740	1082	1086	A1 T	Mutation
23911740	1088	1092	IL-4	Gene
23911740	1104	1109	CD124	Gene
23911740	1110	1121	expression	Gene_expression
23911740	1122	1124	AS	Disease
23911740	1129	1135	lower	Negative_regulation
23911740	1138	1142	IL-4	Gene
23911740	1150	1154	A1 C	Mutation
23911740	1159	1163	IL-4	Gene
23911740	1179	1185	IL-4RA	Gene
23911740	1259	1263	IL-4	Gene
23911740	1303	1306	IPF	Disease
15946381|t|TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT)
BACKGROUND: Fibroblastic foci are characteristic features in lung parenchyma of patients with idiopathic pulmonary fibrosis (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 TGF-beta1 could induce epithelial mesenchymal transition (EMT) in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of TGF-beta1-mediated EMT
METHODS: A549 cells were examined for evidence of EMT after treatment with TGF-beta1
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 TGF-beta1 treatment in the presence or absence of MEK inhibitors
The role of Smad2 in TGF-beta1-mediated EMT was investigated using siRNA
RESULTS: The data showed that TGF-beta1, 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
TGF-beta1-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 TGF-beta1 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	0	9	TGF-beta1	Gene
15946381	18	23	human	Species
15946381	162	170	patients	Species
15946381	176	205	idiopathic pulmonary fibrosis	Disease
15946381	207	210	IPF	Disease
15946381	294	311	epithelial injury	Disease
15946381	351	359	fibrosis	Disease
15946381	490	499	TGF-beta1	Gene
15946381	560	565	human	Species
15946381	645	654	TGF-beta1	Gene
15946381	744	753	TGF-beta1	Gene
15946381	857	868	expression	Gene_expression
15946381	924	927	EDA	Gene
15946381	932	935	EDA	Gene
15946381	996	1006	E-cadherin	Gene
15946381	1008	1013	E-cad	Gene
15946381	1065	1096	connective tissue growth factor	Gene
15946381	1098	1102	CTGF	Gene
15946381	1337	1352	phosphorylated	Phosphorylation
15946381	1352	1358	Erk1/2	Gene
15946381	1363	1368	Smad2	Gene
15946381	1375	1384	TGF-beta1	Gene
15946381	1425	1428	MEK	Gene
15946381	1429	1440	inhibitors	Negative_regulation
15946381	1453	1458	Smad2	Gene
15946381	1462	1471	TGF-beta1	Gene
15946381	1545	1554	TGF-beta1	Gene
15946381	1564	1573	TNF-alpha	Gene
15946381	1577	1585	IL-1beta	Gene
15946381	1785	1796	expression	Gene_expression
15946381	1836	1839	EDA	Gene
15946381	1844	1852	vimentin	Gene
15946381	1923	1928	E-cad	Gene
15946381	1979	1988	enhanced	Positive_regulation
15946381	1988	1999	expression	Gene_expression
15946381	2065	2069	CTGF	Gene
15946381	2071	2076	MMP-2	Gene
15946381	2108	2117	TGF-beta1	Gene
15946381	2147	2163	phosphorylation	Phosphorylation
15946381	2166	2171	Smad2	Gene
15946381	2193	2198	Smad2	Gene
15946381	2204	2214	silencing	Negative_regulation
15946381	2215	2218	MEK	Gene
15946381	2219	2230	inhibitors	Negative_regulation
15946381	2240	2250	attenuate	Negative_regulation
15946381	2272	2277	Smad2	Gene
15946381	2278	2294	phosphorylation	Phosphorylation
15946381	2363	2372	TGF-beta1	Gene
15946381	2373	2381	induces	Positive_regulation
15946381	2431	2436	Smad2	Gene
15946381	2437	2448	activation	Positive_regulation
19701206|t|NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury
Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O(2) 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 (gp91(phox)), 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 (H(2)O(2)) 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 lung injury
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	0	15	NADPH oxidase-4	Gene
19701206	78	89	lung injury	Disease
19701206	106	111	NADPH	Chemical
19701206	194	200	oxygen	Chemical
19701206	215	225	increased	Positive_regulation
19701206	377	386	mammalian	Species
19701206	628	633	NOX-2	Gene
19701206	651	661	expressed	Gene_expression
19701206	749	753	NOX4	Gene
19701206	825	857	Transforming growth factor-beta1	Gene
19701206	859	868	TGF-beta1	Gene
19701206	870	878	induces	Positive_regulation
19701206	878	883	NOX-4	Gene
19701206	884	895	expression	Gene_expression
19701206	925	931	SMAD-3	Gene
19701206	997	1002	NOX-4	Gene
19701206	1027	1044	hydrogen peroxide	Chemical
19701206	1072	1081	TGF-beta1	Gene
19701206	1178	1183	NOX-4	Gene
19701206	1211	1215	mice	Species
19701206	1229	1249	noninfectious injury	Disease
19701206	1266	1271	human	Species
19701206	1272	1301	idiopathic pulmonary fibrosis	Disease
19701206	1347	1352	NOX-4	Gene
19701206	1383	1389	murine	Species
19701206	1400	1411	lung injury	Disease
19701206	1450	1454	NOX4	Gene
19701206	1523	1533	targeting	Localization
19701206	1536	1541	NOX-4	Gene
19701206	1558	1576	fibrotic disorders	Disease
12055267|t|TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells
Transforming growth factor-beta 1 (TGF-beta 1) has important roles in lung fibrosis 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 fibrosis
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 TGF-beta 1 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 fibrosis (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 TGF-beta 1 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 TGF-beta 1 and HP BALF created proapoptotic effects comparable with the IPF BALF
In vivo, the administration of TGF-beta 1 could enhance Fas-mediated epithelial cell apoptosis and lung injury via caspase-3 activation in mice
Our results demonstrate a novel role of TGF-beta 1 in the pathophysiology of pulmonary fibrosis as an enhancer of Fas-mediated apoptosis of lung epithelial cells
12055267	0	10	TGF-beta 1	Gene
12055267	78	111	Transforming growth factor-beta 1	Gene
12055267	113	123	TGF-beta 1	Gene
12055267	153	161	fibrosis	Disease
12055267	309	318	ligation	Binding
12055267	356	374	pulmonary fibrosis	Disease
12055267	404	413	TGF-beta1	Gene
12055267	485	494	caspase-3	Gene
12055267	495	506	activation	Positive_regulation
12055267	510	526	down-regulation	Negative_regulation
12055267	563	566	p21	Gene
12055267	586	596	TGF-beta 1	Gene
12055267	768	778	Fas ligand	Gene
12055267	827	835	patients	Species
12055267	841	870	idiopathic pulmonary fibrosis	Disease
12055267	872	875	IPF	Disease
12055267	1017	1025	patients	Species
12055267	1031	1059	hypersensitivity pneumonitis	Disease
12055267	1061	1063	HP	Disease
12055267	1167	1177	Fas ligand	Gene
12055267	1201	1211	TGF-beta 1	Gene
12055267	1225	1233	patients	Species
12055267	1239	1242	IPF	Disease
12055267	1302	1310	patients	Species
12055267	1316	1318	HP	Disease
12055267	1388	1398	TGF-beta 1	Gene
12055267	1403	1405	HP	Disease
12055267	1460	1463	IPF	Disease
12055267	1501	1511	TGF-beta 1	Gene
12055267	1569	1580	lung injury	Disease
12055267	1585	1594	caspase-3	Gene
12055267	1609	1613	mice	Species
12055267	1655	1665	TGF-beta 1	Gene
12055267	1692	1710	pulmonary fibrosis	Disease
26072676|t|Novel Mechanisms for the Antifibrotic Action of Nintedanib
Idiopathic pulmonary fibrosis (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 mechanism(s) 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	48	58	Nintedanib	Chemical
26072676	60	89	Idiopathic pulmonary fibrosis	Disease
26072676	91	94	IPF	Disease
26072676	165	175	Nintedanib	Chemical
26072676	177	186	BIBF-1120	Chemical
26072676	202	210	tyrosine	Chemical
26072676	218	228	inhibitor	Negative_regulation
26072676	308	311	IPF	Disease
26072676	364	374	nintedanib	Chemical
26072676	436	446	nintedanib	Chemical
26072676	489	497	patients	Species
26072676	503	506	IPF	Disease
26072676	847	857	Nintedanib	Chemical
26072676	858	873	down-regulated	Negative_regulation
26072676	890	901	expression	Transcription
26072676	941	952	fibronectin	Gene
26072676	1063	1073	Nintedanib	Chemical
26072676	1087	1095	beclin-1	Gene
26072676	1107	1111	ATG7	Gene
26072676	1135	1145	Nintedanib	Chemical
26072676	1214	1224	Nintedanib	Chemical
26072676	1225	1235	inhibited	Negative_regulation
26072676	1281	1289	tyrosine	Chemical
26072676	1281	1290	tyrosine	Entity
26072676	1290	1306	phosphorylation	Phosphorylation
26072676	1337	1348	activation	Positive_regulation
26072676	1351	1356	SMAD3	Gene
26072676	1362	1365	p38	Gene
26072676	1400	1410	Nintedanib	Chemical
26072676	1479	1482	IPF	Disease
27765762|t|MicroRNA-29c regulates apoptosis sensitivity via modulation of the cell-surface death receptor, Fas, in lung fibroblasts
UNASSIGNED: MicroRNAs play an important role in the development and progression of various diseases, such as idiopathic pulmonary fibrosis (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	0	12	MicroRNA-29c	Gene
27765762	231	260	idiopathic pulmonary fibrosis	Disease
27765762	262	265	IPF	Disease
27765762	358	361	IPF	Disease
27765762	530	533	IPF	Disease
27765762	671	682	inhibition	Negative_regulation
27765762	685	692	miR-29c	Gene
27765762	789	796	miR-29c	Gene
27765762	797	807	inhibitor	Negative_regulation
27765762	811	818	miR-29c	Gene
27765762	839	846	miR-29c	Gene
27765762	847	857	regulated	Regulation
27765762	857	868	expression	Gene_expression
27765762	1051	1065	downregulated	Negative_regulation
27765762	1069	1080	expression	Gene_expression
27765762	1083	1090	miR-29c	Gene
27765762	1190	1197	miR-29c	Gene
27765762	1220	1225	TGF-b	Gene
27765762	1329	1344	downregulation	Negative_regulation
27765762	1366	1369	IPF	Disease
27765762	1436	1439	IPF	Disease
27765762	1461	1476	downregulation	Negative_regulation
27765762	1540	1543	IPF	Disease
27765762	1718	1721	IPF	Disease
15681824|t|Insulin-like growth factor binding proteins 3 and 5 are overexpressed in idiopathic pulmonary fibrosis and contribute to extracellular matrix deposition
Idiopathic pulmonary fibrosis (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	56	70	overexpressed	Positive_regulation
15681824	73	102	idiopathic pulmonary fibrosis	Disease
15681824	154	183	Idiopathic pulmonary fibrosis	Disease
15681824	185	188	IPF	Disease
15681824	195	211	fibrotic disease	Disease
15681824	305	308	IPF	Disease
15681824	378	406	insulin-like growth factor-I	Gene
15681824	408	413	IGF-I	Gene
15681824	438	446	fibrosis	Disease
15681824	464	475	expression	Gene_expression
15681824	491	551	insulin-like growth factor binding proteins (IGFBP)-3 and -5	Gene
15681824	555	558	IPF	Disease
15681824	560	574	IGFBP-3 and -5	Gene
15681824	587	597	increased	Positive_regulation
15681824	608	611	IPF	Disease
15681824	667	670	IPF	Disease
15681824	700	703	IPF	Disease
15681824	748	753	bind	Binding
15681824	753	758	IGF-I	Gene
15681824	771	780	secreted	Localization
15681824	803	808	bind	Binding
15681824	935	943	fibrosis	Disease
15681824	974	981	induce	Positive_regulation
15681824	985	996	production	Gene_expression
15681824	1059	1070	fibronectin	Gene
15681824	1164	1171	IGFBP-3	Gene
15681824	1234	1241	IGFBP-5	Gene
15681824	1258	1268	increased	Positive_regulation
15681824	1397	1405	fibrosis	Disease
15681824	1409	1412	IPF	Disease
27185272|t|Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor-dependent and independent pathways
BACKGROUND AND OBJECTIVE: The roles of bile acid microaspiration and bile acid-activated farnesoid X receptor (FXR) in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remain unclear
We hypothesized that bile acids activate alveolar epithelial cells (AECs) and lung fibroblasts, which may be regulated by FXR activation
METHODS: Human AECs and normal or IPF-derived lung fibroblast cells were incubated with the three major bile acids: lithocholic acid (LCA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA)
The AECs injury indices, epithelial-mesenchymal transition (EMT) and lung fibroblast activation were evaluated
FXR expression in IPF lungs and the roles of FXR and FXR-independent pathways in bile acid-induced profibrotic effects were also investigated
RESULTS: LCA, DCA and CDCA reduced cell viability and increased intracellular reactive oxygen species (ROS) production in A549 cells
They all induced EMT, as shown by enhanced a-SMA and vimentin and decreased E-cadherin levels
LCA directly induced differentiation of lung fibroblasts to myofibroblasts
All three bile acids promoted cellular migration but not proliferation of lung fibroblasts
FXR expression was upregulated in IPF lungs, and inhibition of FXR restrained the bile acid-induced EMT and lung fibroblast activation
Differentiation and proliferation were enhanced in lung fibroblasts exposed to conditioned medium from bile acid-stimulated A549 cells, which contained increased levels of profibrotic factors
TGF-b/Smad3 signaling was also involved in the bile acid-induced EMT and lung fibroblast differentiation
CONCLUSION: Bile acid microaspiration may promote the development of pulmonary fibrosis by inducing activation of AECs and lung fibroblasts via FXR-dependent and independent pathways
27185272	0	10	Bile acids	Chemical
27185272	183	192	bile acid	Chemical
27185272	213	222	bile acid	Chemical
27185272	356	366	bile acids	Chemical
27185272	577	587	bile acids	Chemical
27185272	589	605	lithocholic acid	Chemical
27185272	607	610	LCA	Chemical
27185272	613	629	deoxycholic acid	Chemical
27185272	631	634	DCA	Chemical
27185272	640	661	chenodeoxycholic acid	Chemical
27185272	663	667	CDCA	Chemical
27185272	786	797	expression	Gene_expression
27185272	863	872	bile acid	Chemical
27185272	934	937	LCA	Chemical
27185272	939	942	DCA	Chemical
27185272	947	951	CDCA	Chemical
27185272	1012	1018	oxygen	Chemical
27185272	1068	1076	induced	Positive_regulation
27185272	1154	1157	LCA	Chemical
27185272	1240	1250	bile acids	Chemical
27185272	1326	1337	expression	Gene_expression
27185272	1341	1353	upregulated	Positive_regulation
27185272	1371	1382	inhibition	Negative_regulation
27185272	1404	1413	bile acid	Chemical
27185272	1561	1570	bile acid	Chemical
27185272	1698	1707	bile acid	Chemical
27185272	1769	1778	Bile acid	Chemical
28414923|t|Determining the True Selectivity Profile of av Integrin Ligands Using Radioligand Binding: Applying an Old Solution to a New Problem
The arginyl-glycinyl-aspartic acid (RGD) integrin subfamily contains five members that partner with the av subunit: avb1, avb3, avb5, avb6, and avb8
Within the av integrins, the epithelially restricted avb6 has been identified as playing a key role in the activation of transforming growth factor b that is hypothesized to be pivotal in the development of idiopathic pulmonary fibrosis (IPF)
As part of a drug discovery program to identify a selective avb6 RGD mimetic for IPF, cell adhesion and radioligand binding assays were investigated to screen compounds to determine affinity and av integrin selectivity
In this study, a pan-av radioligand was characterized against all the av integrins and used to determine accurate selectivity profiles for literature and novel RGD ligands, as well as enable an early readout on avb6 dissociation kinetics
It has been shown that while cell adhesion offers a high throughput and reliable format for ranking compounds, there are downsides to this format when comparing selectivity across av integrins
By accurately defining the relationship between these assay formats, a medicinal chemistry effort has identified novel, high-affinity, and selective avb6 RGD mimetics with slow dissociation kinetics, with the potential to be developed into clinical candidates for IPF
28414923	138	168	arginyl-glycinyl-aspartic acid	Chemical
27941755|t|Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial-mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis
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 alveolar epithelial cells that have undergone epithelial-mesenchymal transition (EMT)
We found that FF dissociated capillary vessels from the alveolar epithelia, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100    m below the alveolar epithelia
Furthermore, the alveolar epithelial cells covering the FF exhibited a partial EMT phenotype
In addition, normal human alveolar epithelial 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 alveolar epithelia and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned alveolar epithelia 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 alveolar epithelial cells in vitro, is a potential strategy for treating IPF
27941755	32	50	alveolar epithelia	Disease
27941755	62	95	epithelial-mesenchymal transition	Disease
27941755	105	119	alveolar septa	Disease
27941755	148	177	idiopathic pulmonary fibrosis	Disease
27941755	179	208	Idiopathic pulmonary fibrosis	Disease
27941755	210	213	IPF	Disease
27941755	241	266	interstitial lung disease	Disease
27941755	285	288	IPF	Disease
27941755	339	361	interstitial pneumonia	Disease
27941755	674	707	epithelial-mesenchymal transition	Disease
27941755	709	712	EMT	Disease
27941755	771	789	alveolar epithelia	Disease
27941755	940	958	alveolar epithelia	Disease
27941755	1039	1042	EMT	Disease
27941755	1074	1079	human	Species
27941755	1133	1136	EMT	Disease
27941755	1327	1345	alveolar epithelia	Disease
27941755	1477	1495	alveolar epithelia	Disease
27941755	1638	1652	alveolar septa	Disease
27941755	1706	1720	alveolar septa	Disease
27941755	1802	1805	IPF	Disease
27941755	1912	1915	EMT	Disease
27941755	1996	1999	IPF	Disease
15298857|t|Connective tissue growth factor expression and induction by transforming growth factor-beta is abrogated by simvastatin via a Rho signaling mechanism
Connective tissue growth factor (CTGF), a potent profibrotic mediator, acts downstream and in concert with transforming growth factor (TGF)-beta to drive fibrogenesis
Significant upregulation of CTGF has been reported in fibrogenic diseases, 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 CTGF 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 CTGF/TGF-beta interaction were evaluated using transient reporter transfection of a CTGF promoter construct
Inhibition of CTGF 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 CTGF 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 CTGF 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 CTGF expression and interaction with TGF-beta
15298857	0	31	Connective tissue growth factor	Gene
15298857	32	43	expression	Gene_expression
15298857	47	57	induction	Positive_regulation
15298857	60	91	transforming growth factor-beta	Gene
15298857	95	105	abrogated	Negative_regulation
15298857	108	119	simvastatin	Chemical
15298857	151	182	Connective tissue growth factor	Gene
15298857	184	188	CTGF	Gene
15298857	331	344	upregulation	Positive_regulation
15298857	347	351	CTGF	Gene
15298857	373	392	fibrogenic diseases	Disease
15298857	404	433	idiopathic pulmonary fibrosis	Disease
15298857	435	438	IPF	Disease
15298857	624	635	Simvastatin	Chemical
15298857	737	742	human	Species
15298857	743	746	IPF	Disease
15298857	827	838	Simvastatin	Chemical
15298857	839	847	reduces	Negative_regulation
15298857	853	857	CTGF	Gene
15298857	875	886	expression	Gene_expression
15298857	922	930	TGF-beta	Gene
15298857	931	941	induction	Positive_regulation
15298857	967	978	cholesterol	Chemical
15298857	1025	1036	simvastatin	Chemical
15298857	1050	1054	CTGF	Gene
15298857	1055	1063	TGF-beta	Gene
15298857	1134	1138	CTGF	Gene
15298857	1159	1170	Inhibition	Negative_regulation
15298857	1173	1177	CTGF	Gene
15298857	1199	1210	simvastatin	Chemical
15298857	1233	1236	muM	Species
15298857	1293	1301	TGF-beta	Gene
15298857	1325	1328	IPF	Disease
15298857	1385	1412	geranylgeranylpyrophosphate	Chemical
15298857	1414	1418	GGPP	Chemical
15298857	1429	1450	farnesylpyrophosphate	Chemical
15298857	1452	1460	induces	Positive_regulation
15298857	1460	1464	CTGF	Gene
15298857	1493	1504	simvastatin	Chemical
15298857	1575	1578	IPF	Disease
15298857	1772	1780	TGF-beta	Gene
15298857	1789	1793	CTGF	Gene
15298857	1936	1940	RhoA	Gene
15298857	1977	1988	simvastatin	Chemical
15298857	2047	2056	modulate	Regulation
15298857	2056	2060	CTGF	Gene
15298857	2061	2072	expression	Gene_expression
15298857	2076	2088	interaction	Binding
15298857	2093	2101	TGF-beta	Gene
26249221|t|Increased Galectin-9 Concentration and Number of CD4+Foxp3high+Cells in Bronchoalveolar Lavage Fluid of Patients with Cryptogenic Organizing Pneumonia
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 interstitial pneumonias, 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	118	150	Cryptogenic Organizing Pneumonia	Disease
26249221	547	570	interstitial pneumonias	Disease
26249221	572	604	cryptogenic organizing pneumonia	Disease
26249221	606	609	COP	Disease
26249221	628	657	idiopathic pulmonary fibrosis	Disease
26249221	659	662	IPF	Disease
26249221	803	806	COP	Disease
26249221	811	814	IPF	Disease
26249221	899	910	expressing	Gene_expression
26249221	1147	1150	COP	Disease
26249221	1173	1176	IPF	Disease
26249221	1266	1269	COP	Disease
26249221	1289	1292	IPF	Disease
26249221	1294	1297	Gal	Chemical
26249221	1492	1495	COP	Disease
26249221	1725	1742	lung inflammation	Disease
26249221	1747	1755	fibrosis	Disease
26249221	1773	1776	COP	Disease
15030461|t|Cytokine gene polymorphisms in idiopathic pulmonary fibrosis
Pro- and anti-fibrotic cytokine gene polymorphisms may affect expression of idiopathic pulmonary fibrosis (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-1)Ra 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 (p(corr) = 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	31	60	idiopathic pulmonary fibrosis	Disease
15030461	138	167	idiopathic pulmonary fibrosis	Disease
15030461	169	172	IPF	Disease
15030461	255	259	IL-6	Gene
15030461	261	300	transforming growth factor (TGF)-beta 1	Gene
15030461	302	308	tumour	Disease
15030461	309	317	necrosis	Disease
15030461	326	336	TNF)-alpha	Gene
15030461	341	363	interleukin-1 (IL-1)Ra	Gene
15030461	373	381	patients	Species
15030461	387	390	IPF	Disease
15030461	703	709	IL-1Ra	Gene
15030461	760	764	IL-6	Gene
15030461	766	775	-174G > C	Mutation
15030461	784	793	TNF-alpha	Gene
15030461	795	804	-308G > A	Mutation
15030461	815	825	TGF-beta 1	Gene
15030461	827	835	Arg25Pro	Mutation
15030461	842	851	TNF-alpha	Gene
15030461	896	899	IPF	Disease
15030461	954	957	IPF	Disease
15030461	1005	1014	TNF-alpha	Gene
15030461	1032	1035	A/G	Mutation
15030461	1292	1296	IL-6	Gene
15030461	1298	1308	TGF-beta 1	Gene
15030461	1313	1319	IL-1Ra	Gene
15030461	1453	1465	association	Binding
15030461	1472	1481	TNF-alpha	Gene
15030461	1503	1506	IPF	Disease
10188109|t|Regulation of human lung fibroblast C1q-receptors by transforming growth factor-beta and tumor necrosis factor-alpha
Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) are two polypeptide mediators which are believed to play a role in the evolution of idiopathic pulmonary fibrosis (IPF)
We have evaluated the effect of these two substances on the expression of receptors for collagen (cC1q-R) and globular (gC1q-R) domains of C1q and on type I collagen in human lung fibroblasts
Two fibroblast subpopulations differing in C1q 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 C1q 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 TGF-beta and TNF-alpha 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 TGF-beta and TNF-alpha contained 1.4 and 1.6 times as much cC1q-R mRNA, respectively, whereas in HH cells cC1q-R mRNA increased 2.0- and 2.4-fold
The gC1q-R mRNA levels increased to a lesser extent in both cells
These increases were not reflected in protein levels of CC1q-R and gC1q-R, which were similar to or less than controls
Both TGF-beta and TNF-alpha also increased procollagen [I] mRNA levels in both cells
Overall, TNF-alpha caused a greater increase and the degree of response by HH fibroblasts to both TGF-beta and TNF-alpha was higher than NL cells
These results indicated that TGF-beta and TNF-alpha upregulate the mRNA levels for cC1q-R and collagen and that they do not affect gC1q-R mRNA levels significantly
They also indicated different subsets of human lung fibroblasts respond differently to inflammatory mediators
10188109	0	11	Regulation	Regulation
10188109	14	19	human	Species
10188109	36	39	C1q	Gene
10188109	53	84	transforming growth factor-beta	Gene
10188109	89	116	tumor necrosis factor-alpha	Gene
10188109	118	149	Transforming growth factor-beta	Gene
10188109	151	159	TGF-beta	Gene
10188109	165	192	tumor necrosis factor-alpha	Gene
10188109	194	203	TNF-alpha	Gene
10188109	289	318	idiopathic pulmonary fibrosis	Disease
10188109	320	323	IPF	Disease
10188109	348	355	effect	Regulation
10188109	386	397	expression	Gene_expression
10188109	424	430	cC1q-R	Gene
10188109	446	452	gC1q-R	Gene
10188109	465	468	C1q	Gene
10188109	495	500	human	Species
10188109	562	574	C1q receptor	Gene
10188109	575	586	expression	Gene_expression
10188109	613	618	human	Species
10188109	733	736	C1q	Gene
10188109	737	745	binding	Binding
10188109	887	895	TGF-beta	Gene
10188109	900	909	TNF-alpha	Gene
10188109	1051	1054	SDS	Chemical
10188109	1055	1069	polyacrylamide	Chemical
10188109	1132	1140	TGF-beta	Gene
10188109	1145	1154	TNF-alpha	Gene
10188109	1191	1197	cC1q-R	Gene
10188109	1238	1244	cC1q-R	Gene
10188109	1283	1289	gC1q-R	Gene
10188109	1302	1312	increased	Positive_regulation
10188109	1402	1408	CC1q-R	Gene
10188109	1413	1419	gC1q-R	Gene
10188109	1471	1479	TGF-beta	Gene
10188109	1484	1493	TNF-alpha	Gene
10188109	1499	1509	increased	Positive_regulation
10188109	1561	1570	TNF-alpha	Gene
10188109	1650	1658	TGF-beta	Gene
10188109	1663	1672	TNF-alpha	Gene
10188109	1728	1736	TGF-beta	Gene
10188109	1741	1750	TNF-alpha	Gene
10188109	1751	1762	upregulate	Positive_regulation
10188109	1771	1778	levels	Transcription
10188109	1782	1788	cC1q-R	Gene
10188109	1823	1830	affect	Regulation
10188109	1830	1836	gC1q-R	Gene
10188109	1905	1910	human	Species
23764846|t|Sorafenib ameliorates bleomycin-induced pulmonary fibrosis: potential roles in the inhibition of epithelial-mesenchymal transition and fibroblast activation
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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	0	9	Sorafenib	Chemical
23764846	22	31	bleomycin	Chemical
23764846	40	58	pulmonary fibrosis	Disease
23764846	158	187	Idiopathic pulmonary fibrosis	Disease
23764846	189	192	IPF	Disease
23764846	236	248	lung disease	Disease
23764846	578	595	fibrotic diseases	Disease
23764846	597	625	transforming growth factor-b	Gene
23764846	627	632	TGF-b	Gene
23764846	772	777	TGF-b	Gene
23764846	831	839	fibrosis	Disease
23764846	974	983	sorafenib	Chemical
23764846	998	1003	TGF-b	Gene
23764846	1017	1022	mouse	Species
23764846	1118	1127	sorafenib	Chemical
23764846	1131	1140	bleomycin	Chemical
23764846	1142	1145	BLM	Chemical
23764846	1155	1173	pulmonary fibrosis	Disease
23764846	1177	1181	mice	Species
23764846	1212	1221	sorafenib	Chemical
23764846	1242	1252	inhibited	Negative_regulation
23764846	1252	1258	TGF-b1	Gene
23764846	1259	1267	induced	Positive_regulation
23764846	1325	1333	reduced	Negative_regulation
23764846	1364	1374	synthesis	Gene_expression
23764846	1439	1448	sorafenib	Chemical
23764846	1521	1525	mice	Species
23764846	1581	1589	patients	Species
23764846	1595	1598	IPF	Disease
21871427|t|Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis
Conversely, MMP-3-null mice were protected against bleomycin-induced pulmonary fibrosis
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	44	62	pulmonary fibrosis	Disease
21871427	64	93	Idiopathic pulmonary fibrosis	Disease
21871427	95	98	IPF	Disease
21871427	466	477	importance	Positive_regulation
21871427	480	506	matrix metalloproteinase-3	Gene
21871427	508	513	MMP-3	Gene
21871427	538	541	IPF	Disease
21871427	570	575	MMP-3	Gene
21871427	590	598	patients	Species
21871427	604	607	IPF	Disease
21871427	647	657	relevance	Positive_regulation
21871427	660	665	MMP-3	Gene
21871427	692	700	fibrosis	Disease
21871427	862	867	human	Species
21871427	906	911	MMP-3	Gene
21871427	915	918	IPF	Disease
21871427	980	991	expression	Gene_expression
21871427	1006	1011	MMP-3	Gene
21871427	1015	1018	rat	Species
21871427	1071	1089	pulmonary fibrosis	Disease
21871427	1103	1108	MMP-3	Gene
21871427	1114	1118	mice	Species
21871427	1142	1151	bleomycin	Chemical
21871427	1160	1178	pulmonary fibrosis	Disease
21871427	1247	1252	MMP-3	Gene
21871427	1265	1276	activation	Positive_regulation
21871427	1283	1292	b-catenin	Gene
21871427	1316	1325	cleavage	Protein_catabolism
21871427	1328	1338	E-cadherin	Gene
21871427	1426	1435	bleomycin	Chemical
21871427	1444	1449	MMP-3	Gene
21871427	1455	1459	mice	Species
21871427	1486	1500	translocation	Localization
21871427	1503	1512	b-catenin	Gene
21871427	1517	1526	cyclin D1	Gene
21871427	1527	1538	expression	Gene_expression
21871427	1583	1588	MMP-3	Gene
21871427	1612	1615	IPF	Disease
21871427	1625	1636	activation	Positive_regulation
21871427	1639	1648	b-catenin	Gene
23915349|t|Microarray profiling reveals suppressed interferon stimulated gene program in fibroblasts from scleroderma-associated interstitial lung disease
BACKGROUND: Interstitial lung disease 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	29	40	suppressed	Negative_regulation
23915349	118	143	interstitial lung disease	Disease
23915349	157	182	Interstitial lung disease	Disease
23915349	230	248	systemic sclerosis	Disease
23915349	250	253	SSc	Disease
23915349	320	338	pulmonary fibrosis	Disease
23915349	461	464	SSc	Disease
23915349	737	740	SSc	Disease
23915349	957	965	patients	Species
23915349	971	989	pulmonary fibrosis	Disease
23915349	1006	1009	SSc	Disease
23915349	1011	1018	SSc-ILD	Disease
23915349	1080	1086	cancer	Disease
23915349	1122	1130	patients	Species
23915349	1136	1165	idiopathic pulmonary fibrosis	Disease
23915349	1167	1170	IPF	Disease
23915349	1581	1588	SSc-ILD	Disease
23915349	1596	1599	IPF	Disease
23915349	1704	1714	increased	Positive_regulation
23915349	1714	1725	expression	Gene_expression
23915349	1730	1735	TGF-b	Gene
23915349	1765	1773	fibrosis	Disease
23915349	1869	1880	suppressed	Negative_regulation
23915349	1880	1891	expression	Gene_expression
23915349	2031	2042	expression	Gene_expression
23915349	2124	2129	STAT1	Gene
23915349	2135	2141	CXCL10	Gene
23915349	2350	2361	expression	Gene_expression
23915349	2486	2504	pulmonary fibrosis	Disease
17391951|t|Effects of antifibrotic agents on TGF-beta1, CTGF and IFN-gamma expression in patients with idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 IFN-gamma-1b and colchicine, on biomarkers expression associated with fibrosis (TGF-beta, CTGF) and immunomodulatory/antimicrobial activity (IFN-gamma), in the lungs of patients with IPF
Fourteen (14) patients with an established diagnosis of IPF received either 200 microg of IFN-gamma-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 (TGF-beta1), connective-tissue growth factor (CTGF), and interferon-gamma (IFN-gamma) genes in lung tissue before and after treatment with IFN-gamma-1b or colchicine
Marked mRNA expression of TGF-beta1 and CTGF, but complete lack of interferon-gamma was detected in fibrotic lung tissue at entry
After treatment, both groups exhibited increased expression of IFN-gamma gene at 6 months that was sustained at 24 months
The expression of CTGF and TGF-beta1 remained almost stable before and after treatment, in the IFN-gamma-1b group, while TGF-beta1 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 IFN-gamma-1b group (p=0.04)
In addition, the IFN-gamma-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 (IFN-gamma-1b and colchicine) in TGF-beta, CTGF, and endogenous IFN-gamma gene expression, in human fibrosis
However, extended studies are needed to verify the pathophysiological consequences of these findings
17391951	0	8	Effects	Regulation
17391951	34	43	TGF-beta1	Gene
17391951	45	49	CTGF	Gene
17391951	54	63	IFN-gamma	Gene
17391951	64	75	expression	Gene_expression
17391951	78	86	patients	Species
17391951	92	121	idiopathic pulmonary fibrosis	Disease
17391951	123	152	Idiopathic pulmonary fibrosis	Disease
17391951	154	157	IPF	Disease
17391951	219	234	corticosteroids	Chemical
17391951	362	371	IFN-gamma	Gene
17391951	379	389	colchicine	Chemical
17391951	405	416	expression	Gene_expression
17391951	432	440	fibrosis	Disease
17391951	452	456	CTGF	Gene
17391951	503	512	IFN-gamma	Gene
17391951	531	539	patients	Species
17391951	545	548	IPF	Disease
17391951	564	572	patients	Species
17391951	606	609	IPF	Disease
17391951	640	649	IFN-gamma	Gene
17391951	705	715	colchicine	Chemical
17391951	777	791	transcription	Transcription
17391951	801	833	transforming growth factor beta1	Gene
17391951	835	844	TGF-beta1	Gene
17391951	847	878	connective-tissue growth factor	Gene
17391951	880	884	CTGF	Gene
17391951	891	907	interferon-gamma	Gene
17391951	909	918	IFN-gamma	Gene
17391951	973	982	IFN-gamma	Gene
17391951	989	999	colchicine	Chemical
17391951	1013	1024	expression	Transcription
17391951	1027	1036	TGF-beta1	Gene
17391951	1041	1045	CTGF	Gene
17391951	1060	1065	lack	Negative_regulation
17391951	1068	1084	interferon-gamma	Gene
17391951	1171	1181	increased	Positive_regulation
17391951	1181	1192	expression	Gene_expression
17391951	1195	1204	IFN-gamma	Gene
17391951	1259	1270	expression	Gene_expression
17391951	1273	1277	CTGF	Gene
17391951	1282	1291	TGF-beta1	Gene
17391951	1308	1315	stable	Positive_regulation
17391951	1350	1359	IFN-gamma	Gene
17391951	1376	1385	TGF-beta1	Gene
17391951	1404	1414	decreased	Negative_regulation
17391951	1436	1446	colchicine	Chemical
17391951	1491	1495	DLCO	Chemical
17391951	1561	1570	IFN-gamma	Gene
17391951	1607	1616	IFN-gamma	Gene
17391951	1655	1658	PO2	Chemical
17391951	1669	1679	colchicine	Chemical
17391951	1752	1759	effect	Regulation
17391951	1783	1792	IFN-gamma	Gene
17391951	1800	1810	colchicine	Chemical
17391951	1825	1829	CTGF	Gene
17391951	1846	1855	IFN-gamma	Gene
17391951	1861	1872	expression	Gene_expression
17391951	1876	1881	human	Species
17391951	1882	1890	fibrosis	Disease
20685750|t|NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1-induced fibroblast differentiation into myofibroblasts
BACKGROUND: Persistence of myofibroblasts is believed to contribute to the development of fibrosis in idiopathic pulmonary fibrosis (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
NOX4, 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) NOX4 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 NOX4, 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 NOX4 small interfering RNA (siRNA); (4) NOX4 modulated alpha-SMA and procollagen I (alpha1) expression by controlling activation of Smad2/3; and (5) NOX4 modulated PDGF-induced fibroblast migration
CONCLUSION: NOX4 is critical for modulation of the pulmonary myofibroblast phenotype in IPF, probably by modulating the response to TGFbeta1 and PDGF
20685750	0	4	NOX4	Gene
20685750	5	10	NADPH	Chemical
20685750	19	30	expression	Gene_expression
20685750	33	43	increased	Positive_regulation
20685750	73	81	patients	Species
20685750	87	116	idiopathic pulmonary fibrosis	Disease
20685750	130	138	TGFbeta1	Gene
20685750	285	293	fibrosis	Disease
20685750	297	326	idiopathic pulmonary fibrosis	Disease
20685750	328	331	IPF	Disease
20685750	334	366	Transforming growth factor beta1	Gene
20685750	368	376	TGFbeta1	Gene
20685750	452	460	express	Gene_expression
20685750	502	510	produce	Gene_expression
20685750	582	588	oxygen	Chemical
20685750	597	606	produced	Gene_expression
20685750	609	614	NADPH	Chemical
20685750	719	729	expressed	Gene_expression
20685750	784	792	TGFbeta1	Gene
20685750	927	935	patients	Species
20685750	941	944	IPF	Disease
20685750	946	950	NOX4	Gene
20685750	1006	1017	expression	Gene_expression
20685750	1027	1033	oxygen	Chemical
20685750	1057	1064	Smad2/3	Gene
20685750	1065	1081	phosphorylation	Phosphorylation
20685750	1086	1097	quantified	Positive_regulation
20685750	1152	1160	TGFbeta1	Gene
20685750	1283	1287	NOX4	Gene
20685750	1320	1332	upregulated	Positive_regulation
20685750	1362	1370	patients	Species
20685750	1376	1379	IPF	Disease
20685750	1405	1416	expression	Transcription
20685750	1466	1474	TGFbeta1	Gene
20685750	1475	1487	upregulated	Positive_regulation
20685750	1487	1491	NOX4	Gene
20685750	1530	1541	expression	Gene_expression
20685750	1556	1559	IPF	Disease
20685750	1628	1639	expression	Gene_expression
20685750	1642	1651	response	Positive_regulation
20685750	1654	1662	TGFbeta1	Gene
20685750	1667	1677	inhibited	Negative_regulation
20685750	1702	1706	NOX4	Gene
20685750	1742	1746	NOX4	Gene
20685750	1794	1805	expression	Gene_expression
20685750	1808	1820	controlling	Regulation
20685750	1820	1831	activation	Positive_regulation
20685750	1834	1841	Smad2/3	Gene
20685750	1851	1855	NOX4	Gene
20685750	1913	1917	NOX4	Gene
20685750	1952	1975	pulmonary myofibroblast	Disease
20685750	1989	1992	IPF	Disease
20685750	2033	2041	TGFbeta1	Gene
25533688|t|[The expressions and meanings of BMP-7 and TGF-b in idiopathic pulmonary fibrosis and idiopathic nonspecific interstitial pneumonia]
OBJECTIVE: To investigate the expressions of cytokines in idiopathic pulmonary fibrosis (IPF) and in idiopathic nonspecific interstitial pneumonia (INSIP); To discuss expressions and meanings of bone morphogenetic protein 7 (BMP-7) and transforming growth factor beta (TGF-b) 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 BMP-7 and TGF-b 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,BMP-7 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 BMP-7 more than fibrosing pattern's (t = -5.341, P < 0.001)
There were dramatically increasing expressions of TGF-b 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 BMP-7(group IPF: r = -0.771, P < 0.001; group INSIP: r = -0.729, P < 0.001)
(3) Clinical follow-up data showed, the stability(improvement), deterioration and death rates of the group IPF and the group INSIP were, respectively, 0(0%), 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 BMP-7 expression and the part with relatively lower BMP-7 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 TGF-b, BMP-7 was inhibited in IIP patients, which would remind the degree of fibrosis and prognosis of IIP
BMP-7 would be expected to be a novel target for IIP pathogenesis and prognostic research
25533688	33	38	BMP-7	Gene
25533688	43	48	TGF-b	Gene
25533688	52	81	idiopathic pulmonary fibrosis	Disease
25533688	86	131	idiopathic nonspecific interstitial pneumonia	Disease
25533688	192	221	idiopathic pulmonary fibrosis	Disease
25533688	223	226	IPF	Disease
25533688	235	280	idiopathic nonspecific interstitial pneumonia	Disease
25533688	282	287	INSIP	Disease
25533688	329	357	bone morphogenetic protein 7	Gene
25533688	359	364	BMP-7	Gene
25533688	370	401	transforming growth factor beta	Gene
25533688	403	408	TGF-b	Gene
25533688	413	416	IPF	Disease
25533688	421	424	IPF	Disease
25533688	456	489	idiopathic interstitial pneumonia	Disease
25533688	491	494	IIP	Disease
25533688	607	610	IPF	Disease
25533688	615	618	IPF	Disease
25533688	630	635	INSIP	Disease
25533688	637	645	22 INSIP	Mutation
25533688	640	645	INSIP	Disease
25533688	988	1000	expressions	Gene_expression
25533688	1003	1008	BMP-7	Gene
25533688	1013	1018	TGF-b	Gene
25533688	1060	1068	patients	Species
25533688	1246	1260	up-expression	Gene_expression
25533688	1288	1291	TNF	Disease
25533688	1325	1341	down-expression	Gene_expression
25533688	1387	1392	BMP-5	Gene
25533688	1393	1399	BMP-8B	Gene
25533688	1404	1410	BMP-15	Gene
25533688	1493	1498	BMP-7	Gene
25533688	1525	1528	IPF	Disease
25533688	1533	1538	INSIP	Disease
25533688	1615	1618	IPF	Disease
25533688	1635	1640	INSIP	Disease
25533688	1667	1672	INSIP	Disease
25533688	1680	1688	patients	Species
25533688	1719	1724	BMP-7	Gene
25533688	1804	1815	increasing	Positive_regulation
25533688	1815	1827	expressions	Gene_expression
25533688	1830	1835	TGF-b	Gene
25533688	1839	1842	IPF	Disease
25533688	1847	1852	INSIP	Disease
25533688	1984	1989	BMP-7	Gene
25533688	1996	1999	IPF	Disease
25533688	2030	2035	INSIP	Disease
25533688	2168	2171	IPF	Disease
25533688	2186	2191	INSIP	Disease
25533688	2382	2387	BMP-7	Gene
25533688	2434	2439	BMP-7	Gene
25533688	2465	2468	IPF	Disease
25533688	2534	2539	INSIP	Disease
25533688	2667	2670	IPF	Disease
25533688	2675	2680	INSIP	Disease
25533688	2681	2689	patients	Species
25533688	2715	2725	activated	Positive_regulation
25533688	2725	2730	TGF-b	Gene
25533688	2732	2737	BMP-7	Gene
25533688	2755	2758	IIP	Disease
25533688	2759	2767	patients	Species
25533688	2802	2810	fibrosis	Disease
25533688	2828	2831	IIP	Disease
25533688	2833	2838	BMP-7	Gene
25533688	2882	2885	IIP	Disease
21056957|t|Increased deposition of chondroitin/dermatan sulfate glycosaminoglycan and upregulation of b1,3-glucuronosyltransferase I in pulmonary fibrosis
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 pulmonary fibrosis (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-b(1) (TGF-b(1))-treated normal lung fibroblasts expressed increased amounts of hyaluronan and 4- and 6-sulfated chondroitin, and neutralizing anti-TGF-b(1) antibody diminished the same
TGF-b(1) upregulated GlcAT-I and versican expression in lung fibroblasts, and signaling through TGF-b type I receptor/p38 MAPK was required for TGF-b(1)-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	0	10	Increased	Positive_regulation
21056957	75	88	upregulation	Positive_regulation
21056957	125	143	pulmonary fibrosis	Disease
21056957	145	163	Pulmonary fibrosis	Disease
21056957	165	167	PF	Disease
21056957	326	334	fibrosis	Disease
21056957	364	366	PF	Disease
21056957	386	394	changes	Regulation
21056957	452	463	expression	Gene_expression
21056957	538	548	synthesis	Gene_expression
21056957	568	597	idiopathic pulmonary fibrosis	Disease
21056957	599	602	IPF	Disease
21056957	604	612	patients	Species
21056957	636	639	rat	Species
21056957	649	658	bleomycin	Chemical
21056957	660	663	BLM	Chemical
21056957	673	675	PF	Disease
21056957	737	748	expression	Gene_expression
21056957	882	894	carbohydrate	Chemical
21056957	925	929	rats	Species
21056957	996	999	rat	Species
21056957	1050	1061	expression	Gene_expression
21056957	1096	1127	4- and 6-sulfated disaccharides	Chemical
21056957	1200	1204	rats	Species
21056957	1259	1290	transforming growth factor-b(1)	Gene
21056957	1292	1300	TGF-b(1)	Gene
21056957	1380	1409	4- and 6-sulfated chondroitin	Chemical
21056957	1433	1441	TGF-b(1)	Gene
21056957	1472	1480	TGF-b(1)	Gene
21056957	1481	1493	upregulated	Positive_regulation
21056957	1514	1525	expression	Gene_expression
21056957	1603	1612	required	Positive_regulation
21056957	1616	1623	TGF-b(1	Gene
21056957	1653	1664	expression	Gene_expression
21056957	1713	1723	increased	Positive_regulation
21056957	1723	1734	expression	Gene_expression
21056957	1760	1763	IPF	Disease
21056957	1774	1777	rat	Species
21056957	1886	1899	upregulation	Positive_regulation
21056957	1964	1966	PF	Disease
28081703|t|Identification and validation of differentially expressed transcripts by RNA-sequencing of formalin-fixed, paraffin-embedded (FFPE) lung tissue from patients with Idiopathic Pulmonary Fibrosis
BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease of unknown etiology
A major limitation in transcriptomic profiling of lung tissue in IPF has been a dependence on snap-frozen fresh tissues (FF)
In this project we sought to determine whether genome scale transcript profiling using RNA Sequencing (RNA-Seq) could be applied to archived Formalin-Fixed Paraffin-Embedded (FFPE) IPF tissues
RESULTS: We isolated total RNA from 7 IPF and 5 control FFPE lung tissues and performed 50 base pair paired-end sequencing on Illumina 2000 HiSeq
TopHat2 was used to map sequencing reads to the human genome
On average ~62 million reads (53.4% of ~116 million reads) were mapped per sample
4,131 genes were differentially expressed between IPF and controls (1,920 increased and 2,211 decreased (FDR   <   0.05)
We compared our results to differentially expressed genes calculated from a previously published dataset generated from FF tissues analyzed on Agilent microarrays (GSE47460)
The overlap of differentially expressed genes was very high (760 increased and 1,413 decreased, FDR   <   0.05)
Only 92 differentially expressed genes changed in opposite directions
Pathway enrichment analysis performed using MetaCore confirmed numerous IPF relevant genes and pathways including extracellular remodeling, TGF-beta, and WNT
Gene network analysis of MMP7, a highly differentially expressed gene in both datasets, revealed the same canonical pathways and gene network candidates in RNA-Seq and microarray data
For validation by NanoString nCounter   we selected 35 genes that had a fold change of 2 in at least one dataset (10 discordant, 10 significantly differentially expressed in one dataset only and 15 concordant genes)
High concordance of fold change and FDR was observed for each type of the samples (FF vs FFPE) with both microarrays (r   =   0.92) and RNA-Seq (r   =   0.90) and the number of discordant genes was reduced to four
CONCLUSIONS: Our results demonstrate that RNA sequencing of RNA obtained from archived FFPE lung tissues is feasible
The results obtained from FFPE tissue are highly comparable to FF tissues
The ability to perform RNA-Seq on archived FFPE IPF tissues should greatly enhance the availability of tissue biopsies for research in IPF
28081703	91	99	formalin	Chemical
28081703	107	115	paraffin	Chemical
28081703	149	157	patients	Species
28081703	803	808	human	Species
28081703	1186	1194	GSE47460	Chemical
28081703	1565	1569	MMP7	Gene
28081703	1595	1605	expressed	Gene_expression
11394717|t|Increased TGF-beta1 in the lungs of asbestos-exposed rats and mice: reduced expression in TNF-alpha receptor knockout mice
Inhalation of numerous fibrogenic agents causes interstitial pulmonary fibrosis (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 (TGF-beta1) 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 TGF-beta1 is rapidly expressed post-exposure at sites of initial asbestos-induced lung injury in both rats and mice
The TGF-beta1 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 TGF-beta1, as we have demonstrated previously for PDGF-A and -B, TGF-alpha, and TNF-alpha
TGF-beta1 expression is accompanied by collagen and fibronectin production in asbestos-exposed animals
Most interesting, TGF-beta1 expression is largely absent in the lungs of TNF-alpha 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 TNF-alpha, are reduced in the fibrosis-resistant knockout mice
In this article, we show that TGF-beta1 is included in this group of cytokines, supporting the postulate that TNF-alpha is necessary for the expression of other, more downstream growth factors, and the consequent development of idiopathic pulmonary fibrosis (IPF)
11394717	0	10	Increased	Positive_regulation
11394717	10	19	TGF-beta1	Gene
11394717	53	57	rats	Species
11394717	62	66	mice	Species
11394717	68	76	reduced	Negative_regulation
11394717	76	87	expression	Gene_expression
11394717	90	99	TNF-alpha	Gene
11394717	118	122	mice	Species
11394717	172	203	interstitial pulmonary fibrosis	Disease
11394717	205	208	IPF	Disease
11394717	213	219	humans	Species
11394717	379	412	Transforming growth factor beta 1	Gene
11394717	414	423	TGF-beta1	Gene
11394717	541	550	produced	Gene_expression
11394717	650	659	TGF-beta1	Gene
11394717	671	681	expressed	Transcription
11394717	732	743	lung injury	Disease
11394717	752	756	rats	Species
11394717	761	765	mice	Species
11394717	771	780	TGF-beta1	Gene
11394717	784	794	expressed	Gene_expression
11394717	915	919	rats	Species
11394717	924	928	mice	Species
11394717	929	937	express	Gene_expression
11394717	944	953	TGF-beta1	Gene
11394717	994	1007	PDGF-A and -B	Gene
11394717	1009	1018	TGF-alpha	Gene
11394717	1024	1033	TNF-alpha	Gene
11394717	1035	1044	TGF-beta1	Gene
11394717	1045	1056	expression	Gene_expression
11394717	1087	1098	fibronectin	Gene
11394717	1099	1110	production	Gene_expression
11394717	1157	1166	TGF-beta1	Gene
11394717	1167	1178	expression	Gene_expression
11394717	1189	1196	absent	Negative_regulation
11394717	1212	1221	TNF-alpha	Gene
11394717	1240	1244	mice	Species
11394717	1351	1364	PDGF-A and -B	Gene
11394717	1369	1378	TGF-alpha	Gene
11394717	1388	1397	TNF-alpha	Gene
11394717	1403	1411	reduced	Negative_regulation
11394717	1418	1426	fibrosis	Disease
11394717	1446	1450	mice	Species
11394717	1482	1491	TGF-beta1	Gene
11394717	1562	1571	TNF-alpha	Gene
11394717	1680	1709	idiopathic pulmonary fibrosis	Disease
11394717	1711	1714	IPF	Disease
25725128|t|Discovery and validation of extracellular/circulating microRNAs during idiopathic pulmonary fibrosis disease progression
BACKGROUND: Idiopathic pulmonary fibrosis (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	71	108	idiopathic pulmonary fibrosis disease	Disease
25725128	134	163	Idiopathic pulmonary fibrosis	Disease
25725128	165	168	IPF	Disease
25725128	193	218	interstitial lung disease	Disease
25725128	396	399	IPF	Disease
25725128	538	541	IPF	Disease
25725128	542	550	patients	Species
25725128	640	645	human	Species
25725128	956	959	IPF	Disease
25725128	960	968	patients	Species
25725128	1222	1232	expressed	Gene_expression
25725128	1330	1334	PI3K	Gene
25725128	1403	1408	HIF-1	Gene
25725128	1439	1450	Regulation	Regulation
25725128	1647	1653	miR-21	Gene
25725128	1668	1676	miR-200c	Gene
25725128	1678	1684	miR-31	Gene
25725128	1698	1704	let-7d	Gene
25725128	1781	1784	IPF	Disease
25725128	1808	1811	IPF	Disease
25725128	1812	1820	patients	Species
25725128	1903	1909	miR-21	Gene
25725128	1928	1936	miR-200c	Gene
25725128	1956	1966	increased	Positive_regulation
25725128	1979	1982	IPF	Disease
25725128	1983	1991	patients	Species
25725128	1998	2004	miR-31	Gene
25725128	2018	2024	let-7d	Gene
25725128	2073	2076	IPF	Disease
25725128	2077	2085	patients	Species
25725128	2286	2289	IPF	Disease
22088447|t|Idiopathic pulmonary fibrosis in relation to gene polymorphisms of transforming growth factor-b1 and plasminogen activator inhibitor 1
BACKGROUND: Idiopathic pulmonary fibrosis (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	0	29	Idiopathic pulmonary fibrosis	Disease
22088447	67	96	transforming growth factor-b1	Gene
22088447	101	134	plasminogen activator inhibitor 1	Gene
22088447	148	177	Idiopathic pulmonary fibrosis	Disease
22088447	179	182	IPF	Disease
22088447	212	233	fibrotic lung disease	Disease
22088447	341	370	Transforming growth factor-b1	Gene
22088447	372	378	TGF-b1	Gene
22088447	415	448	plasminogen activator inhibitor 1	Gene
22088447	450	455	PAI-1	Gene
22088447	500	518	pulmonary fibrosis	Disease
22088447	616	622	TGF-b1	Gene
22088447	623	632	869 T > C	Mutation
22088447	637	642	PAI-1	Gene
22088447	675	678	IPF	Disease
22088447	835	841	TGF-b1	Gene
22088447	845	853	869T > C	Mutation
22088447	858	863	PAI-1	Gene
22088447	876	879	IPF	Disease
22088447	880	888	patients	Species
22088447	1008	1016	869T > C	Mutation
22088447	1042	1048	TGF-b1	Gene
22088447	1057	1060	IPF	Disease
22088447	1159	1162	IPF	Disease
22088447	1268	1271	IPF	Disease
22088447	1361	1366	PAI-1	Gene
22088447	1405	1408	IPF	Disease
22088447	1480	1486	TGF-b1	Gene
22088447	1490	1498	869T > C	Mutation
22088447	1503	1508	PAI-1	Gene
22088447	1519	1526	affect	Regulation
22088447	1548	1551	IPF	Disease
24529509|t|Comparative study of transforming growth factor-b signalling and regulatory molecules in human and canine idiopathic pulmonary fibrosis
Activation of transforming growth factor (TGF)-b is a key event in the progression of fibrosis in human lung tissue
Idiopathic pulmonary fibrosis (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	89	94	human	Species
24529509	99	105	canine	Species
24529509	106	135	idiopathic pulmonary fibrosis	Disease
24529509	223	231	fibrosis	Disease
24529509	235	240	human	Species
24529509	254	283	Idiopathic pulmonary fibrosis	Disease
24529509	285	288	IPF	Disease
24529509	367	372	human	Species
24529509	373	401	usual interstitial pneumonia	Disease
24529509	403	406	UIP	Disease
24529509	446	449	IPF	Disease
24529509	454	489	non-specific interstitial pneumonia	Disease
24529509	491	495	NSIP	Disease
24529509	566	571	TGF-b	Gene
24529509	661	666	TGF-b	Gene
24529509	684	691	LTBP)-1	Gene
24529509	696	707	fibrillin-2	Gene
24529509	738	741	IPF	Disease
24529509	798	803	human	Species
24529509	804	807	UIP	Disease
24529509	812	816	NSIP	Disease
24529509	820	825	Smad2	Gene
24529509	855	860	TGF-b	Gene
24529509	910	913	IPF	Disease
24529509	959	969	localized	Localization
24529509	1035	1038	UIP	Disease
24529509	1043	1047	NSIP	Disease
24529509	1049	1059	Increased	Positive_regulation
24529509	1090	1096	LTBP-1	Gene
24529509	1137	1140	IPF	Disease
24529509	1228	1234	canine	Species
24529509	1387	1390	UIP	Disease
24529509	1399	1403	NSIP	Disease
24529509	1427	1438	fibrillin-2	Gene
24529509	1495	1501	people	Species
24529509	1507	1510	UIP	Disease
24529509	1557	1560	IPF	Disease
24529509	1565	1571	people	Species
24529509	1577	1581	NSIP	Disease
24529509	1646	1649	IPF	Disease
24529509	1694	1704	increased	Positive_regulation
24529509	1704	1709	TGF-b	Gene
24529509	1725	1736	expression	Gene_expression
24529509	1767	1773	LTBP-1	Gene
24529509	1778	1789	fibrillin-2	Gene
24529509	1835	1841	canine	Species
24529509	1842	1845	IPF	Disease
23344525|t|TGF-b1 T869C polymorphism may affect susceptibility to idiopathic pulmonary fibrosis and disease severity
BACKGROUND: Transforming growth factor-b1 (TGF-b1) is a key cytokine that plays a critical role in idiopathic pulmonary fibrosis (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 D(A-a)O2 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	7	12	T869C	Mutation
23344525	55	84	idiopathic pulmonary fibrosis	Disease
23344525	206	235	idiopathic pulmonary fibrosis	Disease
23344525	237	240	IPF	Disease
23344525	260	265	T869C	Mutation
23344525	324	345	fibrotic lung disease	Disease
23344525	415	425	nucleotide	Chemical
23344525	439	448	T   >   C	Mutation
23344525	541	544	IPF	Disease
23344525	672	675	IPF	Disease
23344525	782	785	IPF	Disease
23344525	870	873	IPF	Disease
23344525	925	928	IPF	Disease
23344525	1076	1080	PaO2	Chemical
23344525	1223	1226	IPF	Disease
23344525	1377	1382	T869C	Mutation
23344525	1425	1428	IPF	Disease
23344525	1536	1539	IPF	Disease
21984893|t|Inhibition of PI3K prevents the proliferation and differentiation of human lung fibroblasts into myofibroblasts: the role of class I P110 isoforms
Idiopathic pulmonary fibrosis (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 (PI3K/Akt), have been recently proposed
In this research we established ex-vivo cultures of human lung fibroblasts and we investigated the role of the PI3K/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 PI3Ks 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 PI3K/Akt pathway in lung fibroblast proliferation and differentiation
Moreover, for the first time we show that PI3K 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 PI3K isoforms can be pharmacological targets in IPF
21984893	0	11	Inhibition	Negative_regulation
21984893	14	18	PI3K	Gene
21984893	69	74	human	Species
21984893	148	177	Idiopathic pulmonary fibrosis	Disease
21984893	179	182	IPF	Disease
21984893	201	227	fibroproliferative disease	Disease
21984893	354	368	fatal disorder	Disease
21984893	386	414	transforming growth factor-b	Gene
21984893	416	421	TGF-b	Gene
21984893	552	557	TGF-b	Gene
21984893	639	659	phosphatidylinositol	Chemical
21984893	687	691	PI3K	Gene
21984893	692	695	Akt	Gene
21984893	779	784	human	Species
21984893	838	842	PI3K	Gene
21984893	843	846	Akt	Gene
21984893	913	918	TGF-b	Gene
21984893	1008	1022	pan-inhibitor	Negative_regulation
21984893	1031	1039	LY294002	Chemical
21984893	1064	1069	TGF-b	Gene
21984893	1078	1087	increase	Positive_regulation
21984893	1136	1147	expression	Gene_expression
21984893	1163	1174	production	Gene_expression
21984893	1182	1193	inhibiting	Negative_regulation
21984893	1193	1196	Akt	Gene
21984893	1197	1213	phosphorylation	Phosphorylation
21984893	1255	1259	PI3K	Gene
21984893	1260	1263	Akt	Gene
21984893	1368	1372	PI3K	Gene
21984893	1407	1417	expressed	Gene_expression
21984893	1420	1425	human	Species
21984893	1476	1486	expressed	Gene_expression
21984893	1486	1491	p110a	Gene
21984893	1629	1634	p110a	Gene
21984893	1643	1648	TGF-b	Gene
21984893	1739	1743	PI3K	Gene
21984893	1776	1784	targets	Regulation
21984893	1787	1790	IPF	Disease
15564021|t|Medical treatment for pulmonary fibrosis: current trends, concepts, and prospects
A diagnosis of idiopathic pulmonary fibrosis (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	22	40	pulmonary fibrosis	Disease
15564021	98	127	idiopathic pulmonary fibrosis	Disease
15564021	129	132	IPF	Disease
15564021	499	502	IPF	Disease
15564021	679	687	fibrosis	Disease
27604640|t|Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFb-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis
Transforming growth factor b-1 (TGFb-1)-induced phosphorylation of transcription factors Smad2 and Smad3 plays a crucial role in the pathogenesis of idiopathic pulmonary fibrosis (IPF)
However, the molecular regulation of Smad2/Smad3 proteins stability remains a mystery
Here, we show that ubiquitin carboxyl-terminal hydrolase-L5 (UCHL5 or UCH37) de-ubiquitinates both Smad2 and Smad3, up-regulates their stability, and promotes TGFb-1-induced expression of profibrotic proteins, such as fibronectin (FN) and a-smooth muscle actin (a-SMA)
Inhibition or down-regulation of UCHL5 reduced Smad2/Smad3 levels and TGFb-1-induced the expression of FN and a-SMA in human lung fibroblast
We demonstrate that Smad2 and Smad3 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, Smad2, and Smad3 levels were increased in bleomycin-injured lungs
Administration of UCHL5 inhibitor, b-AP15, reduced the expression of FN, type I collagen, Smad2/Smad3, and the deposition of collagen in lung tissues in a bleomycin-induced model of pulmonary fibrosis
Our studies provide a molecular mechanism by which UCHL5 mitigates TGFb-1 signaling by stabilizing Smad2/Smad3
These data indicate that UCHL5 may contribute to the pathogenesis of IPF and may be a potential therapeutic target
27604640	0	40	Ubiquitin carboxyl-terminal hydrolase-L5	Gene
27604640	50	56	TGFb-1	Gene
27604640	104	109	Smad2	Gene
27604640	110	115	Smad3	Gene
27604640	119	137	pulmonary fibrosis	Disease
27604640	139	169	Transforming growth factor b-1	Gene
27604640	171	177	TGFb-1	Gene
27604640	187	203	phosphorylation	Phosphorylation
27604640	228	233	Smad2	Gene
27604640	238	243	Smad3	Gene
27604640	288	317	idiopathic pulmonary fibrosis	Disease
27604640	319	322	IPF	Disease
27604640	348	359	regulation	Regulation
27604640	362	367	Smad2	Gene
27604640	368	373	Smad3	Gene
27604640	431	471	ubiquitin carboxyl-terminal hydrolase-L5	Gene
27604640	473	478	UCHL5	Gene
27604640	482	487	UCH37	Gene
27604640	511	516	Smad2	Gene
27604640	521	526	Smad3	Gene
27604640	562	571	promotes	Positive_regulation
27604640	571	577	TGFb-1	Gene
27604640	586	597	expression	Gene_expression
27604640	674	679	a-SMA	Gene
27604640	682	693	Inhibition	Negative_regulation
27604640	715	720	UCHL5	Gene
27604640	721	729	reduced	Negative_regulation
27604640	729	734	Smad2	Gene
27604640	735	740	Smad3	Gene
27604640	752	758	TGFb-1	Gene
27604640	759	767	induced	Positive_regulation
27604640	771	782	expression	Gene_expression
27604640	792	797	a-SMA	Gene
27604640	801	806	human	Species
27604640	844	849	Smad2	Gene
27604640	854	859	Smad3	Gene
27604640	879	890	diminished	Negative_regulation
27604640	893	909	over-expression	Positive_regulation
27604640	912	917	UCHL5	Gene
27604640	977	982	UCHL5	Gene
27604640	984	989	UCHL5	Gene
27604640	1000	1010	expressed	Gene_expression
27604640	1013	1016	IPF	Disease
27604640	1024	1029	UCHL5	Gene
27604640	1031	1036	Smad2	Gene
27604640	1042	1047	Smad3	Gene
27604640	1060	1070	increased	Positive_regulation
27604640	1073	1082	bleomycin	Chemical
27604640	1098	1113	Administration	Gene_expression
27604640	1116	1121	UCHL5	Gene
27604640	1133	1139	b-AP15	Chemical
27604640	1141	1149	reduced	Negative_regulation
27604640	1153	1164	expression	Gene_expression
27604640	1188	1193	Smad2	Gene
27604640	1194	1199	Smad3	Gene
27604640	1209	1220	deposition	Negative_regulation
27604640	1253	1262	bleomycin	Chemical
27604640	1280	1298	pulmonary fibrosis	Disease
27604640	1351	1356	UCHL5	Gene
27604640	1357	1367	mitigates	Positive_regulation
27604640	1367	1373	TGFb-1	Gene
27604640	1387	1399	stabilizing	Positive_regulation
27604640	1399	1404	Smad2	Gene
27604640	1405	1410	Smad3	Gene
27604640	1437	1442	UCHL5	Gene
27604640	1481	1484	IPF	Disease
26956419|t|Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis
Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic pulmonary fibrosis (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 (C3aR and C5aR) 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 C3aR and C5aR 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
C3aR/C5aR 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 C5aR, local and systemic induction of soluble C5b-9, and amplified expression of C3aR/C5aR in lesions
The blockade of C3aR and C5aR 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, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis
26956419	0	13	Contribution	Gene_expression
26956419	45	49	C3aR	Gene
26956419	54	58	C5aR	Gene
26956419	83	101	pulmonary fibrosis	Disease
26956419	210	239	idiopathic pulmonary fibrosis	Disease
26956419	241	244	IPF	Disease
26956419	332	335	C3a	Gene
26956419	366	369	C5a	Gene
26956419	374	377	IPF	Disease
26956419	385	394	interact	Binding
26956419	399	404	TGF-b	Gene
26956419	459	462	IPF	Disease
26956419	572	580	binding	Binding
26956419	583	586	C3a	Gene
26956419	587	590	C5a	Gene
26956419	622	626	C3aR	Gene
26956419	631	635	C5aR	Gene
26956419	659	672	lung fibrosis	Disease
26956419	692	697	human	Species
26956419	722	725	C3a	Gene
26956419	730	733	C5a	Gene
26956419	862	866	C3aR	Gene
26956419	871	875	C5aR	Gene
26956419	879	892	lung fibrosis	Disease
26956419	902	911	bleomycin	Chemical
26956419	920	924	mice	Species
26956419	946	955	elevated	Positive_regulation
26956419	961	964	C3a	Gene
26956419	969	972	C5a	Gene
26956419	1140	1151	attenuated	Negative_regulation
26956419	1197	1211	hydroxyproline	Chemical
26956419	1363	1366	C3a	Gene
26956419	1371	1374	C5a	Gene
26956419	1453	1459	TGF-b1	Gene
26956419	1474	1478	C3aR	Gene
26956419	1479	1483	C5aR	Gene
26956419	1496	1507	suppressed	Negative_regulation
26956419	1518	1530	expressions	Transcription
26956419	1533	1538	tgfb2	Gene
26956419	1540	1548	tgfbr1/2	Gene
26956419	1550	1557	ltbp1/2	Gene
26956419	1559	1567	serpine1	Gene
26956419	1569	1573	tsp1	Gene
26956419	1575	1579	bmp1	Gene
26956419	1591	1595	igf1	Gene
26956419	1680	1685	human	Species
26956419	1696	1704	patients	Species
26956419	1710	1713	IPF	Disease
26956419	1714	1724	presented	Positive_regulation
26956419	1730	1740	induction	Positive_regulation
26956419	1743	1747	C5aR	Gene
26956419	1810	1821	expression	Gene_expression
26956419	1824	1828	C3aR	Gene
26956419	1829	1833	C5aR	Gene
26956419	1850	1859	blockade	Negative_regulation
26956419	1862	1866	C3aR	Gene
26956419	1871	1875	C5aR	Gene
26956419	1904	1912	fibrosis	Disease
26956419	1960	1965	TGF-b	Gene
26956419	2083	2091	patients	Species
26956419	2097	2100	IPF	Disease
26956419	2110	2116	Fisher	Species
26956419	2257	2270	Contribution	Gene_expression
26956419	2302	2306	C3aR	Gene
26956419	2311	2315	C5aR	Gene
26956419	2340	2358	pulmonary fibrosis	Disease
18402687|t|Comparison between conventional and "clinical" assessment of experimental lung fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a treatment resistant disease with poor prognosis
Numerous compounds have been demonstrated to efficiently prevent pulmonary fibrosis (PF) in animal models but only a few were successful when given to animals with established fibrosis
Major concerns of current PF models are spontaneous resolution and high variability of fibrosis, 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 fibrosis
CONCLUSION: The progression of pulmonary fibrosis 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	79	87	fibrosis	Disease
18402687	101	130	Idiopathic pulmonary fibrosis	Disease
18402687	132	135	IPF	Disease
18402687	256	274	pulmonary fibrosis	Disease
18402687	367	375	fibrosis	Disease
18402687	464	472	fibrosis	Disease
18402687	626	630	rats	Species
18402687	778	782	rats	Species
18402687	1338	1346	fibrosis	Disease
18402687	1379	1397	pulmonary fibrosis	Disease
18402687	1586	1594	patients	Species
18402687	1600	1603	IPF	Disease
28573228|t|MOXIBUSTION HAS A POSITIVE EFFECT ON PULMONARY FIBROSIS: AN ALTERNATIVE APPROACH
BACKGROUND: An increasing number of people suffered idiopathic fibrosis (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	118	124	people	Species
28573228	134	153	idiopathic fibrosis	Disease
28573228	155	158	IPF	Disease
28573228	402	414	bleomycin A5	Chemical
28573228	423	441	pulmonary fibrosis	Disease
28573228	492	496	rats	Species
28573228	577	587	prednisone	Chemical
28573228	669	679	prednisone	Chemical
28573228	722	726	rats	Species
28573228	732	743	euthanized	Positive_regulation
28573228	763	768	Eosin	Chemical
28573228	790	796	TGF-b1	Gene
28573228	824	834	detection	Transcription
28573228	873	879	TGF-b1	Gene
28573228	898	908	increased	Positive_regulation
28573228	1035	1045	prednisone	Chemical
28573228	1062	1068	TGF-b1	Gene
28573228	1073	1083	decreased	Negative_regulation
28573228	1097	1107	increased	Positive_regulation
28573228	1188	1198	prednisone	Chemical
28573228	1247	1253	TGF-b1	Gene
28573228	1368	1386	pulmonary fibrosis	Disease
28573228	1390	1405	downregulating	Negative_regulation
28573228	1405	1411	TGF-b1	Gene
28573228	1416	1429	upregulating	Positive_regulation
28573228	1511	1521	prednisone	Chemical
28573228	1592	1610	pulmonary fibrosis	Disease
22394287|t|Intratracheal bleomycin causes airway remodeling and airflow obstruction in mice
In addition to parenchymal fibrosis, 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 fibrosis (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 fibrosis 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 fibrosis 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 fibrosis, 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 fibrosis
Thus, this model can be utilized to investigate mechanisms of airway remodeling
22394287	14	23	bleomycin	Chemical
22394287	76	80	mice	Species
22394287	109	117	fibrosis	Disease
22394287	182	208	interstitial lung diseases	Disease
22394287	285	298	lung diseases	Disease
22394287	437	466	idiopathic pulmonary fibrosis	Disease
22394287	468	471	IPF	Disease
22394287	516	525	bleomycin	Chemical
22394287	627	631	mice	Species
22394287	638	647	bleomycin	Chemical
22394287	684	692	fibrosis	Disease
22394287	697	723	peribronchial inflammation	Disease
22394287	845	849	dUTP	Chemical
22394287	914	943	transforming growth factor b1	Gene
22394287	945	950	TGFb1	Gene
22394287	953	958	TGFb2	Gene
22394287	1041	1050	bleomycin	Chemical
22394287	1052	1055	IPF	Disease
22394287	1163	1172	bleomycin	Chemical
22394287	1181	1185	mice	Species
22394287	1223	1235	inflammation	Disease
22394287	1240	1248	fibrosis	Disease
22394287	1296	1305	bleomycin	Chemical
22394287	1357	1383	peribronchial inflammation	Disease
22394287	1410	1421	expression	Gene_expression
22394287	1424	1429	TGFb1	Gene
22394287	1434	1439	TGFb2	Gene
22394287	1444	1457	accumulation	Positive_regulation
22394287	1521	1530	bleomycin	Chemical
22394287	1555	1558	IPF	Disease
22394287	1630	1638	fibrosis	Disease
22394287	1679	1688	bleomycin	Chemical
22394287	1730	1739	bleomycin	Chemical
22394287	1809	1821	inflammation	Disease
22394287	1899	1907	fibrosis	Disease
22227563|t|Role of endoplasmic reticulum stress in age-related susceptibility to lung fibrosis
The incidence of idiopathic pulmonary fibrosis (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 fibrosis compared with young animals
Progressive clinical deterioration and lung fibrosis 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 fibrosis associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways
22227563	75	83	fibrosis	Disease
22227563	102	131	idiopathic pulmonary fibrosis	Disease
22227563	133	136	IPF	Disease
22227563	214	217	IPF	Disease
22227563	279	282	IPF	Disease
22227563	365	369	mice	Species
22227563	379	385	murine	Species
22227563	409	415	murine	Species
22227563	451	455	mice	Species
22227563	475	486	pneumonitis	Disease
22227563	491	499	fibrosis	Disease
22227563	550	581	deterioration and lung fibrosis	Disease
22227563	653	657	mice	Species
22227563	706	710	mice	Species
22227563	834	838	mice	Species
22227563	846	856	elevation	Positive_regulation
22227563	926	932	CXCL12	Gene
22227563	961	994	Analyses of lytic virus infection	Disease
22227563	1036	1040	mice	Species
22227563	1062	1079	chronic infection	Disease
22227563	1142	1146	mice	Species
22227563	1147	1154	showed	Regulation
22227563	1168	1177	increase	Positive_regulation
22227563	1260	1264	dUTP	Chemical
22227563	1300	1309	caspase-3	Gene
22227563	1315	1326	expression	Gene_expression
22227563	1357	1362	Bcl-2	Gene
22227563	1462	1476	up-regulation	Positive_regulation
22227563	1516	1524	binding	Binding
22227563	1564	1587	X-box-binding protein 1	Gene
22227563	1666	1674	fibrosis	Disease
28389561|t|Transforming growth factor b1 (TGFb1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 TGFb1 autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts
NADPH oxidase 4 (NOX4) 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 NOX4 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 NOX4/reactive oxygen species (ROS) signaling that mediates the myofibroblast differentiation
Specifically, we found that NOX4/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 TGFb1/TGFbRI signaling that acts to increase NOX4/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility
Both NOX4 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	0	29	Transforming growth factor b1	Gene
28389561	31	36	TGFb1	Gene
28389561	53	57	NOX4	Gene
28389561	87	116	idiopathic pulmonary fibrosis	Disease
28389561	118	147	Idiopathic pulmonary fibrosis	Disease
28389561	149	152	IPF	Disease
28389561	273	281	fibrosis	Disease
28389561	370	373	IPF	Disease
28389561	464	471	levels	Gene_expression
28389561	507	511	CD44	Gene
28389561	559	564	TGFb1	Gene
28389561	652	667	NADPH oxidase 4	Gene
28389561	669	673	NOX4	Gene
28389561	716	718	O2	Chemical
28389561	722	739	hydrogen peroxide	Chemical
28389561	741	745	H2O2	Chemical
28389561	841	851	regulates	Regulation
28389561	851	855	NOX4	Gene
28389561	967	974	TGF-b-1	Gene
28389561	975	983	induced	Positive_regulation
28389561	1004	1008	NOX4	Gene
28389561	1018	1024	oxygen	Chemical
28389561	1126	1130	NOX4	Gene
28389561	1135	1145	regulates	Regulation
28389561	1174	1188	transcription	Transcription
28389561	1205	1212	effect	Negative_regulation
28389561	1289	1294	TGFb1	Gene
28389561	1325	1334	increase	Positive_regulation
28389561	1334	1338	NOX4	Gene
28389561	1343	1354	production	Gene_expression
28389561	1364	1373	required	Positive_regulation
28389561	1548	1552	NOX4	Gene
28389561	1568	1581	up-regulated	Positive_regulation
28389561	1597	1601	mice	Species
28389561	1628	1639	lung injury	Disease
28389561	1656	1661	human	Species
28389561	1662	1665	IPF	Disease
28389561	1783	1789	murine	Species
28389561	1800	1811	lung injury	Disease
28389561	1865	1873	fibrosis	Disease
28389561	1917	1927	targeting	Localization
28389561	1940	1963	lung fibrosis disorders	Disease
27993290|t|Increased levels of prostaglandin E-major urinary metabolite (PGE-MUM) in chronic fibrosing interstitial pneumonia
BACKGROUND: Dysregulation of the prostaglandin E2 (PGE2) signaling pathway has been implicated in interstitial pneumonia (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	20	35	prostaglandin E	Chemical
27993290	66	69	MUM	Species
27993290	92	114	interstitial pneumonia	Disease
27993290	149	165	prostaglandin E2	Chemical
27993290	167	171	PGE2	Chemical
27993290	214	236	interstitial pneumonia	Disease
27993290	238	240	IP	Disease
27993290	286	290	PGE2	Chemical
27993290	346	350	PGE2	Chemical
27993290	415	430	prostaglandin E	Chemical
27993290	461	464	MUM	Species
27993290	527	529	IP	Disease
27993290	548	577	idiopathic pulmonary fibrosis	Disease
27993290	579	582	IPF	Disease
27993290	592	595	MUM	Species
27993290	622	626	PGE2	Chemical
27993290	652	655	MUM	Species
27993290	717	725	patients	Species
27993290	731	744	lung diseases	Disease
27993290	746	762	bronchial asthma	Disease
27993290	764	766	BA	Disease
27993290	779	816	chronic obstructive pulmonary disease	Disease
27993290	818	822	COPD	Disease
27993290	867	875	fibrosis	Disease
27993290	984	989	COX-2	Gene
27993290	1012	1016	PGE2	Chemical
27993290	1036	1039	IPF	Disease
27993290	1041	1046	Human	Species
27993290	1178	1181	MUM	Species
27993290	1208	1217	elevated	Positive_regulation
27993290	1230	1233	MUM	Species
27993290	1316	1318	IP	Disease
27993290	1329	1334	COX-2	Gene
27993290	1391	1394	IPF	Disease
27993290	1406	1417	expression	Gene_expression
27993290	1470	1473	IPF	Disease
27993290	1475	1480	TGF-b	Gene
27993290	1481	1489	induced	Positive_regulation
27993290	1489	1494	COX-2	Gene
27993290	1495	1506	expression	Gene_expression
27993290	1532	1535	MUM	Species
27993290	1537	1546	elevated	Positive_regulation
27993290	1670	1673	MUM	Species
27993290	1677	1680	IPF	Disease
29351434|t|Cub domain containing protein 1 (CDCP1) negatively regulates TGFb signaling and myofibroblast differentiation
Fibroblasts are thought to be the prime cell type for producing and secreting extracellular matrix (ECM) proteins in the connective tissue
The profibrotic cytokine, transforming growth factor-beta 1 (TGFb1) 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, Cub domain containing protein 1 (CDCP1) to be strongly downregulated by TGFb1
CDCP1 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 TGFb1 on CDCP1 expression and function, using immunofluorescence, FACS, immunoblotting, and siRNA-mediated knockdown of CDCP1
CDCP1 is present on interstitial fibroblasts, but not myofibroblasts, in the normal and IPF lung
In vitro, TGFb1 decreased CDCP1 expression in a time-dependent manner by impacting mRNA and protein levels
Knockdown of CDCP1 enhanced a TGFb1-mediated cell adhesion of fibroblasts
Importantly, CDCP1-depleted cells displayed an enhanced expression of profibrotic markers, such as collagen V or aSMA, which was found to be independent of TGFb1
Our data show, for the very first time, that loss of CDCP1 contributes to fibroblast to myofibroblast differentiation via a potential negative feedback loop between CDCP1 expression and TGFb1 stimulation
29351434	0	31	Cub domain containing protein 1	Gene
29351434	33	38	CDCP1	Gene
29351434	277	310	transforming growth factor-beta 1	Gene
29351434	312	317	TGFb1	Gene
29351434	416	426	increased	Positive_regulation
29351434	430	440	secretion	Localization
29351434	665	696	Cub domain containing protein 1	Gene
29351434	698	703	CDCP1	Gene
29351434	737	742	TGFb1	Gene
29351434	744	749	CDCP1	Gene
29351434	787	798	expression	Gene_expression
29351434	910	917	effect	Regulation
29351434	920	925	TGFb1	Gene
29351434	929	934	CDCP1	Gene
29351434	935	946	expression	Gene_expression
29351434	1027	1037	knockdown	Negative_regulation
29351434	1040	1045	CDCP1	Gene
29351434	1047	1052	CDCP1	Gene
29351434	1135	1138	IPF	Disease
29351434	1155	1160	TGFb1	Gene
29351434	1161	1171	decreased	Negative_regulation
29351434	1171	1176	CDCP1	Gene
29351434	1177	1188	expression	Gene_expression
29351434	1253	1263	Knockdown	Negative_regulation
29351434	1266	1271	CDCP1	Gene
29351434	1283	1288	TGFb1	Gene
29351434	1341	1346	CDCP1	Gene
29351434	1347	1356	depleted	Negative_regulation
29351434	1375	1384	enhanced	Positive_regulation
29351434	1384	1395	expression	Gene_expression
29351434	1469	1481	independent	Positive_regulation
29351434	1484	1489	TGFb1	Gene
29351434	1536	1541	loss	Negative_regulation
29351434	1544	1549	CDCP1	Gene
29351434	1643	1648	loop	Negative_regulation
29351434	1656	1661	CDCP1	Gene
29351434	1662	1673	expression	Gene_expression
29351434	1677	1682	TGFb1	Gene
29351434	1683	1695	stimulation	Positive_regulation
25929803|t|The mannose-6-phosphate analogue, PXS64, inhibits fibrosis via TGF-b1 pathway in human lung fibroblasts
UNASSIGNED: Idiopathic pulmonary fibrosis (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 fibrosis 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 fibrosis
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 fibrosis
25929803	50	58	fibrosis	Disease
25929803	63	69	TGF-b1	Gene
25929803	81	86	human	Species
25929803	117	146	Idiopathic pulmonary fibrosis	Disease
25929803	148	151	IPF	Disease
25929803	267	275	scarring	Disease
25929803	277	289	inflammation	Disease
25929803	365	373	fibrosis	Disease
25929803	658	663	human	Species
25929803	692	697	human	Species
25929803	765	770	human	Species
25929803	771	777	TGF-b1	Gene
25929803	828	838	increased	Positive_regulation
25929803	869	880	fibronectin	Gene
25929803	939	949	increased	Positive_regulation
25929803	959	970	fibronectin	Gene
25929803	992	996	aSMA	Gene
25929803	998	1023	alpha smooth muscle actin	Gene
25929803	1098	1101	IPF	Disease
25929803	1102	1109	patient	Species
25929803	1230	1239	decrease	Negative_regulation
25929803	1270	1274	CTGF	Gene
25929803	1276	1282	TGF-b3	Gene
25929803	1284	1294	tenascin C	Gene
25929803	1296	1300	aSMA	Gene
25929803	1305	1310	THBS1	Gene
25929803	1520	1526	TGF-b1	Gene
25929803	1673	1681	fibrosis	Disease
25929803	1749	1760	inhibiting	Negative_regulation
25929803	1760	1766	TGF-b1	Gene
25929803	1821	1824	IPF	Disease
25929803	1825	1832	patient	Species
25929803	1913	1931	pulmonary fibrosis	Disease
26861876|t|Reduced Ets Domain-containing Protein Elk1 Promotes Pulmonary Fibrosis via Increased Integrin avb6 Expression
Idiopathic pulmonary fibrosis (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	0	8	Reduced	Negative_regulation
26861876	8	42	Ets Domain-containing Protein Elk1	Gene
26861876	52	70	Pulmonary Fibrosis	Disease
26861876	75	85	Increased	Positive_regulation
26861876	111	140	Idiopathic pulmonary fibrosis	Disease
26861876	142	145	IPF	Disease
26861876	164	185	fibrotic lung disease	Disease
26861876	214	219	TGFb1	Gene
26861876	265	268	IPF	Disease
26861876	291	296	TGFb1	Gene
26861876	297	308	activation	Positive_regulation
26861876	372	383	Expression	Gene_expression
26861876	420	430	increased	Positive_regulation
26861876	433	436	IPF	Disease
26861876	456	467	expression	Gene_expression
26861876	470	480	regulated	Regulation
26861876	570	575	ITGB6	Gene
26861876	605	613	repress	Negative_regulation
26861876	645	654	responds	Positive_regulation
26861876	696	700	Elk1	Gene
26861876	702	706	Elk1	Gene
26861876	716	739	glucocorticoid receptor	Gene
26861876	741	743	GR	Gene
26861876	751	755	Elk1	Gene
26861876	760	762	GR	Gene
26861876	767	776	regulate	Regulation
26861876	790	801	expression	Gene_expression
26861876	825	829	Elk1	Gene
26861876	830	838	binding	Binding
26861876	845	850	ITGB6	Gene
26861876	877	890	manipulation	Positive_regulation
26861876	893	897	Elk1	Gene
26861876	901	905	Elk1	Gene
26861876	906	914	binding	Binding
26861876	914	921	alters	Regulation
26861876	921	926	ITGB6	Gene
26861876	984	995	expression	Gene_expression
26861876	1020	1025	loss	Negative_regulation
26861876	1028	1032	Elk1	Gene
26861876	1033	1040	causes	Positive_regulation
26861876	1040	1049	enhanced	Positive_regulation
26861876	1049	1054	Itgb6	Gene
26861876	1055	1066	expression	Gene_expression
26861876	1082	1095	lung fibrosis	Disease
26861876	1119	1127	fibrosis	Disease
26861876	1141	1143	GR	Gene
26861876	1152	1165	dexamethasone	Chemical
26861876	1166	1175	inhibits	Negative_regulation
26861876	1175	1180	Itgb6	Gene
26861876	1181	1192	expression	Gene_expression
26861876	1203	1207	Elk1	Gene
26861876	1208	1222	dysregulation	Regulation
26861876	1252	1260	patients	Species
26861876	1266	1269	IPF	Disease
26861876	1297	1302	role	Regulation
26861876	1306	1310	Elk1	Gene
26861876	1311	1322	regulating	Regulation
26861876	1322	1327	ITGB6	Gene
26861876	1328	1339	expression	Gene_expression
26861876	1357	1371	dysregulation	Regulation
26861876	1374	1378	Elk1	Gene
26861876	1397	1402	human	Species
22694981|t|Pirfenidone inhibits TGF-b1-induced over-expression of collagen type I and heat shock protein 47 in A549 cells
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 heat shock protein (HSP) 47, a collagen-specific molecular chaperone, in human lung fibroblasts stimulated with transforming growth factor (TGF)-b1 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 TGF-b1 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: TGF-b1 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 TGF-b1
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	0	11	Pirfenidone	Chemical
22694981	12	21	inhibits	Negative_regulation
22694981	21	27	TGF-b1	Gene
22694981	36	52	over-expression	Gene_expression
22694981	75	85	heat shock	Disease
22694981	124	135	Pirfenidone	Chemical
22694981	222	230	fibrosis	Disease
22694981	255	263	patients	Species
22694981	269	298	idiopathic pulmonary fibrosis	Disease
22694981	300	303	IPF	Disease
22694981	332	343	pirfenidone	Chemical
22694981	344	353	inhibits	Negative_regulation
22694981	357	373	over-expression	Gene_expression
22694981	399	426	heat shock protein (HSP) 47	Gene
22694981	472	477	human	Species
22694981	582	587	HSP47	Gene
22694981	664	675	pirfenidone	Chemical
22694981	698	716	pulmonary fibrosis	Disease
22694981	728	737	bleomycin	Chemical
22694981	771	779	effects	Regulation
22694981	782	793	pirfenidone	Chemical
22694981	817	822	HSP47	Gene
22694981	823	834	expression	Gene_expression
22694981	841	846	human	Species
22694981	912	923	expression	Gene_expression
22694981	943	948	HSP47	Gene
22694981	953	963	E-cadherin	Gene
22694981	1000	1006	TGF-b1	Gene
22694981	1064	1075	expression	Gene_expression
22694981	1095	1100	HSP47	Gene
22694981	1105	1116	fibronectin	Gene
22694981	1180	1186	TGF-b1	Gene
22694981	1187	1198	stimulated	Positive_regulation
22694981	1218	1223	HSP47	Gene
22694981	1241	1252	expression	Gene_expression
22694981	1271	1282	pirfenidone	Chemical
22694981	1321	1332	Pirfenidone	Chemical
22694981	1338	1348	inhibited	Negative_regulation
22694981	1348	1364	over-expression	Positive_regulation
22694981	1400	1411	fibronectin	Gene
22694981	1437	1443	TGF-b1	Gene
22694981	1504	1515	pirfenidone	Chemical
22694981	1562	1573	inhibition	Negative_regulation
22694981	1592	1603	expression	Gene_expression
22694981	1624	1635	inhibition	Negative_regulation
22694981	1638	1643	HSP47	Gene
22694981	1644	1655	expression	Gene_expression
22694981	1702	1710	reduced	Negative_regulation
22694981	1719	1729	synthesis	Gene_expression
22694981	1737	1745	fibrosis	Disease
22694981	1760	1771	pirfenidone	Chemical
19648289|t|N-acetylcysteine inhibits alveolar epithelial-mesenchymal transition
The ability of transforming growth factor-beta1 (TGF-beta1) 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 idiopathic pulmonary fibrosis (IPF) patients, suggests a role for TGF-beta1-induced EMT in disease pathogenesis
We investigated the effects of N-acetylcysteine (NAC) on TGF-beta1-induced EMT in a rat epithelial cell line (RLE-6TN) and in primary rat alveolar epithelial cells (AEC)
RLE-6TN cells exposed to TGF-beta1 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 TGF-beta1 also underwent EMT that was prevented by NAC
TGF-beta1 decreased cellular GSH levels by 50-80%, whereas NAC restored them to approximately 150% of those found in TGF-beta1-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 TGF-beta1
Finally, inhibition of intracellular ROS generation during TGF-beta1 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 TGF-beta1-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	0	16	N-acetylcysteine	Chemical
19648289	85	117	transforming growth factor-beta1	Gene
19648289	119	128	TGF-beta1	Gene
19648289	291	320	idiopathic pulmonary fibrosis	Disease
19648289	322	325	IPF	Disease
19648289	327	335	patients	Species
19648289	357	366	TGF-beta1	Gene
19648289	435	451	N-acetylcysteine	Chemical
19648289	453	456	NAC	Chemical
19648289	461	470	TGF-beta1	Gene
19648289	488	491	rat	Species
19648289	538	541	rat	Species
19648289	575	582	RLE-6TN	Species
19648289	600	609	TGF-beta1	Gene
19648289	696	711	downregulation	Negative_regulation
19648289	770	780	induction	Positive_regulation
19648289	817	842	alpha-smooth muscle actin	Gene
19648289	844	853	alpha-SMA	Gene
19648289	859	867	vimentin	Chemical
19648289	901	904	NAC	Chemical
19648289	917	927	prevented	Negative_regulation
19648289	927	932	Smad3	Gene
19648289	933	949	phosphorylation	Phosphorylation
19648289	1014	1023	TGF-beta1	Gene
19648289	1065	1068	NAC	Chemical
19648289	1070	1079	TGF-beta1	Gene
19648289	1099	1102	GSH	Chemical
19648289	1129	1132	NAC	Chemical
19648289	1187	1196	TGF-beta1	Gene
19648289	1227	1254	glutathione monoethyl ester	Chemical
19648289	1395	1398	NAC	Chemical
19648289	1443	1449	oxygen	Chemical
19648289	1488	1497	TGF-beta1	Gene
19648289	1558	1567	TGF-beta1	Gene
19648289	1588	1600	alveolar EMT	Disease
19648289	1621	1625	H2O2	Chemical
19648289	1669	1672	NAC	Chemical
19648289	1759	1762	GSH	Chemical
19648289	1788	1797	TGF-beta1	Gene
19648289	1876	1879	NAC	Chemical
19648289	1905	1908	IPF	Disease
19648289	1950	1962	alveolar EMT	Disease
15281432|t|BAL cytokine profile in different interstitial lung diseases: a focus on systemic sclerosis
BACKGROUND AND AIM: Fibrosing alveolitis develops in up to 80% of systemic sclerosis 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	34	60	interstitial lung diseases	Disease
15281432	73	91	systemic sclerosis	Disease
15281432	113	133	Fibrosing alveolitis	Disease
15281432	159	177	systemic sclerosis	Disease
15281432	178	186	patients	Species
15281432	222	230	fibrosis	Disease
15281432	395	403	patients	Species
15281432	409	449	SSc associated interstitial lung disease	Disease
15281432	451	458	SSc-ILD	Disease
15281432	469	498	idiopathic pulmonary fibrosis	Disease
15281432	500	503	IPF	Disease
15281432	523	534	sarcoidosis	Disease
15281432	568	586	Interleukin (IL) 8	Gene
15281432	588	622	monocyte chemoattractant protein 1	Gene
15281432	624	629	MCP-1	Gene
15281432	650	659	IFN-gamma	Gene
15281432	668	672	IL18	Gene
15281432	677	681	IL10	Gene
15281432	686	717	transforming growth factor-beta	Gene
15281432	719	727	TGF-beta	Gene
15281432	794	797	IL8	Gene
15281432	802	807	MCP-1	Gene
15281432	827	836	elevated	Positive_regulation
15281432	839	846	SSc-ILD	Disease
15281432	854	857	IPF	Disease
15281432	920	925	MCP-1	Gene
15281432	961	968	SSc-ILD	Disease
15281432	977	980	IPF	Disease
15281432	1032	1035	IL8	Gene
15281432	1091	1096	MCP-1	Gene
15281432	1135	1144	IFN-gamma	Gene
15281432	1193	1204	sarcoidosis	Disease
15281432	1237	1247	increased	Positive_regulation
15281432	1255	1266	sarcoidosis	Disease
15281432	1271	1278	SSc-ILD	Disease
15281432	1320	1324	IL18	Gene
15281432	1329	1337	TGF-beta	Gene
15281432	1355	1359	IL10	Gene
15281432	1382	1389	SSc-ILD	Disease
15281432	1394	1405	sarcoidosis	Disease
15281432	1427	1430	IPF	Disease
15281432	1493	1496	ILD	Disease
15281432	1522	1525	IPF	Disease
15281432	1537	1548	expression	Gene_expression
15281432	1551	1556	MCP-1	Gene
15281432	1572	1583	expression	Gene_expression
15281432	1635	1639	IL10	Gene
15281432	1658	1669	sarcoidosis	Disease
15281432	1677	1684	SSc-ILD	Disease
15281432	1884	1891	SSc-ILD	Disease
27310652|t|Expression of RXFP1 Is Decreased in Idiopathic Pulmonary Fibrosis
Implications for Relaxin-based Therapies
RATIONALE: Relaxin is a hormone that has been considered as a potential therapy for patients with fibrotic diseases
OBJECTIVES: To gauge the potential efficacy of relaxin-based therapies in idiopathic pulmonary fibrosis (IPF), we studied gene expression for relaxin/insulin-like family peptide receptor 1 (RXFP1) in IPF lungs and controls
METHODS: We analyzed gene expression data obtained from the Lung Tissue Research Consortium and correlated RXFP1 gene expression data with cross-sectional clinical and demographic data
We also employed ex vivo donor and IPF lung fibroblasts to test RXFP1 expression in vitro
We tested CGEN25009, a relaxin-like peptide, in lung fibroblasts and in bleomycin injury
MEASUREMENTS AND MAIN RESULTS: We found that RXFP1 is significantly decreased in IPF
In patients with IPF, the magnitude of RXFP1 gene expression correlated directly with diffusing capacity of the lung for carbon monoxide (P   <   0.0001)
Significantly less RXFP1 was detected in vitro in IPF fibroblasts than in donor controls
Transforming growth factor-b decreased RXFP1 in both donor and IPF lung fibroblasts
CGEN25009 was effective at decreasing bleomycin-induced, acid-soluble collagen deposition in vivo
The relaxin-like actions of CGEN25009 were abrogated by RXFP1 silencing in vitro, and, in comparison with donor lung fibroblasts, IPF lung fibroblasts exhibited decreased sensitivity to the relaxin-like effects of CGEN25009
CONCLUSIONS: IPF is characterized by the loss of RXFP1 expression
RXFP1 expression is directly associated with pulmonary function in patients with IPF
The relaxin-like effects of CGEN25009 in vitro are dependent on expression of RXFP1
Our data suggest that patients with IPF with the highest RXFP1 expression would be predicted to be most sensitive to relaxin-based therapies
27310652	0	11	Expression	Gene_expression
27310652	14	19	RXFP1	Gene
27310652	23	33	Decreased	Negative_regulation
27310652	193	201	patients	Species
27310652	353	364	expression	Gene_expression
27310652	368	414	relaxin/insulin-like family peptide receptor 1	Gene
27310652	416	421	RXFP1	Gene
27310652	557	562	RXFP1	Gene
27310652	568	579	expression	Gene_expression
27310652	700	705	RXFP1	Gene
27310652	706	717	expression	Gene_expression
27310652	737	746	CGEN25009	Chemical
27310652	862	867	RXFP1	Gene
27310652	885	895	decreased	Negative_regulation
27310652	906	914	patients	Species
27310652	942	947	RXFP1	Gene
27310652	953	964	expression	Gene_expression
27310652	1024	1039	carbon monoxide	Chemical
27310652	1077	1082	RXFP1	Gene
27310652	1177	1187	decreased	Negative_regulation
27310652	1187	1192	RXFP1	Gene
27310652	1233	1242	CGEN25009	Chemical
27310652	1260	1271	decreasing	Negative_regulation
27310652	1271	1280	bleomycin	Chemical
27310652	1360	1369	CGEN25009	Chemical
27310652	1388	1393	RXFP1	Gene
27310652	1394	1404	silencing	Negative_regulation
27310652	1546	1555	CGEN25009	Chemical
27310652	1598	1603	loss	Negative_regulation
27310652	1606	1611	RXFP1	Gene
27310652	1612	1623	expression	Gene_expression
27310652	1624	1629	RXFP1	Gene
27310652	1630	1641	expression	Gene_expression
27310652	1691	1699	patients	Species
27310652	1738	1747	CGEN25009	Chemical
27310652	1761	1771	dependent	Regulation
27310652	1774	1785	expression	Gene_expression
27310652	1788	1793	RXFP1	Gene
27310652	1817	1825	patients	Species
27310652	1852	1857	RXFP1	Gene
27310652	1858	1869	expression	Gene_expression
25496490|t|Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (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	25	35	nintedanib	Chemical
25496490	69	77	patients	Species
25496490	83	112	idiopathic pulmonary fibrosis	Disease
25496490	126	155	Idiopathic pulmonary fibrosis	Disease
25496490	157	160	IPF	Disease
25496490	179	191	lung disease	Disease
25496490	234	244	nintedanib	Chemical
25496490	258	301	vascular endothelial growth factor receptor	Gene
25496490	303	308	VEGFR	Gene
25496490	311	350	platelet-derived growth factor receptor	Gene
25496490	352	357	PDGFR	Gene
25496490	528	538	nintedanib	Chemical
25496490	550	555	human	Species
25496490	623	626	IPF	Disease
25496490	627	635	patients	Species
25496490	684	691	effect	Regulation
25496490	694	698	VEGF	Gene
25496490	712	721	basic FGF	Gene
25496490	723	727	bFGF	Gene
25496490	736	746	nintedanib	Chemical
25496490	736	747	nintedanib	Localization
25496490	755	777	expression/activation	Gene_expression
25496490	780	785	VEGFR	Gene
25496490	787	792	PDGFR	Gene
25496490	886	923	tissue inhibitor of metalloproteinase	Gene
25496490	925	929	TIMP	Gene
25496490	959	962	IPF	Disease
25496490	975	985	expressed	Gene_expression
25496490	1002	1007	PDGFR	Gene
25496490	1041	1045	bFGF	Gene
25496490	1051	1055	VEGF	Gene
25496490	1100	1110	prevented	Negative_regulation
25496490	1113	1123	nintedanib	Chemical
25496490	1125	1135	Nintedanib	Chemical
25496490	1178	1188	inhibited	Negative_regulation
25496490	1192	1203	expression	Gene_expression
25496490	1206	1212	TIMP-2	Gene
25496490	1214	1245	Transforming growth factor-beta	Gene
25496490	1254	1264	secretion	Localization
25496490	1281	1291	inhibited	Negative_regulation
25496490	1294	1304	nintedanib	Chemical
25496490	1377	1387	nintedanib	Chemical
25496490	1391	1394	IPF	Disease
20550546|t|Effect of an immunotoxin to folate receptor beta on bleomycin-induced experimental pulmonary fibrosis
It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) by producing proinflammatory and/or fibrogenic cytokines
We showed that inflammatory macrophages expressed folate receptor beta (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 idiopathic pulmonary fibrosis (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	28	48	folate receptor beta	Gene
20550546	52	61	bleomycin	Chemical
20550546	70	101	experimental pulmonary fibrosis	Disease
20550546	207	236	idiopathic pulmonary fibrosis	Disease
20550546	238	241	IPF	Disease
20550546	341	351	expressed	Gene_expression
20550546	351	371	folate receptor beta	Gene
20550546	373	379	FRbeta	Gene
20550546	426	436	expressed	Gene_expression
20550546	456	462	FRbeta	Gene
20550546	518	524	FRbeta	Gene
20550546	525	536	expressing	Gene_expression
20550546	564	572	patients	Species
20550546	578	613	usual idiopathic pulmonary fibrosis	Disease
20550546	615	618	UIP	Disease
20550546	624	628	mice	Species
20550546	634	643	bleomycin	Chemical
20550546	652	670	pulmonary fibrosis	Disease
20550546	672	674	PF	Disease
20550546	712	718	FRbeta	Gene
20550546	719	730	expressing	Gene_expression
20550546	757	766	bleomycin	Chemical
20550546	775	777	PF	Disease
20550546	781	785	mice	Species
20550546	828	834	FRbeta	Gene
20550546	875	881	FRbeta	Gene
20550546	882	893	expressing	Gene_expression
20550546	966	974	patients	Species
20550546	980	983	UIP	Disease
20550546	988	992	mice	Species
20550546	998	1007	bleomycin	Chemical
20550546	1016	1018	PF	Disease
20550546	1156	1162	FRbeta	Gene
20550546	1266	1280	hydroxyproline	Chemical
20550546	1285	1293	fibrosis	Disease
20550546	1297	1306	bleomycin	Chemical
20550546	1315	1317	PF	Disease
20550546	1352	1362	decreased	Negative_regulation
20550546	1373	1379	tumour	Disease
20550546	1380	1388	necrosis	Disease
20550546	1415	1419	CCL2	Gene
20550546	1425	1430	CCL12	Gene
20550546	1431	1441	producing	Gene_expression
20550546	1539	1545	FRbeta	Gene
20550546	1546	1557	expressing	Gene_expression
20550546	1572	1575	IPF	Disease
20550546	1593	1599	FRbeta	Gene
20550546	1600	1611	expressing	Gene_expression
20550546	1655	1658	IPF	Disease
19129758|t|Pulmonary fibrosis: pathogenesis, etiology and regulation
Pulmonary fibrosis 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	0	18	Pulmonary fibrosis	Disease
19129758	59	77	Pulmonary fibrosis	Disease
19129758	211	228	fibrotic diseases	Disease
19129758	413	442	idiopathic pulmonary fibrosis	Disease
19129758	444	447	IPF	Disease
19129758	554	565	lung injury	Disease
19129758	640	657	fibrotic diseases	Disease
19129758	726	750	injury; (2) inflammation	Disease
19129758	776	819	pulmonary fibrotic conditions dysregulation	Disease
19129758	870	890	Chronic inflammation	Disease
19129758	1073	1081	TGFbeta1	Gene
19129758	1082	1093	production	Gene_expression
19129758	1303	1323	dysregulated healing	Disease
19129758	1428	1446	pulmonary fibrosis	Disease
17163490|t|Smooth muscle alpha-actin expression and myofibroblast differentiation by TGFbeta are dependent upon MK2
Fibroblasts play a major role in processes such as wound repair, scarring, and fibrosis
Differentiation into myofibroblasts, characterized by upregulation of smooth muscle alpha-actin (smalpha) in response to profibrotic agents such as TGFbeta is believed to be an important step in fibrosis
Therefore, elucidating mechanisms of myofibroblast differentiation might reveal novel targets in treating diseases such as idiopathic pulmonary fibrosis (IPF)
MK2 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 MK2 knockout (MK2(-/-)) mice, we demonstrate that disrupting expression of MK2 expression reduces filamentous actin and stress fibers
It also causes MK2(-/-) MEF to express less smalpha than their corresponding wild-type (WT) MEF at baseline and in response to TGFbeta
Furthermore, TGFbeta causes downregulation of smalpha in MK2(-/-) MEF, instead of upregulation observed in WT MEF
Expression of other fibroblast markers, such as collagen, is not altered in MK2(-/-) MEF
Our results further suggest that downregulation of smalpha in MK2(-/-) 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 MK2 plays a key role in regulation of smalpha expression, and that targeting MK2 might present a therapeutic approach in managing conditions such as pulmonary fibrosis
17163490	26	37	expression	Gene_expression
17163490	74	81	TGFbeta	Gene
17163490	86	96	dependent	Positive_regulation
17163490	101	104	MK2	Gene
17163490	185	193	fibrosis	Disease
17163490	249	262	upregulation	Positive_regulation
17163490	343	350	TGFbeta	Gene
17163490	390	398	fibrosis	Disease
17163490	523	552	idiopathic pulmonary fibrosis	Disease
17163490	560	563	MK2	Gene
17163490	589	592	p38	Gene
17163490	634	637	p38	Gene
17163490	638	649	activation	Positive_regulation
17163490	682	687	mouse	Species
17163490	721	724	MK2	Gene
17163490	735	738	MK2	Gene
17163490	745	749	mice	Species
17163490	796	799	MK2	Gene
17163490	800	811	expression	Gene_expression
17163490	871	874	MK2	Gene
17163490	983	990	TGFbeta	Gene
17163490	1005	1012	TGFbeta	Gene
17163490	1013	1020	causes	Positive_regulation
17163490	1020	1035	downregulation	Negative_regulation
17163490	1049	1052	MK2	Gene
17163490	1074	1087	upregulation	Positive_regulation
17163490	1099	1105	WT MEF	Disease
17163490	1107	1118	Expression	Gene_expression
17163490	1183	1195	MK2(-/-) MEF	Gene
17163490	1230	1245	downregulation	Negative_regulation
17163490	1259	1262	MK2	Gene
17163490	1279	1283	due	Positive_regulation
17163490	1442	1445	MK2	Gene
17163490	1519	1522	MK2	Gene
17163490	1591	1609	pulmonary fibrosis	Disease
28557137|t|Modulation of CD11c+ lung dendritic cells in respect to TGF-b in experimental pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a deadly, progressive lung disease with very few treatment options till now
Bleomycin-induced pulmonary fibrosis (BIPF) is a commonly used mice model in IPF research
TGF-b1 has been shown to play a key role in pulmonary fibrosis (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 pulmonary fibrosis
Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to TGF-b in PF
First, we established BIPF model in mice and blocked TGF-b expression by the use of inhibitor SB431542
Accumulation of lung CD11c+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of TGF-b
TGF-b 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 CD11c+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of BIPF
Blocking of TGF-b causes decreased expression of CD11c+CD103+ DCs
Another important lung DC subset CD11c+CD11b+ expression is suppressed by the absence of TGF-b after bleomycin administration
CD11c+CD103+ DCs might have anti-inflammatory as well as anti-fibrotic nature in PF
All these data demonstrate differential modulation of CD11c+ lung DCs by TGF-b in experimental PF
28557137	14	19	CD11c	Gene
28557137	56	61	TGF-b	Gene
28557137	78	96	pulmonary fibrosis	Disease
28557137	98	127	Idiopathic pulmonary fibrosis	Disease
28557137	129	132	IPF	Disease
28557137	159	171	lung disease	Disease
28557137	214	223	Bleomycin	Chemical
28557137	232	250	pulmonary fibrosis	Disease
28557137	277	281	mice	Species
28557137	291	294	IPF	Disease
28557137	305	311	TGF-b1	Gene
28557137	349	367	pulmonary fibrosis	Disease
28557137	369	371	PF	Disease
28557137	482	494	inflammation	Disease
28557137	524	532	fibrosis	Disease
28557137	613	631	pulmonary fibrosis	Disease
28557137	733	744	expression	Gene_expression
28557137	783	788	TGF-b	Gene
28557137	792	794	PF	Disease
28557137	832	836	mice	Species
28557137	841	849	blocked	Negative_regulation
28557137	849	854	TGF-b	Gene
28557137	855	866	expression	Gene_expression
28557137	890	898	SB431542	Chemical
28557137	921	926	CD11c	Gene
28557137	1063	1068	TGF-b	Gene
28557137	1070	1075	TGF-b	Gene
28557137	1086	1100	up-regulation	Positive_regulation
28557137	1127	1131	CD86	Gene
28557137	1136	1140	CD80	Gene
28557137	1213	1224	Expression	Gene_expression
28557137	1242	1247	CD11c	Gene
28557137	1248	1253	CD103	Gene
28557137	1272	1282	increased	Positive_regulation
28557137	1340	1349	Blocking	Negative_regulation
28557137	1352	1357	TGF-b	Gene
28557137	1389	1394	CD11c	Gene
28557137	1395	1400	CD103	Gene
28557137	1440	1445	CD11c	Gene
28557137	1446	1451	CD11b	Gene
28557137	1453	1464	expression	Gene_expression
28557137	1467	1478	suppressed	Negative_regulation
28557137	1496	1501	TGF-b	Gene
28557137	1508	1517	bleomycin	Chemical
28557137	1534	1539	CD11c	Gene
28557137	1540	1545	CD103	Gene
28557137	1547	1550	DCs	Chemical
28557137	1615	1617	PF	Disease
28557137	1673	1678	CD11c	Gene
28557137	1692	1697	TGF-b	Gene
28557137	1714	1716	PF	Disease
11306432|t|Microsatellite instability in transforming growth factor-beta 1 type II receptor gene in alveolar lining epithelial cells of idiopathic pulmonary fibrosis
It has been reported that transforming growth factor (TGF)-beta, which plays an integral role in the pathogenesis of idiopathic pulmonary fibrosis (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	0	26	Microsatellite instability	Disease
11306432	125	154	idiopathic pulmonary fibrosis	Disease
11306432	273	302	idiopathic pulmonary fibrosis	Disease
11306432	304	307	IPF	Disease
11306432	383	403	hyperplastic lesions	Disease
11306432	490	493	IPF	Disease
11306432	777	787	T beta RII	Gene
11306432	823	834	polyadenine	Chemical
11306432	858	868	T beta RII	Gene
11306432	936	939	IPF	Disease
11306432	940	948	patients	Species
11306432	1098	1101	IPF	Disease
11306432	1102	1110	patients	Species
11306432	1192	1200	patients	Species
11306432	1354	1364	T beta RII	Gene
11306432	1365	1376	expression	Gene_expression
11306432	1481	1491	T beta RII	Gene
11306432	1547	1550	IPF	Disease
11306432	1595	1611	genetic disorder	Disease
11306432	1667	1670	IPF	Disease
23043088|t|Profibrotic role of miR-154 in pulmonary fibrosis
In this study, we explored the regulation and the role of up-regulated microRNAs in idiopathic pulmonary fibrosis (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 miR-154, 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 miR-154
Mir-154 was increased in IPF fibroblasts, and transfection of NHLF with miR-154 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 miR-154 caused activation of the WNT pathway in NHLF
ICG-001 and XAV939, inhibitors of the WNT/b-catenin pathway, reduced the proliferative effect of miR-154
The potential role of miR-154, 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	20	27	miR-154	Gene
23043088	31	49	pulmonary fibrosis	Disease
23043088	135	164	idiopathic pulmonary fibrosis	Disease
23043088	166	169	IPF	Disease
23043088	186	211	interstitial lung disease	Disease
23043088	274	277	IPF	Disease
23043088	456	466	increased	Positive_regulation
23043088	466	477	expression	Gene_expression
23043088	480	487	miR-154	Gene
23043088	489	496	miR-134	Gene
23043088	510	517	miR-410	Gene
23043088	519	526	miR-382	Gene
23043088	540	548	miR-487b	Gene
23043088	550	556	miR-31	Gene
23043088	562	569	miR-127	Gene
23043088	804	809	SMAD3	Gene
23043088	858	864	TGF-b1	Gene
23043088	880	909	normal human lung fibroblasts	Disease
23043088	887	892	human	Species
23043088	911	915	NHLF	Disease
23043088	991	994	IPF	Disease
23043088	1042	1050	binding	Binding
23043088	1053	1058	SMAD3	Gene
23043088	1075	1084	promoter	Entity
23043088	1087	1094	miR-154	Gene
23043088	1096	1103	Mir-154	Gene
23043088	1121	1124	IPF	Disease
23043088	1158	1162	NHLF	Disease
23043088	1168	1175	miR-154	Gene
23043088	1283	1288	TGF-b	Gene
23043088	1311	1315	NHLF	Disease
23043088	1319	1322	IPF	Disease
23043088	1359	1366	mir-154	Gene
23043088	1396	1403	miR-154	Gene
23043088	1411	1422	activation	Positive_regulation
23043088	1444	1448	NHLF	Disease
23043088	1450	1457	ICG-001	Chemical
23043088	1462	1468	XAV939	Chemical
23043088	1547	1554	miR-154	Gene
23043088	1578	1585	miR-154	Gene
23043088	1637	1650	up-regulated	Positive_regulation
23043088	1653	1656	IPF	Disease
23043088	1746	1749	IPF	Disease
27942594|t|miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways
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 (miRs) can regulate expression of multiple genes and fundamentally alter cellular phenotypes during fibrosis
Although several miRs have been shown to be associated with lung fibrosis, the mechanisms by which miRs modulate epithelial behavior in lung fibrosis are lacking
Here, we identified miR-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 miR-323a-3p augment, and mimics suppress, murine lung fibrosis after bleomycin injury, indicating that this miR may govern profibrotic signals
We demonstrate that miR-323a-3p attenuates TGF-a and TGF-b signaling by directly targeting key adaptors in these important fibrogenic pathways
Moreover, miR-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 miR-323a-3p modulates inhibitory crosstalk with fibroblasts
These studies demonstrate that miR-323a-3p has a central role in lung fibrosis that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation
27942594	0	3	miR	Gene
27942594	22	35	lung fibrosis	Disease
27942594	115	129	chronic injury	Disease
27942594	153	170	fibrotic diseases	Disease
27942594	395	403	fibrosis	Disease
27942594	465	478	lung fibrosis	Disease
27942594	541	554	lung fibrosis	Disease
27942594	588	591	miR	Gene
27942594	606	620	downregulated	Negative_regulation
27942594	652	685	bronchiolitis obliterans syndrome	Disease
27942594	687	690	BOS	Disease
27942594	720	749	idiopathic pulmonary fibrosis	Disease
27942594	751	754	IPF	Disease
27942594	761	767	murine	Species
27942594	768	777	bleomycin	Chemical
27942594	786	794	fibrosis	Disease
27942594	811	814	miR	Gene
27942594	853	859	murine	Species
27942594	860	873	lung fibrosis	Disease
27942594	880	889	bleomycin	Chemical
27942594	919	922	miR	Gene
27942594	975	978	miR	Gene
27942594	998	1003	TGF-a	Gene
27942594	1008	1013	TGF-b	Gene
27942594	1109	1112	miR	Gene
27942594	1128	1137	caspase-3	Gene
27942594	1264	1275	expression	Gene_expression
27942594	1278	1281	miR	Gene
27942594	1370	1373	miR	Gene
27942594	1396	1417	role in lung fibrosis	Disease
27942594	1436	1442	murine	Species
27942594	1447	1452	human	Species
27942594	1466	1480	downregulated	Negative_regulation
27942594	1480	1491	expression	Gene_expression
27942595|t|Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	75	104	idiopathic pulmonary fibrosis	Disease
27942595	106	135	Idiopathic pulmonary fibrosis	Disease
27942595	137	140	IPF	Disease
27942595	154	179	interstitial lung disease	Disease
27942595	216	228	inflammation	Disease
27942595	230	250	alveolar destruction	Disease
27942595	256	264	fibrosis	Disease
27942595	419	422	IPF	Disease
27942595	458	463	human	Species
27942595	557	572	alveolar type 2	Disease
27942595	574	577	AT2	Gene
27942595	681	684	IPF	Disease
27942595	902	905	IPF	Disease
27942595	918	921	IPF	Disease
27942595	939	951	coexpressed	Gene_expression
27942595	968	971	AT1	Gene
27942595	974	977	AT2	Gene
27942595	1187	1192	TGF-b	Gene
27942595	1200	1203	YAP	Gene
27942595	1205	1208	P53	Gene
27942595	1219	1222	AKT	Gene
27942595	1223	1227	PI3K	Gene
27942595	1297	1315	alveolar structure	Disease
27942595	1546	1549	IPF	Disease
24890164|t|Expression of suppressor of cytokine signaling 1 in the peripheral blood of patients with idiopathic pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (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 suppressor of cytokine signaling 1 (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	14	48	suppressor of cytokine signaling 1	Gene
24890164	76	84	patients	Species
24890164	90	119	idiopathic pulmonary fibrosis	Disease
24890164	133	162	Idiopathic pulmonary fibrosis	Disease
24890164	164	167	IPF	Disease
24890164	375	378	IPF	Disease
24890164	379	387	patients	Species
24890164	411	445	suppressor of cytokine signaling 1	Gene
24890164	447	453	SOCS-1	Gene
24890164	523	526	IPF	Disease
24890164	527	535	patients	Species
24890164	608	619	expression	Gene_expression
24890164	622	628	SOCS-1	Gene
24890164	713	726	Interleukin 4	Gene
24890164	728	732	IL-4	Gene
24890164	735	764	transforming growth factor b1	Gene
24890164	766	772	TGF-b1	Gene
24890164	794	805	expression	Gene_expression
24890164	924	927	IPF	Disease
24890164	928	936	patients	Species
24890164	1024	1030	SOCS-1	Gene
24890164	1036	1047	expression	Gene_expression
24890164	1065	1075	decreased	Negative_regulation
24890164	1090	1093	IPF	Disease
24890164	1094	1102	patients	Species
24890164	1151	1155	IL-4	Gene
24890164	1160	1166	TGF-b1	Gene
24890164	1182	1185	IPF	Disease
24890164	1186	1194	patients	Species
24890164	1200	1208	patients	Species
24890164	1220	1231	expression	Gene_expression
24890164	1234	1240	SOCS-1	Gene
24890164	1315	1323	patients	Species
24890164	1325	1331	SOCS-1	Gene
24890164	1390	1394	IL-4	Gene
24890164	1497	1503	SOCS-1	Gene
24890164	1516	1525	detected	Gene_expression
24890164	1544	1559	down-regulated	Negative_regulation
24890164	1562	1565	IPF	Disease
24890164	1566	1574	patients	Species
24890164	1580	1591	expression	Gene_expression
24890164	1594	1600	SOCS-1	Gene
24890164	1636	1639	IPF	Disease
24890164	1640	1648	patients	Species
24890164	1710	1716	SOCS-1	Gene
24890164	1749	1752	IPF	Disease
24890164	1831	1835	IL-4	Gene
26370615|t|The Anti-fibrotic Effects and Mechanisms of MicroRNA-486-5p in Pulmonary Fibrosis
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 pulmonary fibrosis 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 pulmonary fibrosis 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 pulmonary fibrosis (IPF)
In addition, as determined by luciferase assays and Western blotting, SMAD2, a crucial mediator of pulmonary fibrosis, 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	63	81	Pulmonary Fibrosis	Disease
26370615	207	218	expression	Gene_expression
26370615	241	247	silica	Chemical
26370615	256	261	mouse	Species
26370615	271	289	pulmonary fibrosis	Disease
26370615	405	411	silica	Chemical
26370615	479	485	miR-21	Gene
26370615	487	494	miR-455	Gene
26370615	523	531	miR-3107	Gene
26370615	563	569	silica	Chemical
26370615	578	583	mouse	Species
26370615	593	611	pulmonary fibrosis	Disease
26370615	641	650	bleomycin	Chemical
26370615	652	655	BLM	Chemical
26370615	665	670	mouse	Species
26370615	718	728	decreased	Negative_regulation
26370615	752	760	patients	Species
26370615	766	775	silicosis	Disease
26370615	811	819	patients	Species
26370615	825	834	silicosis	Disease
26370615	839	868	idiopathic pulmonary fibrosis	Disease
26370615	870	873	IPF	Disease
26370615	946	951	SMAD2	Gene
26370615	975	993	pulmonary fibrosis	Disease
26370615	1116	1130	overexpressed	Positive_regulation
26370615	1254	1266	lung lesions	Disease
26370615	1285	1291	silica	Chemical
26370615	1366	1369	BLM	Chemical
26370615	1444	1452	fibrosis	Disease
19966781|t|Prostaglandin F(2alpha) receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis, 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 A(2) (cPLA(2)) suppresses bleomycin-induced pulmonary fibrosis, 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 pulmonary fibrosis 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, PGF(2alpha) 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 PGF(2alpha)-FP signaling facilitates pulmonary fibrosis independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF
19966781	0	32	Prostaglandin F(2alpha) receptor	Gene
19966781	55	64	bleomycin	Chemical
19966781	73	91	pulmonary fibrosis	Disease
19966781	142	171	Idiopathic pulmonary fibrosis	Disease
19966781	173	176	IPF	Disease
19966781	459	462	IPF	Disease
19966781	616	624	TGF-beta	Gene
19966781	651	659	fibrosis	Disease
19966781	690	699	bleomycin	Chemical
19966781	708	726	pulmonary fibrosis	Disease
19966781	747	750	IPF	Disease
19966781	769	777	fibrosis	Disease
19966781	883	911	cytosolic phospholipase A(2)	Gene
19966781	913	920	cPLA(2)	Gene
19966781	933	942	bleomycin	Chemical
19966781	951	969	pulmonary fibrosis	Disease
19966781	996	1010	prostaglandins	Chemical
19966781	1017	1021	mice	Species
19966781	1022	1030	lacking	Negative_regulation
19966781	1086	1116	prostaglandin F (PGF) receptor	Gene
19966781	1145	1163	pulmonary fibrosis	Disease
19966781	1200	1221	alveolar inflammation	Disease
19966781	1226	1234	TGF-beta	Gene
19966781	1262	1271	wild-type	Disease
19966781	1273	1275	WT	Disease
19966781	1277	1281	mice	Species
19966781	1292	1305	FP deficiency	Disease
19966781	1295	1306	deficiency	Negative_regulation
19966781	1324	1332	TGF-beta	Gene
19966781	1363	1371	fibrosis	Disease
19966781	1466	1469	IPF	Disease
19966781	1512	1523	production	Gene_expression
19966781	1568	1576	TGF-beta	Gene
19966781	1640	1658	pulmonary fibrosis	Disease
19966781	1676	1684	TGF-beta	Gene
19966781	1749	1752	IPF	Disease
23967091|t|Low-dose paclitaxel ameliorates pulmonary fibrosis by suppressing TGF-b1/Smad3 pathway via miR-140 upregulation
Abnormal TGF-b1/Smad3 activation plays an important role in the pathogenesis of pulmonary fibrosis, 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 pulmonary fibrosis 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 pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis by suppressing the TGF-b1/Smad3 pathway via upregulating miR-140
23967091	9	19	paclitaxel	Chemical
23967091	32	50	pulmonary fibrosis	Disease
23967091	66	72	TGF-b1	Gene
23967091	73	78	Smad3	Gene
23967091	91	98	miR-140	Gene
23967091	122	128	TGF-b1	Gene
23967091	129	134	Smad3	Gene
23967091	135	146	activation	Positive_regulation
23967091	193	211	pulmonary fibrosis	Disease
23967091	239	249	paclitaxel	Chemical
23967091	251	254	PTX	Chemical
23967091	328	331	PTX	Chemical
23967091	379	382	PTX	Chemical
23967091	509	518	increase	Positive_regulation
23967091	521	528	miR-140	Gene
23967091	530	533	PTX	Chemical
23967091	565	574	bleomycin	Chemical
23967091	576	579	BLM	Chemical
23967091	589	607	pulmonary fibrosis	Disease
23967091	611	615	rats	Species
23967091	743	746	PTX	Chemical
23967091	761	768	effect	Regulation
23967091	771	777	TGF-b1	Gene
23967091	781	792	regulating	Regulation
23967091	796	807	expression	Gene_expression
23967091	810	815	Smad3	Gene
23967091	820	835	phosphorylated	Phosphorylation
23967091	835	840	Smad3	Gene
23967091	844	849	Smad3	Gene
23967091	856	865	restored	Positive_regulation
23967091	879	889	E-cadherin	Gene
23967091	891	899	vimentin	Gene
23967091	927	934	miR-140	Gene
23967091	956	985	idiopathic pulmonary fibrosis	Disease
23967091	987	990	IPF	Disease
23967091	992	1000	patients	Species
23967091	1002	1008	TGF-b1	Gene
23967091	1040	1043	rat	Species
23967091	1059	1070	decreasing	Negative_regulation
23967091	1070	1075	Smad3	Gene
23967091	1078	1083	Smad3	Gene
23967091	1084	1095	expression	Gene_expression
23967091	1099	1112	upregulating	Positive_regulation
23967091	1112	1119	miR-140	Gene
23967091	1121	1124	PTX	Chemical
23967091	1191	1209	pulmonary fibrosis	Disease
23967091	1213	1217	rats	Species
23967091	1233	1236	PTX	Chemical
23967091	1251	1257	TGF-b1	Gene
23967091	1251	1266	TGF-b1-induced	Positive_regulation
23967091	1286	1293	miR-140	Gene
23967091	1311	1321	E-cadherin	Gene
23967091	1333	1341	reduced	Negative_regulation
23967091	1345	1356	expression	Gene_expression
23967091	1359	1367	vimentin	Gene
23967091	1369	1374	Smad3	Gene
23967091	1381	1386	Smad3	Gene
23967091	1440	1443	PTX	Chemical
23967091	1453	1471	pulmonary fibrosis	Disease
23967091	1475	1487	suppressing	Negative_regulation
23967091	1491	1497	TGF-b1	Gene
23967091	1498	1503	Smad3	Gene
23967091	1516	1529	upregulating	Positive_regulation
23967091	1529	1536	miR-140	Gene
28860144|t|IPF lung fibroblasts have a senescent phenotype
The mechanisms of aging that are involved in the development of idiopathic pulmonary fibrosis (IPF) are still unclear
Although it has been hypothesized that the proliferation and activation of human lung fibroblasts (hLFs) are essential in IPF, no studies have assessed how this process works in an aging lung
Our goal was to elucidate if there were age-related changes on primary hLFs isolated from IPF lungs compared with age-matched controls
We investigated several hallmarks of aging in hLFs from IPF patients and age-matched controls
IPF hLFs have increased cellular senescence with higher expression of b-galactosidase, p21, p16, p53, and cytokines related to the senescence-associated secretory phenotype (SASP) as well as decreased proliferation/apoptosis compared with age-matched controls
Additionally, we observed shorter telomeres, mitochondrial dysfunction, and upon transforming growth factor-b stimulation, increased markers of endoplasmic reticulum stress
Our data suggest that IPF hLFs develop senescence resulting in a decreased apoptosis and that the development of SASP may be an important contributor to the fibrotic process observed in IPF
These results might change the existing paradigm, which describes fibroblasts as aberrantly activated cells, to a cell with a senescence phenotype
28860144	211	225	proliferation	Gene_expression
28860144	243	248	human	Species
28860144	557	565	patients	Species
28860144	606	616	increased	Positive_regulation
28860144	648	659	expression	Gene_expression
28860144	679	682	p21	Gene
28860144	684	687	p16	Gene
28860144	689	692	p53	Gene
26286721|t|Sphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: role of S1P signalling and autophagy
INTRODUCTION: Idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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 pulmonary fibrosis, 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 pulmonary fibrosis in human IPF and animal models
26286721	0	23	Sphingosine-1-phosphate	Chemical
26286721	61	79	pulmonary fibrosis	Disease
26286721	89	92	S1P	Gene
26286721	133	162	Idiopathic pulmonary fibrosis	Disease
26286721	164	167	IPF	Disease
26286721	285	308	Sphingosine-1-phosphate	Chemical
26286721	310	313	S1P	Gene
26286721	351	369	pulmonary fibrosis	Disease
26286721	380	389	S1P lyase	Gene
26286721	391	395	S1PL	Gene
26286721	397	408	expression	Gene_expression
26286721	523	529	murine	Species
26286721	557	561	S1PL	Gene
26286721	621	628	effect	Regulation
26286721	631	635	S1PL	Gene
26286721	636	647	expression	Gene_expression
26286721	690	693	S1P	Gene
26286721	739	743	S1PL	Gene
26286721	839	847	patients	Species
26286721	853	856	IPF	Disease
26286721	861	870	bleomycin	Chemical
26286721	882	886	mice	Species
26286721	888	893	TGF-b	Gene
26286721	894	904	increased	Positive_regulation
26286721	908	919	expression	Gene_expression
26286721	922	926	S1PL	Gene
26286721	930	935	human	Species
26286721	972	980	binding	Binding
26286721	983	988	Smad3	Gene
26286721	1013	1018	Sgpl1	Gene
26286721	1047	1051	S1PL	Gene
26286721	1063	1068	TGF-b	Gene
26286721	1081	1084	S1P	Gene
26286721	1112	1117	human	Species
26286721	1161	1172	expression	Gene_expression
26286721	1175	1178	LC3	Gene
26286721	1183	1191	beclin 1	Gene
26286721	1193	1203	Knockdown	Negative_regulation
26286721	1206	1210	S1PL	Gene
26286721	1212	1217	Sgpl1	Gene
26286721	1227	1231	mice	Species
26286721	1242	1251	bleomycin	Chemical
26286721	1260	1278	pulmonary fibrosis	Disease
26286721	1284	1292	patients	Species
26286721	1298	1301	IPF	Disease
26286721	1302	1310	reduced	Negative_regulation
26286721	1310	1315	Sgpl1	Gene
26286721	1321	1332	expression	Gene_expression
26286721	1370	1378	fibrosis	Disease
26286721	1443	1447	S1PL	Gene
26286721	1484	1502	pulmonary fibrosis	Disease
26286721	1506	1511	human	Species
26286721	1512	1515	IPF	Disease
23376055|t|Roles of p38 MAPK and JNK in TGF-b1-induced human alveolar epithelial to mesenchymal transition
BACKGROUND AND AIMS: Idiopathic pulmonary fibrosis (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 JNK in TGF-b1-induced human alveolar epithelial to mesenchymal transition (EMT), which could be a possible mechanism of IPF
METHODS: A549 cells were treated with TGF-b1 (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 JNK in TGF-b1-mediated EMT were investigated using gene silencing and inhibitor SB-203580 and SP-600125
RESULTS: The data showed that TGF-b1 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
TGF-b1-induced EMT occurred through phosphorylation of p38 MAPK and JNK and was inhibited by inhibitor SB-203580 and SP-600125 and gene silencing
CONCLUSIONS: TGF-b1 induces A549 alveolar epithelial cells (AECs) to undergo EMT partially via p38 MAPK and JNK activation and supports the concept of EMT in lung epithelial cells
23376055	22	25	JNK	Gene
23376055	29	35	TGF-b1	Gene
23376055	44	49	human	Species
23376055	118	147	Idiopathic pulmonary fibrosis	Disease
23376055	149	152	IPF	Disease
23376055	288	294	roles	Regulation
23376055	310	313	JNK	Gene
23376055	317	323	TGF-b1	Gene
23376055	332	337	human	Species
23376055	430	433	IPF	Disease
23376055	473	479	TGF-b1	Gene
23376055	518	529	expression	Gene_expression
23376055	573	579	desmin	Gene
23376055	581	602	a-smooth muscle actin	Gene
23376055	604	609	a-SMA	Gene
23376055	615	623	vimentin	Gene
23376055	629	640	expression	Gene_expression
23376055	683	693	E-cadherin	Gene
23376055	695	713	zonula occludens-1	Gene
23376055	715	719	ZO-1	Gene
23376055	725	736	aquaporin-5	Gene
23376055	738	742	AQP5	Gene
23376055	801	804	JNK	Gene
23376055	808	814	TGF-b1	Gene
23376055	881	890	SB-203580	Chemical
23376055	895	904	SP-600125	Chemical
23376055	936	942	TGF-b1	Gene
23376055	1096	1107	expression	Gene_expression
23376055	1135	1141	desmin	Gene
23376055	1143	1148	a-SMA	Gene
23376055	1153	1161	vimentin	Gene
23376055	1182	1197	downregulation	Negative_regulation
23376055	1227	1237	E-cadherin	Gene
23376055	1239	1243	ZO-1	Gene
23376055	1248	1252	AQP5	Gene
23376055	1254	1260	TGF-b1	Gene
23376055	1273	1282	occurred	Positive_regulation
23376055	1290	1306	phosphorylation	Phosphorylation
23376055	1322	1325	JNK	Gene
23376055	1357	1366	SB-203580	Chemical
23376055	1371	1380	SP-600125	Chemical
23376055	1414	1420	TGF-b1	Gene
23376055	1509	1512	JNK	Gene
23376055	1513	1524	activation	Positive_regulation
27746237|t|The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (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 (LXR)a 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	70	99	idiopathic pulmonary fibrosis	Disease
27746237	113	142	Idiopathic pulmonary fibrosis	Disease
27746237	144	147	IPF	Disease
27746237	298	301	IPF	Disease
27746237	420	438	microRNA (miR)-155	Gene
27746237	470	476	murine	Species
27746237	511	514	IPF	Disease
27746237	570	588	pulmonary fibrosis	Disease
27746237	599	608	Bleomycin	Chemical
27746237	617	630	lung fibrosis	Disease
27746237	648	655	miR-155	Gene
27746237	659	663	mice	Species
27746237	816	821	mouse	Species
27746237	863	866	IPF	Disease
27746237	974	981	miR-155	Gene
27746237	985	989	mice	Species
27746237	990	1000	developed	Negative_regulation
27746237	1012	1025	lung fibrosis	Disease
27746237	1080	1091	expression	Transcription
27746237	1092	1097	TGF-b	Gene
27746237	1098	1109	production	Gene_expression
27746237	1180	1193	deregulation	Regulation
27746237	1200	1207	miR-155	Gene
27746237	1299	1303	LXRa	Gene
27746237	1320	1333	lung fibrosis	Disease
27746237	1341	1344	IPF	Disease
27746237	1425	1436	expression	Gene_expression
27746237	1439	1446	miR-155	Gene
27746237	1447	1455	reduced	Negative_regulation
27746237	1484	1487	IPF	Disease
27746237	1492	1499	miR-155	Gene
27746237	1579	1586	miR-155	Gene
27746237	1606	1610	LXRa	Gene
27746237	1648	1677	pathogenic pulmonary fibrosis	Disease
27746237	1699	1706	miR-155	Gene
27746237	1754	1757	IPF	Disease
22106015|t|Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition
BACKGROUND: Idiopathic pulmonary fibrosis (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 S1P(2) and S1P(3), 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	0	23	Sphingosine-1-phosphate	Chemical
22106015	40	48	patients	Species
22106015	54	83	idiopathic pulmonary fibrosis	Disease
22106015	147	176	Idiopathic pulmonary fibrosis	Disease
22106015	178	181	IPF	Disease
22106015	291	314	Sphingosine-1-phosphate	Chemical
22106015	316	319	S1P	Chemical
22106015	325	345	sphingosine kinase 1	Gene
22106015	347	352	SPHK1	Gene
22106015	419	424	role	Regulation
22106015	441	452	expression	Gene_expression
22106015	455	463	patients	Species
22106015	469	472	IPF	Disease
22106015	506	509	S1P	Chemical
22106015	591	599	patients	Species
22106015	605	608	IPF	Disease
22106015	665	670	SPHK1	Gene
22106015	671	682	expression	Gene_expression
22106015	715	723	patients	Species
22106015	729	732	IPF	Disease
22106015	843	846	S1P	Chemical
22106015	886	889	S1P	Chemical
22106015	907	917	increased	Positive_regulation
22106015	920	928	patients	Species
22106015	934	937	IPF	Disease
22106015	998	1001	S1P	Chemical
22106015	1014	1024	increased	Positive_regulation
22106015	1027	1035	patients	Species
22106015	1041	1044	IPF	Disease
22106015	1155	1170	carbon monoxide	Chemical
22106015	1285	1293	patients	Species
22106015	1299	1302	IPF	Disease
22106015	1304	1309	SPHK1	Gene
22106015	1314	1326	upregulated	Positive_regulation
22106015	1346	1354	patients	Species
22106015	1360	1363	IPF	Disease
22106015	1407	1415	vimentin	Gene
22106015	1486	1489	S1P	Chemical
22106015	1490	1498	induced	Positive_regulation
22106015	1531	1543	interacting	Binding
22106015	1548	1551	S1P	Chemical
22106015	1559	1562	S1P	Chemical
22106015	1585	1596	activation	Positive_regulation
22106015	1601	1606	Smad3	Gene
22106015	1608	1612	RhoA	Gene
22106015	1613	1616	GTP	Chemical
22106015	1639	1668	transforming growth factor-b1	Gene
22106015	1670	1676	TGF-b1	Gene
22106015	1678	1686	release	Localization
22106015	1700	1706	TGF-b1	Gene
22106015	1750	1753	S1P	Chemical
22106015	1754	1759	SPHK1	Gene
22106015	1760	1771	activation	Positive_regulation
22106015	1801	1807	TGF-b1	Gene
22106015	1816	1819	S1P	Chemical
22106015	1820	1825	SPHK1	Gene
22106015	1845	1848	S1P	Chemical
22106015	1852	1861	elevated	Positive_regulation
22106015	1864	1872	patients	Species
22106015	1878	1881	IPF	Disease
22106015	1921	1930	mediates	Positive_regulation
27508042|t|MiR-338* targeting smoothened to inhibit pulmonary fibrosis by epithelial-mesenchymal transition
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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 pulmonary fibrosis
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
MiR-338* was down-regulated in the lung tissue from mice with bleomycin-induced pulmonary fibrosis
The smoothened (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 pulmonary fibrosis
27508042	0	7	MiR-338	Gene
27508042	19	29	smoothened	Gene
27508042	41	59	pulmonary fibrosis	Disease
27508042	98	127	Idiopathic pulmonary fibrosis	Disease
27508042	129	132	IPF	Disease
27508042	139	159	chronic lung disease	Disease
27508042	170	186	pulmonary injury	Disease
27508042	234	242	fibrosis	Disease
27508042	344	362	pulmonary fibrosis	Disease
27508042	409	416	miR-338	Gene
27508042	419	426	miR-338	Gene
27508042	475	480	tumor	Disease
27508042	537	555	pulmonary fibrosis	Disease
27508042	564	568	mice	Species
27508042	587	596	bleomycin	Chemical
27508042	598	601	BLM	Chemical
27508042	616	619	IPF	Disease
27508042	683	691	miR-338*	Gene
27508042	841	852	expression	Gene_expression
27508042	855	862	miR-338	Gene
27508042	885	888	SMO	Gene
27508042	967	974	MiR-338	Gene
27508042	1019	1023	mice	Species
27508042	1029	1038	bleomycin	Chemical
27508042	1047	1065	pulmonary fibrosis	Disease
27508042	1071	1081	smoothened	Gene
27508042	1083	1086	SMO	Gene
27508042	1110	1117	miR-338	Gene
27508042	1124	1138	knocking-down	Negative_regulation
27508042	1142	1153	expression	Gene_expression
27508042	1156	1159	SMO	Gene
27508042	1209	1214	TGF-b	Gene
27508042	1237	1253	Over-expression	Positive_regulation
27508042	1256	1259	SMO	Gene
27508042	1319	1324	TGF-b	Gene
27508042	1367	1383	over-expression	Gene_expression
27508042	1386	1389	SMO	Gene
27508042	1557	1573	over-expression	Positive_regulation
27508042	1576	1583	miR-338	Gene
27508042	1604	1612	fibrosis	Disease
27508042	1624	1633	bleomycin	Chemical
27508042	1637	1641	mice	Species
27508042	1683	1690	miR-338	Gene
27508042	1703	1706	SMO	Gene
27508042	1772	1790	pulmonary fibrosis	Disease
27144281|t|MAP3K19 Is a Novel Regulator of TGF-b Signaling That Impacts Bleomycin-Induced Lung Injury and Pulmonary Fibrosis
UNASSIGNED: Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment
The cytokine TGF-b has been shown to be a central mediator in the disease process
We investigated the role of a novel kinase, MAP3K19, upregulated in IPF tissue, in TGF-b-induced signal transduction and in bleomycin-induced pulmonary fibrosis
MAP3K19 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
MAP3K19 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 MAP3K19 siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 _ 3 nuclear translocation following TGF-b stimulation
TGF-b-induced gene transcription was also strongly inhibited by both the MAP3K19 inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect
In combination, the MAP3K19 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 MAP3K19 strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically
In summary, these results strongly suggest that inhibition of MAP3K19 may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease
27144281	0	7	MAP3K19	Gene
27144281	32	37	TGF-b	Gene
27144281	61	70	Bleomycin	Chemical
27144281	79	90	Lung Injury	Disease
27144281	95	113	Pulmonary Fibrosis	Disease
27144281	127	156	Idiopathic pulmonary fibrosis	Disease
27144281	158	161	IPF	Disease
27144281	229	240	pirfenidone	Chemical
27144281	245	255	nintedanib	Chemical
27144281	318	323	TGF-b	Gene
27144281	432	439	MAP3K19	Gene
27144281	456	459	IPF	Disease
27144281	471	476	TGF-b	Gene
27144281	512	521	bleomycin	Chemical
27144281	530	548	pulmonary fibrosis	Disease
27144281	550	557	MAP3K19	Gene
27144281	634	641	trachea	Disease
27144281	815	822	MAP3K19	Gene
27144281	844	858	overexpressed	Positive_regulation
27144281	901	904	IPF	Disease
27144281	905	913	patients	Species
27144281	933	941	patients	Species
27144281	988	995	MAP3K19	Gene
27144281	1034	1044	inhibitor	Negative_regulation
27144281	1052	1059	phospho	Chemical
27144281	1102	1107	TGF-b	Gene
27144281	1121	1126	TGF-b	Gene
27144281	1194	1201	MAP3K19	Gene
27144281	1202	1212	inhibitor	Negative_regulation
27144281	1216	1226	nintedanib	Chemical
27144281	1236	1247	pirfenidone	Chemical
27144281	1303	1310	MAP3K19	Gene
27144281	1311	1321	inhibitor	Negative_regulation
27144281	1365	1376	pirfenidone	Chemical
27144281	1380	1390	nintedanib	Chemical
27144281	1488	1491	IPF	Disease
27144281	1493	1504	inhibition	Negative_regulation
27144281	1507	1514	MAP3K19	Gene
27144281	1535	1544	bleomycin	Chemical
27144281	1553	1571	pulmonary fibrosis	Disease
27144281	1681	1692	inhibition	Negative_regulation
27144281	1695	1702	MAP3K19	Gene
27144281	1764	1767	IPF	Disease
17496059|t|Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells
Patients with interstitial lung diseases, 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	0	12	Nitric oxide	Chemical
17496059	88	96	Patients	Species
17496059	102	128	interstitial lung diseases	Disease
17496059	138	167	idiopathic pulmonary fibrosis	Disease
17496059	169	172	IPF	Disease
17496059	178	204	bronchopulmonary dysplasia	Disease
17496059	206	209	BPD	Disease
17496059	224	237	lung fibrosis	Disease
17496059	337	375	Transforming growth factor (TGF)-beta1	Gene
17496059	512	524	nitric oxide	Chemical
17496059	585	617	decreases alveolar myofibroblast	Disease
17496059	694	703	TGF-beta1	Gene
17496059	775	786	production	Gene_expression
17496059	807	840	endothelial nitric oxide synthase	Gene
17496059	852	862	inducible	Positive_regulation
17496059	852	883	inducible nitric oxide synthase	Gene
17496059	885	889	iNOS	Gene
17496059	895	905	expressed	Gene_expression
17496059	975	981	min(-1	Gene
17496059	1011	1020	TGF-beta1	Gene
17496059	1029	1040	suppressed	Negative_regulation
17496059	1045	1056	expression	Gene_expression
17496059	1105	1112	affect	Regulation
17496059	1112	1116	iNOS	Gene
17496059	1117	1128	expression	Gene_expression
17496059	1175	1181	l-NAME	Chemical
17496059	1220	1230	increased	Positive_regulation
17496059	1268	1279	expression	Gene_expression
17496059	1342	1351	TGF-beta1	Gene
17496059	1423	1433	decreased	Negative_regulation
17496059	1444	1455	expression	Gene_expression
17496059	1521	1531	expressed	Gene_expression
17496059	1531	1541	increased	Positive_regulation
17496059	1559	1569	E-cadherin	Gene
17496059	1897	1900	IPF	Disease
17496059	1905	1908	BPD	Disease
19393328|t|N-acetyl-L-cysteine inhibits TGF-beta1-induced profibrotic responses in fibroblasts
BACKGROUND: Excessive production of TGF-beta(1) plays a key role in the tissue remodeling or fibrotic process observed in bronchial asthma, chronic pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF)
TGF-beta(1) 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 TGF-beta(1)-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 TGF-beta(1)-mediated contraction of floating gels and the TGF-beta(1)-induced mediator production
In addition, the effect of NAC on the TGF-beta(1)-induced differentiation to myofibroblasts was evaluated by assessing alpha-smooth muscle actin (alpha-SMA) expression
RESULTS: NAC significantly abolished the TGF-beta(1)-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 TGF-beta(1)-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 TGF-beta(1)-stimulated alpha-SMA expression (p<0.01)
CONCLUSION: These results suggest that NAC can affect the TGF-beta(1)-induced tissue remodeling or fibrotic process in vitro
19393328	0	19	N-acetyl-L-cysteine	Gene
19393328	29	38	TGF-beta1	Gene
19393328	121	132	TGF-beta(1)	Gene
19393328	207	223	bronchial asthma	Disease
19393328	225	250	chronic pulmonary disease	Disease
19393328	252	256	COPD	Disease
19393328	263	292	idiopathic pulmonary fibrosis	Disease
19393328	294	297	IPF	Disease
19393328	300	311	TGF-beta(1)	Gene
19393328	360	371	glutathione	Chemical
19393328	419	425	oxygen	Chemical
19393328	509	528	N-acetyl-l-cysteine	Gene
19393328	530	533	NAC	Gene
19393328	546	556	TGF-beta(1	Gene
19393328	603	612	modulate	Regulation
19393328	616	627	production	Gene_expression
19393328	630	641	fibronectin	Gene
19393328	646	680	vascular endothelial growth factor	Gene
19393328	682	686	VEGF	Gene
19393328	795	800	human	Species
19393328	825	830	HFL-1	Gene
19393328	866	869	NAC	Gene
19393328	877	887	TGF-beta(1	Gene
19393328	935	945	TGF-beta(1	Gene
19393328	1003	1006	NAC	Gene
19393328	1014	1025	TGF-beta(1)	Gene
19393328	1085	1095	assessing	Negative_regulation
19393328	1133	1144	expression	Gene_expression
19393328	1154	1157	NAC	Gene
19393328	1186	1196	TGF-beta(1	Gene
19393328	1338	1341	NAC	Gene
19393328	1361	1371	inhibited	Negative_regulation
19393328	1375	1385	TGF-beta(1	Gene
19393328	1386	1397	-augmented	Positive_regulation
19393328	1397	1408	fibronectin	Gene
19393328	1422	1426	VEGF	Gene
19393328	1436	1447	production	Gene_expression
19393328	1530	1533	NAC	Gene
19393328	1547	1557	TGF-beta(1	Gene
19393328	1640	1643	NAC	Gene
19393328	1659	1669	TGF-beta(1	Gene
28385812|t|Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts
Pulmonary fibrosis is a severe condition with no cure and limited therapeutic options
A better understanding of its pathophysiology is needed
Recent studies have suggested that pulmonary fibrosis may be driven by accelerated aging-related mechanisms
Sirtuins (SIRTs), particularly SIRT1, SIRT3, and SIRT6, are well-known mediators of aging; however, limited data exist on the contribution of sirtuins to lung fibrosis
We assessed the mRNA and protein levels of all seven known sirtuins in primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in comparison with lung fibroblasts from healthy controls
These unbiased tests revealed a tendency for all sirtuins to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7
Similarly, SIRT7 was decreased in lung tissues of bleomycin-challenged mice
Inhibition of SIRT7 with siRNA in cultured lung fibroblasts resulted in an increase in collagen and a-smooth muscle actin (a-SMA)
Reciprocally, overexpression of SIRT7 resulted in lower basal and TGF-b-induced levels of COL1A1, COL1A2, COL3A1, and a-SMA mRNAs, as well as collagen and a-SMA proteins
Induced changes in SIRT7 had no effect on endogenous TGF-b mRNA levels or latent TGF-b activation, but overexpression of SIRT7 reduced the levels of Smad3 mRNA and protein
In conclusion, the decline in SIRT7 in lung fibroblasts has a profibrotic effect, which is mediated by changes in Smad3 levels
28385812	387	392	SIRT1	Gene
28385812	394	399	SIRT3	Gene
28385812	405	410	SIRT6	Gene
28385812	626	634	patients	Species
28385812	915	923	patients	Species
28385812	965	974	decrease	Negative_regulation
28385812	992	997	SIRT7	Gene
28385812	1010	1015	SIRT7	Gene
28385812	1020	1030	decreased	Negative_regulation
28385812	1049	1058	bleomycin	Chemical
28385812	1070	1074	mice	Species
28385812	1076	1087	Inhibition	Negative_regulation
28385812	1090	1095	SIRT7	Gene
28385812	1151	1160	increase	Positive_regulation
28385812	1199	1204	a-SMA	Gene
28385812	1221	1236	overexpression	Positive_regulation
28385812	1239	1244	SIRT7	Gene
28385812	1245	1254	resulted	Positive_regulation
28385812	1273	1278	TGF-b	Gene
28385812	1297	1303	COL1A1	Gene
28385812	1305	1311	COL1A2	Gene
28385812	1313	1319	COL3A1	Gene
28385812	1325	1330	a-SMA	Gene
28385812	1362	1367	a-SMA	Gene
28385812	1378	1386	Induced	Positive_regulation
28385812	1397	1402	SIRT7	Gene
28385812	1410	1417	effect	Regulation
28385812	1431	1436	TGF-b	Gene
28385812	1442	1449	levels	Gene_expression
28385812	1459	1464	TGF-b	Gene
28385812	1465	1476	activation	Positive_regulation
28385812	1481	1496	overexpression	Positive_regulation
28385812	1499	1504	SIRT7	Gene
28385812	1505	1513	reduced	Negative_regulation
28385812	1517	1524	levels	Positive_regulation
28385812	1527	1532	Smad3	Gene
28385812	1581	1586	SIRT7	Gene
28385812	1654	1662	changes	Regulation
28385812	1665	1670	Smad3	Gene
28259823|t|Evaluation of permeability alteration and epithelial-mesenchymal transition induced by transforming growth factor-b1 in A549, NCI-H441, and Calu-3 cells: Development of an in vitro model of respiratory epithelial cells in idiopathic pulmonary fibrosis
INTRODUCTION: Idiopathic pulmonary fibrosis (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	87	116	transforming growth factor-b1	Gene
28259823	126	134	NCI-H441	Species
28259823	140	146	Calu-3	Species
28259823	222	251	idiopathic pulmonary fibrosis	Disease
28259823	267	296	Idiopathic pulmonary fibrosis	Disease
28259823	298	301	IPF	Disease
28259823	315	327	lung disease	Disease
28259823	583	601	pulmonary fibrosis	Disease
28259823	692	695	IPF	Disease
28259823	909	917	NCI-H441	Species
28259823	923	929	Calu-3	Species
28259823	962	968	TGF-b1	Gene
28259823	988	996	NCI-H441	Species
28259823	1002	1008	Calu-3	Species
28259823	1038	1048	E-cadherin	Gene
28259823	1053	1061	vimentin	Gene
28259823	1100	1122	claudins-1, -3, and -5	Gene
28259823	1255	1261	TGF-b1	Gene
28259823	1290	1316	fluorescein isothiocyanate	Chemical
28259823	1365	1371	TGF-b1	Gene
28259823	1394	1402	necrosis	Disease
28259823	1442	1451	Annexin V	Gene
28259823	1456	1464	ethidium	Chemical
28259823	1506	1514	NCI-H441	Species
28259823	1553	1570	claudins-1 and -3	Gene
28259823	1622	1628	TGF-b1	Gene
28259823	1789	1795	Calu-3	Species
28259823	1829	1835	TGF-b1	Gene
28259823	1858	1866	necrosis	Disease
28259823	2011	2014	IPF	Disease
28259823	2053	2059	TGF-b1	Gene
28259823	2068	2076	NCI-H441	Species
28259823	2166	2169	IPF	Disease
29144435|t|Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-b1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt
Idiopathic pulmonary fibrosis (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 TGF-b1 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 TGF-b1 consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the FAK/Akt pathway, whereas FAK depletion was sufficient to abrogate these effects
We also demonstrate a synergy between matrix stiffening and TGF-b1 that was positive for COL1A1 and negative for MMP1
Remarkably, the COL1A1 expression upregulation elicited by TGF-b1 alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger FAK and Akt activities in the former cells
These findings provide new insights on how matrix stiffening and TGF-b1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation
29144435	59	65	TGF-b1	Gene
29144435	86	115	Idiopathic Pulmonary Fibrosis	Disease
29144435	116	124	Patients	Species
29144435	134	137	FAK	Gene
29144435	138	141	Akt	Gene
29144435	143	172	Idiopathic pulmonary fibrosis	Disease
29144435	174	177	IPF	Disease
29144435	185	203	aggressive disease	Disease
29144435	424	430	TGF-b1	Gene
29144435	465	473	control	Regulation
29144435	578	581	IPF	Disease
29144435	582	590	patients	Species
29144435	683	697	polyacrylamide	Chemical
29144435	699	702	PAA	Chemical
29144435	724	730	TGF-b1	Gene
29144435	744	754	increased	Positive_regulation
29144435	754	760	COL1A1	Gene
29144435	767	778	decreasing	Negative_regulation
29144435	778	782	MMP1	Gene
29144435	835	859	fibrotic-like rigidities	Disease
29144435	882	891	enhanced	Positive_regulation
29144435	891	902	activation	Positive_regulation
29144435	909	912	FAK	Gene
29144435	913	916	Akt	Gene
29144435	934	937	FAK	Gene
29144435	938	948	depletion	Negative_regulation
29144435	1050	1056	TGF-b1	Gene
29144435	1066	1075	positive	Gene_expression
29144435	1079	1085	COL1A1	Gene
29144435	1090	1099	negative	Gene_expression
29144435	1103	1107	MMP1	Gene
29144435	1125	1131	COL1A1	Gene
29144435	1132	1143	expression	Gene_expression
29144435	1143	1156	upregulation	Positive_regulation
29144435	1168	1174	TGF-b1	Gene
29144435	1238	1241	IPF	Disease
29144435	1313	1316	FAK	Species
29144435	1321	1324	Akt	Gene
29144435	1422	1428	TGF-b1	Gene
29144435	1484	1487	IPF	Disease
29144435	1521	1524	FAK	Gene
29144435	1525	1528	Akt	Gene
15857893|t|Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts
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 idiopathic pulmonary fibrosis (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	0	17	Hydrogen peroxide	Chemical
15857893	162	168	oxygen	Chemical
15857893	341	349	patients	Species
15857893	355	384	idiopathic pulmonary fibrosis	Disease
15857893	386	389	IPF	Disease
15857893	414	431	hydrogen peroxide	Chemical
15857893	433	437	H2O2	Chemical
15857893	484	516	transforming growth factor-beta1	Gene
15857893	518	527	TGF-beta1	Gene
15857893	543	552	TGF-beta1	Gene
15857893	660	664	H2O2	Chemical
15857893	666	669	IPF	Disease
15857893	712	721	TGF-beta1	Gene
15857893	964	968	H2O2	Chemical
15857893	983	986	IPF	Disease
15857893	1000	1003	IPF	Disease
15857893	1032	1040	express	Gene_expression
15857893	1133	1146	localization	Localization
15857893	1149	1153	H2O2	Chemical
15857893	1221	1231	secretion	Localization
15857893	1234	1238	H2O2	Chemical
15857893	1303	1313	secretion	Localization
15857893	1316	1320	H2O2	Chemical
28336812|t|TGF-b1 stimulates HDAC4 nucleus-to-cytoplasm translocation and NADPH oxidase 4-derived reactive oxygen species in normal human lung fibroblasts
Myofibroblasts are important mediators of fibrogenesis; thus blocking fibroblast-to-myofibroblast differentiation (FMD) may be an effective strategy to treat pulmonary fibrosis (PF)
Previously, we reported that histone deacetylase 4 (HDAC4) activity is necessary for transforming growth factor-b1 (TGF-b1)-induced human lung FMD
Here, we show that TGF-b1 increases NADPH oxidase 4 (NOX4) mRNA and protein expression in normal human lung fibroblasts (NHLFs) and causes nuclear export of HDAC4
Application of the NOX family inhibitor diphenyleneiodonium chloride reduces TGF-b1-induced HDAC4 nuclear export, expression of the myofibroblast marker a-smooth muscle actin (a-SMA), and a-SMA fiber formation
Inhibition of HDAC4 nucleus-to-cytoplasm translocation using leptomycin B (LMB) had little effect on a-SMA expression but blocked a-SMA fiber formation
A coimmunoprecipitation assay showed that HDAC4 associates with a-SMA
Moreover, LMB abolishes TGF-b1-induced a-SMA fiber formation and cell contraction
Relevant to human pulmonary fibrosis, idiopathic PF specimens showed significantly higher NOX4 RNA expression and scant HDAC4 staining within nuclei of fibroblast foci myofibroblasts
Taken together, these results indicate that reactive oxygen species promote TGF-b1-mediated myofibroblast differentiation and HDAC4 nuclear export
The physical association of HDAC4 with a-SMA suggests that HDAC4 has a role in regulating the a-SMA cytoskeleton arrangement
28336812	0	6	TGF-b1	Gene
28336812	7	18	stimulates	Positive_regulation
28336812	18	23	HDAC4	Gene
28336812	24	45	nucleus-to-cytoplasm	Entity
28336812	45	59	translocation	Localization
28336812	63	78	NADPH oxidase 4	Gene
28336812	96	102	oxygen	Chemical
28336812	121	126	human	Species
28336812	357	378	histone deacetylase 4	Gene
28336812	380	385	HDAC4	Gene
28336812	399	409	necessary	Positive_regulation
28336812	413	442	transforming growth factor-b1	Gene
28336812	444	450	TGF-b1	Gene
28336812	460	465	human	Species
28336812	495	501	TGF-b1	Gene
28336812	502	512	increases	Positive_regulation
28336812	512	527	NADPH oxidase 4	Gene
28336812	529	533	NOX4	Gene
28336812	552	563	expression	Transcription
28336812	573	578	human	Species
28336812	615	623	nuclear	Entity
28336812	623	630	export	Localization
28336812	633	638	HDAC4	Gene
28336812	670	680	inhibitor	Negative_regulation
28336812	680	708	diphenyleneiodonium chloride	Chemical
28336812	709	717	reduces	Negative_regulation
28336812	717	723	TGF-b1	Gene
28336812	724	732	induced	Positive_regulation
28336812	732	737	HDAC4	Gene
28336812	746	753	export	Localization
28336812	754	765	expression	Gene_expression
28336812	816	821	a-SMA	Gene
28336812	828	833	a-SMA	Gene
28336812	851	862	Inhibition	Negative_regulation
28336812	865	870	HDAC4	Gene
28336812	912	924	leptomycin B	Chemical
28336812	926	929	LMB	Chemical
28336812	952	957	a-SMA	Gene
28336812	981	986	a-SMA	Gene
28336812	1046	1051	HDAC4	Gene
28336812	1052	1063	associates	Binding
28336812	1068	1073	a-SMA	Gene
28336812	1085	1088	LMB	Chemical
28336812	1099	1105	TGF-b1	Gene
28336812	1114	1119	a-SMA	Gene
28336812	1170	1175	human	Species
28336812	1241	1248	higher	Positive_regulation
28336812	1248	1252	NOX4	Gene
28336812	1257	1268	expression	Gene_expression
28336812	1278	1283	HDAC4	Gene
28336812	1395	1401	oxygen	Chemical
28336812	1418	1424	TGF-b1	Gene
28336812	1468	1473	HDAC4	Gene
28336812	1503	1515	association	Binding
28336812	1518	1523	HDAC4	Gene
28336812	1529	1534	a-SMA	Gene
28336812	1549	1554	HDAC4	Gene
28336812	1584	1589	a-SMA	Gene
19460787|t|Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis
Leukotrienes play an important role in IPF, and leukotriene (LT)B(4) is one of the key eicosanoids in IPF
In this study, we investigated whether ONO-4057, a LTB(4) receptor (BLTR) antagonist is capable of preventing bleomycin-induced pulmonary fibrosis
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 LTB(4), 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 pulmonary fibrosis in mice by decreasing inflammation and altering TGF-beta, IL-6, IL-13 and IFN-gamma
19460787	0	8	Effects	Regulation
19460787	51	60	bleomycin	Chemical
19460787	69	87	pulmonary fibrosis	Disease
19460787	89	118	Idiopathic pulmonary fibrosis	Disease
19460787	120	123	IPF	Disease
19460787	210	213	IPF	Disease
19460787	219	230	leukotriene	Chemical
19460787	258	269	eicosanoids	Chemical
19460787	273	276	IPF	Disease
19460787	317	325	ONO-4057	Chemical
19460787	329	344	LTB(4) receptor	Gene
19460787	346	350	BLTR	Gene
19460787	388	397	bleomycin	Chemical
19460787	406	424	pulmonary fibrosis	Disease
19460787	449	453	mice	Species
19460787	501	510	bleomycin	Chemical
19460787	534	542	ONO-4057	Chemical
19460787	665	674	bleomycin	Chemical
19460787	686	694	ONO-4057	Chemical
19460787	820	834	hydroxyproline	Chemical
19460787	874	892	interleukin (IL)-6	Gene
19460787	894	899	IL-13	Gene
19460787	962	970	TGF-beta	Gene
19460787	971	982	expression	Gene_expression
19460787	1036	1046	decreased	Negative_regulation
19460787	1064	1086	interferon (IFN)-gamma	Gene
19460787	1105	1115	increased	Positive_regulation
19460787	1171	1175	BLTR	Gene
19460787	1216	1225	bleomycin	Chemical
19460787	1234	1252	pulmonary fibrosis	Disease
19460787	1256	1260	mice	Species
19460787	1292	1301	altering	Positive_regulation
19460787	1301	1309	TGF-beta	Gene
19460787	1311	1315	IL-6	Gene
19460787	1317	1322	IL-13	Gene
19460787	1327	1336	IFN-gamma	Gene
26600305|t|Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion
Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices
Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (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 pulmonary fibrosis
The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis
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	114	132	pulmonary fibrosis	Disease
26600305	263	271	patients	Species
26600305	277	306	idiopathic pulmonary fibrosis	Disease
26600305	308	311	IPF	Disease
26600305	516	527	lung injury	Disease
26600305	578	587	bleomycin	Chemical
26600305	599	603	mice	Species
26600305	607	615	patients	Species
26600305	621	624	IPF	Disease
26600305	869	880	lung injury	Disease
26600305	934	943	bleomycin	Chemical
26600305	999	1010	lung injury	Disease
26600305	1039	1048	migration	Disease
26600305	1205	1215	knockdown	Negative_regulation
26600305	1310	1331	lysophosphatidic acid	Chemical
26600305	1335	1367	epidermal growth factor receptor	Gene
26600305	1373	1408	fibroblast growth factor receptor 2	Gene
26600305	1503	1512	bleomycin	Chemical
26600305	1521	1525	mice	Species
26600305	1601	1619	pulmonary fibrosis	Disease
26600305	1750	1768	pulmonary fibrosis	Disease
26600305	1948	1951	IPF	Disease
26600305	1962	1984	fibrotic lung diseases	Disease
27215343|t|Raised serum levels of IGFBP-1 and IGFBP-2 in idiopathic pulmonary fibrosis
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 idiopathic pulmonary fibrosis 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 IGFBP-1 and IGFBP-2 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
IGFBP-2 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 IGFBP-1 and -2 are increased in idiopathic pulmonary fibrosis and IGFBP-2 may be reduced by anti-fibrosing therapy
IGFBPs may be promising biomarkers in IPF
27215343	23	30	IGFBP-1	Gene
27215343	35	42	IGFBP-2	Gene
27215343	46	75	idiopathic pulmonary fibrosis	Disease
27215343	89	118	Idiopathic pulmonary fibrosis	Disease
27215343	120	123	IPF	Disease
27215343	130	151	chronic lung disorder	Disease
27215343	197	202	death	Disease
27215343	408	416	patients	Species
27215343	422	425	IPF	Disease
27215343	470	473	IPF	Disease
27215343	481	484	IPF	Disease
27215343	581	610	idiopathic pulmonary fibrosis	Disease
27215343	684	689	TGF-b	Gene
27215343	694	698	KL-6	Gene
27215343	736	744	control	Regulation
27215343	747	750	IPF	Disease
27215343	777	784	IGFBP-1	Gene
27215343	789	796	IGFBP-2	Gene
27215343	801	805	KL-6	Gene
27215343	839	842	IPF	Disease
27215343	1070	1075	TGF-b	Gene
27215343	1077	1084	IGFBP-2	Gene
27215343	1103	1111	reduced	Negative_regulation
27215343	1118	1126	patients	Species
27215343	1163	1174	pirfenidone	Chemical
27215343	1179	1189	nintedanib	Chemical
27215343	1212	1220	patients	Species
27215343	1324	1338	IGFBP-1 and -2	Gene
27215343	1343	1353	increased	Positive_regulation
27215343	1356	1385	idiopathic pulmonary fibrosis	Disease
27215343	1390	1397	IGFBP-2	Gene
27215343	1405	1413	reduced	Negative_regulation
27215343	1478	1481	IPF	Disease
25446881|t|Sphingolipids in pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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 pulmonary fibrosis 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 pulmonary fibrosis 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 pulmonary fibrosis
Our results suggest that SphK1 and S1PL play critical roles in the pathology of lung fibrosis and may be novel therapeutic targets
25446881	17	35	pulmonary fibrosis	Disease
25446881	37	66	Idiopathic pulmonary fibrosis	Disease
25446881	68	71	IPF	Disease
25446881	250	273	sphingosine-1-phosphate	Chemical
25446881	275	278	S1P	Gene
25446881	381	384	IPF	Disease
25446881	385	393	patients	Species
25446881	415	433	pulmonary fibrosis	Disease
25446881	457	470	contribution	Gene_expression
25446881	473	476	S1P	Gene
25446881	478	488	regulated	Regulation
25446881	495	505	synthesis	Gene_expression
25446881	518	529	Sphingosine	Chemical
25446881	570	573	S1P	Gene
25446881	591	600	S1P lyase	Gene
25446881	602	606	S1PL	Gene
25446881	632	650	pulmonary fibrosis	Disease
25446881	724	732	patients	Species
25446881	738	741	IPF	Disease
25446881	746	751	SphK1	Gene
25446881	754	759	SphK2	Gene
25446881	764	768	S1PL	Gene
25446881	778	782	mice	Species
25446881	787	791	SphK	Gene
25446881	834	837	S1P	Gene
25446881	859	870	expression	Gene_expression
25446881	873	878	SphK1	Gene
25446881	936	944	patients	Species
25446881	950	953	IPF	Disease
25446881	968	980	expressions	Gene_expression
25446881	983	988	SphK1	Gene
25446881	993	997	S1PL	Gene
25446881	1003	1013	increased	Positive_regulation
25446881	1034	1042	patients	Species
25446881	1048	1051	IPF	Disease
25446881	1056	1065	bleomycin	Chemical
25446881	1077	1081	mice	Species
25446881	1091	1101	knockdown	Negative_regulation
25446881	1104	1109	SphK1	Gene
25446881	1119	1124	SphK2	Gene
25446881	1138	1147	bleomycin	Chemical
25446881	1156	1174	pulmonary fibrosis	Disease
25446881	1178	1182	mice	Species
25446881	1189	1198	deletion	Gene_expression
25446881	1201	1205	S1PL	Gene
25446881	1207	1212	SGPL1	Gene
25446881	1222	1226	mice	Species
25446881	1239	1247	fibrosis	Disease
25446881	1253	1262	bleomycin	Chemical
25446881	1274	1279	TGF-b	Gene
25446881	1280	1290	increased	Positive_regulation
25446881	1294	1305	expression	Gene_expression
25446881	1308	1313	SphK1	Gene
25446881	1318	1322	S1PL	Gene
25446881	1326	1331	human	Species
25446881	1353	1363	knockdown	Negative_regulation
25446881	1366	1371	SphK1	Gene
25446881	1390	1394	SphK	Gene
25446881	1395	1405	inhibitor	Negative_regulation
25446881	1416	1419	S1P	Gene
25446881	1420	1431	generation	Gene_expression
25446881	1435	1440	TGF-b	Gene
25446881	1490	1494	S1PL	Gene
25446881	1506	1515	bleomycin	Chemical
25446881	1506	1524	bleomycin-induced	Positive_regulation
25446881	1524	1529	TGF-b	Gene
25446881	1530	1540	secretion	Localization
25446881	1544	1547	S1P	Gene
25446881	1576	1581	human	Species
25446881	1650	1655	SphK1	Gene
25446881	1678	1687	bleomycin	Chemical
25446881	1706	1715	bleomycin	Chemical
25446881	1738	1756	pulmonary fibrosis	Disease
25446881	1783	1788	SphK1	Gene
25446881	1793	1797	S1PL	Gene
25446881	1825	1851	pathology of lung fibrosis	Disease
20566741|t|Inhibition of NF-kappaB signaling reduces virus load and gammaherpesvirus-induced pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 (IFN)gammaR(-/-) 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 pulmonary fibrosis
20566741	82	100	pulmonary fibrosis	Disease
20566741	102	131	Idiopathic pulmonary fibrosis	Disease
20566741	133	136	IPF	Disease
20566741	143	176	chronic progressive lung disorder	Disease
20566741	255	274	pulmonary infection	Disease
20566741	298	301	IPF	Disease
20566741	352	357	mouse	Species
20566741	401	405	mice	Species
20566741	433	459	murine gammaherpesvirus 68	Species
20566741	481	489	fibrosis	Disease
20566741	567	575	fibrosis	Disease
20566741	712	716	mice	Species
20566741	892	909	chronic infection	Disease
20566741	959	963	mice	Species
20566741	1012	1016	mice	Species
20566741	1072	1076	mice	Species
20566741	1118	1128	vasculitis	Disease
20566741	1133	1141	fibrosis	Disease
20566741	1162	1171	infection	Disease
20566741	1173	1184	Inhibition	Negative_regulation
20566741	1234	1245	diminished	Negative_regulation
20566741	1249	1260	expression	Gene_expression
20566741	1299	1333	monocyte chemoattractant protein 1	Gene
20566741	1335	1340	MCP-1	Gene
20566741	1346	1352	CXCL12	Gene
20566741	1440	1449	increase	Positive_regulation
20566741	1449	1460	expression	Gene_expression
20566741	1516	1527	activation	Positive_regulation
20566741	1553	1561	TGF-beta	Gene
20566741	1573	1584	inhibition	Negative_regulation
20566741	1652	1656	mice	Species
20566741	1830	1848	pulmonary fibrosis	Disease
26971883|t|Sustained PI3K Activation exacerbates BLM-induced Lung Fibrosis via activation of pro-inflammatory and pro-fibrotic pathways
Idiopathic pulmonary fibrosis (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 PI3K/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained PI3K 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 (PTEN(MyKO)), 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 PTEN(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 PTEN(MyKO) 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	10	14	PI3K	Gene
26971883	55	63	Fibrosis	Disease
26971883	126	155	Idiopathic pulmonary fibrosis	Disease
26971883	157	160	IPF	Disease
26971883	410	414	PI3K	Gene
26971883	415	419	PTEN	Gene
26971883	519	523	PI3K	Gene
26971883	563	581	genetic deficiency	Disease
26971883	600	604	PTEN	Gene
26971883	615	618	IPF	Disease
26971883	625	631	murine	Species
26971883	641	650	bleomycin	Chemical
26971883	659	677	pulmonary fibrosis	Disease
26971883	708	712	PTEN	Gene
26971883	713	723	deficient	Negative_regulation
26971883	723	727	mice	Species
26971883	729	733	PTEN	Gene
26971883	785	791	TGF-b1	Gene
26971883	841	846	lysyl	Chemical
26971883	1053	1057	PTEN	Gene
26971883	1064	1068	mice	Species
26971883	1135	1144	bleomycin	Chemical
26971883	1160	1189	impaired recruitment function	Disease
26971883	1215	1228	dysregulated	Regulation
26971883	1263	1272	elevated	Positive_regulation
26971883	1272	1283	expression	Gene_expression
26971883	1334	1339	TNF-a	Gene
26971883	1343	1347	PTEN	Gene
26971883	1354	1358	mice	Species
26971883	1585	1593	fibrosis	Disease
29195901|t|Triptolide suppresses paraquat induced idiopathic pulmonary fibrosis by inhibiting TGFB1-dependent epithelial mesenchymal transition
Idiopathic pulmonary fibrosis (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 TGFB1 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	0	10	Triptolide	Chemical
29195901	22	30	paraquat	Chemical
29195901	39	68	idiopathic pulmonary fibrosis	Disease
29195901	83	88	TGFB1	Gene
29195901	134	163	Idiopathic pulmonary fibrosis	Disease
29195901	165	168	IPF	Disease
29195901	174	179	tumor	Disease
29195901	411	415	TGFb	Gene
29195901	462	479	multiple diseases	Disease
29195901	505	512	target	Regulation
29195901	512	517	TGFB1	Gene
29195901	560	570	triptolide	Chemical
29195901	572	575	TPL	Chemical
29195901	626	634	fibrosis	Disease
29195901	703	713	triptolide	Chemical
29195901	723	729	binds	Binding
29195901	732	736	TGFb	Gene
29195901	754	763	increase	Positive_regulation
29195901	763	773	E-cadherin	Gene
29195901	774	785	expression	Gene_expression
29195901	789	798	decrease	Negative_regulation
29195901	798	806	vimentin	Gene
29195901	807	818	expression	Gene_expression
29195901	839	842	TPL	Chemical
29195901	875	897	inhibits lung fibrosis	Disease
29195901	901	905	mice	Species
29195901	975	983	paraquat	Chemical
29195901	984	992	induced	Positive_regulation
29195901	992	995	TPL	Chemical
29195901	1027	1031	TGFb	Gene
23006535|t|N-acetylcysteine downregulation of lysyl oxidase activity alleviating bleomycin-induced pulmonary fibrosis in rats
BACKGROUND: Idiopathic pulmonary fibrosis (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 lysyl oxidase (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-b(1) (TGF-b(1)) and a-smooth muscle actin (a-SMA) expression in bleomycin (BLM)-induced pulmonary fibrosis 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-b(1) 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 pulmonary fibrosis and inhibited TGF-b(1) 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 pulmonary fibrosis
The TGF-b(1)/a-SMA pathway may also play an important role in modulation of LOX activity
23006535	0	16	N-acetylcysteine	Chemical
23006535	17	32	downregulation	Negative_regulation
23006535	35	48	lysyl oxidase	Gene
23006535	70	79	bleomycin	Chemical
23006535	88	106	pulmonary fibrosis	Disease
23006535	110	114	rats	Species
23006535	128	157	Idiopathic pulmonary fibrosis	Disease
23006535	159	162	IPF	Disease
23006535	191	203	lung disease	Disease
23006535	285	301	N-acetylcysteine	Chemical
23006535	303	306	NAC	Chemical
23006535	317	327	prednisone	Chemical
23006535	332	344	azathioprine	Chemical
23006535	388	391	IPF	Disease
23006535	392	400	patients	Species
23006535	523	534	glutathione	Chemical
23006535	536	539	GSH	Chemical
23006535	565	580	downregulation	Negative_regulation
23006535	583	596	lysyl oxidase	Gene
23006535	598	601	LOX	Gene
23006535	622	632	essential	Positive_regulation
23006535	645	656	deposition	Negative_regulation
23006535	718	721	NAC	Chemical
23006535	733	736	IPF	Chemical
23006535	740	751	regulating	Regulation
23006535	751	754	LOX	Gene
23006535	849	863	hydroxyproline	Chemical
23006535	873	876	LOX	Gene
23006535	887	890	GSH	Chemical
23006535	903	934	transforming growth factor-b(1)	Gene
23006535	936	944	TGF-b(1)	Gene
23006535	980	991	expression	Gene_expression
23006535	994	1003	bleomycin	Chemical
23006535	1005	1008	BLM	Chemical
23006535	1018	1036	pulmonary fibrosis	Disease
23006535	1042	1045	rat	Species
23006535	1085	1088	NAC	Chemical
23006535	1103	1106	LOX	Gene
23006535	1126	1129	LOX	Gene
23006535	1143	1153	increased	Positive_regulation
23006535	1187	1190	BLM	Chemical
23006535	1213	1221	TGF-b(1)	Gene
23006535	1262	1265	NAC	Chemical
23006535	1308	1311	LOX	Gene
23006535	1342	1352	increased	Positive_regulation
23006535	1352	1355	GSH	Chemical
23006535	1378	1381	BLM	Chemical
23006535	1388	1392	rats	Species
23006535	1408	1411	NAC	Chemical
23006535	1422	1451	attenuated pulmonary fibrosis	Disease
23006535	1456	1466	inhibited	Negative_regulation
23006535	1466	1474	TGF-b(1)	Gene
23006535	1485	1496	expression	Gene_expression
23006535	1564	1567	NAC	Chemical
23006535	1580	1583	IPF	Disease
23006535	1587	1598	inhibition	Negative_regulation
23006535	1601	1604	LOX	Gene
23006535	1618	1628	elevation	Positive_regulation
23006535	1636	1639	GSH	Chemical
23006535	1643	1646	BLM	Chemical
23006535	1655	1673	pulmonary fibrosis	Disease
23006535	1679	1687	TGF-b(1)	Gene
23006535	1751	1754	LOX	Gene
19117745|t|Cytokine gene polymorphisms and BALF cytokine levels in interstitial lung diseases
BACKGROUND: The aim of our study is to investigate correlations of T(H)1/T(H)2 cytokine gene polymorphisms and bronchoalveolar lavage fluid (BALF) cytokine values in interstitial lung diseases (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(+1902)AA and IL-10(-1082)G allele correlated with higher BALF ENA-78 levels (p=0.0258, p=0.0230)
In the HP group the IL-6(-174)CG and IL-6(nt565)AG 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	56	82	interstitial lung diseases	Disease
19117745	250	276	interstitial lung diseases	Disease
19117745	278	281	ILD	Disease
19117745	299	310	sarcoidosis	Disease
19117745	314	343	idiopathic pulmonary fibrosis	Disease
19117745	345	348	IPF	Disease
19117745	356	384	hypersensitivity pneumonitis	Disease
19117745	386	388	HP	Disease
19117745	390	398	patients	Species
19117745	412	461	IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10	Gene
19117745	468	477	IFN-gamma	Gene
19117745	479	488	TGF-beta1	Gene
19117745	493	502	TNF-alpha	Gene
19117745	547	552	MCP-1	Gene
19117745	553	564	MIP-1 alpha	Gene
19117745	566	576	MIP-1 beta	Gene
19117745	578	584	RANTES	Gene
19117745	586	592	ENA-78	Gene
19117745	599	604	G-CSF	Gene
19117745	606	612	GM-CSF	Gene
19117745	614	623	IFN-gamma	Gene
19117745	625	635	IL-1 alpha	Gene
19117745	637	643	IL-1RA	Gene
19117745	645	684	IL-1 beta, -2, -4, -5, -6, -8, -10, -17	Gene
19117745	686	695	TNF-alpha	Gene
19117745	697	700	Tpo	Gene
19117745	751	760	TNF-alpha	Gene
19117745	771	776	IL-1R	Gene
19117745	844	855	sarcoidosis	Disease
19117745	862	873	IL-4R alpha	Gene
19117745	887	892	IL-10	Gene
19117745	936	942	ENA-78	Gene
19117745	979	981	HP	Disease
19117745	992	996	IL-6	Gene
19117745	1009	1013	IL-6	Gene
19117745	1046	1052	ENA-78	Gene
19117745	1084	1087	IPF	Disease
19117745	1098	1107	IL-1 beta	Gene
19117745	1139	1145	IL-1RA	Gene
19117745	1214	1217	ILD	Disease
19117745	1240	1244	IL-8	Gene
19117745	1276	1287	sarcoidosis	Disease
19117745	1288	1296	patients	Species
19117745	1358	1368	influence	Regulation
19117745	1398	1409	IL-4R alpha	Gene
19117745	1414	1419	IL-10	Gene
19117745	1423	1429	ENA-78	Gene
19117745	1435	1442	levels	Gene_expression
19117745	1445	1456	sarcoidosis	Disease
19117745	1458	1462	IL-6	Gene
19117745	1466	1472	ENA-78	Gene
19117745	1478	1485	levels	Gene_expression
19117745	1488	1490	HP	Disease
19117745	1495	1504	IL-1-beta	Gene
19117745	1508	1514	IL-1RA	Gene
19117745	1520	1527	values	Regulation
19117745	1534	1537	IPF	Disease
19117745	1549	1558	TNF-alpha	Gene
19117745	1587	1592	IL-1R	Gene
25842923|t|[The morphology and molecular bases of damage to the stem cell niche of respiratory acini in idiopathic interstitial pneumonias]
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 idiopathic interstitial pneumonias (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	93	127	idiopathic interstitial pneumonias	Disease
25842923	389	423	idiopathic interstitial pneumonias	Disease
25842923	425	428	IIP	Disease
25842923	441	470	idiopathic pulmonary fibrosis	Disease
25842923	472	475	IPF	Disease
25842923	478	513	desquamative interstitial pneumonia	Disease
25842923	515	518	DIP	Disease
25842923	521	553	cryptogenic organizing pneumonia	Disease
25842923	555	558	COP	Disease
25842923	565	589	bronchiolitis obliterans	Disease
25842923	591	593	BO	Disease
25842923	600	634	nonspecific interstitial pneumonia	Disease
25842923	636	640	NSIP	Disease
25842923	771	779	patients	Species
25842923	802	805	IPF	Disease
25842923	821	825	NSIP	Disease
25842923	841	844	DIP	Disease
25842923	859	862	COP	Disease
25842923	865	867	BO	Disease
25842923	917	928	hematoxylin	Chemical
25842923	933	938	eosin	Chemical
25842923	956	968	picrofuchsin	Chemical
25842923	1030	1035	MMP-1	Gene
25842923	1037	1042	MMP-2	Gene
25842923	1044	1049	MMP-7	Gene
25842923	1082	1090	vimentin	Gene
25842923	1092	1100	Vimentin	Gene
25842923	1123	1126	SMA	Gene
25842923	1149	1154	TGF-b	Gene
25842923	1156	1161	TNF-a	Gene
25842923	1163	1167	CD34	Gene
25842923	1169	1174	Ost-4	Gene
25842923	1180	1185	CD117	Gene
25842923	1202	1206	CD68	Gene
25842923	1212	1215	EMA	Disease
25842923	1307	1311	LSAB	Chemical
25842923	1314	1317	KIT	Chemical
25842923	1600	1614	aggressiveness	Disease
25842923	1872	1877	Oct-4	Gene
25842923	1879	1887	Vimentin	Gene
25842923	1889	1892	SMA	Gene
25842923	1894	1899	CD117	Gene
25842923	1905	1909	CD34	Gene
25842923	1910	1921	expression	Gene_expression
25842923	1983	1993	SCN damage	Disease
22923663|t|Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-b
RATIONALE: Idiopathic pulmonary fibrosis (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	0	11	Lactic acid	Chemical
22923663	27	56	idiopathic pulmonary fibrosis	Disease
22923663	171	200	Idiopathic pulmonary fibrosis	Disease
22923663	202	205	IPF	Disease
22923663	306	317	lactic acid	Chemical
22923663	373	381	patients	Species
22923663	387	390	IPF	Disease
22923663	438	449	lactic acid	Chemical
22923663	487	505	pulmonary fibrosis	Disease
22923663	596	604	patients	Species
22923663	610	613	IPF	Disease
22923663	644	655	lactic acid	Chemical
22923663	660	667	lactate	Chemical
22923663	830	841	Lactic acid	Chemical
22923663	874	877	IPF	Disease
22923663	992	1003	expression	Gene_expression
22923663	1058	1069	Lactic acid	Chemical
22923663	1098	1107	elevated	Positive_regulation
22923663	1110	1113	IPF	Disease
22923663	1180	1191	lactic acid	Chemical
22923663	1234	1245	activation	Positive_regulation
22923663	1248	1253	TGF-b	Gene
22923663	1255	1260	TGF-b	Gene
22923663	1261	1269	induced	Positive_regulation
22923663	1269	1280	expression	Gene_expression
22923663	1292	1319	hypoxia-inducible factor 1a	Gene
22923663	1321	1326	HIF1a	Gene
22923663	1342	1357	overexpression	Positive_regulation
22923663	1365	1370	HIF1a	Gene
22923663	1383	1388	human	Species
22923663	1473	1478	TGF-b	Gene
22923663	1519	1530	inhibition	Negative_regulation
22923663	1538	1543	HIF1a	Gene
22923663	1563	1568	TGF-b	Gene
22923663	1655	1666	lactic acid	Chemical
22923663	1744	1755	activation	Positive_regulation
22923663	1758	1763	TGF-b	Gene
22923663	1963	1981	fibrotic disorders	Disease
11463599|t|Differential mRNA expression of insulin-like growth factor-1 splice variants in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis
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, idiopathic pulmonary fibrosis (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	32	60	insulin-like growth factor-1	Gene
11463599	80	88	patients	Species
11463599	94	123	idiopathic pulmonary fibrosis	Disease
11463599	128	149	pulmonary sarcoidosis	Disease
11463599	151	179	Insulin-like growth factor-1	Gene
11463599	181	186	IGF-1	Gene
11463599	236	241	human	Species
11463599	324	335	expression	Gene_expression
11463599	343	348	IGF-1	Gene
11463599	435	464	idiopathic pulmonary fibrosis	Disease
11463599	466	469	IPF	Disease
11463599	487	495	fibrosis	Disease
11463599	526	534	fibrosis	Disease
11463599	536	557	pulmonary sarcoidosis	Disease
11463599	558	566	patients	Species
11463599	616	619	IPF	Disease
11463599	761	766	IGF-1	Gene
11463599	767	778	expression	Gene_expression
11463599	782	796	downregulated	Negative_regulation
11463599	812	820	patients	Species
11463599	826	829	IPF	Disease
11463599	845	853	patients	Species
11463599	859	870	sarcoidosis	Disease
11463599	1005	1013	induced	Positive_regulation
11463599	1024	1029	IGF-1	Gene
11463599	1030	1041	expression	Gene_expression
11463599	1148	1159	expression	Gene_expression
11463599	1162	1167	IGF-1	Gene
11463599	1206	1217	sarcoidosis	Disease
11463599	1218	1226	patients	Species
11463599	1235	1243	fibrosis	Disease
11463599	1259	1270	expression	Gene_expression
11463599	1319	1327	patients	Species
11463599	1333	1341	fibrosis	Disease
11463599	1448	1456	fibrosis	Disease
11463599	1457	1465	patients	Species
11463599	1511	1522	sarcoidosis	Disease
11463599	1523	1531	patients	Species
11463599	1537	1545	fibrosis	Disease
11463599	1554	1562	express	Gene_expression
11463599	1575	1580	IGF-1	Gene
11463599	1762	1772	expressed	Gene_expression
11463599	1844	1854	increased	Positive_regulation
11463599	2019	2024	IGF-1	Gene
11463599	2102	2107	IGF-1	Gene
23031257|t|The hedgehog system machinery controls transforming growth factor-b-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	113	119	humans	Species
23031257	136	165	idiopathic pulmonary fibrosis	Disease
23031257	167	196	Idiopathic pulmonary fibrosis	Disease
23031257	198	201	IPF	Disease
23031257	311	314	IPF	Disease
23031257	444	455	expression	Gene_expression
23031257	525	528	IPF	Disease
23031257	529	534	human	Species
23031257	794	797	IPF	Disease
23031257	871	876	TGF-b	Gene
23031257	888	893	human	Species
23031257	912	918	TGF-b1	Gene
23031257	933	944	expression	Gene_expression
23031257	1090	1096	TGF-b1	Gene
23031257	1184	1187	IPF	Disease
23031257	1402	1408	TGF-b1	Gene
23031257	1431	1434	IPF	Disease
23031257	1578	1586	fibrosis	Disease
25743626|t|Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis
IPF is a progressive lung disorder characterized by fibroblast proliferation and myofibroblast differentiation
Although neutrophil accumulation within IPF lungs has been negatively correlated with outcomes, the role played by neutrophils in lung fibrosis remains poorly understood
We have demonstrated previously that NE promotes lung cancer cell proliferation and hypothesized that it may have a similar effect on fibroblasts
In the current study, we show that NE(-/-) mice are protected from asbestos-induced lung fibrosis
NE(-/-) mice displayed reduced fibroblast and myofibroblast content when compared with controls
NE directly both lung fibroblast proliferation and myofibroblast differentiation in vitro, as evidenced by proliferation assays, collagen gel contractility assays, and aSMA induction
Furthermore, aSMA induction occurs in a TGF-b-independent fashion
Treatment of asbestos-recipient mice with ONO-5046, a synthetic NE antagonist, reduced hydroxyproline content
Thus, the current study points to a key role for neutrophils and NE in the progression of lung fibrosis
Lastly, the study lends rationale to use of NE-inhibitory approaches as a novel therapeutic strategy for patients with lung fibrosis
25743626	0	19	Neutrophil elastase	Gene
25743626	43	75	differentiation in lung fibrosis	Disease
25743626	550	554	mice	Species
25743626	614	618	mice	Species
25743626	871	875	aSMA	Gene
25743626	900	904	aSMA	Gene
25743626	927	932	TGF-b	Gene
25743626	986	990	mice	Species
25743626	1275	1283	patients	Species
27937011|t|Effects and mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models
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 pulmonary fibrosis (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 pulmonary fibrosis in rat IPF models, which may be related with enhanced caveolin-1, reduced TNF-a, TGF-b1, PDGF
27937011	26	37	pirfenidone	Chemical
27937011	39	49	prednisone	Chemical
27937011	54	68	acetylcysteine	Chemical
27937011	72	90	pulmonary fibrosis	Disease
27937011	94	97	rat	Species
27937011	98	127	idiopathic pulmonary fibrosis	Disease
27937011	181	191	caveolin-1	Gene
27937011	193	196	Cav	Species
27937011	203	214	associated	Binding
27937011	219	232	lung fibrosis	Disease
27937011	255	258	Cav	Species
27937011	261	272	expression	Gene_expression
27937011	275	286	pirfenidone	Chemical
27937011	295	324	idiopathic pulmonary fibrosis	Disease
27937011	326	329	IPF	Disease
27937011	378	381	Cav	Species
27937011	384	395	expression	Gene_expression
27937011	398	409	pirfenidone	Chemical
27937011	418	421	IPF	Disease
27937011	451	462	pirfenidone	Chemical
27937011	468	482	acetylcysteine	Chemical
27937011	487	497	prednisone	Chemical
27937011	501	504	IPF	Disease
27937011	529	532	Rat	Species
27937011	533	536	IPF	Disease
27937011	598	610	bleomycin A5	Chemical
27937011	655	659	rats	Species
27937011	661	672	Pirfenidone	Chemical
27937011	702	712	prednisone	Chemical
27937011	714	715	H	Chemical
27937011	743	757	acetylcysteine	Chemical
27937011	759	760	N	Chemical
27937011	812	815	rat	Species
27937011	903	907	rats	Species
27937011	916	919	IPF	Disease
27937011	1029	1040	expression	Gene_expression
27937011	1043	1046	Cav	Species
27937011	1119	1130	expression	Gene_expression
27937011	1133	1139	tumour	Disease
27937011	1140	1148	necrosis	Disease
27937011	1159	1164	TNF-a	Gene
27937011	1198	1204	TGF-b1	Gene
27937011	1495	1503	fibrosis	Disease
27937011	1539	1550	expression	Gene_expression
27937011	1553	1559	TGF-b1	Gene
27937011	1561	1566	TNF-a	Gene
27937011	1585	1596	expression	Gene_expression
27937011	1599	1602	Cav	Species
27937011	1650	1651	N	Chemical
27937011	1663	1671	fibrosis	Disease
27937011	1718	1729	expression	Gene_expression
27937011	1732	1735	Cav	Species
27937011	1812	1823	expression	Gene_expression
27937011	1826	1829	Cav	Species
27937011	1885	1893	fibrosis	Disease
27937011	1973	1984	expression	Gene_expression
27937011	1987	1993	TGF-b1	Gene
27937011	1995	2000	TNF-a	Gene
27937011	2129	2140	Pirfenidone	Chemical
27937011	2142	2152	prednisone	Chemical
27937011	2157	2171	acetylcysteine	Chemical
27937011	2202	2220	pulmonary fibrosis	Disease
27937011	2224	2227	rat	Species
27937011	2228	2231	IPF	Disease
27937011	2266	2275	enhanced	Positive_regulation
27937011	2275	2285	caveolin-1	Gene
27937011	2287	2295	reduced	Negative_regulation
27937011	2295	2300	TNF-a	Gene
27937011	2302	2308	TGF-b1	Gene
25660181|t|Sustained Activation of Toll-Like Receptor 9 Induces an Invasive Phenotype in Lung Fibroblasts: Possible Implications in Idiopathic Pulmonary Fibrosis
UNASSIGNED: Idiopathic pulmonary fibrosis (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	24	44	Toll-Like Receptor 9	Gene
25660181	121	150	Idiopathic Pulmonary Fibrosis	Disease
25660181	164	193	Idiopathic pulmonary fibrosis	Disease
25660181	195	198	IPF	Disease
25660181	246	261	lung parenchyma	Disease
25660181	325	344	respiratory failure	Disease
25660181	368	371	IPF	Disease
25660181	405	413	patients	Species
25660181	523	544	loss of lung function	Disease
25660181	546	562	Viral infections	Disease
25660181	587	590	IPF	Disease
25660181	717	725	patients	Species
25660181	794	805	expression	Gene_expression
25660181	843	863	Toll-like receptor 9	Gene
25660181	865	869	TLR9	Gene
25660181	886	890	TLR9	Gene
25660181	912	915	IPF	Disease
25660181	919	923	mice	Species
25660181	1002	1006	TLR9	Gene
25660181	1007	1021	up-regulation	Positive_regulation
25660181	1040	1048	fibrosis	Disease
25660181	1163	1166	IPF	Disease
25660181	1181	1191	regulates	Regulation
25660181	1191	1195	TLR9	Gene
25660181	1235	1245	induction	Positive_regulation
25660181	1248	1252	TLR9	Gene
25660181	1253	1264	expression	Gene_expression
25660181	1267	1272	TGF-b	Gene
25660181	1378	1382	TLR9	Gene
25660181	1392	1395	CpG	Chemical
25660181	1409	1413	TLR9	Gene
25660181	1538	1613	matrix metalloproteinase-14(+)/matrix metalloproteinase-2(+) myofibroblasts	Gene
25660181	1621	1629	secrete	Localization
25660181	1719	1726	hypoxia	Disease
25660181	1789	1794	TGF-b	Gene
25660181	1799	1803	TLR9	Gene
25660181	1874	1877	IPF	Disease
21253589|t|PPAR-y ligands repress TGFb-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis
Transforming growth factor beta (TGFb) induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis
Although the typical TGFb signaling pathway involves the Smad family of transcription factors, we have previously reported that peroxisome proliferator-activated receptor-y (PPAR-y) ligands inhibit TGFb-mediated differentiation of human lung fibroblasts to myofibroblasts via a Smad-independent pathway
TGFb also activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway leading to phosphorylation of Akt(S473)
Here, we report that PPAR-y ligands, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-(12,14)-15d-prostaglandin J(2) (15d-PGJ(2)), inhibit human myofibroblast differentiation of normal and idiopathic pulmonary fibrotic (IPF) fibroblasts, by blocking Akt phosphorylation at Ser473 by a PPAR-y-independent mechanism
The PI3K inhibitor LY294002 and a dominant-negative inactive kinase-domain mutant of Akt both inhibited TGFb-stimulated myofibroblast differentiation, as determined by Western blotting for a-smooth muscle actin and calponin
Prostaglandin A(1) (PGA(1)), a structural analogue of 15d-PGJ(2) with an electrophilic center, also reduced TGFb-driven phosphorylation of Akt, while CAY10410, another analogue that lacks an electrophilic center, did not; implying that the activity of 15d-PGJ(2) and CDDO is dependent on their electrophilic properties
PPAR-y ligands inhibited TGFb-induced Akt phosphorylation via both post-translational and post-transcriptional mechanisms
This inhibition is independent of MAPK-p38 and PTEN but is dependent on TGFb-induced phosphorylation of FAK, a kinase that acts upstream of Akt
Thus, PPAR-y ligands inhibit TGFb signaling by affecting two pro-survival pathways that culminate in myofibroblast differentiation
Further studies of PPAR-y ligands and small electrophilic molecules may lead to a new generation of anti-fibrotic therapeutics
21253589	0	4	PPAR	Gene
21253589	23	27	TGFb	Gene
21253589	83	87	PI3K	Gene
21253589	88	91	Akt	Gene
21253589	129	137	fibrosis	Disease
21253589	139	170	Transforming growth factor beta	Gene
21253589	172	176	TGFb	Gene
21253589	205	210	human	Species
21253589	284	302	pulmonary fibrosis	Disease
21253589	325	329	TGFb	Gene
21253589	432	476	peroxisome proliferator-activated receptor-y	Gene
21253589	478	482	PPAR	Gene
21253589	502	506	TGFb	Gene
21253589	535	540	human	Species
21253589	608	612	TGFb	Gene
21253589	618	628	activates	Positive_regulation
21253589	632	652	phosphatidylinositol	Chemical
21253589	662	678	protein kinase B	Gene
21253589	680	684	PI3K	Gene
21253589	685	688	Akt	Gene
21253589	698	706	leading	Positive_regulation
21253589	709	725	phosphorylation	Phosphorylation
21253589	728	731	Akt	Gene
21253589	760	764	PPAR	Gene
21253589	776	821	2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid	Chemical
21253589	823	827	CDDO	Chemical
21253589	833	872	15-deoxy-(12,14)-15d-prostaglandin J(2)	Chemical
21253589	874	884	15d-PGJ(2)	Chemical
21253589	895	900	human	Species
21253589	945	974	idiopathic pulmonary fibrotic	Disease
21253589	976	979	IPF	Disease
21253589	997	1006	blocking	Negative_regulation
21253589	1006	1009	Akt	Gene
21253589	1010	1026	phosphorylation	Phosphorylation
21253589	1041	1045	PPAR	Gene
21253589	1075	1079	PI3K	Gene
21253589	1080	1090	inhibitor	Negative_regulation
21253589	1090	1098	LY294002	Chemical
21253589	1156	1159	Akt	Gene
21253589	1175	1179	TGFb	Gene
21253589	1296	1314	Prostaglandin A(1)	Gene
21253589	1316	1322	PGA(1)	Gene
21253589	1350	1360	15d-PGJ(2)	Chemical
21253589	1396	1404	reduced	Negative_regulation
21253589	1404	1408	TGFb	Gene
21253589	1416	1432	phosphorylation	Phosphorylation
21253589	1435	1438	Akt	Gene
21253589	1446	1454	CAY10410	Chemical
21253589	1548	1558	15d-PGJ(2)	Chemical
21253589	1563	1567	CDDO	Chemical
21253589	1616	1620	PPAR	Gene
21253589	1631	1641	inhibited	Negative_regulation
21253589	1641	1645	TGFb	Gene
21253589	1646	1654	induced	Positive_regulation
21253589	1654	1657	Akt	Gene
21253589	1658	1674	phosphorylation	Phosphorylation
21253589	1786	1790	PTEN	Gene
21253589	1798	1808	dependent	Regulation
21253589	1811	1815	TGFb	Gene
21253589	1816	1824	induced	Positive_regulation
21253589	1824	1840	phosphorylation	Phosphorylation
21253589	1843	1846	FAK	Gene
21253589	1879	1882	Akt	Gene
21253589	1890	1894	PPAR	Gene
21253589	1905	1913	inhibit	Negative_regulation
21253589	1913	1917	TGFb	Gene
21253589	2035	2039	PPAR	Gene
26867691|t|WISP1 mediates IL-6-dependent proliferation in primary human lung fibroblasts
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease
IPF is characterized by epithelial cell injury and reprogramming, increases in (myo)fibroblasts, and altered deposition of extracellular matrix
The Wnt1-inducible signaling protein 1 (WISP1) is involved in impaired epithelial-mesenchymal crosstalk in pulmonary fibrosis
Here, we aimed to further investigate WISP1 regulation and function in primary human lung fibroblasts (phLFs)
We demonstrate that WISP1 is directly upregulated by Transforming growth factor b1 (TGFb1) and Tumor necrosis factor a (TNFa) in phLFs, using a luciferase-based reporter system
WISP1 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, WISP1 is required for TGFb1- and TNFa-dependent induction of interleukin 6 (IL-6), a mechanism that is conserved in IPF phLFs
The siRNA-mediated WISP1 knockdown led to a significant IL-6 reduction after TGFb1 or TNFa stimulation
Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of WISP1 reduced phLFs proliferation, a process that was in part rescued by IL-6
Taken together, these results strongly indicate that WISP1-induced IL-6 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	0	5	WISP1	Gene
26867691	15	19	IL-6	Gene
26867691	55	60	human	Species
26867691	79	108	Idiopathic pulmonary fibrosis	Disease
26867691	110	113	IPF	Disease
26867691	142	167	interstitial lung disease	Disease
26867691	169	172	IPF	Disease
26867691	318	352	Wnt1-inducible signaling protein 1	Gene
26867691	354	359	WISP1	Gene
26867691	376	417	impaired epithelial-mesenchymal crosstalk	Disease
26867691	421	439	pulmonary fibrosis	Disease
26867691	479	484	WISP1	Gene
26867691	485	496	regulation	Regulation
26867691	520	525	human	Species
26867691	572	577	WISP1	Gene
26867691	590	602	upregulated	Positive_regulation
26867691	605	634	Transforming growth factor b1	Gene
26867691	636	641	TGFb1	Gene
26867691	647	670	Tumor necrosis factor a	Gene
26867691	672	676	TNFa	Gene
26867691	730	735	WISP1	Gene
26867691	753	763	secretion	Localization
26867691	763	773	increased	Positive_regulation
26867691	822	827	TGFb1	Gene
26867691	832	836	TNFa	Gene
26867691	901	906	WISP1	Gene
26867691	910	919	required	Positive_regulation
26867691	923	928	TGFb1	Gene
26867691	934	938	TNFa	Gene
26867691	949	959	induction	Positive_regulation
26867691	962	975	interleukin 6	Gene
26867691	977	981	IL-6	Gene
26867691	1017	1020	IPF	Disease
26867691	1047	1052	WISP1	Gene
26867691	1053	1063	knockdown	Negative_regulation
26867691	1084	1088	IL-6	Gene
26867691	1089	1099	reduction	Negative_regulation
26867691	1105	1110	TGFb1	Gene
26867691	1114	1118	TNFa	Gene
26867691	1160	1175	downregulation	Negative_regulation
26867691	1214	1219	WISP1	Gene
26867691	1220	1228	reduced	Negative_regulation
26867691	1287	1291	IL-6	Gene
26867691	1346	1351	WISP1	Gene
26867691	1352	1360	induced	Positive_regulation
26867691	1360	1364	IL-6	Gene
26867691	1365	1376	expression	Gene_expression
26867691	1376	1388	contributes	Positive_regulation
26867691	1520	1525	TGFb1	Gene
26867691	1530	1534	TNFa	Gene
12243323|t|BALF N-acetylglucosaminidase and beta-galactosidase activities in idiopathic pulmonary fibrosis
The lysosomal enzymes N-acetylglucosaminidase (N-ACGA) and beta-galactosidase (beta-gal) are involved in cellular collagen metabolism and may, therefore, be markers of fibrosis in idiopathic interstitial pneumonias, such as idiopathic pulmonary fibrosis (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	33	51	beta-galactosidase	Gene
12243323	66	95	idiopathic pulmonary fibrosis	Disease
12243323	144	150	N-ACGA	Chemical
12243323	156	174	beta-galactosidase	Gene
12243323	176	184	beta-gal	Gene
12243323	265	273	fibrosis	Disease
12243323	277	311	idiopathic interstitial pneumonias	Disease
12243323	321	350	idiopathic pulmonary fibrosis	Disease
12243323	352	355	IPF	Disease
12243323	358	364	N-ACGA	Chemical
12243323	369	377	beta-gal	Gene
12243323	438	446	patients	Species
12243323	478	506	usual interstitial pneumonia	Disease
12243323	508	511	UIP	Disease
12243323	723	731	patients	Species
12243323	753	759	N-ACGA	Chemical
12243323	761	764	UIP	Disease
12243323	824	832	beta-gal	Gene
12243323	834	837	UIP	Disease
12243323	932	940	patients	Species
12243323	946	949	IPF	Disease
12243323	978	986	patients	Species
12243323	1058	1061	IPF	Disease
12243323	1128	1131	IPF	Disease
12243323	1209	1215	N-ACGA	Chemical
12243323	1278	1282	DLCO	Chemical
12243323	1467	1473	N-ACGA	Chemical
12243323	1531	1534	IPF	Disease
27878256|t|Melatonin attenuates TGFb1-induced epithelial-mesenchymal transition in lung alveolar epithelial cells
Idiopathic pulmonary fibrosis (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 TGFb1  -induced epithelial  -mesenchymal transition in the A549 cell line and may potentially be useful in the treatment of IPF
27878256	0	9	Melatonin	Chemical
27878256	21	26	TGFb1	Gene
27878256	104	133	Idiopathic pulmonary fibrosis	Disease
27878256	135	138	IPF	Disease
27878256	159	184	interstitial lung disease	Disease
27878256	244	253	Melatonin	Chemical
27878256	257	266	secreted	Localization
27878256	342	350	fibrosis	Disease
27878256	367	376	melatonin	Chemical
27878256	400	408	fibrosis	Disease
27878256	539	548	melatonin	Chemical
27878256	558	589	transforming growth factor  -b1	Gene
27878256	591	599	TGF  -b1	Gene
27878256	795	804	melatonin	Chemical
27878256	861	868	Smad2/3	Gene
27878256	961	970	melatonin	Chemical
27878256	1005	1014	melatonin	Chemical
27878256	1025	1030	TGFb1	Gene
27878256	1149	1152	IPF	Disease
21700912|t|Transglutaminase 2 and its role in pulmonary fibrosis
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a deadly progressive disease with few treatment options
Transglutaminase 2 (TG2) is a multifunctional protein, but its function in pulmonary fibrosis is unknown
OBJECTIVES: To determine the role of TG2 in pulmonary fibrosis
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 pulmonary fibrosis 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	0	18	Transglutaminase 2	Gene
21700912	35	53	pulmonary fibrosis	Disease
21700912	66	95	Idiopathic pulmonary fibrosis	Disease
21700912	97	100	IPF	Disease
21700912	162	180	Transglutaminase 2	Gene
21700912	182	185	TG2	Gene
21700912	237	255	pulmonary fibrosis	Disease
21700912	305	308	TG2	Gene
21700912	312	330	pulmonary fibrosis	Disease
21700912	366	375	bleomycin	Chemical
21700912	411	414	TG2	Gene
21700912	424	428	mice	Species
21700912	478	488	isopeptide	Chemical
21700912	494	505	expression	Gene_expression
21700912	521	529	formalin	Chemical
21700912	536	541	human	Species
21700912	592	600	patients	Species
21700912	606	609	IPF	Disease
21700912	632	637	human	Species
21700912	674	677	TG2	Gene
21700912	728	731	TG2	Gene
21700912	741	745	mice	Species
21700912	778	786	fibrosis	Disease
21700912	811	815	mice	Species
21700912	833	847	hydroxyproline	Chemical
21700912	871	879	fibrosis	Disease
21700912	898	901	TG2	Gene
21700912	902	913	expression	Gene_expression
21700912	930	940	increased	Positive_regulation
21700912	967	973	humans	Species
21700912	979	982	IPF	Disease
21700912	1031	1046	overexpression	Positive_regulation
21700912	1049	1052	TG2	Gene
21700912	1060	1070	increased	Positive_regulation
21700912	1119	1129	knockdown	Negative_regulation
21700912	1268	1271	TG2	Gene
21700912	1321	1324	TG2	Gene
21700912	1340	1358	pulmonary fibrosis	Disease
21700912	1364	1369	mouse	Species
21700912	1383	1388	human	Species
21700912	1472	1475	TG2	Gene
8680382|t|The role of cytokines in human lung fibrosis
Fibrosis is a disorder characterized by a qualitative and quantitative alteration of the deposition of extracellular matrix with accumulation of mesenchymal cells in replacement of normal tissue
The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in this area
A similar sequence of events occurs in wound healing with formation of normal, limited and transient granulation tissue, while in fibrosis, a maladaptive repair leads to an extensive, exaggerated process with functional impairment
Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair
The evaluation of several human fibrotic lung diseases, five diffuse (idiopathic pulmonary fibrosis (IPF); adult respiratory distress syndrome (ARDS); coal workers' pneumoconiosis (CWP); Hermansky-Pudlak syndrome (HPS); systemic sclerosis (SS)) and two focal (tumour stroma in lung cancer; and obliterative bronchiolitis (OB) after lung transplantation), has shown that several cytokines participate in the local injury and inflammatory reaction (interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-alpha)), while other cytokines are involved in tissue repair and fibrosis (platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF))
A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches
8680382	25	30	human	Species
8680382	31	44	lung fibrosis	Disease
8680382	46	54	Fibrosis	Disease
8680382	276	284	fibrosis	Disease
8680382	346	358	inflammation	Disease
8680382	618	626	fibrosis	Disease
8680382	913	918	human	Species
8680382	919	941	fibrotic lung diseases	Disease
8680382	957	986	idiopathic pulmonary fibrosis	Disease
8680382	988	991	IPF	Disease
8680382	994	1029	adult respiratory distress syndrome	Disease
8680382	1031	1035	ARDS	Disease
8680382	1038	1066	coal workers' pneumoconiosis	Disease
8680382	1068	1071	CWP	Disease
8680382	1074	1099	Hermansky-Pudlak syndrome	Disease
8680382	1101	1104	HPS	Disease
8680382	1107	1125	systemic sclerosis	Disease
8680382	1127	1129	SS	Disease
8680382	1147	1153	tumour	Disease
8680382	1164	1175	lung cancer	Disease
8680382	1181	1207	obliterative bronchiolitis	Disease
8680382	1209	1211	OB	Disease
8680382	1294	1306	local injury	Disease
8680382	1334	1347	interleukin-1	Gene
8680382	1349	1353	IL-1	Gene
8680382	1356	1369	interleukin-8	Gene
8680382	1371	1375	IL-8	Gene
8680382	1378	1408	monocyte chemotactic protein-1	Gene
8680382	1410	1415	MCP-1	Gene
8680382	1422	1428	tumour	Disease
8680382	1452	1461	TNF-alpha	Gene
8680382	1521	1529	fibrosis	Disease
8680382	1570	1598	insulin-like growth factor-1	Gene
8680382	1600	1605	IGF-1	Gene
8680382	1768	1784	in lung fibrosis	Disease
29440315|t|JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study
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 (JAK2) 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 JAK2 as potential target to treat PH in IPF
METHODS AND RESULTS: JAK2 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 JAK2 inhibitor JSI-124 or siRNA-JAK2 and stimulated with transforming growth factor beta
Both JSI-124 and siRNA-JAK2 inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation
JAK2 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>)
JAK2 inhibition activated BK<sub>Ca</sub>channels and reduced intracellular Ca<sup>2+</sup>
JSI-124 1   mg/kg/day, reduced bleomycin-induced lung fibrosis, 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: JAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH
29440315	0	4	JAK2	Gene
29440315	14	27	lung fibrosis	Disease
29440315	29	59	pulmonary vascular remodelling	Disease
29440315	64	76	hypertension	Disease
29440315	80	109	idiopathic pulmonary fibrosis	Disease
29440315	146	168	Pulmonary hypertension	Disease
29440315	170	172	PH	Disease
29440315	212	241	idiopathic pulmonary fibrosis	Disease
29440315	243	246	IPF	Disease
29440315	326	328	PH	Disease
29440315	354	357	IPF	Disease
29440315	453	472	Janus kinase type 2	Gene
29440315	474	478	JAK2	Gene
29440315	514	524	activated	Positive_regulation
29440315	601	603	PH	Disease
29440315	604	615	associated	Binding
29440315	618	620	PH	Disease
29440315	657	661	JAK2	Gene
29440315	691	693	PH	Disease
29440315	697	700	IPF	Disease
29440315	723	727	JAK2	Gene
29440315	728	739	expression	Gene_expression
29440315	743	753	increased	Positive_regulation
29440315	786	789	IPF	Disease
29440315	822	825	IPF	Disease
29440315	826	828	PH	Disease
29440315	903	917	PA remodelling	Disease
29440315	1061	1064	IPF	Disease
29440315	1091	1095	JAK2	Gene
29440315	1096	1106	inhibitor	Negative_regulation
29440315	1123	1127	JAK2	Gene
29440315	1204	1208	JAK2	Gene
29440315	1318	1322	JAK2	Gene
29440315	1323	1334	inhibition	Negative_regulation
29440315	1511	1515	JAK2	Gene
29440315	1516	1527	inhibition	Negative_regulation
29440315	1653	1666	lung fibrosis	Disease
29440315	1668	1682	PA remodelling	Disease
29440315	1690	1713	ventricular hypertrophy	Disease
29440315	1718	1730	hypertension	Disease
29440315	1836	1840	JAK2	Gene
29440315	1857	1871	PA remodelling	Disease
29440315	1876	1883	tension	Disease
29440315	1925	1928	IPF	Disease
29440315	1943	1945	PH	Disease
24669082|t|Ambroxol hydrochloride in the management of idiopathic pulmonary fibrosis: Clinical trials are the need of the hour
Idiopathic pulmonary fibrosis (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	0	22	Ambroxol hydrochloride	Chemical
24669082	44	73	idiopathic pulmonary fibrosis	Disease
24669082	117	146	Idiopathic pulmonary fibrosis	Disease
24669082	148	151	IPF	Disease
24669082	512	534	ambroxol hydrochloride	Chemical
24669082	796	802	block	Negative_regulation
24669082	806	814	release	Localization
24669082	880	894	hydroxyproline	Chemical
24669082	904	915	nitic oxide	Chemical
24669082	971	982	preserving	Positive_regulation
24669082	994	997	GSH	Chemical
24669082	1016	1021	human	Species
24669082	1058	1064	block	Negative_regulation
24669082	1068	1079	expression	Gene_expression
24669082	1082	1090	TGF-beta	Gene
24669082	1095	1104	TNF-alpha	Gene
24669082	1134	1149	carbon monoxide	Chemical
24669082	1185	1196	lung cancer	Disease
24669082	1197	1205	patients	Species
24669082	1234	1242	ambroxol	Chemical
24669082	1327	1330	IPF	Disease
24669082	1374	1379	human	Species
24669082	1443	1446	IPF	Disease
21103368|t|Reactive oxygen species are required for maintenance and differentiation of primary lung fibroblasts in idiopathic pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (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 kinase(s) 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	9	15	oxygen	Chemical
21103368	104	133	idiopathic pulmonary fibrosis	Disease
21103368	147	176	Idiopathic pulmonary fibrosis	Disease
21103368	178	181	IPF	Disease
21103368	358	371	lung fibrosis	Disease
21103368	405	410	human	Species
21103368	411	414	IPF	Disease
21103368	516	519	IPF	Disease
21103368	520	528	patients	Species
21103368	742	745	IPF	Disease
21103368	746	754	patients	Species
21103368	879	882	IPF	Disease
21103368	971	974	IPF	Disease
21103368	986	989	IPF	Disease
21103368	1027	1052	alpha-smooth muscle actin	Disease
21103368	1054	1057	SMA	Disease
21103368	1122	1133	expressing	Gene_expression
21103368	1198	1201	IPF	Disease
21103368	1302	1305	IPF	Disease
21103368	1358	1364	oxygen	Chemical
21103368	1390	1401	activation	Positive_regulation
21103368	1407	1412	NADPH	Chemical
21103368	1461	1469	tyrosine	Chemical
21103368	1577	1580	IPF	Disease
21103368	1725	1728	SMA	Disease
21103368	1860	1871	activation	Positive_regulation
21103368	1874	1882	tyrosine	Chemical
21103368	1936	1939	IPF	Disease
21103368	2040	2043	IPF	Disease
29118928|t|MiR-5100 targets TOB2 to drive epithelial-mesenchymal transition associated with activating smad2/3 in lung epithelial cells
Idiopathic pulmonary fibrosis (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 smad2/3 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 TOB2 as a specific target of miR-5100 and miR-5100 can decrease the accumulation of endogenous TOB2 in A549 and Beas-2B cells
Moreover, the exogenous expression of TOB2 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 TOB2 associated with activating smad2/3 in lung epithlium cells
Our findings may provide novel insights into the pathogenesis of IPF
29118928	0	8	MiR-5100	Gene
29118928	17	21	TOB2	Gene
29118928	81	92	activating	Positive_regulation
29118928	92	99	smad2/3	Gene
29118928	126	155	Idiopathic pulmonary fibrosis	Disease
29118928	157	160	IPF	Disease
29118928	211	214	IPF	Disease
29118928	266	274	miR-5100	Gene
29118928	306	316	metastasis	Disease
29118928	402	410	miR-5100	Gene
29118928	414	423	bleomycin	Chemical
29118928	425	428	BLM	Chemical
29118928	438	443	mouse	Species
29118928	492	498	TGF-b1	Gene
29118928	541	544	EMT	Gene
29118928	582	591	elevated	Positive_regulation
29118928	600	608	miR-5100	Gene
29118928	634	639	mouse	Species
29118928	666	669	EMT	Gene
29118928	723	731	miR-5100	Gene
29118928	745	748	EMT	Gene
29118928	766	775	enhanced	Positive_regulation
29118928	775	781	TGF-b1	Gene
29118928	789	797	induced	Positive_regulation
29118928	797	800	EMT	Gene
29118928	805	815	activated	Positive_regulation
29118928	819	826	smad2/3	Gene
29118928	869	877	miR-5100	Gene
29118928	945	953	miR-5100	Gene
29118928	1061	1065	TOB2	Gene
29118928	1090	1098	miR-5100	Gene
29118928	1103	1111	miR-5100	Gene
29118928	1116	1125	decrease	Negative_regulation
29118928	1156	1160	TOB2	Gene
29118928	1212	1223	expression	Gene_expression
29118928	1226	1230	TOB2	Gene
29118928	1257	1265	miR-5100	Gene
29118928	1269	1272	EMT	Gene
29118928	1346	1354	miR-5100	Gene
29118928	1368	1371	EMT	Gene
29118928	1393	1397	TOB2	Gene
29118928	1398	1409	associated	Binding
29118928	1414	1425	activating	Positive_regulation
29118928	1425	1432	smad2/3	Gene
29118928	1523	1526	IPF	Disease
28821630|t|IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis
Interleukin 17A (IL-17A) and complement (C') activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF)
We have reported that IL-17A 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 lung fibrosis
In the present study, we investigated the role of IL-17A in regulating C' in lung fibrosis
Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that IL-17A (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)
IL-17A 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 IL-17A neutralization and IL-17A 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 IL-17A 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 lung fibrosis, 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 IL-17A is a potential mechanism in ameliorating lung fibrosis.-Cipolla, E., Fisher, A
J., Gu, H., Mickler, E
A., Agarwal, M., Wilke, C
A., Kim, K
K., Moore, B
B., Vittal, R
IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis
28821630	0	6	IL-17A	Gene
28821630	28	37	bleomycin	Chemical
28821630	75	88	lung fibrosis	Disease
28821630	90	105	Interleukin 17A	Gene
28821630	107	113	IL-17A	Gene
28821630	195	224	idiopathic pulmonary fibrosis	Disease
28821630	226	229	IPF	Disease
28821630	254	260	IL-17A	Gene
28821630	291	296	TGF-b	Gene
28821630	300	306	murine	Species
28821630	307	331	bronchiolitis obliterans	Disease
28821630	338	343	TGF-b	Gene
28821630	474	487	lung fibrosis	Disease
28821630	539	545	IL-17A	Gene
28821630	566	579	lung fibrosis	Disease
28821630	638	643	human	Species
28821630	689	695	IL-17A	Gene
28821630	720	725	donor	Species
28821630	812	828	IL8, -6, and -1B	Gene
28821630	853	858	CXCL1	Gene
28821630	886	892	IL-17A	Gene
28821630	893	901	induces	Positive_regulation
28821630	918	929	regulation	Regulation
28821630	954	964	synthesis	Gene_expression
28821630	1004	1009	human	Species
28821630	1062	1066	mice	Species
28821630	1080	1086	IL-17A	Gene
28821630	1106	1112	IL-17A	Gene
28821630	1123	1128	il17a	Gene
28821630	1134	1138	mice	Species
28821630	1162	1171	bleomycin	Chemical
28821630	1173	1177	BLEO	Chemical
28821630	1187	1195	fibrosis	Disease
28821630	1230	1234	BLEO	Chemical
28821630	1243	1248	il17a	Gene
28821630	1252	1256	mice	Species
28821630	1360	1371	caspase-3/7	Gene
28821630	1427	1431	BLEO	Chemical
28821630	1484	1494	C' complex	Species
28821630	1522	1527	il17a	Gene
28821630	1531	1535	mice	Species
28821630	1541	1547	IL-17A	Gene
28821630	1548	1563	neutralization	Localization
28821630	1563	1573	prevented	Negative_regulation
28821630	1746	1751	il17a	Gene
28821630	1764	1768	mice	Species
28821630	1782	1810	progression of lung fibrosis	Disease
28821630	1843	1854	caspase-3/7	Gene
28821630	1937	1940	IPF	Disease
28821630	1941	1949	patients	Species
28821630	2075	2081	IL-17A	Gene
28821630	2123	2136	lung fibrosis	Disease
28821630	2151	2157	Fisher	Species
28821630	2254	2260	IL-17A	Gene
28821630	2282	2291	bleomycin	Chemical
28821630	2329	2342	lung fibrosis	Disease
21743278|t|Inhibitory effect of receptor for advanced glycation end products (RAGE) on the TGF-b-induced alveolar epithelial to mesenchymal transition
Idiopathic pulmonary fibrosis (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 (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation is associated with renal fibrosis during diabetes and liver fibrosis
RAGE 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 RAGE during the epithelial to myofibroblast transition in rat AECs
Our results indicate that AGE inhibited the TGF-b-dependent alveolar EMT by increasing Smad7 expression, and that the effect was abolished by RAGE siRNA treatment
Thus, the induction of Smad7 by the AGE-RAGE interaction limits the development of pulmonary fibrosis by inhibiting TGF-b-dependent signaling in AECs
21743278	21	65	receptor for advanced glycation end products	Gene
21743278	67	71	RAGE	Gene
21743278	80	85	TGF-b	Gene
21743278	141	170	Idiopathic pulmonary fibrosis	Disease
21743278	172	175	IPF	Disease
21743278	189	213	parenchymal lung disease	Disease
21743278	387	431	Receptor for advanced glycation end products	Gene
21743278	433	437	RAGE	Gene
21743278	517	528	activation	Positive_regulation
21743278	553	561	fibrosis	Disease
21743278	569	596	diabetes and liver fibrosis	Disease
21743278	598	602	RAGE	Gene
21743278	606	616	expressed	Gene_expression
21743278	707	719	interaction	Binding
21743278	772	776	RAGE	Gene
21743278	830	833	rat	Species
21743278	884	889	TGF-b	Gene
21743278	900	912	alveolar EMT	Disease
21743278	916	927	increasing	Positive_regulation
21743278	927	932	Smad7	Gene
21743278	933	944	expression	Gene_expression
21743278	982	986	RAGE	Gene
21743278	1014	1024	induction	Positive_regulation
21743278	1027	1032	Smad7	Gene
21743278	1044	1048	RAGE	Gene
21743278	1087	1105	pulmonary fibrosis	Disease
21743278	1120	1125	TGF-b	Gene
26315535|t|miR-9-5p suppresses pro-fibrogenic transformation of fibroblasts and prevents organ fibrosis by targeting NOX4 and TGFBR2
UNASSIGNED: Uncontrolled extracellular matrix (ECM) production by fibroblasts in response to injury contributes to fibrotic diseases, including idiopathic pulmonary fibrosis (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 fibrosis (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
miR-9-5p 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 miR-9-5p abrogates TGF-b1-dependent myofibroblast phenotypic transformation
In the mouse model of bleomycin-induced LF, miR-9-5p dramatically reduces fibrogenesis and inhibition of miR-9-5p and prevents its anti-fibrotic effect both in  vitro and in  vivo
In lung specimens from patients with IPF, high levels of miR-9-5p are found
In omentum-derived mesothelial cells (MCs) from patients subjected to peritoneal dialysis (PD), miR-9-5p also inhibits mesothelial to myofibroblast transformation
We propose that TGF-b1 induces miR-9-5p expression as a self-limiting homeostatic response
26315535	0	8	miR-9-5p	Gene
26315535	84	92	fibrosis	Disease
26315535	96	106	targeting	Binding
26315535	106	110	NOX4	Gene
26315535	115	121	TGFBR2	Gene
26315535	238	255	fibrotic diseases	Disease
26315535	267	296	idiopathic pulmonary fibrosis	Disease
26315535	298	301	IPF	Disease
26315535	313	319	oxygen	Chemical
26315535	380	383	IPF	Disease
26315535	385	414	Transforming growth factor-b1	Gene
26315535	416	422	TGF-b1	Gene
26315535	424	435	stimulates	Positive_regulation
26315535	439	450	production	Gene_expression
26315535	453	468	NADPH oxidase 4	Gene
26315535	470	474	NOX4	Gene
26315535	501	514	lung fibrosis	Disease
26315535	516	518	LF	Disease
26315535	589	591	LF	Disease
26315535	654	657	IPF	Disease
26315535	682	687	human	Species
26315535	721	729	miR-9-5p	Gene
26315535	799	806	effect	Regulation
26315535	833	839	TGFBR2	Gene
26315535	845	849	NOX4	Gene
26315535	850	861	expression	Gene_expression
26315535	862	872	Increased	Positive_regulation
26315535	872	883	expression	Gene_expression
26315535	886	894	miR-9-5p	Gene
26315535	905	911	TGF-b1	Gene
26315535	970	975	mouse	Species
26315535	985	994	bleomycin	Chemical
26315535	1003	1005	LF	Disease
26315535	1007	1015	miR-9-5p	Gene
26315535	1029	1037	reduces	Negative_regulation
26315535	1054	1065	inhibition	Negative_regulation
26315535	1068	1076	miR-9-5p	Gene
26315535	1108	1115	effect	Regulation
26315535	1167	1175	patients	Species
26315535	1181	1184	IPF	Disease
26315535	1201	1209	miR-9-5p	Gene
26315535	1269	1277	patients	Species
26315535	1317	1325	miR-9-5p	Gene
26315535	1401	1407	TGF-b1	Gene
26315535	1408	1416	induces	Positive_regulation
26315535	1416	1424	miR-9-5p	Gene
26315535	1425	1436	expression	Gene_expression
26887531|t|Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) promotes lung fibroblast proliferation, survival and differentiation to myofibroblasts
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressively fatal disease
Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is a glycosylated transmembrane protein that induces the expression of some matrix metalloproteinase (MMP) in neighboring stromal cells through direct epithelial-stromal interactions
EMMPRIN 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 EMMPRIN in IPF is unknown
METHODS: To determine if EMMPRIN contributes to lung fibroblast proliferation, resistance to apoptosis, and differentiation to myofibroblasts, normal Human lung fibroblasts (NHLF) transiently transfected with either EMMPRIN/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 EMMPRIN inhibition on NHLF proliferation, apoptosis, migration and differentiation to myofibroblasts after TGF- b1 treatment was examined using EMMPRIN blocking antibody
We examined the mechanism by which EMMPRIN 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 EMMPRIN had a significant increase in cell proliferation and migration compared to control fibroblasts
Furthermore, EMMPRIN promoted lung fibroblasts resistance to apoptosis
Lung fibroblasts overexpressing EMMPRIN 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 EMMPRIN in lung fibroblasts in a dose-dependent manner
Attenuation of EMMPRIN expression with the use of an EMMPRIN blocking antibody markedly inhibited TGF-b1 induced proliferation, migration, and differentiation of fibroblasts to myofibroblasts
EMMPRIN 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 EMMPRIN that activates b-catenin/canonical Wnt signaling pathway
EMMPRIN 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	0	46	Extracellular Matrix Metalloproteinase Inducer	Gene
26887531	48	55	EMMPRIN	Gene
26887531	157	186	Idiopathic pulmonary fibrosis	Disease
26887531	188	191	IPF	Disease
26887531	235	281	Extracellular Matrix Metalloproteinase Inducer	Gene
26887531	283	290	EMMPRIN	Gene
26887531	337	345	induces	Positive_regulation
26887531	349	360	expression	Gene_expression
26887531	462	475	interactions	Binding
26887531	476	483	EMMPRIN	Gene
26887531	579	582	IPF	Disease
26887531	625	632	EMMPRIN	Gene
26887531	636	639	IPF	Disease
26887531	677	684	EMMPRIN	Gene
26887531	802	807	Human	Species
26887531	868	875	EMMPRIN	Gene
26887531	905	912	TGF- b1	Gene
26887531	978	987	thymidine	Chemical
26887531	1216	1223	EMMPRIN	Gene
26887531	1323	1330	TGF- b1	Gene
26887531	1360	1367	EMMPRIN	Gene
26887531	1422	1429	EMMPRIN	Gene
26887531	1481	1490	b-catenin	Gene
26887531	1591	1606	phosphorylated	Phosphorylation
26887531	1606	1615	b-catenin	Gene
26887531	1626	1631	Human	Species
26887531	1664	1671	EMMPRIN	Gene
26887531	1781	1788	EMMPRIN	Gene
26887531	1872	1879	EMMPRIN	Gene
26887531	1903	1913	increased	Positive_regulation
26887531	1913	1924	expression	Gene_expression
26887531	2024	2030	TGF-b1	Gene
26887531	2059	2066	EMMPRIN	Gene
26887531	2130	2137	EMMPRIN	Gene
26887531	2168	2175	EMMPRIN	Gene
26887531	2213	2219	TGF-b1	Gene
26887531	2308	2315	EMMPRIN	Gene
26887531	2316	2331	overexpression	Positive_regulation
26887531	2374	2383	increase	Positive_regulation
26887531	2505	2511	TGF-b1	Gene
26887531	2535	2542	EMMPRIN	Gene
26887531	2548	2558	activates	Positive_regulation
26887531	2558	2567	b-catenin	Gene
26887531	2601	2608	EMMPRIN	Gene
26887531	2609	2624	overexpression	Positive_regulation
26887531	2769	2772	IPF	Disease
26207697|t|Regulation of 26S Proteasome Activity in Pulmonary Fibrosis
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 diseases of the heart, 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	0	11	Regulation	Regulation
26207697	41	59	Pulmonary Fibrosis	Disease
26207697	392	413	diseases of the heart	Disease
26207697	489	513	fibrotic lung remodeling	Disease
26207697	559	588	idiopathic pulmonary fibrosis	Disease
26207697	590	593	IPF	Disease
26207697	838	843	mouse	Species
26207697	854	867	lung fibrosis	Disease
26207697	881	886	human	Species
26207697	997	1002	TGF-b	Gene
26207697	1003	1012	involves	Regulation
26207697	1012	1023	activation	Positive_regulation
26207697	1102	1106	Rpn6	Gene
26207697	1108	1118	Silencing	Negative_regulation
26207697	1121	1125	Rpn6	Gene
26207697	1137	1142	human	Species
26207697	1173	1178	TGF-b	Gene
26207697	1218	1229	Activation	Positive_regulation
26207697	1255	1265	increased	Positive_regulation
26207697	1265	1276	expression	Gene_expression
26207697	1279	1283	Rpn6	Gene
26207697	1305	1314	bleomycin	Chemical
26207697	1323	1338	lung remodeling	Disease
26207697	1343	1351	fibrosis	Disease
26207697	1366	1370	Rpn6	Gene
26207697	1374	1388	overexpressed	Positive_regulation
26207697	1464	1472	patients	Species
26207697	1478	1481	IPF	Disease
26207697	1571	1575	Rpn6	Gene
26207697	1601	1612	activation	Positive_regulation
26207697	1743	1746	IPF	Disease
17631612|t|TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease
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 (TGF)-beta 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 TGF-beta 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 fibrotic lung disease
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	0	8	TGF-beta	Gene
17631612	54	75	fibrotic lung disease	Disease
17631612	429	437	fibrosis	Disease
17631612	578	586	induces	Positive_regulation
17631612	711	731	hyperplastic type II	Disease
17631612	764	772	patients	Species
17631612	778	807	idiopathic pulmonary fibrosis	Disease
17631612	809	812	IPF	Disease
17631612	933	941	fibrosis	Disease
17631612	1088	1096	fibrosis	Disease
17631612	1176	1184	TGF-beta	Gene
17631612	1360	1381	fibrotic lung disease	Disease
17631612	1397	1405	fibrosis	Disease
17631612	1438	1441	IPF	Disease
17631612	1529	1541	inflammation	Disease
26599507|t|Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis
RATIONALE: Idiopathic pulmonary fibrosis (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: Matriptase 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
Matriptase-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: Matriptase 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	18	33	Serine Protease	Gene
26599507	34	44	Matriptase	Gene
26599507	96	125	Idiopathic pulmonary fibrosis	Disease
26599507	127	130	IPF	Disease
26599507	218	231	characterize	Regulation
26599507	235	246	expression	Gene_expression
26599507	284	299	serine protease	Gene
26599507	300	310	matriptase	Gene
26599507	314	317	IPF	Disease
26599507	321	327	humans	Species
26599507	362	367	human	Species
26599507	418	428	Matriptase	Gene
26599507	429	440	expression	Gene_expression
26599507	478	486	patients	Species
26599507	492	495	IPF	Disease
26599507	638	648	matriptase	Gene
26599507	707	717	Matriptase	Gene
26599507	803	808	human	Species
26599507	896	902	murine	Species
26599507	912	921	bleomycin	Chemical
26599507	930	948	pulmonary fibrosis	Disease
26599507	970	980	matriptase	Gene
26599507	981	991	depletion	Negative_regulation
26599507	1038	1055	camostat mesilate	Chemical
26599507	1098	1108	matriptase	Gene
26599507	1121	1125	mice	Species
26599507	1167	1176	secreted	Localization
26599507	1237	1247	Matriptase	Gene
26599507	1248	1259	expression	Gene_expression
26599507	1277	1290	up-regulated	Positive_regulation
26599507	1293	1296	IPF	Disease
26599507	1301	1310	bleomycin	Chemical
26599507	1319	1337	pulmonary fibrosis	Disease
26599507	1351	1356	human	Species
26599507	1380	1390	matriptase	Gene
26599507	1391	1402	expression	Gene_expression
26599507	1420	1428	induced	Positive_regulation
26599507	1474	1484	matriptase	Gene
26599507	1508	1537	protease-activated receptor-2	Gene
26599507	1539	1544	PAR-2	Gene
26599507	1633	1642	bleomycin	Chemical
26599507	1650	1660	matriptase	Gene
26599507	1661	1671	depletion	Negative_regulation
26599507	1722	1738	down-regulation	Negative_regulation
26599507	1739	1750	diminished	Negative_regulation
26599507	1750	1761	lung injury	Disease
26599507	1772	1783	production	Gene_expression
26599507	1880	1890	increased	Positive_regulation
26599507	1890	1900	matriptase	Gene
26599507	1901	1912	expression	Gene_expression
26599507	1948	1966	pulmonary fibrosis	Disease
26599507	1970	1975	human	Species
26599507	1976	1979	IPF	Disease
26599507	2003	2008	mouse	Species
26599507	2035	2045	matriptase	Gene
26599507	2158	2161	IPF	Disease
26150910|t|Pleural mesothelial cells in pleural and lung diseases
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 idiopathic pulmonary fibrosis (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	29	54	pleural and lung diseases	Disease
26150910	571	600	idiopathic pulmonary fibrosis	Disease
26150910	602	605	IPF	Disease
26150910	945	962	pleural effusions	Disease
26150910	1046	1056	n-cadherin	Gene
26150910	1061	1070	b-catenin	Gene
26150910	1076	1092	phosphorylation	Phosphorylation
26150910	1155	1189	vascular endothelial growth factor	Gene
26150910	1191	1195	VEGF	Gene
26150910	1197	1206	released	Localization
26150910	1273	1319	bacterial and mycobacterial pleural infections	Disease
26150910	1344	1370	malignant pleural effusion	Disease
26150910	1389	1404	pleural disease	Disease
26150910	1409	1439	malignant pleural mesothelioma	Disease
26150910	1488	1500	inflammation	Disease
26150910	1534	1542	fibrosis	Disease
26150910	1544	1552	Fibrosis	Disease
26150910	1575	1601	disordered fibrin turnover	Disease
26150910	1851	1854	IPF	Disease
26150910	2020	2023	IPF	Disease
26150910	2034	2047	lung diseases	Disease
23399488|t|Pleural mesothelial cell differentiation and invasion in fibrogenic lung injury
The origin of the myofibroblast in fibrotic lung disease 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	57	79	fibrogenic lung injury	Disease
23399488	125	137	lung disease	Disease
23399488	189	197	fibrosis	Disease
23399488	243	272	transforming growth factor-b1	Gene
23399488	274	280	TGF-b1	Gene
23399488	544	548	mice	Species
23399488	611	622	Wilms tumor	Disease
23399488	626	628	WT	Disease
23399488	728	743	Carbon monoxide	Chemical
23399488	751	761	induction	Positive_regulation
23399488	764	780	heme oxygenase-1	Gene
23399488	890	896	TGF-b1	Gene
23399488	916	926	induction	Positive_regulation
23399488	926	936	inhibited	Negative_regulation
23399488	999	1007	patients	Species
23399488	1013	1042	idiopathic pulmonary fibrosis	Disease
23399488	1044	1047	IPF	Disease
23399488	1175	1190	Carbon monoxide	Chemical
23399488	1205	1208	IPF	Disease
23399488	1236	1238	WT	Disease
23399488	1311	1314	IPF	Disease
23399488	1338	1343	role	Regulation
23399488	1439	1447	fibrosis	Disease
23399488	1579	1587	fibrosis	Disease
21577212|t|Absence of Thy-1 results in TGF-b induced MMP-9 expression and confers a profibrotic phenotype to human lung fibroblasts
Fibroblasts differ in a variety of phenotypic features, including the expression of Thy-1 a glycophosphatidylinositol-linked glycoprotein
Fibroblasts in idiopathic pulmonary fibrosis (IPF) are Thy-1 negative, whereas most fibroblasts from normal lungs are Thy-1 positive
However, the functional consequences of the absence of Thy-1 are not fully understood
We analyzed the expression of Thy-1 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 Thy-1 in vitro
We identified a primary culture of HP fibroblasts, which did not express Thy-1, and compared several functional activities between Thy-1 (-) and Thy-1 (+) fibroblasts
Thy-1 (-) 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, Thy-1 (-) fibroblasts either spontaneously or after TGF-b stimulation demonstrated stronger contraction of collagen matrices (eg, 0.17  0.03 versus 0.6  0.05 cm   after TGF-b stimulation at 24 h; P<0.01)
Thy-1 (-) lung fibroblasts stimulated with TGF-b1 expressed MMP-9, an enzyme that is usually not produced by lung fibroblasts
TGFb-induced MMP-9 expression was reversible upon re-expression of Thy-1 after transfection with full-length Thy-1
b-glycan, a TGF-b receptor antagonist abolished MMP-9 expression
TGF-b1-induced MMP-9 in Thy-1 (-) fibroblasts depended on the activation of ERK1/2 signaling pathway
Finally, we demonstrated that fibroblasts from IPF fibroblastic foci, which do not express Thy-1 exhibit strong staining for immunoreactive MMP-9 protein in vivo
These findings indicate that loss of Thy-1 in human lung fibroblasts induces a fibrogenic phenotype
21577212	11	16	Thy-1	Gene
21577212	28	33	TGF-b	Gene
21577212	42	47	MMP-9	Gene
21577212	98	103	human	Species
21577212	192	203	expression	Gene_expression
21577212	206	211	Thy-1	Gene
21577212	214	239	glycophosphatidylinositol	Chemical
21577212	276	305	idiopathic pulmonary fibrosis	Disease
21577212	307	310	IPF	Disease
21577212	316	321	Thy-1	Gene
21577212	379	384	Thy-1	Gene
21577212	450	455	Thy-1	Gene
21577212	512	517	Thy-1	Gene
21577212	568	571	IPF	Disease
21577212	573	601	hypersensitivity pneumonitis	Disease
21577212	603	605	HP	Disease
21577212	619	624	human	Species
21577212	706	711	Thy-1	Gene
21577212	757	759	HP	Disease
21577212	795	800	Thy-1	Gene
21577212	853	858	Thy-1	Gene
21577212	867	872	Thy-1	Gene
21577212	890	895	Thy-1	Gene
21577212	1145	1150	Thy-1	Gene
21577212	1197	1202	TGF-b	Gene
21577212	1237	1249	contraction	Binding
21577212	1314	1319	TGF-b	Gene
21577212	1350	1355	Thy-1	Gene
21577212	1393	1399	TGF-b1	Gene
21577212	1410	1415	MMP-9	Gene
21577212	1490	1495	MMP-9	Gene
21577212	1544	1549	Thy-1	Gene
21577212	1586	1591	Thy-1	Gene
21577212	1605	1610	TGF-b	Gene
21577212	1641	1646	MMP-9	Gene
21577212	1659	1665	TGF-b1	Gene
21577212	1674	1679	MMP-9	Gene
21577212	1683	1688	Thy-1	Gene
21577212	1735	1741	ERK1/2	Gene
21577212	1808	1811	IPF	Disease
21577212	1852	1857	Thy-1	Gene
21577212	1901	1906	MMP-9	Gene
21577212	1961	1966	Thy-1	Gene
21577212	1970	1975	human	Species
12899768|t|[Different cytokine profiles in usual interstitial pneumonia and nonspecific interstitial pneumonia]
OBJECTIVE: To study the distribution, the expression and the significance of TGF-beta(1), b-FGF, IL-8, IL-13 and IFN-gamma in different lung tissue compartments in usual interstitial pneumonia/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-beta(1), IL-8 and b-FGF were localized in alveolar epithelial cells, alveolar macrophages, and the bronchial epithelium
Overall intensity of TGF-beta(1), 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-beta(1), 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	32	60	usual interstitial pneumonia	Disease
12899768	65	99	nonspecific interstitial pneumonia	Disease
12899768	126	139	distribution	Gene_expression
12899768	144	155	expression	Gene_expression
12899768	179	190	TGF-beta(1)	Gene
12899768	192	197	b-FGF	Gene
12899768	199	203	IL-8	Gene
12899768	205	210	IL-13	Gene
12899768	215	224	IFN-gamma	Gene
12899768	266	294	usual interstitial pneumonia	Disease
12899768	295	324	idiopathic pulmonary fibrosis	Disease
12899768	326	329	UIP	Disease
12899768	330	333	IPF	Disease
12899768	339	373	nonspecific interstitial pneumonia	Disease
12899768	375	379	NSIP	Disease
12899768	472	480	patients	Species
12899768	486	489	UIP	Disease
12899768	502	506	NSIP	Disease
12899768	575	583	patients	Species
12899768	597	608	lung cancer	Disease
12899768	756	767	TGF-beta(1)	Gene
12899768	769	783	IL-8 and b-FGF	Gene
12899768	789	799	localized	Localization
12899768	889	899	intensity	Negative_regulation
12899768	902	913	TGF-beta(1)	Gene
12899768	915	919	IL-8	Gene
12899768	924	929	b-FGF	Gene
12899768	930	941	expression	Gene_expression
12899768	944	947	UIP	Disease
12899768	980	984	NSIP	Disease
12899768	986	991	IL-13	Gene
12899768	1099	1110	expression	Gene_expression
12899768	1113	1116	UIP	Disease
12899768	1140	1144	NSIP	Disease
12899768	1146	1155	IFN-gamma	Gene
12899768	1160	1170	expressed	Gene_expression
12899768	1216	1227	expression	Gene_expression
12899768	1230	1234	NSIP	Disease
12899768	1261	1264	UIP	Disease
12899768	1279	1284	IL-13	Gene
12899768	1288	1297	IFN-gamma	Gene
12899768	1301	1304	UIP	Disease
12899768	1359	1363	NSIP	Disease
12899768	1430	1433	UIP	Disease
12899768	1441	1445	NSIP	Disease
12899768	1480	1485	IL-13	Gene
12899768	1489	1498	IFN-gamma	Gene
12899768	1502	1506	NSIP	Disease
12899768	1639	1650	expression	Gene_expression
12899768	1653	1664	TGF-beta(1)	Gene
12899768	1666	1670	IL-8	Gene
12899768	1675	1680	b-FGF	Gene
12899768	1684	1687	UIP	Disease
12899768	1692	1696	NSIP	Disease
12899768	1716	1721	IL-13	Gene
12899768	1722	1731	IFN-gamma	Gene
12899768	1739	1748	involved	Regulation
21513813|t|Signalling pathways from NADPH oxidase-4 to idiopathic pulmonary fibrosis
This review focuses on the roles of NADPH oxidase/NOX proteins in idiopathic pulmonary fibrosis (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	25	30	NADPH	Chemical
21513813	44	73	idiopathic pulmonary fibrosis	Disease
21513813	111	116	NADPH	Chemical
21513813	141	170	idiopathic pulmonary fibrosis	Disease
21513813	172	175	IPF	Disease
21513813	236	239	IPF	Disease
21513813	328	334	oxygen	Chemical
21513813	341	346	NADPH	Chemical
21513813	398	402	NOX4	Gene
21513813	406	414	induced	Positive_regulation
21513813	454	459	TGF-b	Gene
21513813	461	466	TGF-b	Gene
21513813	475	482	induce	Positive_regulation
21513813	598	602	NOX4	Gene
21513813	616	622	oxygen	Chemical
21513813	631	641	dependent	Positive_regulation
21513813	641	648	SMAD2/3	Gene
21513813	649	665	phosphorylation	Phosphorylation
21513813	666	670	NOX4	Gene
21513813	674	684	increased	Positive_regulation
21513813	714	717	IPF	Disease
21513813	718	726	patients	Species
21513813	743	747	Nox4	Gene
21513813	751	755	mice	Species
21513813	765	774	bleomycin	Chemical
21513813	783	801	pulmonary fibrosis	Disease
21513813	836	846	targeting	Localization
21513813	849	853	NOX4	Gene
21513813	898	920	fibrotic lung diseases	Disease
25906080|t|Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis
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 pulmonary fibrosis 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 ATG4B 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	23	28	ATG4B	Gene
25906080	55	64	bleomycin	Chemical
25906080	73	91	pulmonary fibrosis	Disease
25906080	285	314	idiopathic pulmonary fibrosis	Disease
25906080	424	437	lung fibrosis	Disease
25906080	541	550	bleomycin	Chemical
25906080	559	572	lung fibrosis	Disease
25906080	590	595	Atg4b	Gene
25906080	596	606	deficient	Negative_regulation
25906080	606	611	mouse	Species
25906080	624	629	Atg4b	Gene
25906080	630	640	deficient	Negative_regulation
25906080	640	644	mice	Species
25906080	713	722	bleomycin	Chemical
25906080	867	872	Atg4b	Gene
25906080	940	948	alveolar	Disease
25906080	996	1005	bleomycin	Chemical
25906080	1019	1024	Atg4b	Gene
25906080	1035	1039	mice	Species
25906080	1076	1084	fibrosis	Disease
25906080	1090	1100	increased	Positive_regulation
25906080	1225	1230	ATG4B	Gene
25906080	1310	1319	bleomycin	Chemical
21278261|t|Interplay between RAGE, CD44, and focal adhesion molecules in epithelial-mesenchymal transition of alveolar epithelial cells
Fibrosis 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 (RAGE) 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 RAGE 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, RAGE 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 RAGE under basal conditions, which was disrupted when challenged with inflammatory cytokines, as ERM in its activated state complexed with membrane-linked CD44
Dual-fluorescence immunohistochemistry of patient idiopathic pulmonary fibrosis (IPF) tissues highlighted marked diminution of RAGE in fibrotic samples, together with enhanced levels of CD44 and double-positive cells for CD44 and phospho (p)ERM
These data suggest that dysregulation of the ERM-RAGE complex might be an important step in rearrangement of the actin cytoskeleton during proinflammatory cytokine-induced EMT of human alveolar epithelial cells
21278261	18	22	RAGE	Gene
21278261	24	28	CD44	Gene
21278261	126	134	Fibrosis	Disease
21278261	585	589	RAGE	Gene
21278261	884	888	RAGE	Gene
21278261	897	906	interact	Binding
21278261	1065	1081	phosphorylation	Phosphorylation
21278261	1085	1100	redistribution	Localization
21278261	1200	1209	blockade	Negative_regulation
21278261	1308	1312	RAGE	Gene
21278261	1313	1324	expression	Gene_expression
21278261	1328	1339	diminished	Negative_regulation
21278261	1409	1441	matrix metalloproteinase (MMP)-9	Gene
21278261	1528	1540	association	Binding
21278261	1556	1560	RAGE	Gene
21278261	1680	1690	complexed	Binding
21278261	1711	1715	CD44	Gene
21278261	1759	1766	patient	Species
21278261	1767	1796	idiopathic pulmonary fibrosis	Disease
21278261	1798	1801	IPF	Disease
21278261	1844	1848	RAGE	Gene
21278261	1884	1893	enhanced	Positive_regulation
21278261	1903	1907	CD44	Gene
21278261	1938	1942	CD44	Gene
21278261	1987	2001	dysregulation	Regulation
21278261	2012	2016	RAGE	Gene
21278261	2142	2147	human	Species
26059457|t|Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGFb1
Aging constitutes a significant risk factor for fibrosis, and idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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 pulmonary fibrosis 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 pulmonary fibrosis
We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases
26059457	0	13	Deregulation	Regulation
26059457	53	71	pulmonary fibrosis	Disease
26059457	85	90	TGFb1	Gene
26059457	140	148	fibrosis	Disease
26059457	154	183	idiopathic pulmonary fibrosis	Disease
26059457	185	188	IPF	Disease
26059457	368	386	pulmonary fibrosis	Disease
26059457	519	530	lung injury	Disease
26059457	538	542	mice	Species
26059457	559	563	mice	Species
26059457	617	621	mice	Species
26059457	632	643	lung injury	Disease
26059457	770	813	Fibroblast to myofibroblast differentiation	Disease
26059457	815	818	FMD	Disease
26059457	847	865	pulmonary fibrosis	Disease
26059457	900	905	TGFb1	Gene
26059457	1039	1042	FMD	Disease
26059457	1055	1060	TGFb1	Gene
26059457	1194	1199	PINK1	Gene
26059457	1200	1211	expression	Gene_expression
26059457	1226	1234	reduced	Negative_regulation
26059457	1263	1272	bleomycin	Chemical
26059457	1279	1284	TGFb1	Gene
26059457	1305	1318	lung fibrosis	Disease
26059457	1320	1325	PINK1	Gene
26059457	1326	1337	expression	Gene_expression
26059457	1345	1353	reduced	Negative_regulation
26059457	1366	1372	murine	Species
26059457	1396	1399	IPF	Disease
26059457	1400	1408	patients	Species
26059457	1444	1454	deficient	Negative_regulation
26059457	1454	1459	PINK1	Gene
26059457	1599	1610	lung injury	Disease
26059457	1666	1684	pulmonary fibrosis	Disease
26059457	1805	1822	fibrotic diseases	Disease
24478701|t|Are mast cells instrumental for fibrotic diseases? 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 fibrotic diseases such as IPF, where the process of tissue repair and remodeling is thought to be dysregulated
24478701	32	49	fibrotic diseases	Disease
24478701	51	80	Idiopathic pulmonary fibrosis	Disease
24478701	82	85	IPF	Disease
24478701	92	111	fatal lung disorder	Disease
24478701	301	304	IPF	Disease
24478701	507	510	IPF	Disease
24478701	860	863	IPF	Disease
24478701	890	902	inflammation	Disease
24478701	907	915	fibrosis	Disease
24478701	978	986	fibrosis	Disease
24478701	1196	1204	fibrosis	Disease
24478701	1293	1311	pulmonary fibrosis	Disease
24478701	1363	1371	fibrosis	Disease
24478701	1710	1727	fibrotic diseases	Disease
24478701	1736	1739	IPF	Disease
23021430|t|Association between cytokine removal by polymyxin B hemoperfusion and improved pulmonary oxygenation in patients with acute exacerbation of idiopathic pulmonary fibrosis
Acute exacerbation of idiopathic pulmonary fibrosis (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	40	51	polymyxin B	Chemical
23021430	104	112	patients	Species
23021430	140	169	idiopathic pulmonary fibrosis	Disease
23021430	193	222	idiopathic pulmonary fibrosis	Disease
23021430	227	230	IPF	Disease
23021430	269	276	dyspnea	Disease
23021430	381	392	polymyxin B	Chemical
23021430	394	397	PMX	Chemical
23021430	428	431	PMX	Chemical
23021430	432	435	DHP	Chemical
23021430	504	512	patients	Species
23021430	521	524	IPF	Disease
23021430	617	623	AE-IPF	Chemical
23021430	658	661	PMX	Chemical
23021430	662	665	DHP	Chemical
23021430	718	721	PMX	Chemical
23021430	742	745	IPF	Disease
23021430	746	754	patients	Species
23021430	790	793	IPF	Disease
23021430	794	802	patients	Species
23021430	842	849	PMX-DHP	Chemical
23021430	860	863	IPF	Disease
23021430	864	872	patients	Species
23021430	959	963	IL-9	Gene
23021430	972	977	IL-17	Gene
23021430	988	992	VEGF	Gene
23021430	1012	1022	decreased	Negative_regulation
23021430	1040	1047	PMX-DHP	Chemical
23021430	1062	1076	VEGF and IL-12	Gene
23021430	1099	1107	reduced	Negative_regulation
23021430	1132	1136	VEGF	Gene
23021430	1138	1143	IL-1b	Gene
23021430	1145	1151	IL-1ra	Gene
23021430	1153	1157	IL-8	Gene
23021430	1159	1164	IL-23	Gene
23021430	1177	1183	GM-CSF	Gene
23021430	1185	1190	IP-10	Gene
23021430	1192	1198	RANTES	Gene
23021430	1203	1208	TGF-b	Gene
23021430	1231	1234	PMX	Chemical
23021430	1295	1302	PMX-DHP	Chemical
23021430	1353	1357	VEGF	Gene
23021430	1462	1465	PMX	Chemical
23021430	1511	1514	PMX	Chemical
23021430	1515	1518	DHP	Chemical
23021430	1525	1528	IPF	Disease
23021430	1539	1547	removal	Negative_regulation
23021430	1550	1554	VEGF	Gene
23021430	1558	1561	PMX	Chemical
23021430	1562	1565	DHP	Chemical
17710235|t|The Role of PPARs in Lung Fibrosis
Pulmonary fibrosis 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	26	34	Fibrosis	Disease
17710235	36	54	Pulmonary fibrosis	Disease
17710235	163	188	loss of alveolar function	Disease
17710235	235	255	respiratory distress	Disease
17710235	271	279	fibrosis	Disease
17710235	291	306	corticosteroids	Chemical
17710235	403	411	patients	Species
17710235	417	446	idiopathic pulmonary fibrosis	Disease
17710235	448	451	IPF	Disease
17710235	522	530	patients	Species
17710235	556	574	pulmonary fibrosis	Disease
17710235	655	658	IPF	Disease
17710235	852	864	inflammation	Disease
17710235	885	894	PPARalpha	Gene
17710235	948	956	inhibit	Negative_regulation
17710235	960	971	production	Gene_expression
17710235	1040	1056	cardiac fibrosis	Disease
17710235	1082	1087	mouse	Species
17710235	1097	1110	lung fibrosis	Disease
17710235	1122	1131	bleomycin	Chemical
17710235	1135	1144	PPARalpha	Gene
17710235	1206	1215	PPARalpha	Gene
17710235	1216	1225	knockout	Negative_regulation
17710235	1225	1229	mice	Species
17710235	1253	1261	fibrosis	Disease
17710235	1263	1271	PPARbeta	Gene
17710235	1344	1356	inflammation	Disease
17710235	1375	1383	PPARbeta	Gene
17710235	1480	1489	PPARgamma	Gene
17710235	1500	1509	PPARgamma	Gene
17710235	1653	1661	fibrosis	Disease
17710235	1663	1672	PPARgamma	Gene
17710235	1696	1713	thiazolidinedione	Chemical
17710235	1763	1776	lung fibrosis	Disease
17710235	1858	1867	PPARalpha	Gene
17710235	1872	1881	PPARgamma	Gene
1892646|t|Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis
Transforming growth factor-beta (TGF-beta) can regulate cell growth and differentiation as well as production of extracellular matrix proteins
Elevated production of TGF-beta has been associated with human and rodent chronic inflammatory and fibrotic diseases
Using immunohistochemical staining, we have examined lung sections of patients with advanced idiopathic pulmonary fibrosis (IPF), a disease characterized by chronic inflammation and fibrosis and demonstrated a marked and consistent increase in TGF-beta production in epithelial cells and macrophages when compared to patients with nonspecific inflammation and those with no inflammation or fibrosis
In patients with advanced IPF, intracellular staining with anti-LC (1-30) TGF-beta antibody was seen prominently in bronchiolar epithelial cells
In addition, epithelial cells of honeycomb cysts and hyperplastic type II pneumocytes stained intensely
Anti-CC (1-30) TGF-beta antibody, which reacts with extracellular TGF-beta, was localized in the lamina propria of bronchioles and in subepithelial regions of honeycomb cysts in areas of dense fibroconnective tissue deposition
The close association of subepithelial TGF-beta to the intracellular form in advanced IPF suggests that TGF-beta was produced and secreted primarily by epithelial cells
Because of the well-known effects of TGF-beta on extracellular matrix formation and on epithelial cell differentiation, the increased production of TGF-beta in advanced IPF may be pathogenic to the pulmonary fibrotic and regenerative responses seen in this disease
1892646	61	92	transforming growth factor-beta	Gene
1892646	96	125	idiopathic pulmonary fibrosis	Disease
1892646	127	158	Transforming growth factor-beta	Gene
1892646	160	168	TGF-beta	Gene
1892646	271	280	Elevated	Positive_regulation
1892646	280	291	production	Gene_expression
1892646	294	302	TGF-beta	Gene
1892646	328	333	human	Species
1892646	370	387	fibrotic diseases	Disease
1892646	459	467	patients	Species
1892646	482	511	idiopathic pulmonary fibrosis	Disease
1892646	513	516	IPF	Disease
1892646	546	566	chronic inflammation	Disease
1892646	571	579	fibrosis	Disease
1892646	621	630	increase	Positive_regulation
1892646	633	641	TGF-beta	Gene
1892646	642	653	production	Gene_expression
1892646	706	714	patients	Species
1892646	732	744	inflammation	Disease
1892646	763	775	inflammation	Disease
1892646	779	787	fibrosis	Disease
1892646	792	800	patients	Species
1892646	815	818	IPF	Disease
1892646	863	871	TGF-beta	Gene
1892646	1055	1063	TGF-beta	Gene
1892646	1106	1114	TGF-beta	Gene
1892646	1120	1130	localized	Localization
1892646	1307	1315	TGF-beta	Gene
1892646	1354	1357	IPF	Disease
1892646	1372	1380	TGF-beta	Gene
1892646	1385	1394	produced	Gene_expression
1892646	1398	1407	secreted	Localization
1892646	1475	1483	TGF-beta	Gene
1892646	1562	1572	increased	Positive_regulation
1892646	1572	1583	production	Gene_expression
1892646	1586	1594	TGF-beta	Gene
1892646	1607	1610	IPF	Disease
11502094|t|TNF-alpha, PDGF, and TGF-beta(1) expression by primary mouse bronchiolar-alveolar epithelial and mesenchymal cells: tnf-alpha induces TGF-beta(1)
The bronchiolar-alveolar epithelium (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 (TGF-beta(1)), and tumor necrosis factor alpha (TNF-alpha)
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 TNF-alpha upregulates expression of TGF-beta(1)
The four GF are produced by both epithelial and mesenchymal cells but with different temporal patterns
TGF-beta(1) is expressed constitutively by BAE and mesenchymal cells, whereas TNF-alpha 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	0	9	TNF-alpha	Gene
11502094	21	32	TGF-beta(1)	Gene
11502094	33	44	expression	Gene_expression
11502094	55	60	mouse	Species
11502094	116	125	tnf-alpha	Gene
11502094	134	145	TGF-beta(1)	Gene
11502094	151	182	bronchiolar-alveolar epithelium	Disease
11502094	184	187	BAE	Disease
11502094	244	255	lung injury	Disease
11502094	437	468	interstitial pulmonary fibrosis	Disease
11502094	470	473	IPF	Disease
11502094	576	579	IPF	Disease
11502094	629	634	mouse	Species
11502094	635	638	BAE	Disease
11502094	722	776	platelet-derived growth factor isoforms (PDGF) A and B	Gene
11502094	778	811	transforming growth factor beta-1	Gene
11502094	813	824	TGF-beta(1)	Gene
11502094	831	858	tumor necrosis factor alpha	Gene
11502094	860	869	TNF-alpha	Gene
11502094	874	879	mouse	Species
11502094	978	981	BAE	Disease
11502094	1042	1051	9 +/- 2.3	Species
11502094	1191	1202	expression	Transcription
11502094	1238	1241	BAE	Disease
11502094	1309	1314	mouse	Species
11502094	1365	1374	TNF-alpha	Gene
11502094	1375	1387	upregulates	Positive_regulation
11502094	1387	1398	expression	Gene_expression
11502094	1401	1412	TGF-beta(1)	Gene
11502094	1430	1439	produced	Gene_expression
11502094	1518	1529	TGF-beta(1)	Gene
11502094	1533	1543	expressed	Gene_expression
11502094	1561	1564	BAE	Disease
11502094	1596	1605	TNF-alpha	Gene
11502094	1606	1617	expression	Gene_expression
11502094	1756	1761	mouse	Species
11502094	1818	1830	lung disease	Disease
27508041|t|MiR-338* suppresses fibrotic pathogenesis in pulmonary fibrosis through targeting LPA1
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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 pulmonary fibrosis through targeting LPA1
Thus, miR-338* can be a potential therapeutic target for the treatment of IPF
27508041	0	7	MiR-338	Gene
27508041	45	63	pulmonary fibrosis	Disease
27508041	82	86	LPA1	Gene
27508041	88	117	Idiopathic pulmonary fibrosis	Disease
27508041	119	122	IPF	Disease
27508041	141	153	lung disease	Disease
27508041	164	180	pulmonary injury	Disease
27508041	228	236	fibrosis	Disease
27508041	537	555	pulmonary fibrosis	Disease
27508041	586	593	miR-338	Gene
27508041	595	602	miR-338	Gene
27508041	651	656	tumor	Disease
27508041	708	713	TGF-b	Gene
27508041	745	761	Over-expression	Positive_regulation
27508041	764	771	miR-338	Gene
27508041	824	829	TGF-b	Gene
27508041	841	845	LPA1	Gene
27508041	886	893	miR-338	Gene
27508041	916	932	over-expression	Positive_regulation
27508041	935	942	miR-338	Gene
27508041	963	971	fibrosis	Disease
27508041	983	992	bleomycin	Chemical
27508041	996	1000	mice	Species
27508041	1043	1050	miR-338	Gene
27508041	1083	1101	pulmonary fibrosis	Disease
27508041	1110	1120	targeting	Localization
27508041	1120	1124	LPA1	Gene
27508041	1132	1139	miR-338	Gene
27508041	1200	1203	IPF	Disease
27576730|t|Metformin attenuates lung fibrosis development via NOX4 suppression
BACKGROUND: Accumulation of profibrotic myofibroblasts in fibroblastic foci (FF) is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis (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 fibrosis 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 fibrosis 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 NOX4 expression
NOX4 knockdown and N-acetylcysteine (NAC) treatment illustrated that NOX4-derived ROS generation was critical for TGF-b-induced SMAD phosphorylation and myofibroblast differentiation
BLM treatment induced development of lung fibrosis with concomitantly enhanced NOX4 expression and SMAD phosphorylation, which was efficiently inhibited by metformin
Increased NOX4 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	0	9	Metformin	Chemical
27576730	10	34	attenuates lung fibrosis	Disease
27576730	51	55	NOX4	Gene
27576730	56	68	suppression	Negative_regulation
27576730	190	198	fibrosis	Disease
27576730	206	235	idiopathic pulmonary fibrosis	Disease
27576730	237	240	IPF	Disease
27576730	366	372	oxygen	Chemical
27576730	441	446	TGF-b	Gene
27576730	486	495	Metformin	Chemical
27576730	501	510	biguanide	Chemical
27576730	569	578	mediated	Positive_regulation
27576730	590	601	activation	Positive_regulation
27576730	604	607	AMP	Chemical
27576730	786	795	metformin	Chemical
27576730	799	812	lung fibrosis	Disease
27576730	829	840	modulating	Regulation
27576730	840	845	TGF-b	Gene
27576730	866	871	TGF-b	Gene
27576730	1019	1028	bleomycin	Chemical
27576730	1030	1033	BLM	Chemical
27576730	1043	1056	lung fibrosis	Disease
27576730	1087	1092	TGF-b	Gene
27576730	1156	1165	metformin	Chemical
27576730	1183	1192	Metformin	Chemical
27576730	1202	1213	activation	Positive_regulation
27576730	1241	1252	inhibiting	Negative_regulation
27576730	1252	1257	TGF-b	Gene
27576730	1258	1266	induced	Positive_regulation
27576730	1266	1270	NOX4	Gene
27576730	1271	1282	expression	Gene_expression
27576730	1283	1287	NOX4	Gene
27576730	1288	1298	knockdown	Negative_regulation
27576730	1302	1318	N-acetylcysteine	Chemical
27576730	1320	1323	NAC	Chemical
27576730	1352	1356	NOX4	Gene
27576730	1384	1393	critical	Positive_regulation
27576730	1397	1402	TGF-b	Gene
27576730	1403	1411	induced	Positive_regulation
27576730	1416	1432	phosphorylation	Phosphorylation
27576730	1467	1470	BLM	Chemical
27576730	1481	1489	induced	Positive_regulation
27576730	1489	1517	development of lung fibrosis	Disease
27576730	1537	1546	enhanced	Positive_regulation
27576730	1546	1550	NOX4	Gene
27576730	1551	1562	expression	Gene_expression
27576730	1571	1587	phosphorylation	Phosphorylation
27576730	1623	1632	metformin	Chemical
27576730	1634	1644	Increased	Positive_regulation
27576730	1644	1648	NOX4	Gene
27576730	1649	1660	expression	Gene_expression
27576730	1695	1698	IPF	Disease
27576730	1726	1729	IPF	Disease
27576730	1730	1738	patients	Species
27576730	1781	1790	metformin	Chemical
27576730	1850	1853	IPF	Disease
27576730	1866	1871	TGF-b	Gene
20483575|t|Investigation of bone marrow mesenchymal stem cells (BM MSCs) involvement in Idiopathic Pulmonary Fibrosis (IPF)
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 Idiopathic Pulmonary Fibrosis (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 10(25) +/- 1.2 x 10(25) and 3.1 x 10(7) +/- 3.1 x 10(7), respectively) compared to controls (0.32 x 10(25) +/- 0.07 x 10(25) and 1.67 x 10(7) +/- 0.30 x 10(7), 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	77	106	Idiopathic Pulmonary Fibrosis	Disease
20483575	108	111	IPF	Disease
20483575	378	407	Idiopathic Pulmonary Fibrosis	Disease
20483575	409	412	IPF	Disease
20483575	504	507	IPF	Disease
20483575	508	516	patients	Species
20483575	708	719	expression	Transcription
20483575	744	755	lung injury	Disease
20483575	759	762	IPF	Disease
20483575	775	809	vascular endothelial growth factor	Gene
20483575	811	815	VEGF	Gene
20483575	850	883	transforming growth factor beta-1	Gene
20483575	885	894	TGF-beta1	Gene
20483575	909	938	stromal-cell-derived factor-1	Gene
20483575	940	945	SDF-1	Gene
20483575	947	952	CXCR4	Gene
20483575	1015	1018	IPF	Disease
20483575	1019	1027	patients	Species
20483575	1167	1175	patients	Species
20483575	1192	1196	VEGF	Gene
20483575	1210	1221	expression	Gene_expression
20483575	1222	1231	TGF-beta1	Gene
20483575	1240	1250	expressed	Gene_expression
20483575	1260	1268	patients	Species
20483575	1296	1305	increase	Positive_regulation
20483575	1308	1317	SDF-1-TR1	Gene
20483575	1322	1327	CXCR4	Gene
20483575	1333	1344	expression	Gene_expression
20483575	1360	1363	IPF	Disease
20483575	1364	1372	patients	Species
20483575	1602	1607	SDF-1	Gene
20483575	1651	1659	patients	Species
20483575	1691	1701	increased	Positive_regulation
20483575	1701	1706	CXCR4	Gene
20483575	1707	1718	expression	Gene_expression
20483575	1721	1728	patient	Species
20483575	1804	1807	IPF	Disease
20483575	1855	1866	lung injury	Disease
20483575	1901	1904	IPF	Disease
8163656|t|Anchorage-independent colony growth of pulmonary fibroblasts derived from fibrotic human lung tissue
Fibroblast heterogeneity is known to exist in chronically inflamed tissue such as pulmonary fibrosis (IPF) and scleroderma
We have previously shown differences in proliferation rates in primary lines and cloned lines of fibroblasts derived from IPF tissue compared with normal lung
In this study, we report that cell lines derived from fibrotic tissue demonstrate anchorage-independent growth in soft agarose culture whereas normal lung fibroblast lines do not
We also show that fibroblast lines derived from neonatal lung tissue form colonies at about the same frequency as the fibrotic cells
Colonies from both fibrotic and neonatal lines were shown to be positive for vimentin, laminin, fibronectin, fibronectin receptor, beta-actin, and tropomyosin by immunohistochemistry but were negative for desmin, keratin, Factor VIII, alpha-smooth muscle cell actin, and tenascin
Treatment with cytokines TGF-beta and PDGF or with corticosteroid modified the colony-forming capacity of fibrotic and neonatal cell lines, however, none of these treatments induced normal lung cell lines to form colonies
The presence of cells in adult fibrotic tissue with growth characteristics similar to those exhibited by neonatal cells is further evidence of fibroblast heterogeneity and suggests newly differentiated fibroblasts may be prevalent in fibrotic tissue and contribute directly to the matrix disorder seen in this disease
8163656	83	88	human	Species
8163656	184	202	pulmonary fibrosis	Disease
8163656	204	207	IPF	Disease
8163656	213	224	scleroderma	Disease
8163656	348	351	IPF	Disease
8163656	764	773	positive	Positive_regulation
8163656	777	785	vimentin	Gene
8163656	796	807	fibronectin	Gene
8163656	809	820	fibronectin	Gene
8163656	831	841	beta-actin	Gene
8163656	892	901	negative	Gene_expression
8163656	905	911	desmin	Gene
8163656	971	979	tenascin	Gene
8163656	1485	1500	matrix disorder	Disease
20952439|t|The pathogenesis of idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	20	49	idiopathic pulmonary fibrosis	Disease
20952439	51	80	Idiopathic pulmonary fibrosis	Disease
20952439	82	85	IPF	Disease
20952439	104	125	fibrotic lung disease	Disease
20952439	359	362	IPF	Disease
20952439	425	428	IPF	Disease
20952439	468	483	alveolar injury	Disease
20952439	512	540	transforming growth factor-b	Gene
20952439	542	547	TGF-b	Gene
20952439	682	687	TGF-b	Gene
20952439	988	991	IPF	Disease
10931794|t|Interstitial fibrosis and growth factors
Interstitial pulmonary fibrosis (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	13	21	fibrosis	Disease
10931794	42	73	Interstitial pulmonary fibrosis	Disease
10931794	75	78	IPF	Disease
10931794	634	637	IPF	Disease
10931794	847	878	transforming growth factor beta	Gene
10931794	987	1014	tumor necrosis factor alpha	Gene
10931794	1118	1121	IPF	Disease
10931794	1199	1205	humans	Species
18344408|t|Overexpression of squamous cell carcinoma antigen in idiopathic pulmonary fibrosis: clinicopathological correlations
BACKGROUND: Idiopathic pulmonary fibrosis (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	18	41	squamous cell carcinoma	Disease
18344408	53	82	idiopathic pulmonary fibrosis	Disease
18344408	130	159	Idiopathic pulmonary fibrosis	Disease
18344408	161	164	IPF	Disease
18344408	325	350	neoplastic transformation	Disease
18344408	420	423	IPF	Disease
18344408	425	448	Squamous cell carcinoma	Disease
18344408	458	462	SCCA	Chemical
18344408	469	475	serine	Chemical
18344408	485	495	inhibitor	Negative_regulation
18344408	505	515	expressed	Gene_expression
18344408	586	607	squamous cell tumours	Disease
18344408	670	673	IPF	Disease
18344408	684	688	SCCA	Chemical
18344408	693	724	transforming growth factor beta	Gene
18344408	726	733	TGFbeta	Gene
18344408	735	746	expression	Gene_expression
18344408	780	788	patients	Species
18344408	794	797	IPF	Disease
18344408	933	937	SCCA	Chemical
18344408	942	949	TGFbeta	Gene
18344408	950	961	expression	Gene_expression
18344408	962	966	SCCA	Chemical
18344408	971	978	TGFbeta	Gene
18344408	990	1001	expression	Gene_expression
18344408	1079	1083	SCCA	Chemical
18344408	1184	1191	TGFbeta	Gene
18344408	1192	1203	expression	Gene_expression
18344408	1248	1252	SCCA	Chemical
18344408	1311	1315	SCCA	Chemical
18344408	1383	1386	IPF	Disease
18344408	1458	1466	patients	Species
18344408	1504	1512	patients	Species
18344408	1518	1521	IPF	Disease
18344408	1523	1527	SCCA	Chemical
18344408	1608	1619	expression	Gene_expression
18344408	1622	1629	TGFbeta	Gene
18344408	1660	1675	carbon monoxide	Chemical
18344408	1692	1700	decline	Negative_regulation
18344408	1817	1821	SCCA	Chemical
18344408	1822	1830	induced	Positive_regulation
18344408	1830	1837	TGFbeta	Gene
18344408	1838	1849	expression	Gene_expression
18344408	1954	1958	SCCA	Chemical
18344408	2036	2039	IPF	Disease
18344408	2041	2045	SCCA	Chemical
29067109|t|TIAM1 inhibits lung fibroblast differentiation in pulmonary fibrosis
The differentiation of fibroblasts to myofibroblasts is critical for the development of idiopathic pulmonary fibrosis (IPF)
T-cell lymphoma invasion and metastasis 1 (TIAM1) 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 TIAM1 in lung fibroblasts during pulmonary fibrosis
It was demonstrated that TIAM1 expression was significantly increased in fibrotic lung tissue and lung fibroblasts from bleomycin (BLM)-treated mice compared with control mice (P<0.05)
TIAM1 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 TIAM1 expression and decreased fibroblast differentiation in human lung fibroblasts (P<0.05)
Similarly, overexpression of TIAM1 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 TIAM1 knockdown increased TGF-b-induced fibroblast differentiation (P<0.05)
These findings suggest that TIAM1 expression is associated with lung fibroblast differentiation in pulmonary fibrosis via an NF-kB-dependent pathway, and that TIAM1 inhibits lung fibroblast differentiation in pulmonary fibrosis
29067109	0	5	TIAM1	Gene
29067109	50	68	pulmonary fibrosis	Disease
29067109	158	187	idiopathic pulmonary fibrosis	Disease
29067109	189	192	IPF	Disease
29067109	195	236	T-cell lymphoma invasion and metastasis 1	Gene
29067109	238	243	TIAM1	Gene
29067109	276	305	amyotrophic lateral sclerosis	Disease
29067109	312	329	colorectal cancer	Disease
29067109	352	355	IPF	Disease
29067109	420	431	expression	Gene_expression
29067109	435	441	roles	Regulation
29067109	444	449	TIAM1	Gene
29067109	477	495	pulmonary fibrosis	Disease
29067109	522	527	TIAM1	Gene
29067109	528	539	expression	Gene_expression
29067109	557	567	increased	Positive_regulation
29067109	617	626	bleomycin	Chemical
29067109	628	631	BLM	Chemical
29067109	641	645	mice	Species
29067109	668	672	mice	Species
29067109	683	688	TIAM1	Gene
29067109	689	700	expression	Gene_expression
29067109	739	751	upregulated	Positive_regulation
29067109	754	759	human	Species
29067109	793	821	transforming growth factor-b	Gene
29067109	823	828	TGF-b	Gene
29067109	970	975	TGF-b	Gene
29067109	984	989	TIAM1	Gene
29067109	990	1001	expression	Gene_expression
29067109	1045	1050	human	Species
29067109	1089	1104	overexpression	Positive_regulation
29067109	1107	1112	TIAM1	Gene
29067109	1137	1142	TGF-b	Gene
29067109	1195	1205	decreased	Negative_regulation
29067109	1205	1216	expression	Gene_expression
29067109	1219	1230	fibronectin	Gene
29067109	1235	1256	a-smooth muscle actin	Gene
29067109	1258	1261	SMA	Gene
29067109	1328	1333	TIAM1	Gene
29067109	1334	1344	knockdown	Negative_regulation
29067109	1354	1359	TGF-b	Gene
29067109	1433	1438	TIAM1	Gene
29067109	1439	1450	expression	Gene_expression
29067109	1504	1522	pulmonary fibrosis	Disease
29067109	1564	1569	TIAM1	Gene
29067109	1614	1632	pulmonary fibrosis	Disease
24641440|t|Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis
BACKGROUND AND PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of pulmonary hypertension (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	80	102	pulmonary hypertension	Disease
24641440	119	132	lung fibrosis	Disease
24641440	158	187	Idiopathic pulmonary fibrosis	Disease
24641440	189	192	IPF	Disease
24641440	211	239	fibro-proliferative disorder	Disease
24641440	313	335	pulmonary hypertension	Disease
24641440	337	339	PH	Disease
24641440	542	561	myocardial fibrosis	Disease
24641440	689	707	pulmonary fibrosis	Disease
24641440	723	725	PH	Disease
24641440	939	952	lung fibrosis	Disease
24641440	1042	1046	mice	Species
24641440	1058	1067	bleomycin	Chemical
24641440	1085	1090	Human	Species
24641440	1260	1264	mice	Species
24641440	1277	1286	bleomycin	Chemical
24641440	1374	1383	ecadotril	Chemical
24641440	1443	1453	sildenafil	Chemical
24641440	1552	1576	established lung disease	Disease
24641440	1642	1646	mice	Species
24641440	1679	1689	sildenafil	Chemical
24641440	1714	1718	TGFb	Gene
24641440	1727	1732	human	Species
24641440	1795	1798	IPF	Disease
24641440	1799	1807	patients	Species
24641440	1923	1936	lung fibrosis	Disease
24641440	1941	1943	PH	Disease
24641440	1962	1971	ecadotril	Chemical
24641440	1976	1986	sildenafil	Chemical
24641440	2156	2164	patients	Species
24641440	2170	2173	IPF	Disease
19614606|t|Role of integrin-mediated TGFbeta activation in the pathogenesis of pulmonary fibrosis
IPF (idiopathic pulmonary fibrosis) 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 TGFbeta (transforming growth factor beta) plays a central role in this process
In normal lung, TGFbeta is maintained in an inactive state that is tightly regulated temporally and spatially
One of the major TGFbeta-activation pathways involves integrins, and the role of the (alpha)vbeta6 integrin has been particularly well described in the pathogenesis of IPF
Owing to the pleiotropic nature of TGFbeta, strategies that inhibit activation of TGFbeta 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 TGFbeta activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with IPF
19614606	17	26	mediated	Positive_regulation
19614606	26	33	TGFbeta	Gene
19614606	34	45	activation	Positive_regulation
19614606	68	86	pulmonary fibrosis	Disease
19614606	88	91	IPF	Disease
19614606	93	122	idiopathic pulmonary fibrosis	Disease
19614606	207	210	IPF	Disease
19614606	421	438	epithelial injury	Disease
19614606	545	553	fibrosis	Disease
19614606	562	595	impaired basement membrane repair	Disease
19614606	750	764	up-regulation	Positive_regulation
19614606	889	896	TGFbeta	Gene
19614606	898	929	transforming growth factor beta	Gene
19614606	985	992	TGFbeta	Gene
19614606	1097	1104	TGFbeta	Gene
19614606	1248	1251	IPF	Disease
19614606	1288	1295	TGFbeta	Gene
19614606	1313	1321	inhibit	Negative_regulation
19614606	1321	1332	activation	Positive_regulation
19614606	1335	1342	TGFbeta	Gene
19614606	1425	1449	fibrotic lung conditions	Disease
19614606	1506	1515	mediated	Positive_regulation
19614606	1515	1522	TGFbeta	Gene
19614606	1523	1534	activation	Positive_regulation
19614606	1664	1672	patients	Species
19614606	1678	1681	IPF	Disease
24756129|t|Microsomal prostaglandin E synthase-1 deficiency exacerbates pulmonary fibrosis induced by bleomycin in mice
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 pulmonary fibrosis (IPF) remained unknown
The current study aimed to investigate the role of mPGES-1 in pulmonary fibrosis 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	0	37	Microsomal prostaglandin E synthase-1	Gene
24756129	38	49	deficiency	Negative_regulation
24756129	61	79	pulmonary fibrosis	Disease
24756129	91	100	bleomycin	Chemical
24756129	104	108	mice	Species
24756129	121	137	prostaglandin E2	Chemical
24756129	150	157	mPGES-1	Gene
24756129	194	210	prostaglandin H2	Chemical
24756129	221	237	prostaglandin E2	Chemical
24756129	239	243	PGE2	Chemical
24756129	316	323	mPGES-1	Gene
24756129	327	356	idiopathic pulmonary fibrosis	Disease
24756129	358	361	IPF	Disease
24756129	432	439	mPGES-1	Gene
24756129	443	461	pulmonary fibrosis	Disease
24756129	473	482	bleomycin	Chemical
24756129	486	490	mice	Species
24756129	506	513	mPGES-1	Gene
24756129	525	532	mPGES-1	Gene
24756129	537	541	mice	Species
24756129	564	580	fibrotic lesions	Disease
24756129	600	604	PGE2	Chemical
24756129	628	637	bleomycin	Chemical
24756129	678	685	mPGES-1	Gene
24756129	690	694	mice	Species
24756129	700	707	mPGES-1	Gene
24756129	730	734	PGE2	Chemical
24756129	766	775	bleomycin	Chemical
24756129	784	791	mPGES-1	Gene
24756129	795	799	mice	Species
24756129	827	834	mPGES-1	Gene
24756129	838	842	mice	Species
24756129	862	869	mPGES-1	Gene
24756129	877	884	mPGES-1	Gene
24756129	888	892	mice	Species
24756129	894	903	bleomycin	Chemical
24756129	914	922	reduced	Negative_regulation
24756129	926	937	expression	Gene_expression
24756129	947	970	E prostanoid receptor 2	Gene
24756129	972	975	EP2	Gene
24756129	981	984	EP4	Gene
24756129	1023	1030	effect	Regulation
24756129	1033	1036	EP1	Gene
24756129	1041	1044	EP3	Gene
24756129	1058	1063	human	Species
24756129	1123	1130	mPGES-1	Gene
24756129	1172	1178	TGF-b1	Gene
24756129	1211	1216	a-SMA	Gene
24756129	1226	1237	expression	Gene_expression
24756129	1284	1288	PGE2	Chemical
24756129	1300	1303	EP2	Gene
24756129	1316	1337	focal adhesion kinase	Gene
24756129	1339	1342	FAK	Gene
24756129	1344	1354	inhibitor	Negative_regulation
24756129	1394	1401	mPGES-1	Gene
24756129	1464	1467	EP2	Gene
24756129	1519	1526	mPGES-1	Gene
24756129	1527	1531	PGE2	Chemical
24756129	1532	1535	EP2	Gene
24756129	1536	1539	FAK	Gene
24756129	1616	1619	IPF	Disease
24756129	1620	1628	patients	Species
28446589|t|Antifibrotic effects of cyclosporine A on TGF-b1-treated lung fibroblasts and lungs from bleomycin-treated mice: role of hypoxia-inducible factor-1a
Idiopathic pulmonary fibrosis (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
TGF-b1 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 cyclosporine A (CsA), which reduces TGF-b1-induced FMD via degradation of hypoxia-inducible factor-1a (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 cyclosporine A on TGF-b1-treated lung fibroblasts and lungs from bleomycin-treated mice: role of hypoxia-inducible factor-1a
28446589	24	38	cyclosporine A	Gene
28446589	42	48	TGF-b1	Gene
28446589	89	98	bleomycin	Chemical
28446589	107	111	mice	Species
28446589	121	148	hypoxia-inducible factor-1a	Gene
28446589	150	179	Idiopathic pulmonary fibrosis	Disease
28446589	181	184	IPF	Disease
28446589	191	212	chronic lung disorder	Disease
28446589	352	358	TGF-b1	Gene
28446589	406	414	fibrosis	Disease
28446589	430	473	fibroblast to myofibroblast differentiation	Disease
28446589	475	478	FMD	Disease
28446589	503	517	up-regulation	Positive_regulation
28446589	554	565	inhibition	Negative_regulation
28446589	568	571	FMD	Disease
28446589	629	632	IPF	Disease
28446589	669	674	human	Species
28446589	693	698	WI-38	Species
28446589	703	708	HFL-1	Gene
28446589	721	735	cyclosporine A	Gene
28446589	737	740	CsA	Gene
28446589	757	763	TGF-b1	Gene
28446589	772	775	FMD	Disease
28446589	795	822	hypoxia-inducible factor-1a	Gene
28446589	824	830	HIF-1a	Gene
28446589	908	915	patient	Species
28446589	921	939	pulmonary fibrosis	Disease
28446589	956	959	CsA	Gene
28446589	967	973	HIF-1a	Gene
28446589	974	984	inhibitor	Negative_regulation
28446589	991	1001	decreased	Negative_regulation
28446589	1005	1016	expression	Gene_expression
28446589	1052	1063	fibronectin	Gene
28446589	1086	1089	CsA	Gene
28446589	1147	1151	mice	Species
28446589	1181	1184	CsA	Gene
28446589	1261	1270	bleomycin	Chemical
28446589	1280	1308	alleviation of lung fibrosis	Disease
28446589	1360	1363	CsA	Gene
28446589	1407	1413	HIF-1a	Gene
28446589	1427	1430	CsA	Gene
28446589	1431	1437	HIF-1a	Gene
28446589	1438	1443	axis	Entity
28446589	1511	1514	IPF	Disease
28446589	1660	1674	cyclosporine A	Gene
28446589	1678	1684	TGF-b1	Gene
28446589	1725	1734	bleomycin	Chemical
28446589	1743	1747	mice	Species
28446589	1757	1784	hypoxia-inducible factor-1a	Gene
27029074|t|Preventive and therapeutic effects of thymosin b4 N-terminal fragment Ac-SDKP in the bleomycin model of pulmonary fibrosis
In this study, the bleomycin model of pulmonary fibrosis was utilized to investigate putative anti-fibrotic activity of Ac-SDKP in vivo
Male CD-1 mice received intra-tracheal bleomycin (BLEO, 1 mg/kg) instillation in the absence or presence of Ac-SDKP (a dose of 0.6 mg/kg delivered intra-peritoneally on the day of BLEO treatment, d0, followed by bi-weekly additional doses)
To evaluate therapeutic effects in a subset of mice, Ac-SDKP was administered one week after BLEO instillation (d7)
Animals were sacrificed at one, two, or three weeks later
Measurement of fluid and collagen content in the lung, Broncho Alveolar Lavage Fluid (BALF) analysis, lung histology, immunohistochemistry (IHC), and molecular analysis were performed
Compared to BLEO-treated mice, animals that received also Ac-SDKP (at both d0 and d7) had significantly decreased mortality, weight loss, inflammation (edema, and leukocyte lung infiltration), lung damage (histological evidence of lung injury), and fibrosis (collagen histological staining and soluble collagen content in the lung) at up to 21 days
Moreover, IHC and quantitative RT-PCR results demonstrated a significant decrease in BLEO-induced IL-17 and TGF-b expression in lung tissue
Importantly, a-SMA expression, the hallmark of myofibroblast differentiation, was also decreased
This is the first report showing not only a preventive protective role of Ac-SDKP but also its significant therapeutic effects in the bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies
27029074	38	46	thymosin	Chemical
27029074	50	51	N	Chemical
27029074	70	77	Ac-SDKP	Chemical
27029074	85	94	bleomycin	Chemical
27029074	143	152	bleomycin	Chemical
27029074	244	251	Ac-SDKP	Chemical
27029074	266	270	CD-1	Gene
27029074	271	275	mice	Species
27029074	300	309	bleomycin	Chemical
27029074	311	315	BLEO	Chemical
27029074	369	376	Ac-SDKP	Chemical
27029074	441	445	BLEO	Chemical
27029074	549	553	mice	Species
27029074	555	562	Ac-SDKP	Chemical
27029074	595	599	BLEO	Chemical
27029074	875	879	BLEO	Chemical
27029074	888	892	mice	Species
27029074	921	928	Ac-SDKP	Chemical
27029074	1286	1295	decrease	Negative_regulation
27029074	1298	1302	BLEO	Chemical
27029074	1311	1316	IL-17	Gene
27029074	1321	1326	TGF-b	Gene
27029074	1327	1338	expression	Gene_expression
27029074	1367	1372	a-SMA	Gene
27029074	1518	1523	role	Negative_regulation
27029074	1526	1533	Ac-SDKP	Chemical
27029074	1586	1595	bleomycin	Chemical
28986385|t|The role of halofuginone in fibrosis: more to be explored? Fibrosis, which can be defined as an abnormal or excessive accumulation of extracellular matrix (ECM), particularly fibrillar collagens, is a key driver of progressive organ dysfunction in many inflammatory and metabolic diseases, including idiopathic pulmonary fibrosis (IPF), cirrhosis, nephropathy, and oral submucous fibrosis (OSF)
It has been estimated to contribute to    45% of deaths in the developed world
Therefore, agents that target specific fibrotic pathways, with the consequence of slowing, arresting, or even reversing the progression of tissue fibrogenesis, are urgently needed
7-Bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4(3H)-quinazolinone (halofuginone), an analog of febrifugine, which specifically targets the pathogenesis of ECM proteins, inhibits tissue fibrosis and regeneration and even affects the development of tumors in various tissues
Four modes of actions of halofuginone against fibrosis have been presented: 1) Inhibition of mothers against decapentaplegic homolog 3 (Smad3) phosphorylation downstream of the TGF-b signaling pathway, 2) reduction of collagen amounts, 3) decreases in ECM protein, and 4) selective prevention of Th17 cell differentiation
In this review, we will mainly focus on the rationale for halofuginone against fibrosis
28986385	12	24	halofuginone	Chemical
28986385	657	737	7-Bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4(3H)-quinazolinone	Chemical
28986385	739	751	halofuginone	Chemical
28986385	767	778	febrifugine	Chemical
28986385	799	807	targets	Regulation
28986385	971	983	halofuginone	Chemical
28986385	1089	1105	phosphorylation	Phosphorylation
28986385	1151	1161	reduction	Negative_regulation
28986385	1185	1195	decreases	Negative_regulation
28986385	1327	1339	halofuginone	Chemical
29279415|t|Leucine-rich a-2 glycoprotein promotes lung fibrosis by modulating TGF-b signaling in fibroblasts
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 lung fibrosis, 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, lung fibrosis 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 lung fibrosis by modulating TGF-b-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts
29279415	0	7	Leucine	Chemical
29279415	39	52	lung fibrosis	Disease
29279415	67	72	TGF-b	Gene
29279415	99	104	TGF-b	Gene
29279415	130	147	fibrotic diseases	Disease
29279415	159	188	idiopathic pulmonary fibrosis	Disease
29279415	190	193	IPF	Disease
29279415	217	222	TGF-b	Gene
29279415	236	254	pulmonary fibrosis	Disease
29279415	337	370	leucine-rich alpha-2 glycoprotein	Gene
29279415	372	375	LRG	Gene
29279415	420	425	TGF-b	Gene
29279415	456	461	tumor	Disease
29279415	503	506	LRG	Gene
29279415	510	528	fibrotic disorders	Disease
29279415	540	543	IPF	Disease
29279415	619	622	LRG	Gene
29279415	626	634	fibrosis	Disease
29279415	648	651	LRG	Gene
29279415	666	670	mice	Species
29279415	676	685	bleomycin	Chemical
29279415	694	707	lung fibrosis	Disease
29279415	728	746	pulmonary fibrosis	Disease
29279415	762	765	LRG	Gene
29279415	782	791	wild-type	Disease
29279415	793	795	WT	Disease
29279415	797	801	mice	Species
29279415	806	816	increased	Positive_regulation
29279415	819	828	bleomycin	Chemical
29279415	853	861	fibrosis	Disease
29279415	878	881	LRG	Gene
29279415	885	889	mice	Species
29279415	891	904	lung fibrosis	Disease
29279415	1031	1033	WT	Disease
29279415	1034	1038	mice	Species
29279415	1066	1069	LRG	Gene
29279415	1073	1077	mice	Species
29279415	1079	1095	phosphorylation	Phosphorylation
29279415	1098	1103	Smad2	Gene
29279415	1108	1116	reduced	Negative_regulation
29279415	1134	1139	a-SMA	Gene
29279415	1175	1177	WT	Disease
29279415	1178	1182	mice	Species
29279415	1220	1223	LRG	Gene
29279415	1224	1233	enhanced	Positive_regulation
29279415	1237	1242	TGF-b	Gene
29279415	1243	1251	induced	Positive_regulation
29279415	1251	1267	phosphorylation	Phosphorylation
29279415	1270	1275	Smad2	Gene
29279415	1284	1295	expression	Gene_expression
29279415	1298	1306	Serpine1	Gene
29279415	1311	1316	Acta2	Gene
29279415	1336	1341	Smad2	Gene
29279415	1368	1376	endoglin	Gene
29279415	1391	1396	TGF-b	Gene
29279415	1424	1427	LRG	Gene
29279415	1439	1444	TGF-b	Gene
29279415	1511	1519	endoglin	Gene
29279415	1557	1560	LRG	Gene
29279415	1564	1572	enhance	Positive_regulation
29279415	1572	1577	Smad2	Gene
29279415	1578	1594	phosphorylation	Phosphorylation
29279415	1648	1651	LRG	Gene
29279415	1661	1674	lung fibrosis	Disease
29279415	1678	1689	modulating	Regulation
29279415	1689	1694	TGF-b	Gene
29279415	1695	1703	induced	Positive_regulation
29279415	1703	1708	Smad2	Gene
29279415	1709	1725	phosphorylation	Phosphorylation
25260753|t|Forkhead Box F1 (FOXF1) represses cell growth, COL1 and ARPC2 expression in lung fibroblasts in vitro
Aberrant expression of master phenotype regulators by lung fibroblasts may play a central role in idiopathic pulmonary fibrosis (IPF)
Interrogating IPF fibroblast transcriptome datasets, we identified Forkhead Box F1 (FOXF1), a DNA-binding protein required for lung development, as a candidate actor in IPF
Thus, we determined FOXF1 expression levels in fibroblasts cultured from normal or IPF lungs in vitro, and explored FOXF1 functions in these cells using transient and stable loss-of-function and gain-of-function models
FOXF1 mRNA and protein were expressed at higher levels in IPF compared with controls
In normal lung fibroblasts, FOXF1 repressed key fibroblast functions such as proliferation, survival, and expression of collagen-1 (COL1) and actin related protein 2/3 complex, subunit 2 (ARPC2)
ARPC2 knockdown mimicked FOXF1 overexpression with regard to proliferation and COL1 expression
FOXF1 expression was induced by the antifibrotic mediator prostaglandin E2 (PGE2)
Ex vivo, FOXF1 knockdown conferred CCL-210 lung fibroblasts the ability to implant and survive in uninjured mouse lungs
In IPF lung fibroblasts, FOXF1 regulated COL1 but not ARPC2 expression
In conclusion, FOXF1 functions and regulation were consistent with an antifibrotic role in lung fibroblasts
Higher FOXF1 levels in IPF fibroblasts may thus participate in a compensatory response to fibrogenesis
25260753	0	15	Forkhead Box F1	Gene
25260753	17	22	FOXF1	Gene
25260753	24	34	represses	Negative_regulation
25260753	56	61	ARPC2	Gene
25260753	62	73	expression	Gene_expression
25260753	201	230	idiopathic pulmonary fibrosis	Disease
25260753	232	235	IPF	Disease
25260753	252	255	IPF	Disease
25260753	305	320	Forkhead Box F1	Gene
25260753	322	327	FOXF1	Gene
25260753	407	410	IPF	Disease
25260753	432	437	FOXF1	Gene
25260753	438	449	expression	Gene_expression
25260753	495	498	IPF	Disease
25260753	528	533	FOXF1	Gene
25260753	632	637	FOXF1	Gene
25260753	660	670	expressed	Gene_expression
25260753	690	693	IPF	Disease
25260753	746	751	FOXF1	Gene
25260753	824	835	expression	Gene_expression
25260753	860	904	actin related protein 2/3 complex, subunit 2	Gene
25260753	906	911	ARPC2	Gene
25260753	914	919	ARPC2	Gene
25260753	920	930	knockdown	Negative_regulation
25260753	939	944	FOXF1	Gene
25260753	945	960	overexpression	Positive_regulation
25260753	998	1009	expression	Gene_expression
25260753	1010	1015	FOXF1	Gene
25260753	1016	1027	expression	Gene_expression
25260753	1031	1039	induced	Positive_regulation
25260753	1068	1084	prostaglandin E2	Chemical
25260753	1086	1090	PGE2	Chemical
25260753	1102	1107	FOXF1	Gene
25260753	1108	1118	knockdown	Negative_regulation
25260753	1201	1206	mouse	Species
25260753	1217	1220	IPF	Disease
25260753	1239	1244	FOXF1	Gene
25260753	1245	1255	regulated	Regulation
25260753	1268	1273	ARPC2	Gene
25260753	1274	1285	expression	Gene_expression
25260753	1301	1306	FOXF1	Gene
25260753	1321	1332	regulation	Regulation
25260753	1402	1407	FOXF1	Gene
25260753	1418	1421	IPF	Disease
25252739|t|Nitrated fatty acids reverse pulmonary fibrosis by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis 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 pulmonary fibrosis by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages
25252739	29	47	pulmonary fibrosis	Disease
25252739	139	168	Idiopathic pulmonary fibrosis	Disease
25252739	170	173	IPF	Disease
25252739	193	206	fatal disease	Disease
25252739	230	258	transforming growth factor b	Gene
25252739	260	264	TGFb	Gene
25252739	353	356	IPF	Disease
25252739	360	380	nitrated fatty acids	Disease
25252739	382	386	NFAs	Disease
25252739	429	473	peroxisome proliferator-activated receptor y	Gene
25252739	475	480	PPARy	Gene
25252739	589	592	IPF	Disease
25252739	626	631	PPARy	Gene
25252739	653	661	patients	Species
25252739	667	670	IPF	Disease
25252739	682	692	knockdown	Negative_regulation
25252739	707	712	PPARy	Gene
25252739	713	724	expression	Gene_expression
25252739	736	741	human	Species
25252739	746	751	mouse	Species
25252739	819	824	human	Species
25252739	842	846	NFAs	Disease
25252739	860	865	PPARy	Gene
25252739	878	882	TGFb	Gene
25252739	906	910	NFAs	Disease
25252739	916	926	converted	Positive_regulation
25252739	926	930	TGFb	Gene
25252739	1033	1041	inhibit	Negative_regulation
25252739	1041	1045	TGFb	Gene
25252739	1065	1069	mice	Species
25252739	1091	1109	pulmonary fibrosis	Disease
25252739	1115	1119	NFAs	Disease
25252739	1152	1156	NFAs	Disease
25252739	1157	1170	up-regulated	Positive_regulation
25252739	1183	1193	targeting	Localization
25252739	1231	1237	MFG-E8	Gene
25252739	1240	1251	stimulated	Positive_regulation
25252739	1271	1283	degradation	Protein_catabolism
25252739	1373	1377	mice	Species
25252739	1383	1413	established pulmonary fibrosis	Disease
25252739	1420	1424	NFAs	Disease
25252739	1550	1553	IPF	Disease
25252739	1559	1563	NFAs	Disease
25252739	1613	1616	IPF	Disease
25252739	1701	1719	pulmonary fibrosis	Disease
22406480|t|Serpin B4 isoform overexpression is associated with aberrant epithelial proliferation and lung cancer in idiopathic pulmonary fibrosis
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 Serpin B4 was expressed only in IPF
CONCLUSIONS: Serpin B3/B4, particularly Serpin B4, 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 lung cancer
22406480	0	9	Serpin B4	Gene
22406480	90	101	lung cancer	Disease
22406480	105	134	idiopathic pulmonary fibrosis	Disease
22406480	191	203	Serpin B3/B4	Gene
22406480	216	245	idiopathic pulmonary fibrosis	Disease
22406480	247	250	IPF	Disease
22406480	252	260	patients	Species
22406480	330	333	IPF	Disease
22406480	334	342	patients	Species
22406480	365	371	cancer	Disease
22406480	386	406	epithelial dysplasia	Disease
22406480	517	529	Serpin B3/B4	Gene
22406480	614	617	IPF	Disease
22406480	618	626	patients	Species
22406480	655	666	expression	Gene_expression
22406480	714	734	fibrotic remodelling	Disease
22406480	736	744	fibrosis	Disease
22406480	759	798	transforming growth factor b expression	Gene
22406480	800	805	TGF-b	Gene
22406480	901	904	IPF	Disease
22406480	905	913	patients	Species
22406480	914	926	Serpin B3/B4	Gene
22406480	1053	1065	Serpin B3/B4	Gene
22406480	1085	1093	patients	Species
22406480	1145	1154	Serpin B3	Gene
22406480	1158	1169	expression	Gene_expression
22406480	1189	1194	TGF-b	Gene
22406480	1213	1220	higher	Positive_regulation
22406480	1223	1231	patients	Species
22406480	1237	1243	cancer	Disease
22406480	1255	1264	dysplasia	Disease
22406480	1266	1275	Serpin B3	Gene
22406480	1280	1290	expressed	Gene_expression
22406480	1312	1321	Serpin B4	Gene
22406480	1326	1336	expressed	Gene_expression
22406480	1344	1347	IPF	Disease
22406480	1362	1374	Serpin B3/B4	Gene
22406480	1389	1398	Serpin B4	Gene
22406480	1472	1483	Evaluation	Negative_regulation
22406480	1486	1498	Serpin B3/B4	Gene
22406480	1576	1584	patients	Species
22406480	1618	1629	lung cancer	Disease
14653626|t|Modulation of specific beta cell gene (re)expression during in vitro expansion of human pancreatic islet cells
The need for transplantable beta cells with a stable phenotype has given rise to several strategies including the expansion of existing pancreatic islets 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
14653626	82	87	human	Species
14653626	248	265	pancreatic islets	Disease
14653626	481	486	loss	Negative_regulation
14653626	489	496	insulin	Gene
14653626	497	507	secretion	Localization
14653626	530	535	human	Species
14653626	577	587	decreased	Negative_regulation
14653626	587	598	expression	Gene_expression
14653626	648	655	insulin	Gene
14653626	657	683	insulin promoting factor-1	Gene
14653626	685	690	IPF-1	Gene
14653626	697	708	glucokinase	Gene
14653626	856	863	insulin	Gene
14653626	864	874	secreting	Localization
14653626	886	901	Sodium butyrate	Chemical
14653626	915	922	factor	Negative_regulation
14653626	925	956	IPF-1, insulin, and glucokinase	Gene
14653626	962	975	reexpression	Gene_expression
14653626	992	1000	induced	Positive_regulation
14653626	1000	1010	secretion	Localization
14653626	1013	1020	gastrin	Gene
14653626	1081	1091	calcitriol	Chemical
14653626	1093	1098	GLP-1	Gene
14653626	1112	1114	A	Entity
14653626	1127	1136	enhanced	Positive_regulation
14653626	1140	1147	glucose	Chemical
14653626	1179	1201	Glut-1 and glucokinase	Gene
14653626	1219	1226	glucose	Chemical
14653626	1385	1390	human	Species
23143540|t|Dehydroepiandrosterone has strong antifibrotic effects and is decreased in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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-IAP)1 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	0	22	Dehydroepiandrosterone	Chemical
23143540	75	104	idiopathic pulmonary fibrosis	Disease
23143540	106	135	Idiopathic pulmonary fibrosis	Disease
23143540	137	140	IPF	Disease
23143540	163	176	lung disorder	Disease
23143540	267	289	Dehydroepiandrosterone	Chemical
23143540	291	295	DHEA	Chemical
23143540	300	307	steroid	Chemical
23143540	321	331	decreases	Negative_regulation
23143540	400	421	degenerative diseases	Disease
23143540	458	462	DHEA	Chemical
23143540	486	490	DHEA	Chemical
23143540	501	504	IPF	Disease
23143540	505	513	patients	Species
23143540	558	562	DHEA	Chemical
23143540	566	571	human	Species
23143540	597	601	DHEA	Chemical
23143540	602	606	DHEA	Chemical
23143540	645	648	IPF	Disease
23143540	649	657	patients	Species
23143540	674	678	DHEA	Chemical
23143540	739	743	DHEA	Chemical
23143540	832	836	DHEA	Chemical
23143540	933	937	DHEA	Chemical
23143540	1092	1103	activation	Positive_regulation
23143540	1106	1115	caspase-9	Gene
23143540	1148	1161	upregulation	Positive_regulation
23143540	1196	1199	Bax	Gene
23143540	1334	1341	c-IAP)1	Gene
23143540	1346	1352	c-IAP2	Gene
23143540	1354	1358	DHEA	Chemical
23143540	1385	1394	decrease	Negative_regulation
23143540	1397	1426	transforming growth factor-b1	Gene
23143540	1444	1455	production	Gene_expression
23143540	1608	1624	disproportionate	Chemical
23143540	1625	1634	decrease	Negative_regulation
23143540	1637	1641	DHEA	Chemical
23143540	1642	1646	DHEA	Chemical
23143540	1652	1655	IPF	Disease
23143540	1656	1664	patients	Species
11713352|t|Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by subpleural fibrosis that progresses to involve all areas of the lung
The expression of transforming growth factor-beta1 (TGF-beta 1), a potent regulator of connective tissue synthesis, is increased in lung sections of patients with IPF
TGF-beta 1 is generally released in a biologically latent form (L-TGF-beta 1)
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-TGF-beta 1, is also important in the biology of TGF-beta 1
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-TGF-beta 1 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
TGF-beta 1 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 TGF-beta 1 for synthesis of connective tissue proteins
Our findings show that biologically active TGF-beta 1 is only present in the lungs of patients with IPF
In addition, the effects of TGF-beta 1 on cells may be further regulated by the expression of T beta Rs
CONCLUSION: Activation of L-TGF-beta 1 and the differential expression of T beta Rs may be important in the pathogenesis of remodelling and fibrosis in IPF
11713352	29	39	TGF-beta 1	Gene
11713352	64	74	TGF-beta 1	Gene
11713352	92	103	expression	Gene_expression
11713352	106	152	TGF-beta receptors (T beta R-I and T beta R-II	Gene
11713352	157	186	idiopathic pulmonary fibrosis	Disease
11713352	200	229	Idiopathic pulmonary fibrosis	Disease
11713352	231	234	IPF	Disease
11713352	267	275	fibrosis	Disease
11713352	344	376	transforming growth factor-beta1	Gene
11713352	378	388	TGF-beta 1	Gene
11713352	475	483	patients	Species
11713352	489	492	IPF	Disease
11713352	494	504	TGF-beta 1	Gene
11713352	518	527	released	Localization
11713352	560	570	TGF-beta 1	Gene
11713352	607	615	TGF-beta	Gene
11713352	624	634	converted	Positive_regulation
11713352	657	666	interact	Binding
11713352	676	736	TGF-beta receptors type I and II (T beta R-I and T beta R-II	Gene
11713352	739	747	TGF-beta	Gene
11713352	775	781	LTBP-1	Gene
11713352	790	802	facilitates	Positive_regulation
11713352	806	814	release	Localization
11713352	834	842	TGF-beta	Gene
11713352	882	892	TGF-beta 1	Gene
11713352	933	941	patients	Species
11713352	947	950	IPF	Disease
11713352	1026	1032	LTBP-1	Gene
11713352	1155	1163	TGF-beta	Gene
11713352	1167	1175	present	Gene_expression
11713352	1210	1218	patients	Species
11713352	1224	1227	IPF	Disease
11713352	1255	1265	TGF-beta 1	Gene
11713352	1299	1307	patients	Species
11713352	1313	1316	IPF	Disease
11713352	1389	1395	LTBP-1	Gene
11713352	1490	1493	IPF	Disease
11713352	1511	1517	LTBP-1	Gene
11713352	1598	1606	patients	Species
11713352	1612	1615	IPF	Disease
11713352	1616	1625	secreted	Localization
11713352	1666	1674	TGF-beta	Gene
11713352	1731	1739	patients	Species
11713352	1740	1749	secreted	Localization
11713352	1759	1767	TGF-beta	Gene
11713352	1785	1793	TGF-beta	Gene
11713352	1860	1863	IPF	Disease
11713352	1864	1872	patients	Species
11713352	1929	1937	TGF-beta	Gene
11713352	1977	1985	patients	Species
11713352	1991	1994	IPF	Disease
11713352	2026	2034	patients	Species
11713352	2103	2111	TGF-beta	Gene
11713352	2112	2121	secreted	Localization
11713352	2184	2192	TGF-beta	Gene
11713352	2254	2262	patients	Species
11713352	2268	2271	IPF	Disease
11713352	2356	2364	patients	Species
11713352	2370	2373	IPF	Disease
11713352	2425	2433	TGF-beta	Gene
11713352	2488	2496	TGF-beta	Gene
11713352	2623	2631	patients	Species
11713352	2661	2669	TGF-beta	Gene
11713352	2896	2904	patients	Species
11713352	2910	2913	IPF	Disease
11713352	2915	2925	TGF-beta 1	Gene
11713352	3209	3219	TGF-beta 1	Gene
11713352	3308	3318	TGF-beta 1	Gene
11713352	3327	3335	present	Gene_expression
11713352	3351	3359	patients	Species
11713352	3365	3368	IPF	Disease
11713352	3398	3408	TGF-beta 1	Gene
11713352	3433	3443	regulated	Regulation
11713352	3450	3461	expression	Gene_expression
11713352	3487	3498	Activation	Positive_regulation
11713352	3503	3513	TGF-beta 1	Gene
11713352	3535	3546	expression	Gene_expression
11713352	3615	3623	fibrosis	Disease
11713352	3627	3630	IPF	Disease
28816543|t|MiR-541-5p regulates lung fibrosis by targeting cyclic nucleotide phosphodiesterase 1A
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 lung fibrosis
28816543	11	21	regulates	Regulation
28816543	21	34	lung fibrosis	Disease
28816543	38	48	targeting	Regulation
28816543	55	65	nucleotide	Chemical
28816543	106	135	Idiopathic pulmonary fibrosis	Disease
28816543	137	140	IPF	Disease
28816543	154	159	human	Species
28816543	269	279	nucleotide	Chemical
28816543	302	307	PDE1A	Gene
28816543	312	316	Ca2+	Chemical
28816543	340	343	PDE	Disease
28816543	401	409	fibrosis	Disease
28816543	473	489	pulmonary damage	Disease
28816543	505	509	rats	Species
28816543	528	537	bleomycin	Chemical
28816543	623	633	silencing	Negative_regulation
28816543	636	641	PDE1A	Gene
28816543	645	648	rat	Species
28816543	686	691	PDE1A	Gene
28816543	725	728	rat	Species
28816543	757	762	Human	Species
28816543	802	806	hFL1	Gene
28816543	811	814	rat	Species
28816543	938	943	PDE1A	Gene
28816543	954	965	expression	Gene_expression
28816543	1179	1184	PDE1A	Gene
28816543	1344	1353	bleomycin	Chemical
28816543	1389	1400	expression	Gene_expression
28816543	1403	1417	downregulated	Negative_regulation
28816543	1420	1425	TGF-b	Gene
28816543	1459	1462	rat	Species
28816543	1473	1481	fibrosis	Disease
28816543	1489	1504	Overexpression	Positive_regulation
28816543	1561	1566	human	Species
28816543	1652	1663	regulating	Regulation
28816543	1663	1668	PDE1A	Gene
28816543	1669	1680	expression	Gene_expression
28816543	1754	1763	bleomycin	Chemical
28816543	1772	1785	lung fibrosis	Disease
26276873|t|Lipoxin A4 Attenuates Constitutive and TGF-b1-Dependent Profibrotic Activity in Human Lung Myofibroblasts
Idiopathic pulmonary fibrosis (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 TGF-b1-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 TGF-b1 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 TGF-b1-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	0	10	Lipoxin A4	Chemical
26276873	39	45	TGF-b1	Gene
26276873	80	85	Human	Species
26276873	107	136	Idiopathic pulmonary fibrosis	Disease
26276873	138	141	IPF	Disease
26276873	191	216	interstitial lung disease	Disease
26276873	284	292	fibrosis	Disease
26276873	315	325	Lipoxin A4	Chemical
26276873	327	331	LXA4	Chemical
26276873	395	407	inflammation	Disease
26276873	477	481	LXA4	Chemical
26276873	493	498	human	Species
26276873	629	633	LXA4	Chemical
26276873	637	643	TGF-b1	Gene
26276873	667	670	IPF	Disease
26276873	676	695	nonfibrotic control	Disease
26276873	697	700	NFC	Disease
26276873	742	745	IPF	Disease
26276873	750	753	NFC	Disease
26276873	754	762	patients	Species
26276873	787	795	effects	Regulation
26276873	798	802	LXA4	Chemical
26276873	835	845	secretion	Localization
26276873	846	867	a-smooth muscle actin	Gene
26276873	869	873	aSMA	Gene
26276873	875	886	expression	Gene_expression
26276873	891	898	Smad2/3	Gene
26276873	899	910	activation	Positive_regulation
26276873	953	959	TGF-b1	Gene
26276873	977	990	LXA4 receptor	Gene
26276873	992	996	ALXR	Gene
26276873	1002	1012	expressed	Gene_expression
26276873	1020	1023	NFC	Disease
26276873	1029	1032	IPF	Disease
26276873	1048	1052	LXA4	Chemical
26276873	1078	1086	reduced	Negative_regulation
26276873	1099	1103	aSMA	Gene
26276873	1171	1178	Smad2/3	Gene
26276873	1248	1252	LXA4	Chemical
26276873	1272	1282	inhibited	Negative_regulation
26276873	1314	1320	TGF-b1	Gene
26276873	1321	1331	dependent	Positive_regulation
26276873	1340	1350	secretion	Localization
26276873	1351	1355	aSMA	Gene
26276873	1372	1379	Smad2/3	Gene
26276873	1380	1388	nuclear	Entity
26276873	1388	1402	translocation	Localization
26276873	1405	1408	IPF	Disease
26276873	1424	1428	LXA4	Chemical
26276873	1437	1445	inhibit	Negative_regulation
26276873	1445	1452	Smad2/3	Gene
26276873	1453	1469	phosphorylation	Phosphorylation
26276873	1482	1486	LXA4	Chemical
26276873	1590	1594	LXA4	Chemical
26276873	1685	1688	IPF	Disease
27070485|t|Establishment of the mouse model of acute exacerbation of idiopathic pulmonary fibrosis
PURPOSE: To explore and establish an animal model of AE-IPF
METHODS: An animal model of idiopathic pulmonary fibrosis (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	21	26	mouse	Species
27070485	58	87	idiopathic pulmonary fibrosis	Disease
27070485	142	148	AE-IPF	Disease
27070485	178	207	idiopathic pulmonary fibrosis	Disease
27070485	209	212	IPF	Disease
27070485	236	245	bleomycin	Chemical
27070485	247	250	BLM	Chemical
27070485	259	262	BLM	Chemical
27070485	314	320	AE-IPF	Disease
27070485	335	340	human	Species
27070485	341	347	AE-IPF	Disease
27070485	421	425	mice	Species
27070485	551	557	AE-IPF	Disease
27070485	642	647	mouse	Species
27070485	725	729	IL-4	Gene
27070485	731	735	IL-6	Gene
27070485	737	742	IL-10	Gene
27070485	744	750	IL-17A	Gene
27070485	752	755	MIG	Gene
27070485	761	767	TGF-b1	Gene
27070485	826	829	IPF	Disease
27070485	834	840	AE-IPF	Disease
27070485	867	873	IL-17A	Gene
27070485	939	942	BLM	Chemical
27070485	980	986	AE-IPF	Disease
27070485	1051	1054	IPF	Disease
27070485	1108	1114	AE-IPF	Disease
27070485	1187	1193	AE-IPF	Disease
27070485	1201	1213	inflammation	Disease
27070485	1218	1226	fibrosis	Disease
27070485	1277	1283	IL-17A	Gene
27070485	1285	1288	MIG	Gene
27070485	1290	1296	CXCL-9	Gene
27070485	1299	1303	IL-6	Gene
27070485	1309	1315	TGF-b1	Gene
27070485	1476	1482	IL-17A	Gene
27070485	1498	1530	attenuated the lung inflammation	Disease
27070485	1531	1539	induced	Positive_regulation
27070485	1548	1551	BLM	Chemical
27070485	1578	1583	mouse	Species
27070485	1593	1599	AE-IPF	Disease
27070485	1648	1651	BLM	Chemical
27070485	1719	1725	AE-IPF	Disease
24276150|t|CCN5 overexpression inhibits profibrotic phenotypes via the PI3K/Akt signaling pathway in lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis and in an in vivo model of lung fibrosis
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 lung fibrosis 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 lung fibrosis
CCN5, 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 CCN5 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, CCN5 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 CCN5
The overexpression of CCN5 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 CCN5 overexpression
Our results also demonstrated that adenovirus-mediated CCN5 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 CCN5 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	0	4	CCN5	Gene
24276150	5	20	overexpression	Positive_regulation
24276150	60	64	PI3K	Gene
24276150	121	129	patients	Species
24276150	135	164	idiopathic pulmonary fibrosis	Disease
24276150	192	205	lung fibrosis	Disease
24276150	207	236	Idiopathic pulmonary fibrosis	Disease
24276150	238	241	IPF	Disease
24276150	272	297	interstitial lung disease	Disease
24276150	445	458	lung fibrosis	Disease
24276150	462	472	secreting	Localization
24276150	567	571	CTGF	Gene
24276150	572	576	CCN2	Gene
24276150	623	627	CCN2	Gene
24276150	631	644	lung fibrosis	Disease
24276150	646	650	CCN5	Gene
24276150	740	757	fibrotic diseases	Disease
24276150	767	783	cardiac fibrosis	Disease
24276150	806	810	CCN5	Gene
24276150	829	832	IPF	Disease
24276150	921	925	CCN2	Gene
24276150	936	946	expressed	Gene_expression
24276150	974	977	IPF	Disease
24276150	1007	1017	expressed	Gene_expression
24276150	1027	1032	human	Species
24276150	1060	1064	CCN5	Gene
24276150	1076	1086	expressed	Gene_expression
24276150	1180	1190	increased	Positive_regulation
24276150	1190	1194	CCN2	Gene
24276150	1195	1206	expression	Gene_expression
24276150	1213	1216	IPF	Disease
24276150	1245	1250	human	Species
24276150	1340	1349	affected	Regulation
24276150	1353	1364	expression	Gene_expression
24276150	1367	1371	CCN5	Gene
24276150	1377	1392	overexpression	Positive_regulation
24276150	1395	1399	CCN5	Gene
24276150	1400	1408	induced	Positive_regulation
24276150	1547	1558	suppressed	Negative_regulation
24276150	1562	1573	expression	Gene_expression
24276150	1576	1580	CCN2	Gene
24276150	1605	1610	a-SMA	Gene
24276150	1637	1643	TGF-b1	Gene
24276150	1652	1665	upregulation	Positive_regulation
24276150	1672	1688	phosphorylation	Phosphorylation
24276150	1711	1715	CCN5	Gene
24276150	1716	1731	overexpression	Positive_regulation
24276150	1767	1777	adenovirus	Species
24276150	1787	1791	CCN5	Gene
24276150	1792	1807	overexpression	Positive_regulation
24276150	1812	1817	mouse	Species
24276150	1827	1836	bleomycin	Chemical
24276150	1845	1848	IPF	Disease
24276150	1863	1873	decreased	Negative_regulation
24276150	1877	1891	hydroxyproline	Chemical
24276150	1925	1931	TGF-b1	Gene
24276150	1932	1943	expression	Gene_expression
24276150	2018	2022	CCN5	Gene
24276150	2184	2187	IPF	Disease
22246864|t|Spiruchostatin A inhibits proliferation and differentiation of fibroblasts from patients with pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disorder characterized by the proliferation of interstitial fibroblasts and the deposition of extracellular matrix causing impaired gas exchange
Spiruchostatin A (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 (myo)fibroblast 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)-b(1) was quantified by methylene blue binding
The acetylation of histone H3, the expression of the cell-cycle inhibitor p21(waf1), 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 p21(waf1) expression, suggesting that direct cell-cycle regulation was the mechanism of inhibiting proliferation
Although treatment with TGF-b(1) 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	0	16	Spiruchostatin A	Gene
22246864	80	88	patients	Species
22246864	94	112	pulmonary fibrosis	Disease
22246864	114	143	Idiopathic pulmonary fibrosis	Disease
22246864	145	148	IPF	Disease
22246864	167	184	scarring disorder	Disease
22246864	322	338	Spiruchostatin A	Gene
22246864	340	343	SpA	Gene
22246864	370	380	inhibitor	Negative_regulation
22246864	638	641	SpA	Gene
22246864	780	788	patients	Species
22246864	794	797	IPF	Disease
22246864	904	907	SpA	Gene
22246864	1016	1030	methylene blue	Chemical
22246864	1044	1056	acetylation	Positive_regulation
22246864	1075	1086	expression	Gene_expression
22246864	1114	1122	p21(waf1	Gene
22246864	1178	1183	a-SMA	Gene
22246864	1214	1225	determined	Regulation
22246864	1311	1314	SpA	Gene
22246864	1552	1564	cytotoxicity	Disease
22246864	1602	1605	SpA	Gene
22246864	1639	1648	increase	Positive_regulation
22246864	1717	1720	SpA	Gene
22246864	1726	1736	increased	Positive_regulation
22246864	1736	1744	p21(waf1	Gene
22246864	1746	1757	expression	Gene_expression
22246864	1874	1881	TGF-b(1	Gene
22246864	1937	1947	increased	Positive_regulation
22246864	1947	1958	expression	Gene_expression
22246864	1961	1966	a-SMA	Gene
22246864	2017	2025	release	Localization
22246864	2069	2072	SpA	Gene
23043074|t|Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective therapeutics
Periostin 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 fibrosis and survival were assessed
Periostin expression was upregulated quickly after treatment with bleomycin and remained elevated
Periostin(-/-) mice were protected from bleomycin-induced fibrosis
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
Periostin 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 fibrosis and is a potential biomarker for disease progression and a target for therapeutic intervention
23043074	0	9	Periostin	Gene
23043074	19	27	fibrosis	Disease
23043074	56	64	patients	Species
23043074	70	99	idiopathic pulmonary fibrosis	Disease
23043074	101	130	Idiopathic pulmonary fibrosis	Disease
23043074	132	135	IPF	Disease
23043074	154	175	fibrotic lung disease	Disease
23043074	208	217	Periostin	Gene
23043074	254	257	IPF	Disease
23043074	258	266	patients	Species
23043074	364	373	periostin	Gene
23043074	386	389	IPF	Disease
23043074	390	398	patients	Species
23043074	413	416	IPF	Disease
23043074	437	446	periostin	Gene
23043074	475	478	IPF	Disease
23043074	479	487	patients	Species
23043074	538	547	periostin	Gene
23043074	703	712	periostin	Gene
23043074	731	734	IPF	Disease
23043074	735	743	patients	Species
23043074	775	784	periostin	Gene
23043074	824	833	bleomycin	Chemical
23043074	842	853	lung injury	Disease
23043074	859	868	periostin	Gene
23043074	955	964	periostin	Gene
23043074	976	985	periostin	Gene
23043074	992	996	mice	Species
23043074	1035	1044	bleomycin	Chemical
23043074	1056	1060	mice	Species
23043074	1080	1089	bleomycin	Chemical
23043074	1128	1135	blocks	Negative_regulation
23043074	1135	1144	periostin	Gene
23043074	1158	1171	interactions	Binding
23043074	1238	1246	fibrosis	Disease
23043074	1275	1284	Periostin	Gene
23043074	1285	1296	expression	Gene_expression
23043074	1300	1312	upregulated	Positive_regulation
23043074	1341	1350	bleomycin	Chemical
23043074	1364	1373	elevated	Positive_regulation
23043074	1374	1383	Periostin	Gene
23043074	1389	1393	mice	Species
23043074	1414	1423	bleomycin	Chemical
23043074	1432	1440	fibrosis	Disease
23043074	1560	1565	mouse	Species
23043074	1627	1636	periostin	Gene
23043074	1670	1679	Periostin	Gene
23043074	1759	1768	periostin	Gene
23043074	1867	1876	periostin	Gene
23043074	1914	1932	pulmonary fibrosis	Disease
25680454|t|Tumor necrosis factor superfamily 14 (LIGHT) controls thymic stromal lymphopoietin to drive pulmonary fibrosis
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 necrosis 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	6	14	necrosis	Disease
25680454	38	43	LIGHT	Disease
25680454	54	82	thymic stromal lymphopoietin	Gene
25680454	92	110	pulmonary fibrosis	Disease
25680454	124	142	Pulmonary fibrosis	Disease
25680454	173	186	accumulation	Positive_regulation
25680454	323	351	Thymic stromal lymphopoietin	Gene
25680454	353	357	TSLP	Gene
25680454	392	400	patients	Species
25680454	406	412	asthma	Disease
25680454	417	446	idiopathic pulmonary fibrosis	Disease
25680454	452	456	TSLP	Gene
25680454	488	519	driver of lung fibrotic disease	Disease
25680454	538	582	tumor necrosis factor superfamily protein 14	Gene
25680454	584	591	TNFSF14	Gene
25680454	598	603	LIGHT	Disease
25680454	614	618	TSLP	Gene
25680454	642	650	fibrosis	Disease
25680454	661	672	Expression	Gene_expression
25680454	675	679	TSLP	Gene
25680454	698	716	pulmonary fibrosis	Disease
25680454	728	737	bleomycin	Chemical
25680454	755	759	mice	Species
25680454	760	770	deficient	Negative_regulation
25680454	773	778	LIGHT	Disease
25680454	807	812	LIGHT	Disease
25680454	845	849	mice	Species
25680454	862	866	TSLP	Gene
25680454	871	879	fibrosis	Disease
25680454	930	935	LIGHT	Disease
25680454	936	946	abolished	Negative_regulation
25680454	951	955	TSLP	Gene
25680454	956	967	expression	Gene_expression
25680454	977	986	bleomycin	Chemical
25680454	1017	1025	absence	Negative_regulation
25680454	1110	1115	LIGHT	Disease
25680454	1138	1146	induced	Positive_regulation
25680454	1151	1162	expression	Gene_expression
25680454	1165	1169	TSLP	Gene
25680454	1266	1275	bleomycin	Chemical
25680454	1296	1300	TSLP	Gene
25680454	1331	1336	LIGHT	Disease
25680454	1337	1345	binding	Binding
25680454	1405	1430	lymphotoxin beta receptor	Gene
25680454	1463	1481	pulmonary fibrosis	Disease
25680454	1532	1537	human	Species
25680454	1586	1590	TSLP	Gene
25680454	1602	1607	LIGHT	Disease
25680454	1608	1616	induced	Positive_regulation
25680454	1616	1620	TSLP	Gene
25680454	1633	1638	human	Species
25680454	1686	1691	IL-13	Gene
25680454	1696	1701	TGF-b	Gene
25680454	1714	1722	promote	Positive_regulation
25680454	1722	1726	TSLP	Gene
25680454	1750	1758	fibrosis	Disease
25680454	1797	1802	LIGHT	Disease
25680454	1859	1863	TSLP	Gene
25680454	1921	1937	fibrotic disease	Disease
28847533|t|High levels of IL-6 and IL-8 characterize early-on idiopathic pulmonary fibrosis acute exacerbations
INTRODUCTION: Controversy exists about the pathogenesis of idiopathic pulmonary fibrosis 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, IL-6, IL-8, 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 IL-6 and IL-8 levels were significantly higher in exacerbated patients (p=0.002 and p=0.046, respectively)
An increase in either IL-6 or IL-8 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 IL-6 and IL-8 characterize early-on IPF-AEs and an increase in the levels of IL-6 and IL-8 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 IL-6 further studies are necessary to clarify the enigma of IPF-AEs etiopathogenesis
28847533	15	19	IL-6	Gene
28847533	24	28	IL-8	Gene
28847533	51	80	idiopathic pulmonary fibrosis	Disease
28847533	161	190	idiopathic pulmonary fibrosis	Disease
28847533	212	215	IPF	Disease
28847533	250	253	IPF	Disease
28847533	300	323	diffuse alveolar damage	Disease
28847533	325	328	DAD	Disease
28847533	335	363	usual interstitial pneumonia	Disease
28847533	365	368	UIP	Disease
28847533	698	701	IPF	Disease
28847533	702	710	patients	Species
28847533	733	736	IPF	Disease
28847533	737	745	patients	Species
28847533	801	804	IPF	Disease
28847533	809	812	IPF	Disease
28847533	904	908	IL-6	Gene
28847533	910	914	IL-8	Gene
28847533	916	921	IL-10	Gene
28847533	927	932	IL-13	Gene
28847533	950	981	transforming growth factor-beta	Gene
28847533	983	988	TGF-b	Gene
28847533	1046	1054	patients	Species
28847533	1248	1256	patients	Species
28847533	1327	1335	patients	Species
28847533	1350	1354	IL-6	Gene
28847533	1359	1363	IL-8	Gene
28847533	1412	1420	patients	Species
28847533	1461	1470	increase	Positive_regulation
28847533	1480	1484	IL-6	Gene
28847533	1488	1492	IL-8	Gene
28847533	1525	1530	death	Disease
28847533	1590	1598	patients	Species
28847533	1671	1678	levels	Positive_regulation
28847533	1681	1685	IL-6	Gene
28847533	1690	1694	IL-8	Gene
28847533	1717	1720	IPF	Disease
28847533	1732	1741	increase	Positive_regulation
28847533	1758	1762	IL-6	Gene
28847533	1767	1771	IL-8	Gene
28847533	1772	1783	associates	Binding
28847533	1809	1817	patients	Species
28847533	1879	1884	TGF-b	Gene
28847533	1886	1891	IL-10	Gene
28847533	1893	1897	IL-4	Gene
28847533	1902	1907	IL-13	Gene
28847533	1917	1927	increased	Positive_regulation
28847533	2001	2005	IL-6	Gene
28847533	2061	2064	IPF	Disease
23436625|t|Mast cell chymase: an indispensable instrument in the pathological symphony of idiopathic pulmonary fibrosis? Idiopathic pulmonary fibrosis (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	79	108	idiopathic pulmonary fibrosis	Disease
23436625	110	139	Idiopathic pulmonary fibrosis	Disease
23436625	141	144	IPF	Disease
23436625	182	194	lung disease	Disease
23436625	305	333	usual interstitial pneumonia	Disease
23436625	335	338	UIP	Disease
23436625	357	378	interstitial fibrosis	Disease
23436625	742	745	IPF	Disease
23436625	1167	1170	IPF	Disease
23436625	1265	1276	activation	Positive_regulation
23436625	1463	1466	IPF	Disease
23436625	1616	1634	pulmonary fibrosis	Disease
16574935|t|Defect of pro-hepatocyte growth factor activation by fibroblasts in idiopathic pulmonary fibrosis
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 idiopathic pulmonary fibrosis (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-beta(1) and PGE(2) 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
PGE(2) stimulated pro-HGF activation through increased expression of HGFA and decreased expression of its inhibitor HAI-2
In contrast, TGF-beta(1) 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 PGE(2) is able to partially correct this defect
16574935	14	38	hepatocyte growth factor	Gene
16574935	68	97	idiopathic pulmonary fibrosis	Disease
16574935	125	149	Hepatocyte growth factor	Gene
16574935	151	154	HGF	Gene
16574935	173	186	lung fibrosis	Disease
16574935	217	220	HGF	Gene
16574935	221	232	activation	Positive_regulation
16574935	235	238	HGF	Gene
16574935	255	266	regulation	Regulation
16574935	284	288	HGFA	Gene
16574935	293	299	serine	Chemical
16574935	314	318	HGFA	Gene
16574935	340	345	HAI-1	Gene
16574935	350	355	HAI-2	Gene
16574935	399	407	patients	Species
16574935	413	442	idiopathic pulmonary fibrosis	Disease
16574935	444	447	IPF	Disease
16574935	489	492	HGF	Gene
16574935	578	581	HGF	Gene
16574935	582	593	activation	Positive_regulation
16574935	596	601	human	Species
16574935	650	658	patients	Species
16574935	664	667	IPF	Disease
16574935	685	689	HGFA	Gene
16574935	691	696	HAI-1	Gene
16574935	702	707	HAI-2	Gene
16574935	708	719	expression	Gene_expression
16574935	815	822	effect	Regulation
16574935	825	836	TGF-beta(1)	Gene
16574935	841	847	PGE(2)	Chemical
16574935	855	858	HGF	Gene
16574935	859	870	activation	Positive_regulation
16574935	874	878	HGFA	Gene
16574935	880	885	HAI-1	Gene
16574935	891	896	HAI-2	Gene
16574935	897	908	expression	Gene_expression
16574935	954	957	HGF	Gene
16574935	972	975	HGF	Gene
16574935	976	987	activation	Positive_regulation
16574935	991	1001	inhibited	Negative_regulation
16574935	1004	1010	serine	Chemical
16574935	1020	1031	inhibitors	Negative_regulation
16574935	1043	1047	HGFA	Gene
16574935	1072	1077	HAI-1	Gene
16574935	1082	1087	HAI-2	Gene
16574935	1093	1096	HGF	Gene
16574935	1097	1108	activation	Positive_regulation
16574935	1111	1114	IPF	Disease
16574935	1131	1139	reduced	Negative_regulation
16574935	1177	1180	IPF	Disease
16574935	1194	1198	HGFA	Gene
16574935	1199	1210	expression	Gene_expression
16574935	1214	1220	lower	Negative_regulation
16574935	1224	1229	HAI-1	Gene
16574935	1234	1239	HAI-2	Gene
16574935	1240	1251	expression	Gene_expression
16574935	1297	1303	PGE(2)	Chemical
16574935	1319	1322	HGF	Gene
16574935	1323	1334	activation	Positive_regulation
16574935	1352	1363	expression	Gene_expression
16574935	1366	1370	HGFA	Gene
16574935	1413	1418	HAI-2	Gene
16574935	1433	1444	TGF-beta(1)	Gene
16574935	1488	1497	activate	Positive_regulation
16574935	1501	1504	HGF	Gene
16574935	1523	1534	expression	Gene_expression
16574935	1537	1541	HGFA	Gene
16574935	1599	1602	IPF	Disease
16574935	1651	1654	HGF	Gene
16574935	1674	1680	level	Negative_regulation
16574935	1683	1687	HGFA	Gene
16574935	1688	1699	expression	Gene_expression
16574935	1718	1723	HAI-1	Gene
16574935	1728	1733	HAI-2	Gene
16574935	1734	1745	expression	Gene_expression
16574935	1750	1756	PGE(2)	Chemical
15734789|t|Lung infection with gamma-herpesvirus induces progressive pulmonary fibrosis in Th2-biased mice
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis and many of the pathological features seen in IPF
15734789	0	14	Lung infection	Disease
15734789	58	76	pulmonary fibrosis	Disease
15734789	91	95	mice	Species
15734789	97	126	Idiopathic pulmonary fibrosis	Disease
15734789	128	131	IPF	Disease
15734789	151	172	fibrotic lung disease	Disease
15734789	218	221	IPF	Disease
15734789	255	258	IPF	Disease
15734789	259	267	patients	Species
15734789	293	312	pulmonary infection	Disease
15734789	366	385	pulmonary infection	Disease
15734789	418	426	fibrosis	Disease
15734789	440	444	mice	Species
15734789	454	460	murine	Species
15734789	499	502	IPF	Disease
15734789	503	511	patients	Species
15734789	570	580	IFN-gammaR	Gene
15734789	597	601	mice	Species
15734789	662	672	IFN-gammaR	Gene
15734789	676	680	mice	Species
15734789	847	858	deposition	Negative_regulation
15734789	891	894	IPF	Disease
15734789	1009	1020	hyperplasia	Disease
15734789	1043	1053	increased	Positive_regulation
15734789	1053	1064	expression	Gene_expression
15734789	1067	1093	matrix metalloproteinase-7	Gene
15734789	1137	1147	IFN-gammaR	Gene
15734789	1151	1155	mice	Species
15734789	1236	1244	patients	Species
15734789	1250	1262	familial IPF	Disease
15734789	1362	1391	extensive alveolar remodeling	Disease
15734789	1425	1444	pulmonary infection	Disease
15734789	1448	1458	IFN-gammaR	Gene
15734789	1462	1466	mice	Species
15734789	1486	1504	pulmonary fibrosis	Disease
15734789	1551	1554	IPF	Disease
21642472|t|Role of von Hippel-Lindau protein in fibroblast proliferation and fibrosis
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 von Hippel-Lindau 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	8	25	von Hippel-Lindau	Disease
21642472	66	74	fibrosis	Disease
21642472	76	105	Idiopathic pulmonary fibrosis	Disease
21642472	107	110	IPF	Disease
21642472	203	214	fibronectin	Gene
21642472	234	245	fibronectin	Gene
21642472	270	280	regulated	Regulation
21642472	283	300	von Hippel-Lindau	Disease
21642472	310	314	pVHL	Gene
21642472	348	352	pVHL	Gene
21642472	368	386	pulmonary fibrosis	Disease
21642472	413	421	patients	Species
21642472	427	430	IPF	Disease
21642472	431	441	expressed	Gene_expression
21642472	461	465	pVHL	Gene
21642472	488	497	Bleomycin	Chemical
21642472	513	521	induced	Positive_regulation
21642472	521	525	pVHL	Gene
21642472	600	604	pVHL	Gene
21642472	667	678	fibronectin	Gene
21642472	711	722	fibronectin	Gene
21642472	737	752	overexpression	Positive_regulation
21642472	755	759	pVHL	Gene
21642472	768	779	expression	Gene_expression
21642472	807	822	Overexpression	Positive_regulation
21642472	825	829	pVHL	Gene
21642472	844	851	hypoxia	Disease
21642472	907	918	expression	Transcription
21642472	921	955	vascular endothelial growth factor	Gene
21642472	969	984	overexpressing	Positive_regulation
21642472	984	988	pVHL	Gene
21642472	1130	1145	overexpressing	Positive_regulation
21642472	1145	1149	pVHL	Gene
21642472	1193	1204	inhibition	Negative_regulation
21642472	1220	1235	Overexpression	Positive_regulation
21642472	1238	1242	pVHL	Gene
21642472	1248	1258	increased	Positive_regulation
21642472	1258	1269	activation	Positive_regulation
21642472	1272	1293	focal adhesion kinase	Gene
21642472	1295	1298	FAK	Gene
21642472	1311	1323	suppression	Negative_regulation
21642472	1326	1330	pVHL	Gene
21642472	1341	1347	TGF-b1	Gene
21642472	1373	1378	mouse	Species
21642472	1444	1453	elevated	Positive_regulation
21642472	1453	1464	expression	Gene_expression
21642472	1467	1471	pVHL	Gene
21642472	1496	1507	fibronectin	Gene
21642472	1508	1519	expression	Gene_expression
21642472	1543	1546	FAK	Gene
21642472	1588	1596	fibrosis	Disease
20643828|t|miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis
Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary fibrosis (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 miR-21 in the lungs of mice with bleomycin-induced fibrosis and also in the lungs of patients with IPF
Increased miR-21 expression was primarily localized to myofibroblasts
Administration of miR-21 antisense probes diminished the severity of experimental lung fibrosis 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 miR-21 expression in primary pulmonary fibroblasts
Increasing miR-21 levels promoted, whereas knocking down miR-21 attenuated, the pro-fibrogenic activity of TGF-beta1 in fibroblasts
A potential mechanism for the role of miR-21 in fibrosis is through regulating the expression of an inhibitory Smad, Smad7
These experiments demonstrate an important role for miR-21 in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory fibrotic diseases, such as IPF
20643828	0	6	miR-21	Gene
20643828	72	80	fibrosis	Disease
20643828	186	203	fibrotic diseases	Disease
20643828	213	242	idiopathic pulmonary fibrosis	Disease
20643828	244	247	IPF	Disease
20643828	444	466	fibrotic lung diseases	Disease
20643828	520	526	miR-21	Gene
20643828	543	547	mice	Species
20643828	553	562	bleomycin	Chemical
20643828	571	579	fibrosis	Disease
20643828	605	613	patients	Species
20643828	619	622	IPF	Disease
20643828	634	640	miR-21	Gene
20643828	713	719	miR-21	Gene
20643828	764	790	experimental lung fibrosis	Disease
20643828	794	798	mice	Species
20643828	858	874	pulmonary injury	Disease
20643828	876	885	TGF-beta1	Gene
20643828	922	939	fibrotic diseases	Disease
20643828	950	956	miR-21	Gene
20643828	1013	1019	miR-21	Gene
20643828	1059	1065	miR-21	Gene
20643828	1109	1118	TGF-beta1	Gene
20643828	1173	1179	miR-21	Gene
20643828	1183	1191	fibrosis	Disease
20643828	1203	1214	regulating	Regulation
20643828	1218	1229	expression	Gene_expression
20643828	1252	1257	Smad7	Gene
20643828	1311	1317	miR-21	Gene
20643828	1321	1343	fibrotic lung diseases	Disease
20643828	1437	1454	fibrotic diseases	Disease
20643828	1464	1467	IPF	Disease
28182573|t|Amplified canonical transforming growth factor-b signalling<i>via</i>heat shock protein 90 in pulmonary fibrosis
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 heat shock protein (HSP)90 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 (myo)fibroblasts 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	69	79	heat shock	Disease
28182573	94	112	pulmonary fibrosis	Disease
28182573	230	259	idiopathic pulmonary fibrosis	Disease
28182573	261	264	IPF	Disease
28182573	351	358	define	Negative_regulation
28182573	370	396	heat shock protein (HSP)90	Gene
28182573	425	428	IPF	Disease
28182573	473	478	HSP90	Gene
28182573	479	490	inhibition	Negative_regulation
28182573	495	501	murine	Species
28182573	511	529	pulmonary fibrosis	Disease
28182573	561	566	HSP90	Gene
28182573	607	610	AAG	Gene
28182573	612	650	17-allylamino-17-demethoxygeldanamycin	Chemical
28182573	721	728	17-DMAG	Chemical
28182573	730	781	17-dimethylaminoethylamino-17-demethoxygeldanamycin	Chemical
28182573	786	790	mice	Species
28182573	796	805	bleomycin	Chemical
28182573	814	832	pulmonary fibrosis	Disease
28182573	833	838	HSP90	Gene
28182573	839	850	expression	Gene_expression
28182573	898	903	human	Species
28182573	908	913	mouse	Species
28182573	947	950	AAG	Gene
28182573	961	967	TGF-b1	Gene
28182573	1152	1157	TGF-b	Gene
28182573	1182	1193	inhibition	Negative_regulation
28182573	1196	1203	Smad2/3	Gene
28182573	1204	1215	activation	Positive_regulation
28182573	1253	1259	HSP90b	Gene
28182573	1260	1271	interacted	Binding
28182573	1276	1281	TGF-b	Gene
28182573	1298	1309	stabilised	Negative_regulation
28182573	1309	1314	TGF-b	Gene
28182573	1339	1346	17-DMAG	Chemical
28182573	1374	1384	decreased	Negative_regulation
28182573	1384	1392	fibrosis	Disease
28182573	1447	1456	bleomycin	Chemical
28182573	1468	1472	mice	Species
28182573	1532	1537	HSP90	Gene
28182573	1538	1549	inhibition	Negative_regulation
28182573	1604	1613	bleomycin	Chemical
28182573	1622	1640	pulmonary fibrosis	Disease
28182573	1644	1648	mice	Species
28420366|t|Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium
BACKGROUND: Oxidative stress is one of the important factors involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF)
The equilibrium of Nuclear factor-erythroid-related factor 2 (Nrf2)/[BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap'n'collar protein) homology 1, Bach1] determines the expression level of antioxidant factors, further regulating the function of oxidation/antioxidation capacity
Pirfenidone (PFD) is one of two currently for IPF therapy approved drugs
PFD regulates intracellular antioxidants, inhibits secretion of inflammatory cytokines and collagen synthesis
However the mechanisms of its antioxidant effects remain elusive
METHODS: Effects of PFD treatment were studied in mouse lung fibroblasts (MLF) following induction by transforming-growth factor beta 1 (TGF-b1) and in mice following bleomycin-induced lung fibrosis
The mRNA and protein levels of oxidative stress-related factors Nrf2/Bach1 and their downstream antioxidant factors heme oxygenase-1 (Ho-1) and glutathione peroxidase 1 (Gpx1) were determined by RT-PCR and Western blot
Fibrosis-related cytokines interleukin-6 (IL-6) and myofibroblast markers type 1 collagen a1 (COL1A1) levels in supernate of MLF, serum, and bronchoalveolar lavage fluid (BALF) as well as malondialdehyde (MDA) in serum and BALF were detected by ELISA, reactive oxygen species (ROS) generation was measured by 2',7'- dichlorofluorescin diacetate (DCFH-DA) assay and lung pathological/morphological alterations in mice were observed by HE and Masson to assess the antioxidant mechanism and therapeutic effects on pulmonary fibrosis induced by bleomycin
RESULTS: PFD inhibited Bach1 mRNA and protein expressions in mouse lung fibroblasts induced by TGF-b1 and lung tissues with pulmonary fibrosis induced by bleomycin
Furthermore, it improved Nrf2, Ho-1 and Gpx1 mRNA and protein expressions
After PFD treatment, COL1A1and IL-6 levels in supernate of MLF, serum, and BALF as well as ROS in lung tissues and MDA in serum and BALF from a mouse with pulmonary fibrosis were significantly decreased, and the infiltration of lung inflammatory cells and fibrosis degree were alleviated
CONCLUSIONS: Theraputic effects of PFD for IPF were involved in Nrf2/Bach1 equilibrium which regulated the capacity of oxidative stress
The study provided new insights into the antioxidant mechanism of PFD
28420366	0	11	Pirfenidone	Chemical
28420366	23	32	bleomycin	Chemical
28420366	63	67	mice	Species
28420366	71	82	regulating	Regulation
28420366	82	86	Nrf2	Gene
28420366	87	92	Bach1	Gene
28420366	255	296	Nuclear factor-erythroid-related factor 2	Gene
28420366	298	302	Nrf2	Gene
28420366	395	400	Bach1	Gene
28420366	417	428	expression	Gene_expression
28420366	527	538	Pirfenidone	Chemical
28420366	540	543	PFD	Chemical
28420366	601	604	PFD	Chemical
28420366	643	652	inhibits	Negative_regulation
28420366	701	711	synthesis	Gene_expression
28420366	798	801	PFD	Chemical
28420366	828	833	mouse	Species
28420366	880	913	transforming-growth factor beta 1	Gene
28420366	915	921	TGF-b1	Gene
28420366	930	934	mice	Species
28420366	945	954	bleomycin	Chemical
28420366	1042	1046	Nrf2	Gene
28420366	1047	1052	Bach1	Gene
28420366	1094	1110	heme oxygenase-1	Gene
28420366	1112	1116	Ho-1	Gene
28420366	1122	1146	glutathione peroxidase 1	Gene
28420366	1148	1152	Gpx1	Gene
28420366	1225	1238	interleukin-6	Gene
28420366	1240	1244	IL-6	Gene
28420366	1292	1298	COL1A1	Gene
28420366	1386	1401	malondialdehyde	Chemical
28420366	1403	1406	MDA	Chemical
28420366	1459	1465	oxygen	Chemical
28420366	1507	1542	2',7'- dichlorofluorescin diacetate	Chemical
28420366	1544	1551	DCFH-DA	Chemical
28420366	1610	1614	mice	Species
28420366	1739	1748	bleomycin	Chemical
28420366	1759	1762	PFD	Chemical
28420366	1763	1773	inhibited	Negative_regulation
28420366	1773	1778	Bach1	Gene
28420366	1796	1808	expressions	Transcription
28420366	1811	1816	mouse	Species
28420366	1845	1851	TGF-b1	Gene
28420366	1904	1913	bleomycin	Chemical
28420366	1931	1940	improved	Positive_regulation
28420366	1940	1944	Nrf2	Gene
28420366	1946	1950	Ho-1	Gene
28420366	1955	1959	Gpx1	Gene
28420366	1977	1989	expressions	Gene_expression
28420366	1996	1999	PFD	Chemical
28420366	2011	2017	COL1A1	Gene
28420366	2021	2025	IL-6	Gene
28420366	2105	2108	MDA	Chemical
28420366	2134	2139	mouse	Species
28420366	2183	2193	decreased	Negative_regulation
28420366	2314	2317	PFD	Chemical
28420366	2343	2347	Nrf2	Gene
28420366	2348	2353	Bach1	Gene
28420366	2482	2485	PFD	Chemical
22661007|t|miR-31 is a negative regulator of fibrogenesis and pulmonary fibrosis
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 miR-31 in regulating the fibrogenic, contractile, and migratory activities of lung fibroblasts and modulating of pulmonary fibrosis 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
miR-31 mimics or inhibitors were transfected into pulmonary fibroblasts
Fibrogenic, contractile, and migratory activities of lung fibroblasts were determined
We found that miR-31 expression is reduced in the lungs of mice with experimental pulmonary fibrosis and in IPF fibroblasts
miR-31 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, miR-31 was shown to directly target integrin a(5) and RhoA, two proteins that have been shown to regulate activation of fibroblasts
We found that levels of integrin a(5) and RhoA are up-regulated in fibrotic mouse lungs
Knockdown of integrin a(5) and RhoA attenuated fibrogenic, contractile, and migratory activities of IPF fibroblasts, in a manner similar to that observed with miR-31
We also found that introduction of miR-31 ameliorated experimental lung fibrosis in mice
Our data suggest that miR-31 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 pulmonary fibrosis
22661007	0	6	miR-31	Gene
22661007	51	69	pulmonary fibrosis	Disease
22661007	192	200	diabetes	Disease
22661007	202	208	cancer	Disease
22661007	214	236	cardiovascular disease	Disease
22661007	269	282	lung fibrosis	Disease
22661007	345	351	miR-31	Gene
22661007	458	476	pulmonary fibrosis	Disease
22661007	494	507	lung fibrosis	Disease
22661007	650	656	miR-31	Gene
22661007	824	830	miR-31	Gene
22661007	869	873	mice	Species
22661007	879	910	experimental pulmonary fibrosis	Disease
22661007	918	921	IPF	Disease
22661007	935	941	miR-31	Gene
22661007	942	951	inhibits	Negative_regulation
22661007	979	985	TGF-b1	Gene
22661007	1017	1028	diminishes	Negative_regulation
22661007	1085	1088	IPF	Disease
22661007	1124	1130	miR-31	Gene
22661007	1153	1160	target	Regulation
22661007	1178	1182	RhoA	Gene
22661007	1271	1278	levels	Gene_expression
22661007	1299	1303	RhoA	Gene
22661007	1308	1321	up-regulated	Positive_regulation
22661007	1333	1338	mouse	Species
22661007	1346	1356	Knockdown	Negative_regulation
22661007	1377	1381	RhoA	Gene
22661007	1446	1449	IPF	Disease
22661007	1505	1511	miR-31	Gene
22661007	1548	1554	miR-31	Gene
22661007	1555	1593	ameliorated experimental lung fibrosis	Disease
22661007	1597	1601	mice	Species
22661007	1625	1631	miR-31	Gene
22661007	1799	1817	fibrotic disorders	Disease
22661007	1829	1847	pulmonary fibrosis	Disease
23815594|t|Cytokine gene polymorphisms and serum cytokine levels in patients with idiopathic pulmonary fibrosis
BACKGROUND: Studies have demonstrated associations between cytokine gene polymorphisms and the risk of idiopathic pulmonary fibrosis (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	57	65	patients	Species
23815594	71	100	idiopathic pulmonary fibrosis	Disease
23815594	205	234	idiopathic pulmonary fibrosis	Disease
23815594	236	239	IPF	Disease
23815594	300	318	interleukin (IL)-6	Gene
23815594	320	325	IL-10	Gene
23815594	327	350	interferon gamma (IFN-y	Gene
23815594	353	380	tumor necrosis factor alpha	Gene
23815594	382	387	TNF-a	Gene
23815594	394	427	transforming growth factor-beta 1	Gene
23815594	429	435	TGF-b1	Gene
23815594	490	493	IPF	Disease
23815594	494	502	patients	Species
23815594	762	770	patients	Species
23815594	776	779	IPF	Disease
23815594	948	956	patients	Species
23815594	1088	1091	IPF	Disease
23815594	1092	1100	patients	Species
23815594	1175	1180	TNF-a	Gene
23815594	1182	1187	IFN-y	Gene
23815594	1189	1193	IL-6	Gene
23815594	1195	1200	IL-10	Gene
23815594	1206	1212	TGF-b1	Gene
23815594	1233	1238	TNF-a	Gene
23815594	1250	1254	IL-6	Gene
23815594	1277	1282	IL-10	Gene
23815594	1384	1389	IL-10	Gene
23815594	1483	1498	carbon monoxide	Chemical
23815594	1562	1568	oxygen	Chemical
23815594	1570	1574	PaO2	Chemical
23815594	1596	1602	TGF-b1	Gene
23815594	1701	1705	PaO2	Chemical
23815594	1738	1744	TGF-b1	Gene
23815594	1782	1790	patients	Species
23815594	1833	1837	PaO2	Chemical
23815594	1934	1940	TGF-b1	Gene
23815594	2107	2115	patients	Species
23815594	2170	2174	IL-6	Gene
23815594	2179	2184	IL-10	Gene
23815594	2230	2235	TNF-a	Gene
23815594	2240	2246	TGF-b1	Gene
23815594	2351	2354	IPF	Disease
23815594	2442	2448	TGF-b1	Gene
23815594	2544	2547	IPF	Disease
23815594	2548	2556	patients	Species
17579094|t|Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice
Pulmonary fibrosis in humans can occur as a result of a large number of conditions
In idiopathic pulmonary fibrosis (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-beta(1) 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 pulmonary fibrosis in mice
We performed histological examinations and quantitative measurements of IL-6, TGF-beta(1), 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-beta(1), 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-beta(1), VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2) both IL-6-dependent proliferation and TGF-beta(1)-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on pulmonary fibrosis
These data may provide a rationale to explore clinical use of Thal for the prevention of pulmonary fibrosis
17579094	0	11	Thalidomide	Chemical
17579094	21	30	bleomycin	Chemical
17579094	39	57	pulmonary fibrosis	Disease
17579094	61	65	mice	Species
17579094	67	85	Pulmonary fibrosis	Disease
17579094	89	95	humans	Species
17579094	154	183	idiopathic pulmonary fibrosis	Disease
17579094	185	188	IPF	Disease
17579094	335	338	IPF	Disease
17579094	371	375	IL-6	Gene
17579094	380	391	TGF-beta(1)	Gene
17579094	478	501	all-trans-retinoic acid	Chemical
17579094	503	507	ATRA	Chemical
17579094	519	528	bleomycin	Chemical
17579094	542	550	fibrosis	Disease
17579094	594	605	Thalidomide	Chemical
17579094	656	663	myeloma	Disease
17579094	697	701	IL-6	Gene
17579094	802	811	bleomycin	Chemical
17579094	820	838	pulmonary fibrosis	Disease
17579094	842	846	mice	Species
17579094	920	924	IL-6	Gene
17579094	926	960	TGF-beta(1), collagen type Ialpha1	Gene
17579094	962	968	COL1A1	Gene
17579094	971	1005	vascular endothelial growth factor	Gene
17579094	1007	1011	VEGF	Gene
17579094	1014	1028	angiopoietin-1	Gene
17579094	1030	1035	Ang-1	Gene
17579094	1041	1055	angiopoietin-2	Gene
17579094	1057	1062	Ang-2	Gene
17579094	1067	1076	bleomycin	Chemical
17579094	1085	1090	mouse	Species
17579094	1180	1189	bleomycin	Chemical
17579094	1198	1206	fibrosis	Disease
17579094	1210	1215	mouse	Species
17579094	1235	1245	decreased	Negative_regulation
17579094	1249	1261	expressions	Gene_expression
17579094	1264	1268	IL-6	Gene
17579094	1270	1281	TGF-beta(1)	Gene
17579094	1283	1287	VEGF	Gene
17579094	1289	1294	Ang-1	Gene
17579094	1295	1300	Ang-2	Gene
17579094	1306	1312	COL1A1	Gene
17579094	1321	1326	mouse	Species
17579094	1432	1440	reduced	Negative_regulation
17579094	1443	1454	production	Gene_expression
17579094	1457	1461	IL-6	Gene
17579094	1463	1474	TGF-beta(1)	Gene
17579094	1476	1480	VEGF	Gene
17579094	1482	1487	Ang-1	Gene
17579094	1502	1512	synthesis	Gene_expression
17579094	1517	1522	human	Species
17579094	1553	1557	IL-6	Gene
17579094	1586	1597	TGF-beta(1)	Gene
17579094	1716	1734	pulmonary fibrosis	Disease
17579094	1825	1843	pulmonary fibrosis	Disease
29113323|t|Reduced expression of BMP3 contributes to the development of pulmonary fibrosis and predicts the unfavorable prognosis in IIP patients
Idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (INSIP) are two related diseases involving varying degrees of pulmonary fibrosis with no effective cure
Bone morphogenetic protein 3 (BMP3) is a member of the transforming growth factor-b (TGF-b) super-family, which has not been implicated in pulmonary fibrosis previously
In this study, we aimed to investigate the potential role of BMP3 playing in pulmonary fibrosis from clinical diagnosis to molecular signaling regulation
RNA sequencing was performed to explore the potential biomarker of IIP patients
The expression of BMP3 was evaluated in 83 cases of IPF and INSIP by immunohistochemistry
The function of BMP3 was investigated in both fibroblast cells and a bleomycin-induced murine pulmonary fibrosis model
The clinical relevance of BMP3 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 BMP3 was significantly down-regulated in lung tissues of patients with IPF and INSIP
Consistently, lower expression of BMP3 also was found in pulmonary fibrotic tissues of bleomycin-induced mice model
Up-regulation of BMP3 prevented pulmonary fibrosis processing through inhibiting cellular proliferation of fibroblasts as well as TGF-b1 signal transduction
Finally, the relatively higher expression of BMP3 in IPF patients was associated with less/worse mortality
Intravenous injection of recombinant BMP3
Taken together, our results suggested that the low expression level of BMP3 may indicate the unfavorable prognosis of IPF patients, targeting BMP3 may represent a novel potential therapeutic method for pulmonary fibrosis management
29113323	0	8	Reduced	Negative_regulation
29113323	8	19	expression	Gene_expression
29113323	22	26	BMP3	Gene
29113323	61	79	pulmonary fibrosis	Disease
29113323	126	134	patients	Species
29113323	136	165	Idiopathic pulmonary fibrosis	Disease
29113323	167	170	IPF	Disease
29113323	176	221	idiopathic nonspecific interstitial pneumonia	Disease
29113323	223	228	INSIP	Disease
29113323	284	302	pulmonary fibrosis	Disease
29113323	327	355	Bone morphogenetic protein 3	Gene
29113323	357	361	BMP3	Gene
29113323	382	410	transforming growth factor-b	Gene
29113323	412	417	TGF-b	Gene
29113323	466	484	pulmonary fibrosis	Disease
29113323	558	562	BMP3	Gene
29113323	574	592	pulmonary fibrosis	Disease
29113323	723	731	patients	Species
29113323	737	748	expression	Gene_expression
29113323	751	755	BMP3	Gene
29113323	760	770	evaluated	Negative_regulation
29113323	785	788	IPF	Disease
29113323	793	798	INSIP	Disease
29113323	840	844	BMP3	Gene
29113323	893	902	bleomycin	Chemical
29113323	911	917	murine	Species
29113323	918	936	pulmonary fibrosis	Disease
29113323	957	967	relevance	Positive_regulation
29113323	970	974	BMP3	Gene
29113323	975	986	expression	Gene_expression
29113323	1010	1018	patients	Species
29113323	1168	1172	BMP3	Gene
29113323	1191	1206	down-regulated	Negative_regulation
29113323	1225	1233	patients	Species
29113323	1239	1242	IPF	Disease
29113323	1247	1252	INSIP	Disease
29113323	1274	1285	expression	Gene_expression
29113323	1288	1292	BMP3	Gene
29113323	1341	1350	bleomycin	Chemical
29113323	1359	1363	mice	Species
29113323	1371	1385	Up-regulation	Positive_regulation
29113323	1388	1392	BMP3	Gene
29113323	1403	1421	pulmonary fibrosis	Disease
29113323	1560	1571	expression	Gene_expression
29113323	1574	1578	BMP3	Gene
29113323	1582	1585	IPF	Disease
29113323	1586	1594	patients	Species
29113323	1674	1678	BMP3	Gene
29113323	1731	1742	expression	Gene_expression
29113323	1751	1755	BMP3	Gene
29113323	1798	1801	IPF	Disease
29113323	1802	1810	patients	Species
29113323	1822	1826	BMP3	Gene
29113323	1882	1900	pulmonary fibrosis	Disease
24594795|t|The antifibrotic effects and mechanisms of microRNA-26a action in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	66	95	idiopathic pulmonary fibrosis	Disease
24594795	97	126	Idiopathic pulmonary fibrosis	Disease
24594795	128	131	IPF	Disease
24594795	179	200	fibrotic lung disease	Disease
24594795	306	327	loss of lung function	Disease
24594795	455	458	IPF	Disease
24594795	480	502	fibrotic lung diseases	Disease
24594795	551	566	downregulation	Negative_regulation
24594795	569	576	miR-26a	Gene
24594795	593	597	mice	Species
24594795	603	634	experimental pulmonary fibrosis	Disease
24594795	642	645	IPF	Disease
24594795	685	698	derepression	Negative_regulation
24594795	701	732	connective tissue growth factor	Gene
24594795	734	738	CTGF	Gene
24594795	745	753	induced	Positive_regulation
24594795	762	773	production	Gene_expression
24594795	792	803	inhibition	Negative_regulation
24594795	806	813	miR-26a	Gene
24594795	834	852	pulmonary fibrosis	Disease
24594795	870	885	overexpression	Positive_regulation
24594795	888	895	miR-26a	Gene
24594795	993	1024	experimental pulmonary fibrosis	Disease
24594795	1028	1032	mice	Species
24594795	1056	1063	miR-26a	Gene
24594795	1068	1082	downregulated	Negative_regulation
24594795	1085	1091	TGF-b1	Gene
24594795	1092	1101	mediated	Positive_regulation
24594795	1101	1117	phosphorylation	Phosphorylation
24594795	1120	1125	Smad3	Gene
24594795	1137	1144	miR-26a	Gene
24594795	1145	1155	inhibited	Negative_regulation
24594795	1159	1167	nuclear	Entity
24594795	1167	1181	translocation	Localization
24594795	1186	1191	Smad3	Gene
24594795	1209	1219	targeting	Regulation
24594795	1219	1224	Smad4	Gene
24594795	1247	1255	nuclear	Entity
24594795	1255	1269	translocation	Localization
24594795	1274	1279	Smad2	Gene
24594795	1280	1285	Smad3	Gene
24594795	1360	1367	miR-26a	Gene
24594795	1371	1393	fibrotic lung diseases	Disease
24594795	1459	1462	IPF	Disease
24594795	1469	1476	miR-26a	Gene
24594795	1550	1557	miR-26a	Gene
24594795	1564	1569	Smad3	Gene
24594795	1592	1610	pulmonary fibrosis	Disease
24392001|t|The K+ channel KCa3.1 as a novel target for idiopathic pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy
We hypothesised that K(Ca)3.1 K(+) channel-dependent cell processes contribute to IPF pathophysiology
METHODS: K(Ca)3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology
The role of K(Ca)3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct K(Ca)3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc])
RESULTS: Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed K(Ca)3.1 channel mRNA and protein
K(Ca)3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls
K(Ca)3.1 currents were increased in myofibroblasts by TGFb1 and basic FGF
K(Ca)3.1 was expressed strongly in IPF tissue
K(Ca)3.1 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 Ca(2+)
CONCLUSIONS: K(Ca)3.1 activity promotes pro-fibrotic human lung myofibroblast function
Blocking K(Ca)3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic
24392001	4	5	K	Chemical
24392001	15	21	KCa3.1	Gene
24392001	44	73	idiopathic pulmonary fibrosis	Disease
24392001	87	116	Idiopathic pulmonary fibrosis	Disease
24392001	118	121	IPF	Disease
24392001	170	195	interstitial lung disease	Disease
24392001	244	245	K	Chemical
24392001	246	248	Ca	Chemical
24392001	253	257	K(+)	Chemical
24392001	305	308	IPF	Disease
24392001	335	336	K	Chemical
24392001	337	339	Ca	Chemical
24392001	366	371	human	Species
24392001	499	500	K	Chemical
24392001	501	503	Ca	Chemical
24392001	573	583	secretion	Localization
24392001	644	645	K	Chemical
24392001	646	648	Ca	Chemical
24392001	663	670	TRAM-34	Chemical
24392001	675	684	ICA-17043	Chemical
24392001	746	749	IPF	Disease
24392001	758	763	human	Species
24392001	784	794	expressed	Gene_expression
24392001	794	795	K	Chemical
24392001	796	798	Ca	Chemical
24392001	829	830	K	Chemical
24392001	831	833	Ca	Chemical
24392001	900	903	IPF	Disease
24392001	949	950	K	Chemical
24392001	951	953	Ca	Chemical
24392001	1003	1008	TGFb1	Gene
24392001	1024	1025	K	Chemical
24392001	1026	1028	Ca	Chemical
24392001	1037	1047	expressed	Gene_expression
24392001	1059	1062	IPF	Disease
24392001	1071	1072	K	Chemical
24392001	1073	1075	Ca	Chemical
24392001	1116	1121	human	Species
24392001	1175	1185	secretion	Localization
24392001	1256	1261	TGFb1	Gene
24392001	1304	1310	Ca(2+)	Chemical
24392001	1325	1326	K	Chemical
24392001	1327	1329	Ca	Chemical
24392001	1365	1370	human	Species
24392001	1409	1410	K	Chemical
24392001	1411	1413	Ca	Chemical
24392001	1457	1460	IPF	Disease
20693406|t|The Epstein-Barr virus latent membrane protein 1 and transforming growth factor--b1 synergistically induce epithelial--mesenchymal transition in lung epithelial cells
The histopathology of idiopathic pulmonary fibrosis (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	4	22	Epstein-Barr virus	Species
20693406	190	219	idiopathic pulmonary fibrosis	Disease
20693406	221	224	IPF	Disease
20693406	434	469	Transforming growth factor (TGF)-b1	Gene
20693406	609	632	Epstein-Barr virus (EBV	Species
20693406	674	682	patients	Species
20693406	688	691	IPF	Disease
20693406	693	696	EBV	Disease
20693406	707	738	latent membrane protein (LMP) 1	Gene
20693406	820	838	pulmonary fibrosis	Disease
20693406	851	856	LMP-1	Gene
20693406	1092	1097	LMP-1	Gene
20693406	1121	1127	TGF-b1	Gene
20693406	1193	1196	EBV	Disease
20693406	1197	1208	expressing	Gene_expression
20693406	1208	1212	LMP1	Gene
20693406	1232	1238	TGF-b1	Gene
20693406	1240	1244	LMP1	Gene
20693406	1366	1404	extracellular signal--regulated kinase	Gene
20693406	1406	1409	ERK	Gene
20693406	1438	1441	ERK	Gene
20693406	1490	1496	TGF-b1	Gene
20693406	1510	1514	LMP1	Gene
20693406	1515	1527	accentuates	Positive_regulation
20693406	1531	1537	TGF-b1	Gene
20693406	1538	1549	activation	Positive_regulation
20693406	1552	1555	ERK	Gene
20693406	1611	1614	EBV	Disease
20693406	1615	1619	LMP1	Gene
20693406	1661	1667	TGF-b1	Gene
20693406	1742	1750	patients	Species
20693406	1756	1759	IPF	Disease
20693406	1796	1800	LMP1	Gene
20693406	1856	1864	patients	Species
20693406	1873	1877	LMP1	Gene
20693406	1885	1894	detected	Gene_expression
23977848|t|An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model
Idiopathic pulmonary fibrosis 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 pulmonary fibrosis 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 pulmonary fibrosis 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 pulmonary fibrosis
23977848	3	13	inhibitor	Negative_regulation
23977848	16	21	NADPH	Chemical
23977848	55	73	pulmonary fibrosis	Disease
23977848	79	93	rodent disease	Disease
23977848	101	130	Idiopathic pulmonary fibrosis	Disease
23977848	355	360	NADPH	Chemical
23977848	409	415	oxygen	Chemical
23977848	491	495	Nox4	Gene
23977848	507	520	up-regulated	Positive_regulation
23977848	536	544	patients	Species
23977848	550	553	IPF	Disease
23977848	579	588	bleomycin	Chemical
23977848	597	639	pulmonary fibrosis and vascular remodeling	Disease
23977848	641	645	Nox4	Gene
23977848	686	696	increased	Positive_regulation
23977848	696	707	expression	Gene_expression
23977848	784	788	Nox4	Gene
23977848	789	793	Nox1	Gene
23977848	794	804	inhibitor	Negative_regulation
23977848	835	839	Nox4	Gene
23977848	905	916	reductions	Positive_regulation
23977848	1008	1019	fibronectin	Gene
23977848	1072	1090	pulmonary fibrosis	Disease
23977848	1095	1102	hypoxia	Disease
23977848	1205	1212	hypoxia	Disease
23977848	1235	1239	Nox4	Gene
23977848	1241	1247	TGF-b1	Gene
23977848	1392	1397	human	Species
23977848	1466	1470	Nox4	Gene
23977848	1525	1531	TGF-b1	Gene
23977848	1680	1694	up-regulation	Positive_regulation
23977848	1807	1811	Nox4	Gene
23977848	1863	1881	pulmonary fibrosis	Disease
25365224|t|TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice
Idiopathic pulmonary fibrosis (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 signal(s) that promote differentiation into myofibroblasts
As transient receptor potential vanilloid 4 (TRPV4) channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether TRPV4 contributes to generation of myofibroblasts and/or experimental lung fibrosis
We determined that TRPV4 activity is upregulated in lung fibroblasts derived from patients with IPF
Moreover, TRPV4-deficient mice were protected from fibrosis
Furthermore, genetic ablation or pharmacological inhibition of TRPV4 function abrogated myofibroblast differentiation, which was restored by TRPV4 reintroduction
TRPV4 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
TRPV4 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 TRPV4 activity mediates pulmonary fibrogenesis and suggest that manipulation of TRPV4 channel activity has potential as a therapeutic approach for fibrotic diseases
25365224	0	5	TRPV4	Gene
25365224	49	67	pulmonary fibrosis	Disease
25365224	71	75	mice	Species
25365224	77	106	Idiopathic pulmonary fibrosis	Disease
25365224	108	111	IPF	Disease
25365224	124	146	fibrotic lung disorder	Disease
25365224	304	314	activated	Positive_regulation
25365224	314	319	TGF-b	Gene
25365224	459	499	transient receptor potential vanilloid 4	Gene
25365224	501	506	TRPV4	Gene
25365224	521	531	activated	Positive_regulation
25365224	623	628	TRPV4	Gene
25365224	698	706	fibrosis	Disease
25365224	727	732	TRPV4	Gene
25365224	745	757	upregulated	Positive_regulation
25365224	790	798	patients	Species
25365224	804	807	IPF	Disease
25365224	819	824	TRPV4	Gene
25365224	825	835	deficient	Negative_regulation
25365224	835	839	mice	Species
25365224	860	868	fibrosis	Disease
25365224	919	930	inhibition	Negative_regulation
25365224	933	938	TRPV4	Gene
25365224	1011	1016	TRPV4	Gene
25365224	1017	1032	reintroduction	Gene_expression
25365224	1033	1038	TRPV4	Gene
25365224	1060	1069	elevated	Positive_regulation
25365224	1250	1261	inhibition	Negative_regulation
25365224	1262	1267	TRPV4	Gene
25365224	1277	1287	modulated	Regulation
25365224	1287	1293	TGF-b1	Gene
25365224	1342	1351	enhanced	Positive_regulation
25365224	1378	1388	increased	Positive_regulation
25365224	1388	1396	nuclear	Entity
25365224	1396	1410	translocation	Localization
25365224	1450	1456	MRTF-A	Gene
25365224	1494	1499	TRPV4	Gene
25365224	1574	1579	TRPV4	Gene
25365224	1641	1658	fibrotic diseases	Disease
26934369|t|Cigarette Smoke Enhances the Expression of Profibrotic Molecules in Alveolar Epithelial Cells
Idiopathic pulmonary fibrosis (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	95	124	Idiopathic pulmonary fibrosis	Disease
26934369	126	129	IPF	Disease
26934369	619	622	IPF	Disease
26934369	795	800	human	Species
26934369	1151	1162	expression	Gene_expression
26934369	1193	1202	increase	Positive_regulation
26934369	1293	1296	Wnt	Gene
26934369	1429	1434	mouse	Species
26934369	1436	1442	MLE-12	Species
26934369	1448	1451	rat	Species
26934369	1453	1460	RLE-6TN	Species
26934369	1484	1494	secretion	Localization
26934369	1497	1507	activated	Positive_regulation
26934369	1507	1513	TGF-b1	Gene
26934369	1514	1524	increased	Positive_regulation
26934369	1586	1602	integrin alpha v	Gene
26934369	1612	1621	silenced	Negative_regulation
26934369	1777	1788	activation	Positive_regulation
26934369	1791	1797	TGF-b1	Gene
26934369	1870	1873	IPF	Disease
26231702|t|Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis
BACKGROUND: The beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (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 fibrosis
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 fibrosis
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	48	60	esomeprazole	Chemical
26231702	87	104	lung inflammation	Disease
26231702	109	117	fibrosis	Disease
26231702	214	243	idiopathic pulmonary fibrosis	Disease
26231702	245	248	IPF	Disease
26231702	490	493	IPF	Disease
26231702	645	657	inflammation	Disease
26231702	662	670	fibrosis	Disease
26231702	792	801	bleomycin	Chemical
26231702	836	848	inflammation	Disease
26231702	853	861	fibrosis	Disease
26231702	910	913	IPF	Disease
26231702	914	922	patients	Species
26231702	949	961	esomeprazole	Chemical
26231702	1024	1036	esomeprazole	Chemical
26231702	1042	1045	rat	Species
26231702	1055	1064	bleomycin	Chemical
26231702	1073	1084	lung injury	Disease
26231702	1138	1163	interstitial lung disease	Disease
26231702	1165	1168	ILD	Disease
26231702	1287	1299	esomeprazole	Chemical
26231702	1309	1321	inflammation	Disease
26231702	1325	1337	suppressing	Negative_regulation
26231702	1341	1352	expression	Gene_expression
26231702	1427	1437	inducible	Positive_regulation
26231702	1437	1449	nitric oxide	Chemical
26231702	1460	1487	tumor necrosis factor-alpha	Gene
26231702	1489	1494	TNF-a	Gene
26231702	1514	1519	IL-1b	Gene
26231702	1524	1528	IL-6	Gene
26231702	1580	1590	induction	Positive_regulation
26231702	1637	1653	heme oxygenase-1	Gene
26231702	1655	1658	HO1	Gene
26231702	1827	1855	transforming growth factor b	Gene
26231702	1857	1861	TGFb	Gene
26231702	1864	1875	fibronectin	Gene
26231702	1927	1939	esomeprazole	Chemical
26231702	2020	2026	murine	Species
26231702	2036	2053	acute lung injury	Disease
26231702	2094	2097	ILD	Disease
26231702	2182	2185	IPF	Disease
26231702	2186	2194	patients	Species
26231702	2238	2241	IPF	Disease
26231702	2242	2250	patients	Species
26231702	2434	2437	IPF	Disease
29351444|t|Activated human T lymphocytes inhibit TGFb-induced fibroblast to myofibroblast differentiation via prostaglandins D2 and E2
In pulmonary fibrosis (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	10	15	human	Species
29351444	38	42	TGFb	Gene
29351444	99	116	prostaglandins D2	Chemical
29351444	128	146	pulmonary fibrosis	Disease
29351444	148	150	PF	Disease
29351444	309	311	PF	Disease
29351444	365	367	PF	Disease
29351444	474	482	fibrosis	Disease
29351444	575	577	PF	Disease
29351444	578	586	patients	Species
29351444	657	671	prostaglandins	Chemical
29351444	903	908	human	Species
29351444	909	915	donors	Species
29351444	920	922	PF	Disease
29351444	923	931	patients	Species
29351444	1024	1029	human	Species
29351444	1078	1080	PF	Disease
29351444	1142	1159	prostaglandins D2	Chemical
29351444	1267	1280	prostaglandin	Chemical
29351444	1433	1441	induced	Positive_regulation
29351444	1441	1446	COX-2	Gene
29351444	1574	1588	prostaglandins	Chemical
29351444	1656	1661	human	Species
29351444	1812	1834	fibrotic lung diseases	Disease
28178340|t|Sputum biomarkers in IPF: Evidence for raised gene expression and protein level of IGFBP-2, IL-8 and MMP-7
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) 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 IPF compared to COPD, a fibrosing airway wall disease
METHODS: In a cross-sectional analysis, 15 IPF 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: IPF patients, like COPD, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS
IPF 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 IPF (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 IPF 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 IPF 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 IPF 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 IPF 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 IPF that may contribute to the disease
28178340	21	24	IPF	Disease
28178340	51	62	expression	Gene_expression
28178340	83	90	IGFBP-2	Gene
28178340	92	96	IL-8	Gene
28178340	101	106	MMP-7	Gene
28178340	120	149	Idiopathic pulmonary fibrosis	Disease
28178340	151	154	IPF	Disease
28178340	166	178	lung disease	Disease
28178340	216	221	death	Disease
28178340	310	340	respiratory tract inflammation	Disease
28178340	369	372	IPF	Disease
28178340	385	389	COPD	Disease
28178340	467	470	IPF	Disease
28178340	471	479	patients	Species
28178340	484	488	COPD	Disease
28178340	574	581	amount	Gene_expression
28178340	584	590	TGF- b	Gene
28178340	592	597	IGF-1	Gene
28178340	599	604	IGF-2	Gene
28178340	606	613	IGFBP-1	Gene
28178340	615	622	IGFBP-2	Gene
28178340	624	631	IGFBP-3	Gene
28178340	633	637	IL-8	Gene
28178340	639	644	IL-13	Gene
28178340	646	651	MMP-7	Gene
28178340	653	658	MMP-9	Gene
28178340	660	666	YKL-40	Gene
28178340	668	673	TNF-a	Gene
28178340	678	682	KL-6	Gene
28178340	742	753	expression	Gene_expression
28178340	769	777	induced	Positive_regulation
28178340	788	793	TGF-b	Gene
28178340	795	800	MMP-7	Gene
28178340	802	808	YKL-40	Gene
28178340	810	817	IGFBP-2	Gene
28178340	819	823	IL-6	Gene
28178340	825	829	IL-8	Gene
28178340	834	839	TNF-a	Gene
28178340	850	853	IPF	Disease
28178340	854	862	patients	Species
28178340	869	873	COPD	Disease
28178340	986	988	HS	Disease
28178340	990	993	IPF	Disease
28178340	1018	1028	increased	Positive_regulation
28178340	1028	1043	concentrations	Localization
28178340	1046	1053	IGFBP-2	Gene
28178340	1055	1059	IL-8	Gene
28178340	1061	1066	TGF-b	Gene
28178340	1068	1073	MMP-7	Gene
28178340	1075	1080	MMP-9	Gene
28178340	1085	1089	KL-6	Gene
28178340	1196	1200	COPD	Disease
28178340	1205	1212	higher	Positive_regulation
28178340	1212	1216	IL-6	Gene
28178340	1221	1226	TNF-a	Gene
28178340	1227	1234	levels	Gene_expression
28178340	1239	1242	IPF	Disease
28178340	1280	1282	HS	Disease
28178340	1330	1334	IL-8	Gene
28178340	1339	1344	MMP-9	Gene
28178340	1350	1352	HS	Disease
28178340	1404	1408	IL-6	Gene
28178340	1413	1418	TNF-a	Gene
28178340	1420	1425	MMP-7	Gene
28178340	1430	1440	increased	Positive_regulation
28178340	1443	1446	IPF	Disease
28178340	1459	1463	COPD	Disease
28178340	1478	1482	KL-6	Gene
28178340	1487	1492	MMP-7	Gene
28178340	1594	1597	IPF	Disease
28178340	1598	1606	patients	Species
28178340	1717	1724	IGFBP-2	Gene
28178340	1726	1730	IL-6	Gene
28178340	1732	1736	IL-8	Gene
28178340	1741	1746	MMP-7	Gene
28178340	1750	1753	IPF	Disease
28178340	1766	1768	HS	Disease
28178340	1828	1835	IGFBP-2	Gene
28178340	1837	1843	YKL-40	Gene
28178340	1845	1849	IL-6	Gene
28178340	1851	1855	IL-8	Gene
28178340	1860	1865	MMP-7	Gene
28178340	1878	1882	COPD	Disease
28178340	1961	1972	expression	Gene_expression
28178340	1975	1980	TGF-b	Gene
28178340	1985	1995	increased	Positive_regulation
28178340	1998	2001	IPF	Disease
28178340	2014	2018	COPD	Disease
28178340	2040	2042	HS	Disease
28178340	2076	2085	increase	Positive_regulation
28178340	2088	2099	expression	Gene_expression
28178340	2103	2114	production	Gene_expression
28178340	2117	2124	IGFBP-2	Gene
28178340	2126	2130	IL-8	Gene
28178340	2135	2140	MMP-7	Gene
28178340	2156	2164	patients	Species
28178340	2170	2173	IPF	Disease
22322297|t|STAT3-mediated signaling dysregulates lung fibroblast-myofibroblast activation and differentiation in UIP/IPF
STAT3 is a latent transcription factor that plays a role in regulating fibroblast function in fibrotic lung diseases
To further understand the role of STAT3 in the phenotypic divergence and function of human lung fibroblasts (LFs), we investigated the effect of basal and cytokine-induced STAT3 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 a(v) b(3) and b(5) integrins
We identified a population of fibroblasts from usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) lungs characterized by constitutively phosphorylated STAT3, lower proliferation rates, and diminished expression of a-SMA, Thy-1/CD90, and b(3) integrins compared with control LFs
Staining of UIP lung biopsy specimens demonstrated that phosphorylated STAT3 was not present in a-SMA-positive fibroblastic foci but was observed in the nuclei of cells located in the areas of dense fibrosis
STAT3 activation in LFs did not significantly influence basal or transforming growth factor b(1)-induced collagen I expression but inhibited expression of a-SMA, Thy-1/CD90, and av b(3) integrins
Suppression of STAT3 signaling diminished resistance of IPF LFs to staurosporine-induced apoptosis and responsiveness to transforming growth factor b(1) but increased basal a-SMA and restored b(3) integrin expression in LFs via an ALK-5-dependent, SMAD3/7-independent mechanism
These data suggest that STAT3 activation regulates several pathways in human LFs associated with normal wound healing, whereas aberrant STAT3 signaling plays a critical role in UIP/IPF pathogenesis
22322297	0	5	STAT3	Gene
22322297	111	116	STAT3	Gene
22322297	205	227	fibrotic lung diseases	Disease
22322297	263	268	STAT3	Gene
22322297	314	319	human	Species
22322297	364	371	effect	Regulation
22322297	401	406	STAT3	Gene
22322297	475	486	expression	Gene_expression
22322297	489	510	a-smooth muscle actin	Gene
22322297	512	517	a-SMA	Gene
22322297	553	558	Thy-1	Gene
22322297	559	563	CD90	Gene
22322297	651	673	interstitial pneumonia	Disease
22322297	680	709	idiopathic pulmonary fibrosis	Disease
22322297	754	769	phosphorylated	Phosphorylation
22322297	769	774	STAT3	Gene
22322297	807	818	diminished	Negative_regulation
22322297	818	829	expression	Gene_expression
22322297	832	837	a-SMA	Gene
22322297	839	844	Thy-1	Gene
22322297	845	849	CD90	Gene
22322297	953	968	phosphorylated	Phosphorylation
22322297	968	973	STAT3	Gene
22322297	982	990	present	Gene_expression
22322297	993	998	a-SMA	Gene
22322297	1096	1104	fibrosis	Disease
22322297	1106	1111	STAT3	Gene
22322297	1112	1123	activation	Positive_regulation
22322297	1171	1202	transforming growth factor b(1)	Gene
22322297	1222	1233	expression	Gene_expression
22322297	1237	1247	inhibited	Negative_regulation
22322297	1247	1258	expression	Gene_expression
22322297	1261	1266	a-SMA	Gene
22322297	1268	1273	Thy-1	Gene
22322297	1274	1278	CD90	Gene
22322297	1318	1323	STAT3	Gene
22322297	1370	1383	staurosporine	Chemical
22322297	1424	1455	transforming growth factor b(1)	Gene
22322297	1476	1481	a-SMA	Gene
22322297	1486	1495	restored	Negative_regulation
22322297	1509	1520	expression	Gene_expression
22322297	1534	1539	ALK-5	Gene
22322297	1551	1556	SMAD3	Gene
22322297	1606	1611	STAT3	Gene
22322297	1612	1623	activation	Positive_regulation
22322297	1653	1658	human	Species
22322297	1718	1723	STAT3	Gene
24418172|t|Peripheral depletion of NK cells and imbalance of the Treg/Th17 axis in idiopathic pulmonary fibrosis patients
The immune response plays an unsettled role in the pathogenesis of idiopathic pulmonary fibrosis (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(+)CD25(high)Foxp-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	72	101	idiopathic pulmonary fibrosis	Disease
24418172	102	110	patients	Species
24418172	179	208	idiopathic pulmonary fibrosis	Disease
24418172	210	213	IPF	Disease
24418172	236	248	inflammation	Disease
24418172	362	381	interleukin (IL)-17	Gene
24418172	382	392	secreting	Localization
24418172	595	598	IPF	Disease
24418172	599	607	patients	Species
24418172	846	849	IPF	Disease
24418172	850	858	patients	Species
24418172	970	976	Foxp-3	Gene
24418172	1018	1021	IPF	Disease
24418172	1022	1030	patients	Species
24418172	1094	1104	expressed	Gene_expression
24418172	1104	1109	TGF-b	Gene
24418172	1204	1207	IPF	Disease
24418172	1208	1216	patients	Species
24418172	1251	1256	TGF-b	Gene
24418172	1257	1262	IL-17	Gene
24418172	1482	1485	IPF	Disease
24418172	1492	1510	autoimmune disease	Disease
24418172	1655	1661	cancer	Disease
16816361|t|Bone morphogenetic protein-4 inhibitor gremlin is overexpressed in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 gremlin in the lung interstitium of IPF patients
Quantitative real-time reverse transcriptase-polymerase chain reaction analyses revealed considerably higher levels of gremlin 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 gremlin, 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 gremlin mRNA expression
In addition, A549 cells transfected to overexpress gremlin 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	0	28	Bone morphogenetic protein-4	Gene
16816361	39	46	gremlin	Gene
16816361	50	64	overexpressed	Positive_regulation
16816361	67	96	idiopathic pulmonary fibrosis	Disease
16816361	98	127	Idiopathic pulmonary fibrosis	Disease
16816361	129	132	IPF	Disease
16816361	139	167	usual interstitial pneumonia	Disease
16816361	288	295	Gremlin	Gene
16816361	319	327	cysteine	Chemical
16816361	343	369	bone morphogenetic protein	Gene
16816361	371	374	BMP	Gene
16816361	412	417	BMP-4	Gene
16816361	488	503	overexpression	Positive_regulation
16816361	506	513	gremlin	Gene
16816361	542	545	IPF	Disease
16816361	546	554	patients	Species
16816361	665	672	levels	Positive_regulation
16816361	675	682	gremlin	Gene
16816361	710	713	IPF	Disease
16816361	714	722	patients	Species
16816361	816	819	IPF	Disease
16816361	820	828	patients	Species
16816361	834	844	expressed	Gene_expression
16816361	844	853	elevated	Positive_regulation
16816361	863	870	gremlin	Gene
16816361	950	955	BMP-4	Gene
16816361	957	988	Transforming growth factor-beta	Gene
16816361	1100	1110	induction	Positive_regulation
16816361	1113	1120	gremlin	Gene
16816361	1126	1137	expression	Gene_expression
16816361	1189	1196	gremlin	Gene
16816361	1222	1253	transforming growth factor-beta	Gene
16816361	1300	1307	Gremlin	Gene
16816361	1331	1336	BMP-4	Gene
16816361	1451	1466	overexpression	Positive_regulation
16816361	1496	1499	IPF	Disease
28495857|t|TGF-b1 induces Fstl1 via the Smad3-c-Jun pathway in lung fibroblasts
Transforming growth factor (TGF)-b1 has long been regarded as a central mediator of tissue fibrosis
Follistatin-like 1 (Fstl1) 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 TGF-b1 upregulates Fstl1 expression in mouse pulmonary fibroblasts
TGF-b1 regulated Fstl1 expression at both the transcriptional and translational levels
Although TGF-b1 rapidly activated the Smad, MAPK, and Akt pathways in lung fibroblasts, only Smad2/3 inhibition eliminated TGF-b1-induced Fstl1 expression
Analysis of the luciferase reporter activity identified a functional c-Jun transcription site in the Fstl1 promoter
Our results suggested a critical role for the Smad3-c-Jun pathway in the regulation of Fstl1 expression by TGF-b1 during fibrogenesis
28495857	0	6	TGF-b1	Gene
28495857	7	15	induces	Positive_regulation
28495857	15	20	Fstl1	Gene
28495857	29	34	Smad3	Gene
28495857	35	40	c-Jun	Gene
28495857	70	105	Transforming growth factor (TGF)-b1	Gene
28495857	161	169	fibrosis	Disease
28495857	171	189	Follistatin-like 1	Gene
28495857	191	196	Fstl1	Gene
28495857	244	256	upregulated	Positive_regulation
28495857	393	399	TGF-b1	Gene
28495857	400	412	upregulates	Positive_regulation
28495857	412	417	Fstl1	Gene
28495857	418	429	expression	Gene_expression
28495857	432	437	mouse	Species
28495857	461	467	TGF-b1	Gene
28495857	468	478	regulated	Regulation
28495857	478	483	Fstl1	Gene
28495857	484	495	expression	Gene_expression
28495857	558	564	TGF-b1	Gene
28495857	573	583	activated	Positive_regulation
28495857	642	649	Smad2/3	Gene
28495857	650	661	inhibition	Negative_regulation
28495857	661	672	eliminated	Positive_regulation
28495857	672	678	TGF-b1	Gene
28495857	672	687	TGF-b1-induced	Positive_regulation
28495857	687	692	Fstl1	Gene
28495857	693	704	expression	Gene_expression
28495857	774	779	c-Jun	Gene
28495857	806	811	Fstl1	Gene
28495857	855	860	role	Regulation
28495857	868	873	Smad3	Gene
28495857	874	879	c-Jun	Gene
28495857	895	906	regulation	Regulation
28495857	909	914	Fstl1	Gene
28495857	915	926	expression	Gene_expression
28495857	929	935	TGF-b1	Gene
21471103|t|Role of protease-activated receptor-2 in idiopathic pulmonary fibrosis
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 idiopathic pulmonary fibrosis (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-b(1), 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	8	37	protease-activated receptor-2	Gene
21471103	41	70	idiopathic pulmonary fibrosis	Disease
21471103	146	164	pulmonary fibrosis	Disease
21471103	337	349	investigate	Positive_regulation
21471103	353	364	importance	Gene_expression
21471103	367	402	protease-activated receptor (PAR)-2	Gene
21471103	455	468	tissue factor	Gene
21471103	497	526	idiopathic pulmonary fibrosis	Disease
21471103	528	531	IPF	Disease
21471103	543	554	Expression	Gene_expression
21471103	574	579	PAR-2	Gene
21471103	616	619	IPF	Disease
21471103	648	653	PAR-2	Gene
21471103	759	764	PAR-2	Gene
21471103	790	793	IPF	Disease
21471103	879	909	Transforming growth factor-b(1	Gene
21471103	962	967	PAR-2	Gene
21471103	982	987	human	Species
21471103	1040	1045	human	Species
21471103	1104	1109	PAR-2	Gene
21471103	1201	1206	PAR-2	Gene
21471103	1358	1369	production	Gene_expression
21471103	1459	1469	abrogated	Negative_regulation
21471103	1503	1515	Hyperplastic	Disease
21471103	1606	1609	IPF	Disease
21471103	1647	1652	PAR-2	Gene
21471103	1686	1689	IPF	Disease
21471103	1714	1719	PAR-2	Gene
21471103	1771	1789	pulmonary fibrosis	Disease
21471103	1885	1888	IPF	Disease
24204629|t|Type V collagen induced tolerance suppresses collagen deposition, TGF-b and associated transcripts in pulmonary fibrosis
RATIONALE: Idiopathic pulmonary fibrosis (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-col(V) immunity in IPF patients
The objective of our study was to determine the specificity of col(V) expression profile and anti-col(V) immunity relative to col(I) in clinical IPF and the efficacy of nebulized col(V) in pre-clinical IPF models
METHODS: Col(V) and col(I) expression profile was analyzed in normal human and IPF tissues
C57-BL6 mice were intratracheally instilled with bleomycin (0.025 U) followed by col(V) 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 col(V) and col(I)
Systemic anti-col(V) antibody concentrations, but not of anti-col(I), were higher in IPF patients
Nebulized col(V), but not col(I), prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation
Col(V) treatment suppressed systemic levels of anti-col(V) antibodies, IL-6 and TNF-a; and local Il-17a transcripts
Compared to controls, nebulized col(V)-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 col(V) 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 TGF-b superfamily (Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb)
CONCLUSIONS: Anti-col(V) immunity is pathogenic in IPF, and col(V)-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- b-related signaling pathways
24204629	66	71	TGF-b	Gene
24204629	102	120	pulmonary fibrosis	Disease
24204629	133	162	Idiopathic pulmonary fibrosis	Disease
24204629	164	167	IPF	Disease
24204629	180	205	interstitial lung disease	Disease
24204629	319	322	IPF	Disease
24204629	378	381	IPF	Disease
24204629	382	390	patients	Species
24204629	537	540	IPF	Disease
24204629	594	597	IPF	Disease
24204629	615	618	Col	Chemical
24204629	675	680	human	Species
24204629	685	688	IPF	Disease
24204629	706	710	mice	Species
24204629	747	756	bleomycin	Chemical
24204629	909	912	IPF	Disease
24204629	953	964	expression	Gene_expression
24204629	1092	1095	IPF	Disease
24204629	1096	1104	patients	Species
24204629	1140	1150	prevented	Negative_regulation
24204629	1150	1159	bleomycin	Chemical
24204629	1168	1176	fibrosis	Disease
24204629	1251	1262	suppressed	Negative_regulation
24204629	1305	1309	IL-6	Gene
24204629	1314	1319	TNF-a	Gene
24204629	1331	1337	Il-17a	Gene
24204629	1408	1418	abrogated	Negative_regulation
24204629	1480	1491	production	Gene_expression
24204629	1494	1500	IL-17A	Gene
24204629	1502	1506	IL-6	Gene
24204629	1508	1513	TNF-a	Gene
24204629	1518	1523	IFN-y	Gene
24204629	1562	1570	fibrosis	Disease
24204629	1595	1605	decreased	Negative_regulation
24204629	1614	1625	deposition	Negative_regulation
24204629	1637	1646	revealed	Negative_regulation
24204629	1646	1661	downregulation	Negative_regulation
24204629	1682	1690	fibrosis	Disease
24204629	1692	1697	Tgf-b	Gene
24204629	1699	1704	Il-1b	Gene
24204629	1706	1711	Pdgfb	Gene
24204629	1722	1727	Acta2	Gene
24204629	1729	1735	Col1a2	Gene
24204629	1737	1743	Col3a1	Gene
24204629	1745	1748	Lox	Gene
24204629	1750	1757	Itgb1/6	Gene
24204629	1759	1766	Itga2/3	Gene
24204629	1787	1792	TGF-b	Gene
24204629	1806	1814	Tgfbr1/2	Gene
24204629	1816	1823	Smad2/3	Gene
24204629	1825	1830	Ltbp1	Gene
24204629	1832	1840	Serpine1	Gene
24204629	1847	1850	Sp1	Gene
24204629	1851	1856	Cebpb	Gene
24204629	1910	1913	IPF	Disease
24204629	1954	1963	bleomycin	Chemical
24204629	2004	2010	TGF- b	Gene
22900087|t|Syndecan-2 is a novel target of insulin-like growth factor binding protein-3 and is over-expressed in fibrosis
Extracellular matrix deposition and tissue scarring characterize the process of fibrosis
Transforming growth factor beta (TGFb) and Insulin-like growth factor binding protein-3 (IGFBP-3) have been implicated in the pathogenesis of fibrosis in various tissues by inducing mesenchymal cell proliferation and extracellular matrix deposition
We identified Syndecan-2 (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 fibrosis (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 fibrosis
Increased SDC2 expression is due, at least in part, to the activity of two pro-fibrotic factors, TGFb and IGFBP-3
22900087	0	10	Syndecan-2	Gene
22900087	22	29	target	Binding
22900087	32	76	insulin-like growth factor binding protein-3	Gene
22900087	84	99	over-expressed	Positive_regulation
22900087	102	110	fibrosis	Disease
22900087	192	200	fibrosis	Disease
22900087	202	233	Transforming growth factor beta	Gene
22900087	235	239	TGFb	Gene
22900087	245	289	Insulin-like growth factor binding protein-3	Gene
22900087	291	298	IGFBP-3	Gene
22900087	344	352	fibrosis	Disease
22900087	466	476	Syndecan-2	Gene
22900087	478	482	SDC2	Gene
22900087	505	509	TGFb	Gene
22900087	516	523	IGFBP-3	Gene
22900087	542	546	TGFb	Gene
22900087	547	557	induction	Positive_regulation
22900087	560	564	SDC2	Gene
22900087	591	598	IGFBP-3	Gene
22900087	600	607	IGFBP-3	Gene
22900087	622	630	induced	Positive_regulation
22900087	630	641	production	Gene_expression
22900087	644	648	SDC2	Gene
22900087	699	704	human	Species
22900087	727	738	expressing	Gene_expression
22900087	738	745	IGFBP-3	Gene
22900087	767	774	IGFBP-3	Gene
22900087	775	783	induces	Positive_regulation
22900087	783	787	SDC2	Gene
22900087	799	804	human	Species
22900087	885	890	Mknk2	Gene
22900087	902	910	induced	Positive_regulation
22900087	913	920	IGFBP-3	Gene
22900087	922	929	IGFBP-3	Gene
22900087	930	940	triggered	Positive_regulation
22900087	940	945	Mknk2	Gene
22900087	946	962	phosphorylation	Phosphorylation
22900087	962	972	resulting	Positive_regulation
22900087	979	990	activation	Positive_regulation
22900087	991	996	Mknk2	Gene
22900087	1011	1019	induced	Positive_regulation
22900087	1019	1023	SDC2	Gene
22900087	1027	1032	human	Species
22900087	1045	1052	IGFBP-3	Gene
22900087	1056	1071	over-expressed	Gene_expression
22900087	1104	1108	SDC2	Gene
22900087	1144	1152	patients	Species
22900087	1158	1176	systemic sclerosis	Disease
22900087	1178	1181	SSc	Disease
22900087	1203	1211	patients	Species
22900087	1217	1246	idiopathic pulmonary fibrosis	Disease
22900087	1248	1251	IPF	Disease
22900087	1254	1258	SDC2	Gene
22900087	1271	1281	increased	Positive_regulation
22900087	1320	1328	patients	Species
22900087	1334	1337	SSc	Disease
22900087	1361	1369	patients	Species
22900087	1375	1378	IPF	Disease
22900087	1416	1425	elevated	Positive_regulation
22900087	1435	1439	SDC2	Gene
22900087	1443	1451	fibrosis	Disease
22900087	1453	1463	Increased	Positive_regulation
22900087	1463	1467	SDC2	Gene
22900087	1468	1479	expression	Gene_expression
22900087	1482	1486	due	Positive_regulation
22900087	1550	1554	TGFb	Gene
22900087	1559	1566	IGFBP-3	Gene
24279676|t|Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes
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 (TGF)b 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 idiopathic pulmonary fibrosis (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	21	50	idiopathic pulmonary fibrosis	Disease
24279676	321	341	fibrotic scar tissue	Disease
24279676	378	391	accumulation	Positive_regulation
24279676	440	451	fibronectin	Gene
24279676	908	927	interleukin (IL)-13	Gene
24279676	1320	1328	fibrosis	Disease
24279676	1531	1544	fibrotic lung	Disease
24279676	1553	1582	idiopathic pulmonary fibrosis	Disease
24279676	1584	1587	IPF	Disease
24279676	1744	1752	patients	Species
24279676	1758	1761	IPF	Disease
23896962|t|Epithelial-mesenchymal transition in chronic hypersensitivity pneumonitis
Chronic hypersensitivity pneumonitis (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	45	73	hypersensitivity pneumonitis	Disease
23896962	75	111	Chronic hypersensitivity pneumonitis	Disease
23896962	113	115	HP	Disease
23896962	153	171	pulmonary fibrosis	Disease
23896962	217	246	idiopathic pulmonary fibrosis	Disease
23896962	248	251	IPF	Disease
23896962	431	434	IPF	Disease
23896962	530	532	HP	Disease
23896962	564	566	HP	Disease
23896962	582	590	patients	Species
23896962	604	606	HP	Disease
23896962	929	933	mice	Species
23896962	975	979	mice	Species
23896962	1038	1050	expressions	Transcription
23896962	1053	1058	IL-13	Gene
23896962	1063	1069	TGF-b1	Gene
23896962	1075	1083	fibrosis	Disease
23896962	1127	1131	mice	Species
23896962	1136	1141	human	Species
23896962	1223	1231	patients	Species
23896962	1237	1265	usual interstitial pneumonia	Disease
23896962	1297	1305	patients	Species
23896962	1323	1345	interstitial pneumonia	Disease
23896962	1379	1387	fibrosis	Disease
23896962	1470	1472	HP	Disease
29459894|t|Idiopathic Pulmonary Fibrosis: Aging, Mitochondrial Dysfunction, and Cellular Bioenergetics
At present, the etiology of idiopathic pulmonary fibrosis (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	0	29	Idiopathic Pulmonary Fibrosis	Disease
29459894	121	150	idiopathic pulmonary fibrosis	Disease
29459894	152	155	IPF	Disease
29459894	292	315	metabolic dysregulation	Disease
29459894	397	400	IPF	Disease
29459894	459	462	IPF	Disease
29459894	568	574	oxygen	Chemical
29459894	685	722	removal of dysfunctional mitochondria	Disease
29459894	745	748	IPF	Disease
29459894	877	888	activation	Positive_regulation
29459894	891	896	TGF-b	Gene
29459894	934	952	pulmonary fibrosis	Disease
29459894	954	957	IPF	Disease
29459894	1230	1233	IPF	Disease
29459894	1347	1350	IPF	Disease
29459894	1487	1490	IPF	Disease
27909724|t|HSP27 regulates TGF-b mediated lung fibroblast differentiation through the Smad3 and ERK pathways
Idiopathic pulmonary fibrosis  (IPF) is a chronic lethal interstitial lung disease with unknown etiology
Recent studies have indicated that heat-shock protein  27  (HSP27) contributes to the pathogenesis of IPF through the regulation of epithelial-mesenchymal transition  (EMT)
However, the expression and role of HSP27 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 HSP27 in fibrotic lung tissue and fibroblasts from bleomycin  (BLM)-challenged mice and human lung fibroblasts treated with transforming growth factor-b  (TGF-b)
The results revealed that the expression of HSP27 was significantly increased in fibrotic lung tissue and fibroblasts from BLM-challenged mice
In  vitro, TGF-b stimulated HSP27 expression in and the differentiation of human lung fibroblasts
The knockdown of Smad3 expression or nuclear factor-kB  p65 subunit attenuated the TGF-b-induced increase in HSP27 expression and the differentiation of human lung fibroblasts
In addition, the knockdown of HSP27 expression attenuated the TGF-b-induced activation of ERK and Smad3, and inhibited the differentiation of human lung fibroblasts
On the whole, the findings of our study demonstrate that HSP27 expression is upregulated in lung fibroblasts during pulmonary fibrosis, and subsequently, HSP27 modulates lung fibroblast differentiation through the Smad3 and ERK pathways
27909724	0	5	HSP27	Gene
27909724	16	21	TGF-b	Gene
27909724	75	80	Smad3	Gene
27909724	85	88	ERK	Gene
27909724	99	128	Idiopathic pulmonary fibrosis	Disease
27909724	131	134	IPF	Disease
27909724	156	181	interstitial lung disease	Disease
27909724	265	270	HSP27	Gene
27909724	307	310	IPF	Disease
27909724	323	334	regulation	Regulation
27909724	392	403	expression	Gene_expression
27909724	415	420	HSP27	Gene
27909724	571	582	expression	Gene_expression
27909724	585	590	HSP27	Gene
27909724	636	645	bleomycin	Chemical
27909724	648	651	BLM	Chemical
27909724	664	668	mice	Species
27909724	673	678	human	Species
27909724	709	737	transforming growth factor-b	Gene
27909724	740	745	TGF-b	Gene
27909724	778	789	expression	Gene_expression
27909724	792	797	HSP27	Gene
27909724	816	826	increased	Positive_regulation
27909724	871	874	BLM	Chemical
27909724	886	890	mice	Species
27909724	903	908	TGF-b	Gene
27909724	909	920	stimulated	Positive_regulation
27909724	920	925	HSP27	Gene
27909724	926	937	expression	Gene_expression
27909724	967	972	human	Species
27909724	995	1005	knockdown	Negative_regulation
27909724	1008	1013	Smad3	Gene
27909724	1014	1025	expression	Gene_expression
27909724	1047	1050	p65	Gene
27909724	1074	1079	TGF-b	Gene
27909724	1100	1105	HSP27	Gene
27909724	1106	1117	expression	Gene_expression
27909724	1144	1149	human	Species
27909724	1185	1195	knockdown	Negative_regulation
27909724	1198	1203	HSP27	Gene
27909724	1204	1215	expression	Gene_expression
27909724	1215	1226	attenuated	Negative_regulation
27909724	1230	1235	TGF-b	Gene
27909724	1236	1244	induced	Positive_regulation
27909724	1244	1255	activation	Positive_regulation
27909724	1258	1261	ERK	Gene
27909724	1266	1271	Smad3	Gene
27909724	1310	1315	human	Species
27909724	1391	1396	HSP27	Gene
27909724	1397	1408	expression	Gene_expression
27909724	1411	1423	upregulated	Positive_regulation
27909724	1450	1468	pulmonary fibrosis	Disease
27909724	1488	1493	HSP27	Gene
27909724	1548	1553	Smad3	Gene
27909724	1558	1561	ERK	Gene
23434591|t|Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis
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 pulmonary fibrosis (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	84	102	pulmonary fibrosis	Disease
23434591	197	214	fibrotic diseases	Disease
23434591	349	357	fibrosis	Disease
23434591	587	614	megakaryoblastic leukemia 1	Gene
23434591	616	620	MKL1	Gene
23434591	718	723	mouse	Species
23434591	733	746	lung fibrosis	Disease
23434591	754	759	human	Species
23434591	774	803	idiopathic pulmonary fibrosis	Disease
23434591	805	808	IPF	Disease
23434591	823	834	activation	Positive_regulation
23434591	859	868	enhanced	Positive_regulation
23434591	907	911	MKL1	Gene
23434591	912	932	cytoplasmic-nuclear	Entity
23434591	1028	1035	fasudil	Chemical
23434591	1098	1113	downregulation	Negative_regulation
23434591	1116	1121	BCL-2	Gene
23434591	1202	1209	fasudil	Chemical
23434591	1256	1267	lung injury	Disease
23434591	1291	1295	Mkl1	Gene
23434591	1306	1310	mice	Species
23434591	1329	1342	lung fibrosis	Disease
23434591	1516	1534	fibrotic disorders	Disease
16842247|t|Extracellular superoxide dismutase has a highly specific localization in idiopathic pulmonary fibrosis/usual interstitial pneumonia
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 idiopathic pulmonary fibrosis (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	0	34	Extracellular superoxide dismutase	Gene
16842247	57	70	localization	Localization
16842247	73	102	idiopathic pulmonary fibrosis	Disease
16842247	103	131	usual interstitial pneumonia	Disease
16842247	217	235	pulmonary fibrosis	Disease
16842247	278	312	extracellular superoxide dismutase	Gene
16842247	314	319	ECSOD	Gene
16842247	382	387	human	Species
16842247	411	440	idiopathic pulmonary fibrosis	Disease
16842247	442	445	IPF	Disease
16842247	458	486	usual interstitial pneumonia	Disease
16842247	488	491	UIP	Disease
16842247	555	558	UIP	Disease
16842247	582	590	absence	Negative_regulation
16842247	593	598	ECSOD	Gene
16842247	690	695	ECSOD	Gene
16842247	802	807	ECSOD	Gene
16842247	822	825	UIP	Disease
16842247	900	905	ECSOD	Gene
16842247	977	983	tumour	Disease
16842247	984	992	necrosis	Disease
16842247	1010	1048	transforming growth factor (TGF)-beta1	Gene
16842247	1106	1114	Patients	Species
16842247	1120	1123	UIP	Disease
16842247	1230	1235	ECSOD	Gene
16842247	1237	1246	Arg213Gly	Mutation
16842247	1291	1296	ECSOD	Gene
16842247	1410	1413	UIP	Disease
16842247	1414	1422	patients	Species
16842247	1520	1525	ECSOD	Gene
16842247	1559	1562	UIP	Disease
21511034|t|Early growth response transcription factors: key mediators of fibrosis and novel targets for anti-fibrotic therapy
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 fibrosis involves multiple cell types and extracellular signals, of which transforming growth factor-   (TGF-  ) is pre-eminent
The prevalence of fibrosis 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 fibrosis
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 fibrosis (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 fibrosis
As a novel profibrotic mediator, Egr-1 thus appears to be a promising potential target for the development of anti-fibrotic therapies
21511034	62	70	fibrosis	Disease
21511034	116	124	Fibrosis	Disease
21511034	230	235	human	Species
21511034	257	264	obesity	Disease
21511034	296	304	fibrosis	Disease
21511034	443	451	fibrosis	Disease
21511034	643	648	Egr-1	Gene
21511034	672	680	fibrosis	Disease
21511034	682	687	Egr-1	Gene
21511034	840	846	injury	Disease
21511034	934	939	c-jun	Gene
21511034	944	951	Smad2/3	Gene
21511034	1005	1021	phosphorylation	Phosphorylation
21511034	1033	1047	translocation	Localization
21511034	1048	1053	Egr-1	Gene
21511034	1066	1076	regulated	Regulation
21511034	1084	1097	biosynthesis	Gene_expression
21511034	1107	1112	Egr-1	Gene
21511034	1113	1124	expression	Gene_expression
21511034	1153	1159	cancer	Disease
21511034	1161	1173	inflammation	Disease
21511034	1175	1190	atherosclerosis	Disease
21511034	1196	1211	ischemic injury	Disease
21511034	1266	1271	Egr-1	Gene
21511034	1315	1323	Fibrosis	Disease
21511034	1353	1358	human	Species
21511034	1376	1387	scleroderma	Disease
21511034	1398	1427	idiopathic pulmonary fibrosis	Disease
21511034	1461	1466	Egr-1	Gene
21511034	1467	1478	expression	Gene_expression
21511034	1488	1493	Egr-1	Gene
21511034	1584	1589	Egr-1	Gene
21511034	1595	1599	mice	Species
21511034	1619	1627	fibrosis	Disease
21511034	1662	1667	Egr-1	Gene
21166126|t|[A role for mesothelial cells in the genesis of idiopathic pulmonary fibrosis?]
Idiopathic pulmonary fibrosis (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	48	77	idiopathic pulmonary fibrosis	Disease
21166126	81	110	Idiopathic pulmonary fibrosis	Disease
21166126	112	115	IPF	Disease
21166126	215	223	fibrosis	Disease
21166126	247	250	IPF	Disease
21166126	286	289	IPF	Disease
21166126	354	370	pleural fibrosis	Disease
21166126	382	392	adenovirus	Species
21166126	501	514	accumulation	Positive_regulation
21166126	548	570	sub-pleural parenchyma	Disease
21166126	577	597	sub-pleural fibrosis	Disease
21166126	973	989	pleural fibrosis	Disease
21166126	1031	1034	IPF	Disease
26846484|t|Effects of the tumor suppressor PTEN on the pathogenesis of idiopathic pulmonary fibrosis in Chinese patients
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 tumor 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	0	8	Effects	Gene_expression
26846484	15	20	tumor	Disease
26846484	32	36	PTEN	Gene
26846484	60	89	idiopathic pulmonary fibrosis	Disease
26846484	101	109	patients	Species
26846484	111	140	Idiopathic pulmonary fibrosis	Disease
26846484	142	145	IPF	Disease
26846484	179	200	interstitial fibrosis	Disease
26846484	290	293	IPF	Disease
26846484	381	384	IPF	Disease
26846484	389	395	cancer	Disease
26846484	439	450	expression	Gene_expression
26846484	464	469	tumor	Disease
26846484	538	542	PTEN	Gene
26846484	555	563	patients	Species
26846484	569	572	IPF	Disease
26846484	648	652	PTEN	Gene
26846484	675	693	pulmonary fibrosis	Disease
26846484	695	699	PTEN	Gene
26846484	704	718	overexpressed	Positive_regulation
26846484	769	774	human	Species
26846484	839	843	PTEN	Gene
26846484	875	883	patients	Species
26846484	889	892	IPF	Disease
26846484	949	953	PTEN	Gene
26846484	954	969	overexpression	Positive_regulation
26846484	1073	1077	PTEN	Gene
26846484	1103	1111	inhibit	Negative_regulation
26846484	1111	1119	TGF  -b1	Gene
26846484	1172	1187	Overexpression	Positive_regulation
26846484	1190	1194	PTEN	Gene
26846484	1211	1227	phosphorylation	Phosphorylation
26846484	1230	1233	Akt	Gene
26846484	1238	1243	Smad3	Gene
26846484	1263	1274	expression	Gene_expression
26846484	1325	1333	TGF  -b1	Gene
26846484	1344	1352	fibrosis	Disease
26846484	1389	1423	matrix metalloproteinase (MMP)  -2	Gene
26846484	1428	1435	MMP  -9	Gene
26846484	1466	1470	PTEN	Gene
26846484	1483	1491	TGF  -b1	Gene
26846484	1581	1601	phosphatidylinositol	Chemical
26846484	1613	1616	Akt	Gene
26846484	1621	1628	TGF  -b	Gene
26846484	1629	1634	Smad3	Gene
16211459|t|Different effects of growth factors on proliferation and matrix production of normal and fibrotic human lung fibroblasts
OBJECTIVES AND METHODS: In idiopathic pulmonary fibrosis (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 ([(3)H]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 (TGFbeta(1)), 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, TGFbeta(1), 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, TGFbeta(1), 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	149	178	idiopathic pulmonary fibrosis	Disease
16211459	180	183	IPF	Disease
16211459	257	273	pulmonary damage	Disease
16211459	278	303	respiratory insufficiency	Disease
16211459	399	402	IPF	Disease
16211459	437	448	pneumonitis	Disease
16211459	450	453	UIP	Disease
16211459	490	505	[(3)H]thymidine	Chemical
16211459	615	625	synthesis	Gene_expression
16211459	680	683	UIP	Disease
16211459	908	935	tumor necrosis factor alpha	Disease
16211459	937	945	TNFalpha	Disease
16211459	948	979	Transforming growth factor-beta	Disease
16211459	1125	1128	UIP	Disease
16211459	1179	1190	expression	Gene_expression
16211459	1235	1243	induced	Positive_regulation
16211459	1269	1277	TNFalpha	Disease
16211459	1317	1320	UIP	Disease
16211459	1391	1401	synthesis	Gene_expression
16211459	1412	1421	enhanced	Positive_regulation
16211459	1433	1443	synthesis	Gene_expression
16211459	1446	1449	UIP	Disease
16211459	1502	1510	TNFalpha	Disease
16211459	1577	1580	UIP	Disease
16211459	1703	1706	UIP	Disease
16211459	1817	1835	pulmonary fibrosis	Disease
16211459	1853	1856	UIP	Disease
22802283|t|The impact of TGF-b on lung fibrosis: from targeting to biomarkers
Transforming growth factor-b (TGF-b) is extensively involved in the development of fibrosis 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 fibrosis (IPF) is a chronic, devastating disease, in which TGF-b\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 TGF-b and its direct or indirect targeting for disease modulation
22802283	14	19	TGF-b	Gene
22802283	28	36	fibrosis	Disease
22802283	68	96	Transforming growth factor-b	Gene
22802283	98	103	TGF-b	Gene
22802283	151	159	fibrosis	Disease
22802283	328	357	Idiopathic pulmonary fibrosis	Disease
22802283	359	362	IPF	Disease
22802283	408	413	TGF-b	Gene
22802283	823	828	TGF-b	Gene
24050627|t|Pathogenesis of idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	16	45	idiopathic pulmonary fibrosis	Disease
24050627	47	76	Idiopathic pulmonary fibrosis	Disease
24050627	78	81	IPF	Disease
24050627	98	123	interstitial lung disease	Disease
24050627	210	232	interstitial pneumonia	Disease
24050627	283	286	IPF	Disease
24050627	375	378	IPF	Disease
24050627	582	585	IPF	Disease
24050627	764	767	IPF	Disease
19850962|t|SNAI transcription factors mediate epithelial-mesenchymal transition in lung fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterised by accumulation of activated (myo)fibroblasts and excessive extracellular matrix deposition
The enhanced accumulation of (myo)fibroblasts 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	72	85	lung fibrosis	Disease
19850962	99	128	Idiopathic pulmonary fibrosis	Disease
19850962	130	133	IPF	Disease
19850962	146	171	interstitial lung disease	Disease
19850962	371	403	transforming growth factor beta1	Gene
19850962	405	413	TGFbeta1	Gene
19850962	538	565	alveolar epithelial type II	Disease
19850962	567	571	ATII	Disease
19850962	785	788	IPF	Disease
19850962	987	992	role	Transcription
19850962	995	1000	SNAI1	Gene
19850962	1005	1010	SNAI2	Gene
19850962	1014	1022	TGFbeta1	Gene
19850962	1038	1042	ATII	Disease
19850962	1080	1091	expression	Gene_expression
19850962	1154	1159	human	Species
19850962	1160	1163	IPF	Disease
19850962	1182	1190	TGFbeta1	Gene
19850962	1201	1211	increased	Positive_regulation
19850962	1215	1226	expression	Gene_expression
19850962	1230	1238	nuclear	Entity
19850962	1238	1251	accumulation	Positive_regulation
19850962	1254	1259	SNAI1	Gene
19850962	1264	1269	SNAI2	Gene
19850962	1287	1297	induction	Positive_regulation
19850962	1307	1311	ATII	Disease
19850962	1324	1339	overexpression	Positive_regulation
19850962	1438	1446	TGFbeta1	Gene
19850962	1455	1459	ATII	Disease
19850962	1489	1500	expression	Gene_expression
19850962	1504	1513	elevated	Positive_regulation
19850962	1533	1538	human	Species
19850962	1539	1542	IPF	Disease
19850962	1573	1577	ATII	Disease
19850962	1635	1643	TGFbeta1	Gene
19850962	1659	1663	ATII	Disease
19850962	1703	1714	expression	Gene_expression
19850962	1718	1726	nuclear	Entity
19850962	1771	1781	Increased	Positive_regulation
19850962	1781	1786	SNAI1	Gene
19850962	1791	1796	SNAI2	Gene
19850962	1797	1808	expression	Gene_expression
19850962	1828	1833	human	Species
19850962	1834	1837	IPF	Disease
19850962	1919	1948	idiopathic pulmonary fibrosis	Disease
22802287|t|TGF-b activation and lung fibrosis
Lung fibrosis can affect the parenchyma and the airways, classically giving rise to idiopathic pulmonary fibrosis (IPF) in the parenchyma or airway remodeling in asthma and chronic obstructive pulmonary disease
TGF-b activation has been implicated in the fibrosis of both IPF and airway remodeling
However, the mechanisms of TGF-b activation appear to differ depending on the cellular and anatomical compartments, with implications on disease pathogenesis
Although it appears that epithelial cell activation of TGF-b by the avb6 integrin is central in IPF, mesenchymal activation of TGF-b by the avb5 and avb8 integrins appears to predominate in airway remodeling
Interestingly, the mechanism of TGF-b by the integrins avb6 and avb5 is shared, relying on cytoskeletal changes, whereas activation of TGF-b by the avb8 integrin is distinct, relying on proteolytic cleavage of the latency-associated peptide of TGF-b by matrix metalloproteinase 14
This article describes the mechanisms through which epithelial cells activate TGF-b by the avb6 integrin and mesenchymal cells activate TGF-b by the avb5 integrin, and highlights their roles in lung fibrosis
22802287	0	5	TGF-b	Gene
22802287	26	34	fibrosis	Disease
22802287	41	49	fibrosis	Disease
22802287	120	149	idiopathic pulmonary fibrosis	Disease
22802287	151	154	IPF	Disease
22802287	198	204	asthma	Disease
22802287	209	246	chronic obstructive pulmonary disease	Disease
22802287	248	253	TGF-b	Gene
22802287	254	265	activation	Positive_regulation
22802287	292	300	fibrosis	Disease
22802287	309	312	IPF	Disease
22802287	363	368	TGF-b	Gene
22802287	369	380	activation	Positive_regulation
22802287	536	547	activation	Positive_regulation
22802287	550	555	TGF-b	Gene
22802287	591	594	IPF	Disease
22802287	608	619	activation	Positive_regulation
22802287	622	627	TGF-b	Gene
22802287	736	741	TGF-b	Gene
22802287	825	836	activation	Positive_regulation
22802287	839	844	TGF-b	Gene
22802287	948	953	TGF-b	Gene
22802287	957	984	matrix metalloproteinase 14	Gene
22802287	1055	1064	activate	Positive_regulation
22802287	1064	1069	TGF-b	Gene
22802287	1113	1122	activate	Positive_regulation
22802287	1122	1127	TGF-b	Gene
22802287	1185	1193	fibrosis	Disease
23468849|t|Herpes virus infection is associated with vascular remodeling and pulmonary hypertension in idiopathic pulmonary fibrosis
BACKGROUND: Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (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	7	22	virus infection	Disease
23468849	66	88	pulmonary hypertension	Disease
23468849	92	121	idiopathic pulmonary fibrosis	Disease
23468849	135	157	Pulmonary hypertension	Disease
23468849	159	161	PH	Disease
23468849	203	232	idiopathic pulmonary fibrosis	Disease
23468849	234	237	IPF	Disease
23468849	265	272	patient	Species
23468849	379	382	IPF	Disease
23468849	412	414	PH	Disease
23468849	431	434	IPF	Disease
23468849	499	502	IPF	Disease
23468849	503	511	patients	Species
23468849	543	545	PH	Disease
23468849	560	565	mouse	Species
23468849	594	597	MHV	Species
23468849	610	628	pulmonary fibrosis	Disease
23468849	685	688	IPF	Disease
23468849	689	697	patients	Species
23468849	1110	1113	MHV	Species
23468849	1126	1130	mice	Species
23468849	1197	1200	IPF	Disease
23468849	1201	1209	patients	Species
23468849	1576	1581	TGF-b	Gene
23468849	1792	1807	Viral infection	Disease
23468849	1970	1973	MHV	Species
23468849	1986	1990	mice	Species
23468849	2040	2048	patients	Species
23468849	2107	2119	development	Negative_regulation
23468849	2122	2124	PH	Disease
23468849	2128	2131	IPF	Disease
23468849	2132	2140	patients	Species
20560295|t|N-acetylcysteine inhibits TNF-alpha, sTNFR, and TGF-beta1 release by alveolar macrophages in idiopathic pulmonary fibrosis in vitro
BACKGROUND: N-acetylcysteine (NAC) can act as an antioxidant
NAC slows the rate of decline of lung function in idiopathic pulmonary fibrosis (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 (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12 (p70), IL-18, transforming growth factor (TGF)-beta1, 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 TNF-alpha, its soluble receptors, and TGF-beta1 by AMs in a dose-dependent manner
At the highest concentration of NAC (10 mM), the spontaneous or LPS-stimulated production ofTNF-alpha, sTNFR1, sTNFR2, and TGF-beta1 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 TNF-alpha and their soluble receptors, as well as TGF-beta1 and LPS-stimulated IL-1beta, by AM in IPF in vitro
NAC may have anti-inflammatory and anti-fibrotic effects
20560295	0	16	N-acetylcysteine	Chemical
20560295	17	26	inhibits	Negative_regulation
20560295	26	35	TNF-alpha	Gene
20560295	48	57	TGF-beta1	Gene
20560295	93	122	idiopathic pulmonary fibrosis	Disease
20560295	145	161	N-acetylcysteine	Chemical
20560295	163	166	NAC	Chemical
20560295	195	198	NAC	Chemical
20560295	245	274	idiopathic pulmonary fibrosis	Disease
20560295	276	279	IPF	Disease
20560295	281	289	patients	Species
20560295	316	326	prednisone	Chemical
20560295	331	343	azathioprine	Chemical
20560295	390	397	effect	Regulation
20560295	400	403	NAC	Chemical
20560295	411	422	production	Gene_expression
20560295	425	446	tumor necrosis factor	Gene
20560295	448	458	TNF)-alpha	Gene
20560295	460	482	interleukin (IL)-1beta	Gene
20560295	484	488	IL-6	Gene
20560295	490	494	IL-8	Gene
20560295	496	501	IL-10	Gene
20560295	510	513	p70	Gene
20560295	516	521	IL-18	Gene
20560295	523	561	transforming growth factor (TGF)-beta1	Gene
20560295	645	648	IPF	Disease
20560295	649	657	patients	Species
20560295	726	729	IPF	Disease
20560295	730	738	patients	Species
20560295	866	869	NAC	Chemical
20560295	906	909	NAC	Chemical
20560295	910	921	suppressed	Negative_regulation
20560295	925	936	production	Gene_expression
20560295	939	948	TNF-alpha	Gene
20560295	977	986	TGF-beta1	Gene
20560295	990	993	AMs	Chemical
20560295	1054	1057	NAC	Chemical
20560295	1101	1112	production	Gene_expression
20560295	1145	1154	TGF-beta1	Gene
20560295	1174	1182	reduced	Negative_regulation
20560295	1202	1210	IL-1beta	Gene
20560295	1211	1222	production	Gene_expression
20560295	1231	1242	suppressed	Negative_regulation
20560295	1251	1254	NAC	Chemical
20560295	1269	1272	NAC	Chemical
20560295	1294	1308	down-regulate	Negative_regulation
20560295	1312	1323	production	Gene_expression
20560295	1326	1335	TNF-alpha	Gene
20560295	1376	1385	TGF-beta1	Gene
20560295	1405	1413	IL-1beta	Gene
20560295	1424	1427	IPF	Disease
20560295	1438	1441	NAC	Chemical
23380438|t|Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis
PRM-151, recombinant human Pentraxin-2 (PTX-2) also referred to as serum amyloid P (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 pulmonary fibrosis (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 pulmonary fibrosis 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	18	33	serum amyloid P	Gene
23380438	60	68	patients	Species
23380438	74	92	pulmonary fibrosis	Disease
23380438	115	120	human	Species
23380438	121	132	Pentraxin-2	Gene
23380438	134	139	PTX-2	Gene
23380438	161	176	serum amyloid P	Gene
23380438	178	181	SAP	Gene
23380438	222	230	fibrosis	Disease
23380438	243	248	Human	Species
23380438	545	548	SAP	Gene
23380438	654	657	SAP	Gene
23380438	727	730	SAP	Gene
23380438	788	806	pulmonary fibrosis	Disease
23380438	808	810	PF	Disease
23380438	812	820	patients	Species
23380438	878	881	SAP	Gene
23380438	921	923	PF	Disease
23380438	924	932	patients	Species
23380438	1173	1191	pulmonary fibrosis	Disease
23380438	1192	1200	patients	Species
23380438	1241	1250	urticaria	Disease
23380438	1363	1366	SAP	Gene
23380438	1547	1549	PF	Disease
23380438	1550	1558	patients	Species
23380438	1747	1749	PF	Disease
23380438	1750	1758	patients	Species
24300094|t|Protective role of andrographolide in bleomycin-induced pulmonary fibrosis in mice
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis
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 pulmonary fibrosis
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 pulmonary fibrosis
24300094	19	34	andrographolide	Chemical
24300094	38	47	bleomycin	Chemical
24300094	56	74	pulmonary fibrosis	Disease
24300094	78	82	mice	Species
24300094	84	113	Idiopathic pulmonary fibrosis	Disease
24300094	115	118	IPF	Disease
24300094	217	229	inflammation	Disease
24300094	341	344	IPF	Disease
24300094	421	431	activated	Positive_regulation
24300094	434	437	IPF	Disease
24300094	493	496	IPF	Disease
24300094	546	561	andrographolide	Chemical
24300094	565	574	bleomycin	Chemical
24300094	583	595	inflammation	Disease
24300094	600	608	fibrosis	Disease
24300094	612	616	mice	Species
24300094	643	658	andrographolide	Chemical
24300094	680	684	mice	Species
24300094	690	699	bleomycin	Chemical
24300094	708	726	pulmonary fibrosis	Disease
24300094	820	825	TNF-a	Gene
24300094	1012	1026	hydroxyproline	Chemical
24300094	1064	1070	TGF-b1	Gene
24300094	1075	1080	a-SMA	Gene
24300094	1113	1124	Activation	Positive_regulation
24300094	1233	1242	bleomycin	Chemical
24300094	1256	1271	andrographolide	Chemical
24300094	1289	1299	inhibited	Negative_regulation
24300094	1326	1331	TNF-a	Gene
24300094	1402	1416	hydroxyproline	Chemical
24300094	1432	1441	bleomycin	Chemical
24300094	1474	1489	andrographolide	Chemical
24300094	1519	1534	andrographloide	Chemical
24300094	1535	1546	suppressed	Negative_regulation
24300094	1546	1552	TGF-b1	Gene
24300094	1557	1562	a-SMA	Gene
24300094	1580	1591	expression	Transcription
24300094	1594	1603	bleomycin	Chemical
24300094	1612	1630	pulmonary fibrosis	Disease
24300094	1643	1658	andrographolide	Chemical
24300094	1690	1700	inhibited	Negative_regulation
24300094	1713	1720	phospho	Chemical
24300094	1765	1773	binding	Binding
24300094	1812	1827	andrographolide	Chemical
24300094	1840	1849	bleomycin	Chemical
24300094	1858	1880	pulmonary inflammation	Disease
24300094	1885	1893	fibrosis	Disease
24300094	1911	1924	inactivation	Negative_regulation
24300094	1934	1949	Andrographolide	Chemical
24300094	2016	2034	pulmonary fibrosis	Disease
17982242|t|Transforming growth factor beta1 induces epithelial-to-mesenchymal transition of A549 cells
Idiopathic pulmonary fibrosis (IPF) comprises an aggregate of mesenchymal cells
However, the cellular origin of these mesenchymal phenotypes remains unclear
Transforming growth factor beta1 (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	0	32	Transforming growth factor beta1	Gene
17982242	93	122	Idiopathic pulmonary fibrosis	Disease
17982242	124	127	IPF	Disease
17982242	252	284	Transforming growth factor beta1	Gene
17982242	286	295	TGF-beta1	Gene
17982242	365	368	IPF	Disease
17982242	421	430	TGF-beta1	Gene
17982242	498	503	human	Species
17982242	564	569	snail	Gene
17982242	793	803	E-cadherin	Gene
17982242	830	835	snail	Gene
17982242	976	985	TGF-beta1	Gene
17982242	1104	1113	TGF-beta1	Gene
17982242	1194	1199	loss	Negative_regulation
17982242	1328	1336	vimentin	Gene
17982242	1347	1355	IL-1beta	Gene
17982242	1419	1428	TGF-beta1	Gene
17982242	1433	1441	IL-1beta	Gene
17982242	1540	1545	snail	Gene
17982242	1599	1604	loss	Negative_regulation
17982242	1607	1617	E-cadherin	Gene
17982242	1618	1629	expression	Gene_expression
17982242	1649	1654	snail	Gene
17982242	1697	1706	TGF-beta1	Gene
17982242	1712	1720	IL-1beta	Gene
17982242	1748	1753	snail	Gene
17982242	1838	1843	snail	Gene
11812353|t|[The potential role of cytokines expression in idiopathic pulmonary fibrosis]
OBJECTIVE: To investigate the protein and gene expression in bronchoalveolar lavage cells and open lung biopsies from patients with IPF
METHODS: The immunohistochemical methods were used to analyze the expression of PDGF, TGF-beta in bronchoalveolar lavage cells of patients with IPF
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 IPF
Though there were no differences between IPF 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 IPF 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	47	76	idiopathic pulmonary fibrosis	Disease
11812353	197	205	patients	Species
11812353	211	214	IPF	Disease
11812353	282	293	expression	Gene_expression
11812353	302	310	TGF-beta	Gene
11812353	346	354	patients	Species
11812353	360	363	IPF	Disease
11812353	507	514	PDGF-AA	Chemical
11812353	525	533	TGF-beta	Gene
11812353	552	560	alveolar	Disease
11812353	576	584	patients	Species
11812353	644	655	sarcoidosis	Disease
11812353	865	873	patients	Species
11812353	901	909	TGF-beta	Gene
11812353	937	978	hyperplastic bronchio-alveolar epithelial	Disease
11812353	1012	1020	alveolar	Disease
11812353	1365	1373	TGF-beta	Gene
11812353	1400	1409	detected	Gene_expression
11812353	1412	1440	bronchio-alveolar epithelial	Disease
11812353	1515	1523	TGF-beta	Gene
11812353	1534	1542	present	Gene_expression
11812353	1638	1646	TGF-beta	Gene
11812353	1714	1725	fibroplasia	Disease
23492187|t|X-linked inhibitor of apoptosis regulates lung fibroblast resistance to Fas-mediated apoptosis
The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear
A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (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 (TGF)b-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	0	31	X-linked inhibitor of apoptosis	Gene
23492187	204	233	idiopathic pulmonary fibrosis	Disease
23492187	235	238	IPF	Disease
23492187	374	405	X-linked inhibitor of apoptosis	Gene
23492187	407	411	XIAP	Gene
23492187	466	470	XIAP	Gene
23492187	474	484	localized	Localization
23492187	508	511	IPF	Disease
23492187	527	542	prostaglandin E	Chemical
23492187	546	557	suppresses	Negative_regulation
23492187	557	561	XIAP	Gene
23492187	562	573	expression	Gene_expression
23492187	680	684	XIAP	Gene
23492187	694	704	regulated	Regulation
23492187	800	810	increased	Positive_regulation
23492187	810	814	XIAP	Gene
23492187	859	862	IPF	Disease
23492187	917	921	XIAP	Gene
23492187	922	933	expression	Gene_expression
23492187	947	950	IPF	Disease
23492187	1022	1028	TGF-b1	Gene
23492187	1032	1036	ET-1	Gene
23492187	1050	1054	XIAP	Gene
23492187	1158	1162	XIAP	Gene
23492187	1248	1251	IPF	Disease
23492187	1375	1378	IPF	Disease
23492187	1429	1439	increased	Positive_regulation
23492187	1445	1449	XIAP	Gene
23492187	1450	1461	expression	Gene_expression
23492187	1476	1482	TGF-b1	Gene
23492187	1487	1491	ET-1	Gene
23492187	1492	1500	induced	Positive_regulation
23492187	1500	1504	XIAP	Gene
23492187	1513	1524	expression	Gene_expression
23492187	1574	1578	XIAP	Gene
23492187	1698	1709	activation	Positive_regulation
23492187	1770	1774	XIAP	Gene
23492187	1815	1818	IPF	Disease
22295148|t|Idiopathic pulmonary fibrosis: immunohistochemical analysis provides fresh insights into lung tissue remodelling with implications for novel prognostic markers
AIM: This study explored the cellular and biological interrelationships involved in Idiopathic Pulmonary Fibrosis (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	0	29	Idiopathic pulmonary fibrosis	Disease
22295148	245	274	Idiopathic Pulmonary Fibrosis	Disease
22295148	276	279	IPF	Disease
22295148	362	365	IPF	Disease
22295148	568	578	E-cadherin	Gene
22295148	583	593	expressed	Gene_expression
22295148	596	599	IPF	Disease
22295148	613	629	Alveolar type II	Disease
22295148	653	656	IPF	Disease
22295148	663	674	expression	Gene_expression
22295148	677	687	N-cadherin	Gene
22295148	859	869	expressed	Gene_expression
22295148	917	946	Transforming Growth Factor- b	Gene
22295148	948	953	TGF-b	Gene
22295148	992	1002	increased	Positive_regulation
22295148	1005	1008	IPF	Disease
22295148	1200	1205	a-SMA	Gene
22295148	1221	1231	expressed	Gene_expression
22295148	1305	1313	present	Gene_expression
22295148	1318	1321	IPF	Disease
22295148	1329	1332	IPF	Disease
22295148	1366	1386	Surfactant Protein-C	Gene
22295148	1428	1431	IPF	Disease
22295148	1529	1534	TGF-b	Gene
22295148	1731	1741	N-cadherin	Gene
22295148	1890	1893	IPF	Disease
23439433|t|PI3K p110y overexpression in idiopathic pulmonary fibrosis lung tissue and fibroblast cells: in vitro effects of its inhibition
Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease whose molecular pathogenesis remains unclear
In a recent paper, we demonstrated a key role for the PI3K 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 PI3K 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 PI3K 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 PI3K 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 PI3K p110y isoform may have an important role in the etio-pathology of IPF and can be a specific pharmacological target
23439433	0	4	PI3K	Gene
23439433	11	26	overexpression	Positive_regulation
23439433	29	63	idiopathic pulmonary fibrosis lung	Disease
23439433	129	158	Idiopathic pulmonary fibrosis	Disease
23439433	160	163	IPF	Disease
23439433	309	313	PI3K	Gene
23439433	394	399	human	Species
23439433	430	435	TGF-b	Gene
23439433	471	482	expression	Gene_expression
23439433	493	497	PI3K	Gene
23439433	498	502	p110	Gene
23439433	515	518	IPF	Disease
23439433	647	658	inhibition	Negative_regulation
23439433	661	665	p110	Gene
23439433	678	681	IPF	Disease
23439433	764	767	IPF	Disease
23439433	781	792	Expression	Gene_expression
23439433	802	806	PI3K	Gene
23439433	807	811	p110	Gene
23439433	941	944	IPF	Disease
23439433	1138	1141	IPF	Disease
23439433	1198	1209	expression	Gene_expression
23439433	1212	1216	PI3K	Gene
23439433	1217	1221	p110	Gene
23439433	1274	1284	expressed	Gene_expression
23439433	1292	1295	IPF	Disease
23439433	1394	1397	IPF	Disease
23439433	1539	1548	cyclin D1	Gene
23439433	1749	1752	IPF	Disease
23439433	1788	1792	PI3K	Gene
23439433	1859	1862	IPF	Disease
18621908|t|Alveolar epithelial cell injury with Epstein-Barr virus upregulates TGFbeta1 expression
Idiopathic pulmonary fibrosis (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 (TGFbeta1) transcript expression in association with reduced cell proliferation and increased caspase 3/7 activity
Exposing EBV-infected cells to ganciclovir resulted in TGFbeta1 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 TGFbeta1 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	37	55	Epstein-Barr virus	Species
18621908	56	68	upregulates	Positive_regulation
18621908	68	76	TGFbeta1	Gene
18621908	77	88	expression	Gene_expression
18621908	89	118	Idiopathic pulmonary fibrosis	Disease
18621908	120	123	IPF	Disease
18621908	152	177	interstitial lung disease	Disease
18621908	286	309	Epstein-Barr virus (EBV	Species
18621908	373	376	IPF	Disease
18621908	377	385	patients	Species
18621908	553	556	EBV	Chemical
18621908	573	581	fibrosis	Disease
18621908	607	612	human	Species
18621908	681	684	EBV	Disease
18621908	686	689	EBV	Disease
18621908	712	722	increased	Positive_regulation
18621908	739	771	transforming growth factor-beta1	Gene
18621908	773	781	TGFbeta1	Gene
18621908	794	805	expression	Gene_expression
18621908	856	866	increased	Positive_regulation
18621908	866	875	caspase 3	Gene
18621908	897	900	EBV	Disease
18621908	919	930	ganciclovir	Chemical
18621908	943	951	TGFbeta1	Gene
18621908	952	965	deregulation	Regulation
18621908	969	977	reduced	Negative_regulation
18621908	977	988	expression	Gene_expression
18621908	991	994	EBV	Disease
18621908	1037	1046	targeted	Positive_regulation
18621908	1071	1080	products	Gene_expression
18621908	1081	1084	Rta	Gene
18621908	1089	1092	Zta	Chemical
18621908	1137	1151	normalization	Localization
18621908	1154	1162	TGFbeta1	Gene
18621908	1266	1271	human	Species
18621908	1388	1391	IPF	Disease
26268659|t|CXCL9 Regulates TGF-b1-Induced Epithelial to Mesenchymal Transition in Human Alveolar Epithelial Cells
UNASSIGNED: Epithelial to mesenchymal cell transition (EMT), whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (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 EMT and CXCR3 expression in human IPF surgical lung biopsies and assessed whether CXCR3 and its ligand CXCL9 modulate EMT 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 TGF-b1 and CXCL9, with Smad2, Smad3, and Smad7 expression and cellular localization examined by Western blotting
We found that significantly more cells were undergoing EMT 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 EMT
In vitro, CXCL9 abrogated TGF-b1-induced EMT
A decrease in TGF-b1-induced phosphorylation of Smad2 and Smad3 occurred with CXCL9 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 EMT in the pathogenesis of IPF and provides a novel mechanism for the inhibitory effects of CXCL9 on TGF-b1-induced EMT
26268659	0	5	CXCL9	Gene
26268659	16	22	TGF-b1	Gene
26268659	71	76	Human	Species
26268659	159	162	EMT	Gene
26268659	293	322	idiopathic pulmonary fibrosis	Disease
26268659	324	327	IPF	Disease
26268659	330	335	CXCR3	Gene
26268659	356	367	recognized	Binding
26268659	396	414	pulmonary fibrosis	Disease
26268659	474	477	EMT	Gene
26268659	482	487	CXCR3	Gene
26268659	488	499	expression	Gene_expression
26268659	502	507	human	Species
26268659	508	511	IPF	Disease
26268659	556	561	CXCR3	Gene
26268659	577	582	CXCL9	Gene
26268659	583	592	modulate	Regulation
26268659	592	595	EMT	Gene
26268659	626	639	Coexpression	Gene_expression
26268659	664	694	thyroid transcription factor-1	Gene
26268659	748	753	CXCR3	Gene
26268659	754	765	expression	Gene_expression
26268659	813	816	IPF	Disease
26268659	974	979	human	Species
26268659	1026	1032	TGF-b1	Gene
26268659	1037	1042	CXCL9	Gene
26268659	1049	1054	Smad2	Gene
26268659	1056	1061	Smad3	Gene
26268659	1067	1072	Smad7	Gene
26268659	1073	1084	expression	Gene_expression
26268659	1097	1110	localization	Localization
26268659	1195	1198	EMT	Gene
26268659	1242	1245	IPF	Disease
26268659	1276	1281	CXCR3	Gene
26268659	1286	1296	expressed	Gene_expression
26268659	1392	1395	EMT	Gene
26268659	1407	1412	CXCL9	Gene
26268659	1423	1429	TGF-b1	Gene
26268659	1438	1441	EMT	Gene
26268659	1445	1454	decrease	Negative_regulation
26268659	1457	1463	TGF-b1	Gene
26268659	1472	1488	phosphorylation	Phosphorylation
26268659	1491	1496	Smad2	Gene
26268659	1501	1506	Smad3	Gene
26268659	1521	1526	CXCL9	Gene
26268659	1563	1573	increased	Positive_regulation
26268659	1573	1583	shuttling	Localization
26268659	1586	1591	Smad7	Gene
26268659	1616	1626	cytoplasm	Entity
26268659	1635	1644	inhibits	Negative_regulation
26268659	1649	1665	phosphorylation	Phosphorylation
26268659	1691	1694	EMT	Gene
26268659	1718	1721	IPF	Disease
26268659	1783	1788	CXCL9	Gene
26268659	1792	1798	TGF-b1	Gene
26268659	1807	1810	EMT	Gene
10337028|t|Expression of mucosa-related integrin alphaEbeta7 on alveolar T cells in interstitial lung diseases
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 lymphocytic alveolitis 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	0	11	Expression	Gene_expression
10337028	53	63	alveolar T	Disease
10337028	73	99	interstitial lung diseases	Disease
10337028	105	116	expression	Gene_expression
10337028	306	317	expression	Gene_expression
10337028	350	372	lymphocytic alveolitis	Disease
10337028	376	401	interstitial lung disease	Disease
10337028	403	406	ILD	Disease
10337028	416	427	expression	Gene_expression
10337028	430	433	CD4	Gene
10337028	439	442	CD8	Gene
10337028	566	574	patients	Species
10337028	580	609	idiopathic pulmonary fibrosis	Disease
10337028	611	614	IPF	Disease
10337028	625	653	hypersensitivity pneumonitis	Disease
10337028	655	657	HP	Disease
10337028	671	682	sarcoidosis	Disease
10337028	774	781	patient	Species
10337028	898	901	CD8	Gene
10337028	924	937	co-expressed	Gene_expression
10337028	963	966	CD8	Gene
10337028	1010	1020	increased	Positive_regulation
10337028	1023	1025	HP	Disease
10337028	1026	1034	patients	Species
10337028	1066	1069	CD4	Gene
10337028	1116	1119	IPF	Disease
10337028	1140	1142	HP	Disease
10337028	1229	1240	sarcoidosis	Disease
10337028	1253	1264	expression	Gene_expression
10337028	1272	1275	CD4	Gene
10337028	1420	1430	increased	Positive_regulation
10337028	1628	1639	expression	Gene_expression
10337028	1702	1705	CD8	Gene
10337028	1728	1736	express	Gene_expression
10337028	1790	1801	expression	Gene_expression
10337028	1813	1816	CD4	Gene
10337028	1833	1844	sarcoidosis	Disease
19924381|t|Effects of cigarette smoke extract on A549 cells and human lung fibroblasts treated with transforming growth factor-beta1 in a coculture system
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 cigarette smoke extract (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	11	34	cigarette smoke extract	Disease
19924381	53	58	human	Species
19924381	89	121	transforming growth factor-beta1	Gene
19924381	174	203	idiopathic pulmonary fibrosis	Disease
19924381	205	208	IPF	Disease
19924381	321	344	cigarette smoke extract	Disease
19924381	346	349	CSE	Disease
19924381	369	374	human	Species
19924381	405	437	transforming growth factor-beta1	Gene
19924381	641	644	CSE	Disease
19924381	716	719	CSE	Disease
19924381	773	776	CSE	Disease
19924381	828	845	hydrogen peroxide	Chemical
19924381	1079	1082	IPF	Disease
19924381	1084	1087	CSE	Disease
19924381	1143	1146	IPF	Disease
22703534|t|Nuclear factor erythroid 2-related factor 2 nuclear translocation induces myofibroblastic dedifferentiation in idiopathic pulmonary fibrosis
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 myofibroblastic dedifferentiation 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	0	43	Nuclear factor erythroid 2-related factor 2	Gene
22703534	74	107	myofibroblastic dedifferentiation	Disease
22703534	111	140	idiopathic pulmonary fibrosis	Disease
22703534	204	233	idiopathic pulmonary fibrosis	Disease
22703534	235	238	IPF	Disease
22703534	328	371	nuclear factor erythroid 2-related factor 2	Gene
22703534	373	377	Nrf2	Gene
22703534	568	571	IPF	Disease
22703534	621	625	Nrf2	Gene
22703534	626	637	expression	Gene_expression
22703534	701	712	expression	Gene_expression
22703534	802	806	Nrf2	Gene
22703534	807	817	knockdown	Negative_regulation
22703534	834	838	Nrf2	Gene
22703534	842	847	Keap1	Gene
22703534	854	867	transfection	Gene_expression
22703534	883	895	sulforaphane	Chemical
22703534	897	900	SFN	Chemical
22703534	906	910	Nrf2	Gene
22703534	982	990	fibrosis	Disease
22703534	1003	1031	transforming growth factor b	Gene
22703534	1033	1038	TGF-b	Gene
22703534	1051	1061	Decreased	Negative_regulation
22703534	1061	1065	Nrf2	Gene
22703534	1066	1077	expression	Gene_expression
22703534	1126	1129	IPF	Disease
22703534	1165	1169	Nrf2	Gene
22703534	1170	1180	knockdown	Negative_regulation
22703534	1277	1281	Nrf2	Gene
22703534	1282	1293	activation	Positive_regulation
22703534	1364	1367	IPF	Disease
22703534	1381	1384	SFN	Chemical
22703534	1395	1405	decreased	Negative_regulation
22703534	1419	1427	induced	Positive_regulation
22703534	1427	1431	Nrf2	Gene
22703534	1432	1443	expression	Gene_expression
22703534	1462	1495	myofibroblastic dedifferentiation	Disease
22703534	1499	1502	IPF	Disease
22703534	1516	1519	SFN	Chemical
22703534	1530	1535	TGF-b	Gene
22703534	1571	1574	IPF	Disease
22703534	1634	1638	Nrf2	Gene
22703534	1639	1649	knockdown	Negative_regulation
22703534	1649	1659	abolished	Negative_regulation
22703534	1659	1662	SFN	Chemical
22703534	1711	1715	Nrf2	Gene
22703534	1797	1801	Nrf2	Gene
22703534	1859	1862	SFN	Chemical
22703534	1871	1876	human	Species
22703534	1929	1933	Nrf2	Gene
22703534	1934	1945	activation	Positive_regulation
22703534	1952	1956	Nrf2	Gene
22703534	1996	1999	IPF	Disease
23986222|t|Rapamycin regulates connective tissue growth factor expression of lung epithelial cells via phosphoinositide 3-kinase
The pathogenesis of idiopathic pulmonary fibrosis (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	0	9	Rapamycin	Chemical
23986222	139	168	idiopathic pulmonary fibrosis	Disease
23986222	170	173	IPF	Disease
23986222	220	223	IPF	Disease
23986222	338	346	produce	Gene_expression
23986222	399	403	CTGF	Gene
23986222	593	602	rapamycin	Chemical
23986222	606	617	regulating	Regulation
23986222	647	651	CTGF	Gene
23986222	652	663	expression	Gene_expression
23986222	713	718	human	Species
23986222	719	737	pulmonary alveolar	Disease
23986222	821	830	rapamycin	Chemical
23986222	916	920	CTGF	Gene
23986222	926	937	expression	Gene_expression
23986222	1010	1020	detecting	Gene_expression
23986222	1020	1024	CTGF	Gene
23986222	1191	1199	SB431542	Chemical
23986222	1237	1247	inhibitor	Negative_regulation
23986222	1248	1256	LY294002	Chemical
23986222	1280	1289	rapamycin	Chemical
23986222	1360	1365	human	Species
23986222	1410	1419	rapamycin	Chemical
23986222	1452	1458	TGF-b1	Gene
23986222	1459	1467	induced	Positive_regulation
23986222	1467	1471	CTGF	Gene
23986222	1472	1483	expression	Gene_expression
23986222	1484	1492	LY294002	Chemical
23986222	1498	1506	SB431542	Chemical
23986222	1534	1541	effect	Regulation
23986222	1544	1553	rapamycin	Chemical
23986222	1557	1561	CTGF	Gene
23986222	1562	1573	expression	Gene_expression
23986222	1608	1617	rapamycin	Chemical
23986222	1676	1685	rapamycin	Chemical
23986222	1796	1805	mammalian	Species
23986222	1816	1825	rapamycin	Chemical
23986222	1868	1873	human	Species
23986222	1874	1887	lung fibrosis	Disease
29130366|t|Autophagy and inflammation in chronic respiratory disease
Persistent inflammation within the respiratory tract underlies the pathogenesis of numerous chronic pulmonary diseases including chronic obstructive pulmonary disease, asthma and pulmonary fibrosis
Chronic inflammation 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 inflammation 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	14	26	inflammation	Disease
29130366	38	57	respiratory disease	Disease
29130366	70	82	inflammation	Disease
29130366	159	177	pulmonary diseases	Disease
29130366	188	225	chronic obstructive pulmonary disease	Disease
29130366	227	233	asthma	Disease
29130366	238	256	pulmonary fibrosis	Disease
29130366	258	278	Chronic inflammation	Disease
29130366	761	770	infection	Disease
29130366	837	871	spontaneous pulmonary inflammation	Disease
29130366	932	941	infection	Disease
29130366	1063	1074	lung injury	Disease
29130366	1200	1213	lung diseases	Disease
29130366	1289	1309	AR allergic rhinitis	Disease
29130366	1355	1373	CF cystic fibrosis	Disease
29130366	1379	1385	cystic	Disease
29130366	1436	1473	chronic obstructive pulmonary disease	Disease
29130366	1555	1562	hypoxia	Disease
29130366	1567	1596	idiopathic pulmonary fibrosis	Disease
29130366	1601	1626	interstitial lung disease	Disease
29130366	1688	1691	MTB	Species
29130366	1692	1718	Mycobacterium tuberculosis	Species
29130366	1746	1755	rapamycin	Chemical
29130366	1798	1825	OSA obstructive sleep apnea	Disease
29130366	1830	1861	pulmonary arterial hypertension	Disease
29130366	1865	1887	pulmonary hypertension	Disease
29130366	1901	1907	oxygen	Chemical
29130366	1960	1965	tumor	Disease
29130366	1966	1974	necrosis	Disease
23258233|t|Bone morphogenetic protein-inducer tilorone identified by high-throughput screening is antifibrotic in vivo
Idiopathic pulmonary fibrosis (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	0	26	Bone morphogenetic protein	Gene
23258233	35	43	tilorone	Chemical
23258233	109	138	Idiopathic pulmonary fibrosis	Disease
23258233	140	143	IPF	Disease
23258233	162	174	lung disease	Disease
23258233	255	263	patients	Species
23258233	269	272	IPF	Disease
23258233	278	288	increased	Positive_regulation
23258233	303	329	bone morphogenetic protein	Gene
23258233	331	334	BMP	Gene
23258233	346	353	gremlin	Gene
23258233	397	400	BMP	Gene
23258233	545	548	BMP	Gene
23258233	610	618	fibrosis	Disease
23258233	655	673	pulmonary fibrosis	Disease
23258233	805	814	increase	Positive_regulation
23258233	814	817	BMP	Gene
23258233	984	992	effects	Regulation
23258233	995	998	BMP	Gene
23258233	1036	1052	phosphorylation	Phosphorylation
23258233	1059	1064	mouse	Species
23258233	1074	1080	silica	Chemical
23258233	1089	1107	pulmonary fibrosis	Disease
23258233	1144	1152	tilorone	Chemical
23258233	1162	1165	BMP	Gene
23258233	1202	1212	increased	Positive_regulation
23258233	1216	1227	expression	Gene_expression
23258233	1230	1235	BMP-7	Gene
23258233	1242	1245	BMP	Gene
23258233	1259	1262	Id3	Gene
23258233	1300	1305	mouse	Species
23258233	1315	1333	pulmonary fibrosis	Disease
23258233	1335	1343	tilorone	Chemical
23258233	1344	1354	decreased	Negative_regulation
23258233	1359	1373	hydroxyproline	Chemical
23258233	1390	1401	expression	Gene_expression
23258233	1419	1425	Col1A1	Gene
23258233	1430	1436	Col3A1	Gene
23258233	1438	1442	Mice	Species
23258233	1456	1464	tilorone	Chemical
23258233	1537	1541	mice	Species
23258233	1572	1580	tilorone	Chemical
23470623|t|Peptide-mediated inhibition of mitogen-activated protein kinase-activated protein kinase-2 ameliorates bleomycin-induced pulmonary fibrosis
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 pulmonary fibrosis (IPF)
Expression is localized to fibroblasts and epithelial cells
In the murine bleomycin model of pulmonary fibrosis, 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	31	90	mitogen-activated protein kinase-activated protein kinase-2	Gene
23470623	103	112	bleomycin	Chemical
23470623	121	139	pulmonary fibrosis	Disease
23470623	141	200	Mitogen-activated protein kinase-activated protein kinase-2	Gene
23470623	202	210	MAPKAPK2	Gene
23470623	215	218	MK2	Gene
23470623	223	229	serine	Chemical
23470623	230	239	threonine	Chemical
23470623	322	334	inflammation	Disease
23470623	339	347	fibrosis	Disease
23470623	437	447	activated	Positive_regulation
23470623	447	450	MK2	Gene
23470623	483	491	patients	Species
23470623	497	526	idiopathic pulmonary fibrosis	Disease
23470623	528	531	IPF	Disease
23470623	602	608	murine	Species
23470623	609	618	bleomycin	Chemical
23470623	628	646	pulmonary fibrosis	Disease
23470623	678	681	MK2	Gene
23470623	682	693	expression	Gene_expression
23470623	783	786	MK2	Gene
23470623	787	798	inhibition	Negative_regulation
23470623	871	875	mice	Species
23470623	899	908	bleomycin	Chemical
23470623	963	966	MK2	Gene
23470623	967	977	inhibitor	Negative_regulation
23470623	1131	1140	bleomycin	Chemical
23470623	1268	1278	abrogated	Negative_regulation
23470623	1333	1343	activated	Positive_regulation
23470623	1343	1346	MK2	Gene
23470623	1347	1358	expression	Gene_expression
23470623	1369	1379	decreased	Negative_regulation
23470623	1391	1396	TNF-a	Gene
23470623	1401	1405	IL-6	Gene
23470623	1426	1436	modulated	Positive_regulation
23470623	1451	1462	expression	Transcription
23470623	1486	1491	il-1b	Gene
23470623	1514	1520	col1a2	Gene
23470623	1522	1528	col3a1	Gene
23470623	1534	1537	lox	Gene
23470623	1598	1603	smad3	Gene
23470623	1605	1613	serpine1	Gene
23470623	1615	1619	pai1	Gene
23470623	1626	1633	smad6/7	Gene
23470623	1667	1678	attenuated	Negative_regulation
23470623	1684	1687	MK2	Gene
23470623	1724	1734	secretion	Localization
23470623	1754	1765	fibronectin	Gene
23470623	1775	1786	activation	Positive_regulation
23470623	1820	1830	activated	Positive_regulation
23470623	1830	1833	MK2	Gene
23470623	1838	1849	attenuated	Negative_regulation
23470623	1888	1899	inhibition	Negative_regulation
23470623	1902	1905	MK2	Gene
23470623	1906	1914	affects	Regulation
23470623	2010	2013	IPF	Disease
25182202|t|Reviews and prospectives of signaling pathway analysis in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (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	58	87	idiopathic pulmonary fibrosis	Disease
25182202	89	118	Idiopathic pulmonary fibrosis	Disease
25182202	120	123	IPF	Disease
25182202	142	159	fibrosing disease	Disease
25182202	376	379	IPF	Disease
25182202	587	590	IPF	Disease
25182202	612	616	VEGF	Gene
25182202	674	677	IPF	Disease
25182202	969	972	IPF	Disease
25182202	1103	1106	IPF	Disease
25182202	1323	1326	IPF	Disease
25182202	1354	1357	IPF	Disease
16933466|t|Membrane type-matrix metalloproteinases in idiopathic pulmonary fibrosis
BACKGROUND: Idiopathic pulmonary fibrosis (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	43	72	idiopathic pulmonary fibrosis	Disease
16933466	86	115	Idiopathic pulmonary fibrosis	Disease
16933466	117	120	IPF	Disease
16933466	207	216	secreted	Localization
16933466	252	256	MMP2	Gene
16933466	268	280	upregulated	Positive_regulation
16933466	294	317	Membrane-type (MT)-MMPs	Gene
16933466	337	348	activation	Positive_regulation
16933466	355	359	MMP2	Gene
16933466	445	448	MT1	Gene
16933466	450	453	MT2	Gene
16933466	455	458	MT3	Gene
16933466	464	471	MT5-MMP	Gene
16933466	553	558	MMP-2	Gene
16933466	728	737	TGF-beta1	Gene
16933466	742	751	IFN-gamma	Gene
16933466	762	769	MT1-MMP	Gene
16933466	813	816	MT2	Gene
16933466	822	829	MT5-MMP	Gene
16933466	863	870	MT3-MMP	Gene
16933466	888	901	localization	Localization
16933466	902	919	MT1- and MT2-MMPs	Gene
16933466	934	942	alveolar	Disease
16933466	961	968	MT3-MMP	Gene
16933466	1011	1030	alveolar epithelial	Disease
16933466	1041	1048	MT5-MMP	Gene
16933466	1103	1111	squamous	Disease
16933466	1124	1128	MMP2	Gene
16933466	1133	1143	localized	Localization
16933466	1146	1154	alveolar	Disease
16933466	1288	1297	TGF-beta1	Gene
16933466	1331	1338	MT3-MMP	Gene
16933466	1439	1449	inhibitor	Negative_regulation
16933466	1502	1512	inhibitor	Negative_regulation
16933466	1513	1522	IFN-gamma	Gene
16933466	1563	1573	expressed	Gene_expression
16933466	1607	1611	MMP2	Gene
16933466	1750	1757	MT3-MMP	Gene
16933466	1822	1831	TGF-beta1	Gene
17379848|t|Endothelin-1 induces alveolar epithelial-mesenchymal transition through endothelin type A receptor-mediated production of TGF-beta1
Endothelin-1 (ET-1) is implicated in the pathogenesis of idiopathic pulmonary fibrosis (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 ET-1 contributes to the induction of EMT in AEC is unknown
The aims of this study were to evaluate AEC production of ET-1 and to determine if ET-1 induces EMT in AEC
We demonstrate that ET-1 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 ET-1
In addition, ET-1 induces EMT through ET-A activation
Furthermore, TGF-beta1 synthesis is increased by ET-1, ET-1 induces Smad3 phosphorylation, and ET-1-induced EMT is attenuated by a TGF-beta1-neutralizing antibody
Thus, ET-1 is an important mediator of EMT in AEC, acting through ET-A-mediated TGF-beta1 production
These findings increase our basic understanding of the role of ET-1 in pulmonary fibrosis and suggest potential roles for AEC-derived ET-1 in the pathogenesis of other alveolar epithelial-mediated lung diseases
17379848	0	12	Endothelin-1	Gene
17379848	13	21	induces	Positive_regulation
17379848	99	108	mediated	Positive_regulation
17379848	108	119	production	Gene_expression
17379848	122	131	TGF-beta1	Gene
17379848	133	145	Endothelin-1	Gene
17379848	147	151	ET-1	Gene
17379848	190	219	idiopathic pulmonary fibrosis	Disease
17379848	221	224	IPF	Disease
17379848	487	490	IPF	Disease
17379848	510	528	pulmonary fibrosis	Disease
17379848	538	542	ET-1	Gene
17379848	642	653	production	Gene_expression
17379848	656	660	ET-1	Gene
17379848	681	685	ET-1	Gene
17379848	726	730	ET-1	Gene
17379848	885	893	express	Gene_expression
17379848	898	905	levels	Positive_regulation
17379848	908	935	endothelin type A receptors	Gene
17379848	937	941	ET-A	Gene
17379848	960	984	extent, type B receptors	Gene
17379848	986	990	ET-B	Gene
17379848	1049	1053	ET-1	Gene
17379848	1068	1072	ET-1	Gene
17379848	1093	1097	ET-A	Gene
17379848	1123	1132	TGF-beta1	Gene
17379848	1133	1143	synthesis	Gene_expression
17379848	1146	1156	increased	Positive_regulation
17379848	1159	1163	ET-1	Gene
17379848	1165	1169	ET-1	Gene
17379848	1170	1178	induces	Positive_regulation
17379848	1178	1183	Smad3	Gene
17379848	1184	1200	phosphorylation	Phosphorylation
17379848	1205	1209	ET-1	Gene
17379848	1241	1250	TGF-beta1	Gene
17379848	1280	1284	ET-1	Gene
17379848	1340	1344	ET-A	Gene
17379848	1354	1363	TGF-beta1	Gene
17379848	1364	1375	production	Gene_expression
17379848	1439	1443	ET-1	Gene
17379848	1447	1465	pulmonary fibrosis	Disease
17379848	1510	1514	ET-1	Gene
17379848	1544	1586	alveolar epithelial-mediated lung diseases	Disease
26093215|t|Effect of glycosides based standardized fenugreek seed extract in bleomycin-induced pulmonary fibrosis in rats: Decisive role of Bax, Nrf2, NF-kB, Muc5ac, TNF-a and IL-1b
BACKGROUND: Idiopathic pulmonary fibrosis (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 pulmonary fibrosis 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 pulmonary fibrosis
26093215	66	75	bleomycin	Chemical
26093215	84	102	pulmonary fibrosis	Disease
26093215	106	110	rats	Species
26093215	129	132	Bax	Gene
26093215	134	138	Nrf2	Gene
26093215	140	145	NF-kB	Gene
26093215	147	153	Muc5ac	Gene
26093215	155	160	TNF-a	Gene
26093215	165	170	IL-1b	Gene
26093215	184	213	Idiopathic pulmonary fibrosis	Disease
26093215	215	218	IPF	Disease
26093215	245	267	multifactorial disease	Disease
26093215	356	362	SFSE-G	Chemical
26093215	459	465	SFSE-G	Chemical
26093215	474	483	bleomycin	Chemical
26093215	485	488	BLM	Chemical
26093215	498	516	pulmonary fibrosis	Disease
26093215	600	615	laboratory rats	Species
26093215	640	643	IPF	Disease
26093215	664	683	Sprague-Dawley rats	Species
26093215	708	711	BLM	Chemical
26093215	743	749	SFSE-G	Chemical
26093215	783	801	methylprednisolone	Chemical
26093215	972	978	SFSE-G	Chemical
26093215	1045	1048	BLM	Chemical
26093215	1226	1232	SFSE-G	Chemical
26093215	1275	1281	oxygen	Chemical
26093215	1296	1299	BLM	Chemical
26093215	1344	1350	SFSE-G	Chemical
26093215	1362	1368	SFSE-G	Chemical
26093215	1383	1392	enhanced	Positive_regulation
26093215	1438	1449	modulating	Regulation
26093215	1458	1461	GSH	Chemical
26093215	1470	1473	MDA	Chemical
26093215	1488	1492	Nrf2	Gene
26093215	1494	1498	HO-1	Gene
26093215	1504	1515	expression	Gene_expression
26093215	1558	1562	5-HT	Chemical
26093215	1572	1578	SFSE-G	Chemical
26093215	1635	1652	lung inflammation	Disease
26093215	1654	1659	TNF-a	Gene
26093215	1661	1666	IL-1b	Gene
26093215	1668	1672	IL-6	Gene
26093215	1684	1692	fibrosis	Disease
26093215	1694	1699	TGF-b	Gene
26093215	1701	1717	collagen-1, ET-1	Gene
26093215	1719	1725	Muc5ac	Gene
26093215	1727	1732	NF-kB	Gene
26093215	1734	1738	VEGF	Gene
26093215	1740	1746	Smad-3	Gene
26093215	1763	1766	Bax	Gene
26093215	1768	1773	Bcl-2	Gene
26093215	1778	1787	Caspase-3	Gene
26093215	1821	1827	SFSE-G	Chemical
26093215	1839	1842	BLM	Chemical
26093215	1925	1931	SFSE-G	Chemical
26093215	1963	1966	BLM	Chemical
26093215	2089	2095	SFSE-G	Chemical
26093215	2156	2159	BLM	Chemical
26093215	2179	2185	SFSE-G	Chemical
26093215	2237	2240	BLM	Chemical
26093215	2324	2330	SFSE-G	Chemical
26093215	2378	2388	induction	Positive_regulation
26093215	2391	2395	Nrf2	Gene
26093215	2520	2523	BLM	Chemical
26093215	2532	2550	pulmonary fibrosis	Disease
15677772|t|Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts
Simvastatin is best known for its antilipidemic action and use in cardiovascular disease 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	0	11	Simvastatin	Chemical
15677772	103	114	Simvastatin	Chemical
15677772	169	191	cardiovascular disease	Disease
15677772	217	273	3-hydroxy-3-methylglutaryl CoenzymeA (HMG CoA) reductase	Gene
15677772	295	306	cholesterol	Chemical
15677772	507	538	Connective tissue growth factor	Gene
15677772	540	544	CTGF	Gene
15677772	626	642	fibrotic disease	Disease
15677772	644	673	idiopathic pulmonary fibrosis	Disease
15677772	675	678	IPF	Disease
15677772	703	708	human	Species
15677772	751	754	IPF	Disease
15677772	772	783	Simvastatin	Chemical
15677772	784	792	effects	Regulation
15677772	795	799	CTGF	Gene
15677772	817	828	expression	Gene_expression
15677772	873	884	Simvastatin	Chemical
15677772	899	909	inhibited	Negative_regulation
15677772	920	924	CTGF	Gene
15677772	942	953	expression	Gene_expression
15677772	982	1014	transforming growth factor-beta1	Gene
15677772	1031	1039	inducer	Positive_regulation
15677772	1042	1046	CTGF	Gene
15677772	1053	1064	Simvastatin	Chemical
15677772	1167	1175	fibrosis	Disease
15677772	1203	1214	expression	Gene_expression
15677772	1377	1388	Simvastatin	Chemical
15677772	1403	1435	transforming growth factor-beta1	Gene
15677772	1486	1497	Simvastatin	Chemical
15677772	1613	1616	IPF	Chemical
25064447|t|Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFb1
BACKGROUND: Idiopathic pulmonary fibrosis (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 tenascin-C (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	14	24	tenascin-C	Gene
25064447	25	38	upregulation	Positive_regulation
25064447	97	105	induced	Positive_regulation
25064447	127	156	Idiopathic pulmonary fibrosis	Disease
25064447	158	161	IPF	Disease
25064447	180	204	parenchymal lung disease	Disease
25064447	289	297	fibrosis	Disease
25064447	462	473	expression	Gene_expression
25064447	512	515	IPF	Disease
25064447	658	687	idiopathic pulmonary fibrosis	Disease
25064447	689	692	IPF	Disease
25064447	695	723	hypersensitivity pneumonitis	Disease
25064447	725	727	HP	Disease
25064447	754	757	cHP	Species
25064447	867	875	patients	Species
25064447	901	911	tenascin-C	Gene
25064447	913	916	TNC	Gene
25064447	918	928	synthesis	Gene_expression
25064447	1014	1017	IPF	Disease
25064447	1019	1022	TNC	Gene
25064447	1079	1091	upregulated	Positive_regulation
25064447	1110	1113	IPF	Disease
25064447	1118	1121	cHP	Species
25064447	1273	1276	TNC	Gene
25064447	1334	1337	cHP	Species
25064447	1389	1400	associated	Binding
25064447	1405	1408	TNC	Gene
25064447	1474	1477	IPF	Disease
25064447	1478	1486	patients	Species
25064447	1502	1514	synthesized	Gene_expression
25064447	1531	1534	TNC	Gene
25064447	1560	1563	TNC	Gene
25064447	1578	1586	induced	Positive_regulation
25064447	1637	1640	TNC	Gene
25064447	1793	1819	interstitial lung diseases	Disease
25064447	1859	1872	lung fibrosis	Disease
25064447	1878	1887	increase	Positive_regulation
25064447	1890	1893	TNC	Gene
22014187|t|Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis
BACKGROUND: Although mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in cystic fibrosis (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	60	75	cystic fibrosis	Disease
22014187	80	109	idiopathic pulmonary fibrosis	Disease
22014187	183	195	inflammation	Disease
22014187	234	249	cystic fibrosis	Disease
22014187	251	253	CF	Disease
22014187	259	288	idiopathic pulmonary fibrosis	Disease
22014187	290	293	IPF	Disease
22014187	435	443	patients	Species
22014187	449	451	CF	Disease
22014187	453	456	IPF	Disease
22014187	621	629	patients	Species
22014187	635	637	CF	Disease
22014187	658	666	patients	Species
22014187	669	672	IPF	Disease
22014187	688	696	patients	Species
22014187	864	875	expression	Gene_expression
22014187	878	882	IL-6	Gene
22014187	887	892	TGF-b	Gene
22014187	910	929	alveolar parenchyma	Disease
22014187	944	952	patients	Species
22014187	958	960	CF	Disease
22014187	1011	1023	inflammation	Disease
22014187	1027	1035	fibrosis	Disease
22014187	1129	1131	CF	Disease
22014187	1145	1154	elevated	Positive_regulation
22014187	1154	1165	expression	Gene_expression
22014187	1168	1172	IL-6	Gene
22014187	1177	1179	CF	Disease
22014187	1275	1283	patients	Species
22014187	1289	1292	IPF	Disease
22014187	1369	1388	alveolar parenchyma	Disease
22014187	1394	1404	increased	Positive_regulation
22014187	1414	1425	expression	Gene_expression
22014187	1428	1433	TGF-b	Gene
22014187	1532	1535	IPF	Disease
22014187	1631	1639	fibrosis	Disease
22014187	1645	1655	increased	Positive_regulation
22014187	1688	1699	expression	Gene_expression
22014187	1702	1707	TGF-b	Gene
22014187	1736	1743	patient	Species
22014187	1877	1896	alveolar parenchyma	Disease
22014187	1958	1960	CF	Disease
22014187	1965	1968	IPF	Disease
22854509|t|EMT and interstitial lung disease: a mysterious relationship
PURPOSE OF REVIEW: Pathogenesis of interstitial lung diseases (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 (myo)fibroblasts 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 (myo)fibroblasts, 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	8	33	interstitial lung disease	Disease
22854509	97	123	interstitial lung diseases	Disease
22854509	125	128	ILD	Disease
22854509	196	199	ILD	Disease
22854509	201	230	idiopathic pulmonary fibrosis	Disease
22854509	232	235	IPF	Disease
22854509	353	363	producing	Gene_expression
22854509	383	386	IPF	Disease
22854509	524	532	fibrosis	Disease
22854509	601	609	fibrosis	Disease
22854509	625	638	interactions	Binding
22854509	644	649	Smad3	Gene
22854509	651	660	b-catenin	Gene
22854509	731	736	a-SMA	Gene
22854509	738	747	promoter	Entity
22854509	793	821	transforming growth factor-b	Gene
22854509	823	827	TGFb	Gene
22854509	833	842	b-catenin	Gene
22854509	972	992	EMT in lung fibrosis	Disease
22854509	1144	1164	EMT to lung fibrosis	Disease
22854509	1340	1351	inhibition	Negative_regulation
11491168|t|Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF
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 (IPF)
Using human fibrotic lung tissue obtained from eight autopsy cases and four biopsy cases with IPF, 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 IPF, 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 connective tissue growth factor which modulates fibroblast proliferation and extracellular matrix production
11491168	71	102	connective tissue growth factor	Gene
11491168	106	109	IPF	Disease
11491168	111	142	Connective tissue growth factor	Gene
11491168	144	148	CTGF	Gene
11491168	346	350	CTGF	Gene
11491168	401	411	expressed	Gene_expression
11491168	420	428	fibrosis	Disease
11491168	433	442	bleomycin	Chemical
11491168	451	469	pulmonary fibrosis	Disease
11491168	473	477	mice	Species
11491168	515	527	investigate	Negative_regulation
11491168	531	544	localization	Localization
11491168	547	551	CTGF	Gene
11491168	573	584	expression	Transcription
11491168	615	623	patients	Species
11491168	629	658	idiopathic pulmonary fibrosis	Disease
11491168	660	663	IPF	Disease
11491168	672	677	human	Species
11491168	760	763	IPF	Disease
11491168	929	933	CTGF	Gene
11491168	947	957	increased	Positive_regulation
11491168	979	987	patients	Species
11491168	993	996	IPF	Disease
11491168	1028	1047	immunolocalization	Localization
11491168	1050	1054	CTGF	Gene
11491168	1226	1230	CTGF	Gene
11491168	1258	1262	CTGF	Gene
11491168	1272	1282	localized	Localization
11491168	1433	1437	CTGF	Gene
11491168	1447	1457	expressed	Gene_expression
11491168	1648	1666	pulmonary fibrosis	Disease
11491168	1680	1711	connective tissue growth factor	Gene
25032514|t|Anti-fibrotic Role of aB-crystallin Inhibition in Pleural and Subpleural Fibrosis
Idiopathic pulmonary fibrosis (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	73	81	Fibrosis	Disease
25032514	83	112	Idiopathic pulmonary fibrosis	Disease
25032514	114	117	IPF	Disease
25032514	229	232	IPF	Disease
25032514	617	620	IPF	Disease
25032514	661	667	TGF-b1	Gene
25032514	688	696	fibrosis	Disease
25032514	730	740	expressed	Gene_expression
25032514	922	928	TGF-b1	Gene
25032514	942	951	favoring	Positive_regulation
25032514	951	956	Smad4	Gene
25032514	1066	1080	overexpressed	Positive_regulation
25032514	1117	1120	IPF	Disease
25032514	1121	1129	patients	Species
25032514	1154	1181	pleural/subpleural fibrosis	Disease
25032514	1183	1206	aB-crystallin-deficient	Disease
25032514	1207	1211	mice	Species
25032514	1231	1258	pleural/subpleural fibrosis	Disease
25032514	1304	1319	overexpression	Positive_regulation
25032514	1322	1328	TGF-b1	Gene
25032514	1362	1371	bleomycin	Chemical
25032514	1386	1392	carbon	Chemical
25032514	1431	1442	inhibition	Negative_regulation
25032514	1450	1455	Smad4	Gene
25032514	1456	1464	nuclear	Entity
25032514	1464	1477	localization	Localization
25032514	1544	1547	MMT	Chemical
25032514	1549	1572	aB-crystallin-deficient	Disease
25032514	1701	1732	fibrosis in the lung parenchyma	Disease
25032514	1868	1871	IPF	Disease
23499992|t|Fibrosis of two: Epithelial cell-fibroblast interactions in pulmonary fibrosis
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: Fibrosis: Translation of basic research to human disease
23499992	0	8	Fibrosis	Disease
23499992	60	78	pulmonary fibrosis	Disease
23499992	80	109	Idiopathic pulmonary fibrosis	Disease
23499992	111	114	IPF	Disease
23499992	299	302	IPF	Disease
23499992	461	469	fibrosis	Disease
23499992	578	581	IPF	Disease
23499992	762	767	death	Disease
23499992	1010	1041	alveolar epithelial cell injury	Disease
23499992	1046	1051	death	Disease
23499992	1289	1292	IPF	Disease
23499992	1411	1429	pulmonary fibrosis	Disease
23499992	1484	1497	interactions	Binding
23499992	1527	1535	fibrosis	Disease
23499992	1634	1650	prostaglandin E2	Chemical
23499992	1652	1666	angiotensin II	Gene
23499992	1680	1686	oxygen	Chemical
23499992	1746	1754	Fibrosis	Disease
23499992	1789	1794	human	Species
29125826|t|Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with few effective therapeutic options
Structural remodelling of the extracellular matrix [i.e
collagen cross-linking mediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4)] might contribute to disease pathogenesis and represent a therapeutic target
This study aimed to further our understanding of the mechanisms by which LO inhibitors might improve lung fibrosis
Lung tissues from IPF and non-IPF subjects were examined for collagen structure (second harmonic generation imaging) and LO gene (microarray analysis) and protein (immunohistochemistry and western blotting) levels
Functional effects (collagen structure and tissue stiffness using atomic force microscopy) of LO inhibitors on collagen remodelling were examined in two models, collagen hydrogels and decellularized human lung matrices
LOXL1/LOXL2 gene expression and protein levels were increased in IPF versus non-IPF
Increased collagen fibril thickness in IPF versus non-IPF lung tissues correlated with increased LOXL1/LOXL2, and decreased LOX, protein expression
b-Aminoproprionitrile (b-APN; pan-LO inhibitor) but not Compound A (LOXL2-specific inhibitor) interfered with transforming growth factor-b-induced collagen remodelling in both models
The b-APN treatment group was tested further, and b-APN was found to interfere with stiffening in the decellularized matrix model
LOXL1 activity might drive collagen remodelling in IPF lungs
The interrelationship between collagen structural remodelling and LOs is disrupted in IPF lungs
Inhibition of LO activity alleviates fibrosis by limiting fibrillar collagen cross-linking, thereby potentially impeding the formation of a pathological microenvironment in IPF
29125826	0	5	Lysyl	Chemical
29125826	15	24	regulate	Regulation
29125826	277	291	cross-linking	Binding
29125826	307	312	lysyl	Chemical
29125826	779	787	effects	Regulation
29125826	1005	1016	expression	Gene_expression
29125826	1040	1050	increased	Positive_regulation
29125826	1073	1083	Increased	Positive_regulation
29125826	1160	1170	increased	Positive_regulation
29125826	1187	1197	decreased	Negative_regulation
29125826	1210	1221	expression	Gene_expression
29125826	1222	1243	b-Aminoproprionitrile	Chemical
29125826	1245	1250	b-APN	Chemical
29125826	1305	1315	inhibitor	Negative_regulation
29125826	1316	1327	interfered	Negative_regulation
29125826	1410	1415	b-APN	Chemical
29125826	1456	1461	b-APN	Chemical
29125826	1696	1707	Inhibition	Negative_regulation
29125826	1773	1787	cross-linking	Binding
24958208|t|Crosstalk between TGF-b1 and complement activation augments epithelial injury in pulmonary fibrosis
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 (TGF-b1) and down-regulates CIPs
In the current study, we examined the mechanistic role of TGF-b1 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 TGF-b1 (10 ng/ml), C3a, or C5a (100 nM), we observed loss of CIPs and increased poly(ADP-ribose) polymerase (PARP) activation [also observed with RNA interference (RNAi) of CD46/CD55]
TGF-b1-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 TGF-b1 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 TGF-b1-induced loss of CIPs leading to complement activation that down-regulates CIPs and induces TGF-b1 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 TGF-b1 and complement activation augments epithelial injury in pulmonary fibrosis
24958208	18	24	TGF-b1	Gene
24958208	71	99	injury in pulmonary fibrosis	Disease
24958208	116	146	complement inhibitory proteins	Disease
24958208	148	152	CIPs	Disease
24958208	192	196	CD46	Gene
24958208	201	205	CD55	Gene
24958208	277	306	idiopathic pulmonary fibrosis	Disease
24958208	308	311	IPF	Disease
24958208	353	359	IL-17A	Gene
24958208	369	386	epithelial injury	Disease
24958208	391	420	transforming growth factor b1	Gene
24958208	422	428	TGF-b1	Gene
24958208	449	453	CIPs	Disease
24958208	513	519	TGF-b1	Gene
24958208	561	578	epithelial injury	Disease
24958208	582	585	IPF	Disease
24958208	647	650	IPF	Disease
24958208	708	715	levels	Positive_regulation
24958208	750	753	C3a	Gene
24958208	758	761	C5a	Gene
24958208	808	813	human	Species
24958208	865	871	TGF-b1	Gene
24958208	884	887	C3a	Gene
24958208	892	895	C5a	Gene
24958208	918	930	loss of CIPs	Disease
24958208	935	945	increased	Positive_regulation
24958208	945	972	poly(ADP-ribose) polymerase	Gene
24958208	974	978	PARP	Gene
24958208	1038	1042	CD46	Gene
24958208	1043	1047	CD55	Gene
24958208	1050	1056	TGF-b1	Gene
24958208	1066	1078	loss of CIPs	Disease
24958208	1083	1088	Snail	Gene
24958208	1100	1105	SNAI1	Gene
24958208	1138	1148	E-cadherin	Gene
24958208	1150	1155	E-CAD	Gene
24958208	1173	1184	inhibiting	Negative_regulation
24958208	1227	1235	SB203580	Chemical
24958208	1246	1256	silencing	Negative_regulation
24958208	1259	1264	SNAI1	Gene
24958208	1266	1269	C3a	Gene
24958208	1275	1278	C5a	Gene
24958208	1288	1300	loss of CIPs	Disease
24958208	1329	1340	inhibition	Negative_regulation
24958208	1347	1350	C3a	Gene
24958208	1386	1389	C3a	Gene
24958208	1394	1397	C5a	Gene
24958208	1398	1413	down-regulated	Negative_regulation
24958208	1413	1418	SMAD7	Gene
24958208	1429	1439	regulator	Negative_regulation
24958208	1462	1468	TGF-b1	Gene
24958208	1469	1477	induced	Positive_regulation
24958208	1477	1480	C3a	Gene
24958208	1481	1493	C5a receptor	Gene
24958208	1495	1499	C3aR	Gene
24958208	1500	1504	C5aR	Gene
24958208	1506	1517	expression	Gene_expression
24958208	1532	1536	C3aR	Gene
24958208	1537	1541	C5aR	Gene
24958208	1542	1553	inhibition	Negative_regulation
24958208	1571	1574	C3a	Gene
24958208	1576	1579	C5a	Gene
24958208	1589	1594	loss	Negative_regulation
24958208	1589	1601	loss of CIPs	Disease
24958208	1644	1661	epithelial injury	Disease
24958208	1665	1668	IPF	Disease
24958208	1714	1720	TGF-b1	Gene
24958208	1729	1741	loss of CIPs	Disease
24958208	1795	1799	CIPs	Disease
24958208	1812	1818	TGF-b1	Gene
24958208	1819	1834	expression.-Gu	Gene_expression
24958208	1972	1978	TGF-b1	Gene
24958208	2025	2053	injury in pulmonary fibrosis	Disease
16776827|t|RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis
BACKGROUND: Idiopathic Pulmonary Fibrosis (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 RhoA signaling
As RhoA-mediated regulation is also involved in cell cycle progression, we hypothesise that this pathway is key to lung fibroblast turnover through modulation of cyclin D1 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 cyclin D1 mRNA; protein expression was confirmed by western blotting
Effects of Rho signaling were investigated using transient transfection of constitutively active and dominant negative RhoA constructs as well as pharmacological inhibitors
Cellular proliferation of lung fibroblasts was determined by BrdU incorporation ELISA
To further explore RhoA regulation of cyclin D1 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 cyclin D1 expression, which was restored following treatment with fibrogenic growth factors (TGF-beta1 and CTGF)
RhoA inhibition, using a dominant negative mutant and a pharmacological inhibitor (C3 exotoxin), suppressed levels of cyclin D1 mRNA and protein in IPF fibroblasts, with significant abrogation of cell turnover (p < 0.05)
Furthermore, Simvastatin dose-dependently inhibited fibroblast cyclin D1 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 cyclin D1 expression is deregulated in IPF through a RhoA dependent mechanism that influences lung fibroblast proliferation
This potentially unravels new molecular targets for future anti-IPF strategies; accordingly, Simvastatin inhibition of Rho-mediated cyclin D1 expression in IPF fibroblasts merits further exploitation
16776827	0	4	RhoA	Gene
16776827	15	25	modulates	Regulation
16776827	25	34	cyclin D1	Gene
16776827	35	46	expression	Gene_expression
16776827	49	54	human	Species
16776827	90	119	idiopathic pulmonary fibrosis	Disease
16776827	133	162	Idiopathic Pulmonary Fibrosis	Disease
16776827	164	167	IPF	Disease
16776827	260	297	aggressive lung structural remodeling	Disease
16776827	473	477	CTGF	Gene
16776827	478	493	overexpression	Positive_regulation
16776827	524	527	IPF	Disease
16776827	543	553	dependent	Regulation
16776827	556	560	RhoA	Gene
16776827	575	579	RhoA	Gene
16776827	589	600	regulation	Regulation
16776827	720	731	modulation	Regulation
16776827	734	743	cyclin D1	Gene
16776827	752	763	expression	Gene_expression
16776827	773	782	Cyclin D1	Gene
16776827	783	794	expression	Gene_expression
16776827	818	821	IPF	Disease
16776827	822	829	patient	Species
16776827	947	958	expression	Gene_expression
16776827	968	977	cyclin D1	Gene
16776827	1157	1161	RhoA	Gene
16776827	1310	1318	explore	Negative_regulation
16776827	1318	1322	RhoA	Gene
16776827	1323	1334	regulation	Regulation
16776827	1337	1346	cyclin D1	Gene
16776827	1425	1435	inhibitor	Negative_regulation
16776827	1436	1447	Simvastatin	Chemical
16776827	1491	1500	Cyclin D1	Gene
16776827	1501	1512	expression	Gene_expression
16776827	1516	1528	upregulated	Positive_regulation
16776827	1531	1534	IPF	Disease
16776827	1637	1647	inhibited	Negative_regulation
16776827	1647	1656	cyclin D1	Gene
16776827	1657	1668	expression	Gene_expression
16776827	1679	1688	restored	Negative_regulation
16776827	1740	1749	TGF-beta1	Gene
16776827	1754	1758	CTGF	Gene
16776827	1761	1765	RhoA	Gene
16776827	1766	1777	inhibition	Negative_regulation
16776827	1858	1869	suppressed	Negative_regulation
16776827	1869	1876	levels	Gene_expression
16776827	1879	1888	cyclin D1	Gene
16776827	1909	1912	IPF	Disease
16776827	1996	2007	Simvastatin	Chemical
16776827	2025	2035	inhibited	Negative_regulation
16776827	2046	2055	cyclin D1	Gene
16776827	2073	2084	expression	Gene_expression
16776827	2309	2318	cyclin D1	Gene
16776827	2319	2330	expression	Gene_expression
16776827	2333	2345	deregulated	Regulation
16776827	2348	2351	IPF	Disease
16776827	2362	2366	RhoA	Gene
16776827	2498	2501	IPF	Disease
16776827	2527	2538	Simvastatin	Chemical
16776827	2539	2550	inhibition	Negative_regulation
16776827	2557	2566	mediated	Positive_regulation
16776827	2566	2575	cyclin D1	Gene
16776827	2576	2587	expression	Gene_expression
16776827	2590	2593	IPF	Disease
21420029|t|MicroRNAs in idiopathic pulmonary fibrosis
In this review, we describe the recent advances in the understanding of the role of microRNAs in idiopathic pulmonary fibrosis (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	13	42	idiopathic pulmonary fibrosis	Disease
21420029	141	170	idiopathic pulmonary fibrosis	Disease
21420029	172	175	IPF	Disease
21420029	211	232	fibrotic lung disease	Disease
21420029	298	301	IPF	Disease
21420029	418	429	miR-17   92	Gene
21420029	460	467	mir-155	Gene
21420029	472	478	mir-21	Gene
21420029	660	666	mir-21	Gene
21420029	677	685	fibrosis	Disease
21420029	693	702	bleomycin	Chemical
21420029	712	725	lung fibrosis	Disease
21420029	744	751	mir-155	Gene
21420029	854	867	lung fibrosis	Disease
21420029	928	931	IPF	Disease
21420029	954	983	transforming growth factor b1	Gene
21420029	985	990	TGFb1	Gene
21420029	996	1005	regulate	Regulation
21420029	1005	1010	TGFb1	Gene
21420029	1102	1110	release	Localization
21420029	1132	1137	TGFb1	Gene
21420029	1261	1264	IPF	Disease
21420029	1291	1296	TGFb1	Gene
21420029	1319	1322	p53	Gene
21420029	1328	1362	vascular endothelial growth factor	Gene
21420029	1447	1450	IPF	Disease
21420029	1495	1503	fibrosis	Disease
21420029	1573	1576	IPF	Disease
12485463|t|Titration of non-replicating adenovirus as a vector for transducing active TGF-beta1 gene expression causing inflammation and fibrogenesis in the lungs of C57BL/6 mice
Investigators have shown that interstitial pulmonary fibrosis (IPF) can be induced in rats by overexpressing transforming growth factor beta1 (TGF-beta1) 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 TGF-beta1, 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 TGF-beta1 (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 TGF-beta1
The findings here show that 10(6) plaque-forming units (pfu) of AVTGFbeta1, provide essentially a 'no-effect' dose, but even this amount of TGF-beta1 causes a significant increase in whole-lung collagen by day 28 after treatment
In contrast, 10(8) and 10(9) pfu cause severe IPF in 4 days, whereas 10(7) and 5 x 10(7) are intermediate for all parameters studied, i.e
TGF-beta protein, inflammatory cells, cell proliferation, pro-alpha 1(I) collagen gene expression and whole-lung collagen accumulation, and expression of growth factors such as TGF-beta1, TNF-alpha and PDGF-A and -B
Interestingly enough, TGF-beta1, 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 TGF-beta1 biological activity and allows us to manipulate this potent factor as a mediator of interstitial fibrogenesis
12485463	29	39	adenovirus	Species
12485463	56	68	transducing	Positive_regulation
12485463	75	84	TGF-beta1	Gene
12485463	90	101	expression	Gene_expression
12485463	109	121	inflammation	Disease
12485463	163	167	mice	Species
12485463	199	230	interstitial pulmonary fibrosis	Disease
12485463	232	235	IPF	Disease
12485463	255	259	rats	Species
12485463	263	278	overexpressing	Gene_expression
12485463	278	310	transforming growth factor beta1	Gene
12485463	312	321	TGF-beta1	Gene
12485463	367	377	adenovirus	Species
12485463	469	472	IPF	Disease
12485463	497	503	tumour	Disease
12485463	559	563	mice	Species
12485463	662	671	TGF-beta1	Gene
12485463	681	706	interstitial lung disease	Disease
12485463	708	711	ILD	Disease
12485463	976	986	adenovirus	Species
12485463	1031	1040	TGF-beta1	Gene
12485463	1263	1266	IPF	Disease
12485463	1306	1315	TGF-beta1	Gene
12485463	1457	1466	TGF-beta1	Gene
12485463	1488	1497	increase	Positive_regulation
12485463	1593	1596	IPF	Disease
12485463	1773	1784	expression	Gene_expression
12485463	1808	1821	accumulation	Positive_regulation
12485463	1826	1837	expression	Gene_expression
12485463	1863	1872	TGF-beta1	Gene
12485463	1925	1934	TGF-beta1	Gene
12485463	2096	2099	IPF	Disease
12485463	2177	2186	TGF-beta1	Gene
21169469|t|Yin yang 1 is a novel regulator of pulmonary fibrosis
RATIONALE: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (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 YY1(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 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-YY1(f/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 pulmonary fibrosis
21169469	0	10	Yin yang 1	Gene
21169469	35	53	pulmonary fibrosis	Disease
21169469	146	175	idiopathic pulmonary fibrosis	Disease
21169469	177	180	IPF	Disease
21169469	208	218	Yin Yang 1	Gene
21169469	220	223	YY1	Gene
21169469	327	340	lung diseases	Disease
21169469	403	406	YY1	Gene
21169469	448	461	lung fibrosis	Disease
21169469	546	551	tumor	Disease
21169469	595	598	YY1	Gene
21169469	604	625	a-smooth muscle actin	Gene
21169469	627	630	SMA	Gene
21169469	716	729	lung fibrosis	Disease
21169469	757	760	YY1	Gene
21169469	761	771	deficient	Negative_regulation
21169469	771	776	mouse	Species
21169469	783	786	YY1	Gene
21169469	813	818	mouse	Species
21169469	842	848	silica	Chemical
21169469	852	861	bleomycin	Chemical
21169469	894	899	TGF-b	Gene
21169469	904	909	tumor	Disease
21169469	928	941	up-regulated	Positive_regulation
21169469	941	944	YY1	Gene
21169469	945	956	expression	Gene_expression
21169469	977	982	TGF-b	Gene
21169469	977	991	TGF-b-induced	Positive_regulation
21169469	991	994	YY1	Gene
21169469	995	1006	expression	Gene_expression
21169469	1023	1033	decreased	Negative_regulation
21169469	1039	1049	inhibitor	Negative_regulation
21169469	1091	1094	YY1	Gene
21169469	1112	1126	overexpressed	Gene_expression
21169469	1134	1139	human	Species
21169469	1140	1143	IPF	Disease
21169469	1148	1154	murine	Species
21169469	1165	1178	lung fibrosis	Disease
21169469	1299	1302	YY1	Gene
21169469	1319	1324	a-SMA	Gene
21169469	1362	1365	YY1	Gene
21169469	1366	1376	deficient	Negative_regulation
21169469	1377	1380	YY1	Gene
21169469	1387	1391	mice	Species
21169469	1426	1439	lung fibrosis	Disease
21169469	1467	1478	attenuated	Negative_regulation
21169469	1478	1483	a-SMA	Gene
21169469	1497	1508	expression	Gene_expression
21169469	1518	1529	decreasing	Negative_regulation
21169469	1529	1532	YY1	Gene
21169469	1533	1544	expression	Gene_expression
21169469	1562	1572	adenovirus	Species
21169469	1587	1590	YY1	Gene
21169469	1596	1600	mice	Species
21169469	1601	1622	reduced lung fibrosis	Disease
21169469	1637	1640	YY1	Gene
21169469	1644	1658	overexpressed	Positive_regulation
21169469	1681	1686	human	Species
21169469	1687	1690	IPF	Disease
21169469	1695	1701	murine	Species
21169469	1742	1745	YY1	Gene
21169469	1789	1800	increasing	Positive_regulation
21169469	1800	1805	a-SMA	Gene
21169469	1819	1830	expression	Gene_expression
21169469	1831	1842	Decreasing	Negative_regulation
21169469	1842	1845	YY1	Gene
21169469	1846	1857	expression	Gene_expression
21169469	1900	1918	pulmonary fibrosis	Disease
27390284|t|Age-driven developmental drift in the pathogenesis of idiopathic pulmonary fibrosis
UNASSIGNED: Idiopathic pulmonary fibrosis (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	54	83	idiopathic pulmonary fibrosis	Disease
27390284	97	126	Idiopathic pulmonary fibrosis	Disease
27390284	128	131	IPF	Disease
27390284	240	243	IPF	Disease
27390284	829	832	IPF	Disease
27390284	1004	1007	IPF	Disease
27390284	1187	1190	IPF	Disease
27390284	1371	1374	IPF	Disease
27390284	1517	1520	IPF	Disease
23055696|t|Current and novel drug therapies for idiopathic pulmonary fibrosis
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 idiopathic pulmonary fibrosis (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	37	66	idiopathic pulmonary fibrosis	Disease
23055696	128	136	patients	Species
23055696	247	276	idiopathic pulmonary fibrosis	Disease
23055696	278	281	IPF	Disease
23055696	379	382	IPF	Disease
23055696	476	492	fibrotic illness	Disease
23055696	730	733	IPF	Disease
23055696	749	760	pirfenidone	Chemical
23055696	830	833	IPF	Disease
23055696	845	856	pirfenidone	Chemical
23055696	1055	1058	IPF	Disease
16246848|t|Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-beta1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK
Idiopathic pulmonary fibrosis (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 transforming growth factor-beta1 (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 fibroblast growth factor-2 (FGF-2)
Primary lung fibroblasts obtained from normal rat lungs cultured with TGF-beta1 expressed increased levels of phosphorylated p38 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 p38 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 p38 MAPK and JNK
16246848	67	99	transforming growth factor-beta1	Gene
16246848	133	159	fibroblast growth factor-2	Gene
16246848	164	180	phosphorylation	Phosphorylation
16246848	183	186	p38	Gene
16246848	201	230	Idiopathic pulmonary fibrosis	Disease
16246848	232	235	IPF	Disease
16246848	251	263	lung disease	Disease
16246848	412	415	IPF	Disease
16246848	495	503	express	Gene_expression
16246848	561	593	transforming growth factor-beta1	Gene
16246848	595	604	TGF-beta1	Gene
16246848	623	626	rat	Species
16246848	750	753	Cys	Chemical
16246848	761	764	Cys	Chemical
16246848	790	797	serines	Chemical
16246848	812	820	release	Localization
16246848	843	852	TGF-beta1	Gene
16246848	912	915	IPF	Disease
16246848	1028	1041	[3H]thymidine	Chemical
16246848	1173	1199	fibroblast growth factor-2	Gene
16246848	1201	1206	FGF-2	Gene
16246848	1255	1258	rat	Species
16246848	1279	1288	TGF-beta1	Gene
16246848	1289	1299	expressed	Gene_expression
16246848	1299	1309	increased	Positive_regulation
16246848	1319	1334	phosphorylated	Phosphorylation
16246848	1334	1337	p38	Gene
16246848	1360	1366	ERK1/2	Gene
16246848	1384	1393	TGF-beta1	Gene
16246848	1394	1401	caused	Positive_regulation
16246848	1414	1422	release	Localization
16246848	1439	1444	FGF-2	Gene
16246848	1492	1501	presence	Positive_regulation
16246848	1509	1514	FGF-2	Gene
16246848	1525	1540	phosphorylated	Phosphorylation
16246848	1540	1543	p38	Gene
16246848	1562	1572	abrogated	Negative_regulation
16246848	1573	1581	TGF-beta	Gene
16246848	1613	1625	suppression	Negative_regulation
16246848	1628	1633	c-Myc	Gene
16246848	1638	1648	induction	Positive_regulation
16246848	1707	1716	TGF-beta1	Gene
16246848	1727	1738	regulation	Regulation
16246848	1741	1746	c-Myc	Gene
16246848	1750	1760	induction	Positive_regulation
16246848	1895	1904	TGF-beta1	Gene
16246848	1937	1946	TGF-beta1	Gene
16246848	1965	1973	release	Localization
16246848	1976	1981	FGF-2	Gene
16246848	1989	1997	induces	Positive_regulation
16246848	1997	2013	phosphorylation	Phosphorylation
16246848	2016	2019	p38	Gene
23517551|t|Secreted protein acidic and rich in cysteine (SPARC) is upregulated by transforming growth factor (TGF)-b and is required for TGF-b-induced hydrogen peroxide production in fibroblasts
BACKGROUND: Idiopathic pulmonary fibrosis (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 (SPARC), a matricellular protein regulating ECM deposition, in the pathogenesis of fibrosis, factors regulating SPARC expression or roles of SPARC in fibrosis have not been fully elucidated
RESULTS: Among the profibrotic factors examined in cultured fibroblasts, we showed that SPARC expression was upregulated mainly by transforming growth factor (TGF)-b
We also showed that expression of SPARC in the lung was upregulated in the murine bleomycin-induced pulmonary fibrosis model, which was inhibited by TGF-b receptor I inhibitor
Knockdown of SPARC in fibroblasts using siRNA or treatment with the antioxidant N-acetylcysteine attenuated epithelial cell injury induced by TGF-b-activated fibroblasts in a coculture system
We also demonstrated that SPARC was required for hydrogen peroxide (H2O2) production in fibroblasts treated with TGF-b
Furthermore, TGF-b activated integrin-linked kinase (ILK), which was inhibited by SPARC siRNA
Knockdown of ILK attenuated extracellular H2O2 generation in TGF-b-stimulated fibroblasts
Our results indicated that SPARC is upregulated by TGF-b and is required for TGF-b-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 SPARC plays a role in epithelial damage in the IPF lung via enhanced H2O2 production from fibroblasts activated by TGF-b
Therefore, SPARC inhibition may prevent epithelial injury in IPF lung and represent a potential therapeutic approach for IPF
23517551	0	44	Secreted protein acidic and rich in cysteine	Gene
23517551	46	51	SPARC	Gene
23517551	126	131	TGF-b	Gene
23517551	140	157	hydrogen peroxide	Chemical
23517551	197	226	Idiopathic pulmonary fibrosis	Disease
23517551	228	231	IPF	Disease
23517551	529	573	secreted protein acidic and rich in cysteine	Gene
23517551	575	580	SPARC	Gene
23517551	657	665	fibrosis	Disease
23517551	675	686	regulating	Regulation
23517551	686	691	SPARC	Gene
23517551	692	703	expression	Gene_expression
23517551	715	720	SPARC	Gene
23517551	724	732	fibrosis	Disease
23517551	853	858	SPARC	Gene
23517551	859	870	expression	Gene_expression
23517551	874	886	upregulated	Positive_regulation
23517551	952	963	expression	Gene_expression
23517551	966	971	SPARC	Gene
23517551	988	1000	upregulated	Positive_regulation
23517551	1007	1013	murine	Species
23517551	1014	1023	bleomycin	Chemical
23517551	1032	1050	pulmonary fibrosis	Disease
23517551	1081	1086	TGF-b	Gene
23517551	1098	1108	inhibitor	Negative_regulation
23517551	1109	1119	Knockdown	Negative_regulation
23517551	1122	1127	SPARC	Gene
23517551	1189	1205	N-acetylcysteine	Chemical
23517551	1217	1239	epithelial cell injury	Disease
23517551	1251	1256	TGF-b	Gene
23517551	1328	1333	SPARC	Gene
23517551	1351	1368	hydrogen peroxide	Chemical
23517551	1370	1374	H2O2	Chemical
23517551	1415	1420	TGF-b	Gene
23517551	1435	1440	TGF-b	Gene
23517551	1441	1451	activated	Positive_regulation
23517551	1451	1473	integrin-linked kinase	Gene
23517551	1475	1478	ILK	Gene
23517551	1491	1501	inhibited	Negative_regulation
23517551	1504	1509	SPARC	Gene
23517551	1530	1533	ILK	Gene
23517551	1559	1563	H2O2	Chemical
23517551	1578	1583	TGF-b	Gene
23517551	1635	1640	SPARC	Gene
23517551	1644	1656	upregulated	Positive_regulation
23517551	1659	1664	TGF-b	Gene
23517551	1672	1681	required	Positive_regulation
23517551	1685	1690	TGF-b	Gene
23517551	1699	1703	H2O2	Chemical
23517551	1719	1730	activation	Positive_regulation
23517551	1733	1736	ILK	Gene
23517551	1747	1751	H2O2	Chemical
23517551	1802	1824	epithelial cell injury	Disease
23517551	1888	1893	SPARC	Gene
23517551	1935	1938	IPF	Disease
23517551	1948	1957	enhanced	Positive_regulation
23517551	1957	1961	H2O2	Chemical
23517551	1962	1973	production	Gene_expression
23517551	2003	2008	TGF-b	Gene
23517551	2021	2026	SPARC	Gene
23517551	2027	2038	inhibition	Negative_regulation
23517551	2050	2067	epithelial injury	Disease
23517551	2071	2074	IPF	Disease
23517551	2131	2134	IPF	Disease
23220917|t|Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-b1-induced pulmonary fibrosis
RATIONALE: Lymphocytes are increasingly associated with idiopathic pulmonary fibrosis (IPF)
Semaphorin 7a (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	0	13	Semaphorin 7a	Gene
23220917	66	95	idiopathic pulmonary fibrosis	Disease
23220917	156	174	pulmonary fibrosis	Disease
23220917	232	261	idiopathic pulmonary fibrosis	Disease
23220917	263	266	IPF	Disease
23220917	269	282	Semaphorin 7a	Gene
23220917	284	291	Sema 7a	Gene
23220917	379	386	Sema 7a	Gene
23220917	406	409	IPF	Disease
23220917	457	464	Sema 7a	Gene
23220917	481	487	humans	Species
23220917	493	496	IPF	Disease
23220917	506	511	mouse	Species
23220917	521	534	lung fibrosis	Disease
23220917	571	586	overexpression	Positive_regulation
23220917	589	595	TGF-b1	Gene
23220917	623	630	Sema 7a	Gene
23220917	631	642	expression	Gene_expression
23220917	645	650	human	Species
23220917	655	661	murine	Species
23220917	761	774	coexpressing	Gene_expression
23220917	774	780	Sema7a	Gene
23220917	797	801	CD19	Gene
23220917	803	806	CD4	Gene
23220917	811	814	CD4	Gene
23220917	815	819	CD25	Gene
23220917	820	825	FoxP3	Gene
23220917	830	836	TGF-b1	Gene
23220917	845	851	murine	Species
23220917	912	915	IPF	Disease
23220917	921	932	expression	Gene_expression
23220917	935	942	Sema 7a	Gene
23220917	951	954	CD4	Gene
23220917	978	981	CD4	Gene
23220917	986	990	CD19	Gene
23220917	999	1006	Sema 7a	Gene
23220917	1007	1018	expression	Gene_expression
23220917	1021	1031	increased	Positive_regulation
23220917	1034	1037	CD4	Gene
23220917	1049	1052	CD4	Gene
23220917	1053	1057	CD25	Gene
23220917	1058	1063	FoxP3	Gene
23220917	1093	1097	CD19	Gene
23220917	1135	1138	IPF	Disease
23220917	1140	1147	Sema 7a	Gene
23220917	1151	1161	expressed	Gene_expression
23220917	1176	1187	expressing	Gene_expression
23220917	1187	1190	CD4	Gene
23220917	1199	1203	CD19	Gene
23220917	1231	1237	TGF-b1	Gene
23220917	1238	1253	transgenic mice	Species
23220917	1255	1262	Sema 7a	Gene
23220917	1263	1274	expressing	Gene_expression
23220917	1307	1320	lung fibrosis	Disease
23220917	1335	1346	production	Gene_expression
23220917	1384	1388	IL-4	Gene
23220917	1390	1396	IL-17A	Gene
23220917	1402	1407	IL-10	Gene
23220917	1423	1431	require	Positive_regulation
23220917	1431	1434	CD4	Gene
23220917	1443	1447	CD19	Gene
23220917	1466	1477	Sema 7a-CD4	Gene
23220917	1478	1482	CD25	Gene
23220917	1483	1488	FoxP3	Gene
23220917	1497	1503	Sema7a	Gene
23220917	1504	1507	CD4	Gene
23220917	1508	1512	CD25	Gene
23220917	1513	1518	FoxP3	Gene
23220917	1581	1586	IL-10	Gene
23220917	1633	1641	fibrosis	Disease
23220917	1664	1670	TGF-b1	Gene
23220917	1679	1685	murine	Species
23220917	1705	1712	Sema 7a	Gene
23220917	1713	1716	CD4	Gene
23220917	1717	1721	CD25	Gene
23220917	1722	1727	FoxP3	Gene
23220917	1805	1808	IPF	Disease
23220917	1820	1828	fibrosis	Disease
23220917	1836	1842	TGF-b1	Gene
23220917	1851	1857	murine	Species
22095546|t|Regulation of transforming growth factor-b1-driven lung fibrosis by galectin-3
RATIONALE: Idiopathic pulmonary fibrosis (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 fibrosis
METHODS: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis
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 fibrosis 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 fibrosis 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 fibrosis 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 fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF
22095546	56	64	fibrosis	Disease
22095546	68	78	galectin-3	Gene
22095546	91	120	Idiopathic pulmonary fibrosis	Disease
22095546	122	125	IPF	Disease
22095546	165	191	alveolar epithelial injury	Disease
22095546	396	406	Galectin-3	Gene
22095546	414	425	galactoside	Chemical
22095546	426	434	binding	Binding
22095546	456	466	expressed	Gene_expression
22095546	543	553	galectin-3	Gene
22095546	557	575	pulmonary fibrosis	Disease
22095546	662	668	murine	Species
22095546	679	692	lung fibrosis	Disease
22095546	766	774	patients	Species
22095546	780	783	IPF	Disease
22095546	816	850	Transforming growth factor (TGF)-b	Gene
22095546	855	864	bleomycin	Chemical
22095546	873	886	lung fibrosis	Disease
22095546	915	919	mice	Species
22095546	920	930	deficient	Negative_regulation
22095546	933	943	galectin-3	Gene
22095546	957	965	reduced	Negative_regulation
22095546	965	971	TGF-b1	Gene
22095546	1026	1037	production	Gene_expression
22095546	1038	1048	Galectin-3	Gene
22095546	1049	1057	reduced	Negative_regulation
22095546	1057	1073	phosphorylation	Phosphorylation
22095546	1077	1085	nuclear	Entity
22095546	1085	1099	translocation	Localization
22095546	1102	1111	b-catenin	Gene
22095546	1123	1130	effect	Regulation
22095546	1133	1140	Smad2/3	Gene
22095546	1141	1157	phosphorylation	Phosphorylation
22095546	1166	1176	inhibitor	Negative_regulation
22095546	1179	1189	galectin-3	Gene
22095546	1206	1211	TGF-b	Gene
22095546	1220	1229	b-catenin	Gene
22095546	1230	1241	activation	Positive_regulation
22095546	1307	1320	lung fibrosis	Disease
22095546	1327	1336	bleomycin	Chemical
22095546	1348	1358	increased	Positive_regulation
22095546	1358	1369	expression	Gene_expression
22095546	1372	1382	galectin-3	Gene
22095546	1434	1442	patients	Species
22095546	1485	1509	interstitial pneumonitis	Disease
22095546	1588	1598	galectin-3	Gene
22095546	1625	1633	fibrosis	Disease
22095546	1666	1672	block	Negative_regulation
22095546	1672	1682	galectin-3	Gene
22095546	1784	1794	galectin-3	Gene
22095546	1829	1837	fibrosis	Disease
22095546	1876	1886	galectin-3	Gene
22095546	1887	1898	inhibition	Negative_regulation
21475793|t|Reduced transcription of the Smad4 gene during pulmonary carcinogenesis in idiopathic pulmonary fibrosis
Patients with idiopathic pulmonary fibrosis (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 Smad4 gene was identified in all eight tumor samples from the lung cancer/IPF patients using real-time RT-PCR
Expression levels of Smad4 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 Smad4 was performed using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)
The methylation status of the Smad4 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 Smad4 promoter in two of the eight tumors with reduced Smad4 expression
Promoter reporter assays showed that the activity of the Smad4 promoter containing the sequence of the methylated region was significantly stronger than that of the Smad4 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 Smad4 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	0	8	Reduced	Negative_regulation
21475793	8	22	transcription	Transcription
21475793	29	34	Smad4	Gene
21475793	47	71	pulmonary carcinogenesis	Disease
21475793	75	104	idiopathic pulmonary fibrosis	Disease
21475793	106	114	Patients	Species
21475793	120	149	idiopathic pulmonary fibrosis	Disease
21475793	151	154	IPF	Disease
21475793	193	204	lung cancer	Disease
21475793	272	275	IPF	Disease
21475793	325	335	lung tumor	Disease
21475793	348	356	patients	Species
21475793	362	373	lung cancer	Disease
21475793	378	381	IPF	Disease
21475793	383	394	lung cancer	Disease
21475793	503	511	Reduced	Negative_regulation
21475793	511	522	expression	Gene_expression
21475793	529	534	Smad4	Gene
21475793	568	573	tumor	Disease
21475793	591	602	lung cancer	Disease
21475793	607	615	patients	Species
21475793	640	651	Expression	Gene_expression
21475793	661	666	Smad4	Gene
21475793	695	701	tumors	Disease
21475793	707	718	lung cancer	Disease
21475793	723	731	patients	Species
21475793	751	762	lung cancer	Disease
21475793	763	771	patients	Species
21475793	780	783	IPF	Disease
21475793	790	801	lung cancer	Disease
21475793	850	859	b type II	Species
21475793	873	878	Smad4	Gene
21475793	1007	1012	Smad4	Gene
21475793	1141	1146	tumor	Disease
21475793	1205	1210	Smad4	Gene
21475793	1234	1246	eight tumors	Disease
21475793	1252	1260	reduced	Negative_regulation
21475793	1260	1265	Smad4	Gene
21475793	1266	1277	expression	Gene_expression
21475793	1335	1340	Smad4	Gene
21475793	1443	1448	Smad4	Gene
21475793	1575	1580	TGF-b	Gene
21475793	1598	1632	crucial in pulmonary carcinogensis	Disease
21475793	1658	1669	lung cancer	Disease
21475793	1673	1676	IPF	Disease
21475793	1677	1685	patients	Species
21475793	1694	1699	TGF-b	Gene
21475793	1703	1717	overexpressed	Gene_expression
21475793	1742	1747	Smad4	Gene
21475793	1893	1904	lung cancer	Disease
21475793	1905	1913	patients	Species
21475793	1919	1922	IPF	Disease
19700647|t|Abrogation of TGF-beta1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition
Idiopathic pulmonary fibrosis (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 (TGF)-beta1 promotes differentiation of fibroblasts into myofibroblasts in vitro and in vivo
In the current study, we investigated the molecular link between TGF-beta1-mediated myofibroblast differentiation and histone deacetylase (HDAC) activity
Treatment of normal human lung fibroblasts (NHLFs) with the pan-HDAC inhibitor trichostatin A (TSA) inhibited TGF-beta1-mediated alpha-smooth muscle actin (alpha-SMA) and alpha1 type I collagen mRNA induction
TSA also blocked the TGF-beta1-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 TGF-beta1-mediated alpha-SMA induction in a dose-dependent manner
HDAC4 knockdown was effective in inhibiting TGF-beta1-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 TGF-beta1-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	14	23	TGF-beta1	Gene
19700647	76	95	histone deacetylase	Gene
19700647	96	107	inhibition	Negative_regulation
19700647	108	137	Idiopathic pulmonary fibrosis	Disease
19700647	139	142	IPF	Disease
19700647	243	246	IPF	Disease
19700647	299	312	synthesizers	Gene_expression
19700647	332	370	Transforming growth factor (TGF)-beta1	Gene
19700647	518	527	TGF-beta1	Gene
19700647	571	590	histone deacetylase	Gene
19700647	592	596	HDAC	Gene
19700647	628	633	human	Species
19700647	672	676	HDAC	Gene
19700647	687	701	trichostatin A	Chemical
19700647	703	706	TSA	Chemical
19700647	708	718	inhibited	Negative_regulation
19700647	718	727	TGF-beta1	Gene
19700647	728	737	mediated	Positive_regulation
19700647	779	801	alpha1 type I collagen	Gene
19700647	807	817	induction	Positive_regulation
19700647	818	821	TSA	Chemical
19700647	839	848	TGF-beta1	Gene
19700647	891	902	inhibition	Negative_regulation
19700647	915	926	expression	Gene_expression
19700647	929	932	TSA	Chemical
19700647	953	961	reduced	Negative_regulation
19700647	961	977	phosphorylation	Phosphorylation
19700647	1007	1017	inhibitor	Negative_regulation
19700647	1032	1041	TGF-beta1	Gene
19700647	1099	1104	HDAC4	Gene
19700647	1132	1143	inhibiting	Negative_regulation
19700647	1143	1152	TGF-beta1	Gene
19700647	1153	1164	stimulated	Positive_regulation
19700647	1200	1216	phosphorylation	Phosphorylation
19700647	1238	1249	inhibitors	Negative_regulation
19700647	1282	1286	PP2A	Gene
19700647	1291	1294	PP1	Gene
19700647	1308	1317	TGF-beta1	Gene
19700647	1377	1380	TSA	Chemical
19700647	1470	1475	HDAC4	Gene
19700647	1490	1499	requires	Positive_regulation
19700647	1499	1515	phosphorylation	Phosphorylation
20061443|t|Curcumin inhibits fibrosis-related effects in IPF fibroblasts and in mice following bleomycin-induced lung injury
Idiopathic pulmonary fibrosis (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 fibrosis 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	0	8	Curcumin	Chemical
20061443	18	26	fibrosis	Disease
20061443	46	49	IPF	Disease
20061443	69	73	mice	Species
20061443	84	93	bleomycin	Chemical
20061443	102	113	lung injury	Disease
20061443	115	144	Idiopathic pulmonary fibrosis	Disease
20061443	146	149	IPF	Disease
20061443	188	200	lung disease	Disease
20061443	507	515	secrete	Localization
20061443	525	533	Curcumin	Chemical
20061443	642	645	IPF	Disease
20061443	734	742	curcumin	Chemical
20061443	809	814	human	Species
20061443	854	857	IPF	Disease
20061443	858	866	patients	Species
20061443	915	923	curcumin	Chemical
20061443	927	930	IPF	Disease
20061443	966	974	fibrosis	Disease
20061443	978	987	bleomycin	Chemical
20061443	996	1000	mice	Species
20061443	1015	1023	curcumin	Chemical
20061443	1083	1086	IPF	Disease
20061443	1181	1209	transforming growth factor-b	Gene
20061443	1211	1216	TGF-b	Gene
20061443	1251	1259	curcumin	Chemical
20061443	1312	1321	bleomycin	Chemical
20061443	1340	1344	mice	Species
20061443	1370	1378	curcumin	Chemical
20061443	1406	1416	inhibited	Negative_regulation
20061443	1416	1428	inflammation	Disease
20061443	1514	1522	curcumin	Chemical
20061443	1591	1600	bleomycin	Chemical
20061443	1609	1621	inflammation	Disease
20061443	1766	1769	IPF	Disease
23315259|t|Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis
Idiopathic pulmonary fibrosis (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 pulmonary fibrosis in bleomycin-challenged mice
Administration of SphK inhibitor reduced bleomycin-induced mortality and pulmonary fibrosis 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	10	30	sphingosine kinase 1	Gene
23315259	42	51	bleomycin	Chemical
23315259	60	78	pulmonary fibrosis	Disease
23315259	80	109	Idiopathic pulmonary fibrosis	Disease
23315259	111	114	IPF	Disease
23315259	145	170	interstitial lung disease	Disease
23315259	180	208	transforming growth factor b	Gene
23315259	210	215	TGF-b	Gene
23315259	221	244	sphingosine-1-phosphate	Chemical
23315259	246	249	S1P	Chemical
23315259	285	293	fibrosis	Disease
23315259	316	329	contribution	Gene_expression
23315259	332	343	sphingosine	Chemical
23315259	457	465	patients	Species
23315259	471	474	IPF	Disease
23315259	479	484	SphK1	Gene
23315259	489	494	SphK2	Gene
23315259	495	505	knockdown	Negative_regulation
23315259	505	509	mice	Species
23315259	588	599	expression	Gene_expression
23315259	602	609	SphK1/2	Gene
23315259	667	675	patients	Species
23315259	681	684	IPF	Disease
23315259	696	707	expression	Gene_expression
23315259	710	715	SphK1	Gene
23315259	720	730	increased	Positive_regulation
23315259	751	759	patients	Species
23315259	765	768	IPF	Chemical
23315259	773	782	bleomycin	Chemical
23315259	794	798	mice	Species
23315259	800	810	Knockdown	Negative_regulation
23315259	813	818	SphK1	Gene
23315259	828	833	SphK2	Gene
23315259	872	890	pulmonary fibrosis	Disease
23315259	894	903	bleomycin	Chemical
23315259	915	919	mice	Species
23315259	944	954	inhibitor	Negative_regulation
23315259	962	971	bleomycin	Chemical
23315259	994	1012	pulmonary fibrosis	Disease
23315259	1016	1020	mice	Species
23315259	1022	1032	Knockdown	Negative_regulation
23315259	1035	1040	SphK1	Gene
23315259	1064	1074	inhibitor	Negative_regulation
23315259	1074	1085	attenuated	Negative_regulation
23315259	1089	1100	generation	Gene_expression
23315259	1104	1109	TGF-b	Gene
23315259	1110	1120	secretion	Localization
23315259	1125	1134	bleomycin	Chemical
23315259	1143	1156	lung fibrosis	Disease
23315259	1157	1162	mouse	Species
23315259	1193	1201	reduced	Negative_regulation
23315259	1201	1217	phosphorylation	Phosphorylation
23315259	1220	1225	Smad2	Gene
23315259	1262	1271	bleomycin	Chemical
23315259	1262	1280	bleomycin-induced	Positive_regulation
23315259	1280	1291	expression	Gene_expression
23315259	1294	1299	SphK1	Gene
23315259	1335	1340	TGF-b	Gene
23315259	1393	1398	SphK1	Gene
23315259	1428	1454	pathology of lung fibrosis	Disease
27583344|t|Data on CUX1 isoforms in idiopathic pulmonary fibrosis lung and systemic sclerosis skin tissue sections
UNASSIGNED: This data article contains complementary figures related to the research article entitled, "Transforming growth factor-b-induced CUX1 isoforms are associated with fibrosis in systemic sclerosis lung fibroblasts" (Ikeda et al
(2016) [2], http://dx.doi.org/10.1016/j.bbrep.2016.06.022), which presents that TGF-b increased CUX1 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, CUX1 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 CUX1" (Ikeda et al., 2016) [2]
Here we show that CUX1 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, CUX1 and a-SMA are co-localized
In addition, at the fibrotic loci in the IPF lung tissue sections, CUX1 localized within the a-smooth muscle actin (a-SMA) positive cells
27583344	8	12	CUX1	Gene
27583344	25	59	idiopathic pulmonary fibrosis lung	Disease
27583344	64	82	systemic sclerosis	Disease
27583344	246	250	CUX1	Gene
27583344	280	288	fibrosis	Disease
27583344	292	310	systemic sclerosis	Disease
27583344	423	428	TGF-b	Gene
27583344	429	439	increased	Positive_regulation
27583344	439	443	CUX1	Gene
27583344	444	452	binding	Binding
27583344	497	503	COL1A2	Gene
27583344	508	518	regulated	Regulation
27583344	540	551	scleroderma	Disease
27583344	567	590	diffuse alveolar damage	Disease
27583344	606	610	CUX1	Gene
27583344	656	661	a-SMA	Gene
27583344	663	672	positive	Gene_expression
27583344	742	751	suppress	Negative_regulation
27583344	796	800	CUX1	Gene
27583344	846	850	CUX1	Gene
27583344	864	874	localized	Localization
27583344	903	912	positive	Gene_expression
27583344	934	963	idiopathic pulmonary fibrosis	Disease
27583344	965	968	IPF	Disease
27583344	1073	1077	CUX1	Gene
27583344	1082	1087	a-SMA	Gene
27583344	1092	1105	co-localized	Localization
27583344	1147	1150	IPF	Disease
27583344	1173	1177	CUX1	Gene
27583344	1222	1227	a-SMA	Gene
24762191|t|Arsenic trioxide inhibits transforming growth factor-b1-induced fibroblast to myofibroblast differentiation in vitro and bleomycin induced lung fibrosis in vivo
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 fibroblast to myofibroblast differentiation (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 fibroblast to myofibroblast differentiation and decreases bleomycin induced pulmonary fibrosis
24762191	0	16	Arsenic trioxide	Chemical
24762191	64	107	fibroblast to myofibroblast differentiation	Disease
24762191	121	130	bleomycin	Chemical
24762191	144	152	fibrosis	Disease
24762191	174	203	Idiopathic pulmonary fibrosis	Disease
24762191	205	208	IPF	Disease
24762191	291	297	deaths	Disease
24762191	440	443	IPF	Disease
24762191	445	451	TGF-b1	Gene
24762191	455	465	expressed	Gene_expression
24762191	495	538	fibroblast to myofibroblast differentiation	Disease
24762191	540	543	FMD	Disease
24762191	613	629	Arsenic trioxide	Chemical
24762191	633	636	ATO	Chemical
24762191	678	683	human	Species
24762191	727	730	ATO	Chemical
24762191	770	776	TGF-b1	Gene
24762191	854	857	ATO	Chemical
24762191	884	892	fibrosis	Disease
24762191	910	914	mice	Species
24762191	933	942	bleomycin	Chemical
24762191	975	978	ATO	Chemical
24762191	1131	1142	expression	Gene_expression
24762191	1193	1198	a-SMA	Gene
24762191	1258	1261	ATO	Chemical
24762191	1299	1308	inhibits	Negative_regulation
24762191	1308	1314	TGF-b1	Gene
24762191	1346	1351	a-SMA	Gene
24762191	1394	1405	expression	Gene_expression
24762191	1406	1409	ATO	Chemical
24762191	1430	1436	TGF-b1	Gene
24762191	1477	1480	ATO	Chemical
24762191	1543	1554	inhibition	Negative_regulation
24762191	1557	1560	Akt	Gene
24762191	1573	1578	Smad2	Gene
24762191	1579	1584	Smad3	Gene
24762191	1585	1601	phosphorylation	Phosphorylation
24762191	1602	1608	TGF-b1	Gene
24762191	1617	1621	H2O2	Chemical
24762191	1626	1631	NOX-4	Gene
24762191	1637	1648	expression	Gene_expression
24762191	1657	1665	blocked	Negative_regulation
24762191	1668	1671	ATO	Chemical
24762191	1673	1676	ATO	Chemical
24762191	1686	1696	reduction	Negative_regulation
24762191	1699	1704	Smad3	Gene
24762191	1705	1721	phosphorylation	Phosphorylation
24762191	1739	1749	reduction	Negative_regulation
24762191	1739	1774	reduction of promyelocytic leukemia	Disease
24762191	1776	1779	PML	Gene
24762191	1800	1803	PML	Gene
24762191	1812	1823	expression	Gene_expression
24762191	1824	1827	PML	Gene
24762191	1831	1836	mouse	Species
24762191	1873	1883	decreased	Negative_regulation
24762191	1883	1894	fibronectin	Gene
24762191	1899	1904	PAI-1	Gene
24762191	1905	1916	expression	Gene_expression
24762191	1931	1937	TGF-b1	Gene
24762191	1974	1977	ATO	Chemical
24762191	2000	2004	mice	Species
24762191	2005	2014	inhibits	Negative_regulation
24762191	2014	2023	bleomycin	Chemical
24762191	2024	2032	induced	Positive_regulation
24762191	2074	2085	expression	Gene_expression
24762191	2158	2161	ATO	Chemical
24762191	2170	2176	TGF-b1	Gene
24762191	2185	2228	fibroblast to myofibroblast differentiation	Disease
24762191	2243	2252	bleomycin	Chemical
24762191	2261	2279	pulmonary fibrosis	Disease
26538547|t|Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-b and WNT7B in Human Lung Fibroblasts
The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (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 TGF-b1 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 TGF-b1 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 TGF-b1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF
26538547	0	11	Expression	Gene_expression
26538547	14	19	WNT5A	Gene
26538547	23	52	Idiopathic Pulmonary Fibrosis	Disease
26538547	61	69	Control	Regulation
26538547	72	77	TGF-b	Gene
26538547	82	87	WNT7B	Gene
26538547	91	96	Human	Species
26538547	222	232	expressed	Gene_expression
26538547	235	243	patients	Species
26538547	249	277	usual interstitial pneumonia	Disease
26538547	279	282	UIP	Disease
26538547	334	339	Wnt5A	Gene
26538547	362	370	patients	Species
26538547	376	405	idiopathic pulmonary fibrosis	Disease
26538547	407	410	IPF	Disease
26538547	469	474	human	Species
26538547	496	499	IPF	Disease
26538547	540	548	patients	Species
26538547	564	567	IPF	Disease
26538547	571	574	UIP	Disease
26538547	595	614	immunolocalization	Localization
26538547	617	622	Wnt5A	Gene
26538547	674	677	IPF	Disease
26538547	678	683	human	Species
26538547	723	738	overexpression	Positive_regulation
26538547	754	759	Wnt7B	Gene
26538547	776	782	TGF-b1	Gene
26538547	819	824	Wnt5A	Gene
26538547	833	844	expression	Gene_expression
26538547	845	850	Wnt5A	Gene
26538547	855	865	expressed	Gene_expression
26538547	868	871	IPF	Disease
26538547	1027	1042	overexpression	Positive_regulation
26538547	1045	1050	Wnt7B	Gene
26538547	1067	1073	TGF-b1	Gene
26538547	1098	1108	increased	Positive_regulation
26538547	1108	1113	Wnt5A	Gene
26538547	1122	1133	expression	Gene_expression
26538547	1143	1148	human	Species
26538547	1196	1199	IPF	Disease
26538547	1221	1226	Wnt5A	Gene
26538547	1246	1256	expressed	Gene_expression
26538547	1304	1309	Wnt5A	Gene
26538547	1310	1321	expression	Gene_expression
26538547	1337	1340	IPF	Disease
26538547	1395	1400	Wnt7B	Gene
26538547	1405	1411	TGF-b1	Gene
26538547	1509	1512	IPF	Disease
16179636|t|Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10)
RATIONALE: Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis (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 (PTEN) 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 PTEN 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 PTEN inhibits alpha-SMA, fibroblast proliferation, and collagen production
RESULTS: In human lung specimens of IPF, myofibroblasts within fibroblastic foci demonstrated diminished PTEN expression
Furthermore, inhibition of PTEN in mice worsened bleomycin-induced fibrosis
In pten(-/-) fibroblasts, and in normal fibroblasts in which PTEN 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 PTEN decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of PTEN in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation
It was observed that both the protein and lipid phosphatase actions of PTEN were capable of modulating the myofibroblast phenotype
CONCLUSIONS: The results indicate that in IPF, myofibroblasts have diminished PTEN expression
Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro
16179636	56	60	PTEN	Gene
16179636	176	205	idiopathic pulmonary fibrosis	Disease
16179636	207	210	IPF	Disease
16179636	457	461	PTEN	Gene
16179636	605	613	patients	Species
16179636	619	622	IPF	Disease
16179636	626	635	localize	Positive_regulation
16179636	635	646	expression	Gene_expression
16179636	649	653	PTEN	Gene
16179636	721	725	pten	Gene
16179636	857	861	PTEN	Gene
16179636	862	871	inhibits	Negative_regulation
16179636	921	932	production	Gene_expression
16179636	945	950	human	Species
16179636	969	972	IPF	Disease
16179636	1027	1038	diminished	Negative_regulation
16179636	1038	1042	PTEN	Gene
16179636	1043	1054	expression	Gene_expression
16179636	1068	1079	inhibition	Negative_regulation
16179636	1082	1086	PTEN	Gene
16179636	1090	1094	mice	Species
16179636	1104	1113	bleomycin	Chemical
16179636	1122	1130	fibrosis	Disease
16179636	1135	1139	pten	Gene
16179636	1193	1197	PTEN	Gene
16179636	1252	1263	production	Gene_expression
16179636	1267	1279	upregulated	Positive_regulation
16179636	1352	1356	pten	Gene
16179636	1444	1448	pten	Gene
16179636	1479	1483	PTEN	Gene
16179636	1484	1494	decreased	Negative_regulation
16179636	1544	1555	production	Gene_expression
16179636	1564	1579	overexpression	Positive_regulation
16179636	1582	1586	PTEN	Gene
16179636	1758	1762	PTEN	Gene
16179636	1861	1864	IPF	Disease
16179636	1886	1897	diminished	Negative_regulation
16179636	1897	1901	PTEN	Gene
16179636	1902	1913	expression	Gene_expression
16179636	1914	1925	Inhibition	Negative_regulation
16179636	1928	1932	PTEN	Gene
16179636	1950	1958	fibrosis	Disease
16179636	1964	1968	PTEN	Gene