Oxidant-antioxidant|oxidant-antioxidant|JJ|O imbalance|imbalance|NN|O as|as|IN|O a|a|DT|O potential|potential|JJ|O contributor|contributor|NN|O to|to|TO|O the|the|DT|O progression|progression|NN|O of|of|IN|O human|human|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O the|the|DT|O most|much|RBS|O common|common|JJ|O idiopathic|idiopathic|JJ|O interstitial|interstitial|JJ|O pneumonia|pneumonia|NN|O .|.|.|O 
IPF|IPF|NN|O is|be|VBZ|O a|a|DT|O disease|disease|NN|O with|with|IN|O poor|poor|JJ|O prognosis|prognosis|NN|O and|and|CC|O an|a|DT|O aggressive|aggressive|JJ|O nature|nature|NN|O ,|,|,|O and|and|CC|O poses|pose|VBZ|O major|major|JJ|O challenges|challenge|NNS|O to|to|TO|O clinicians|clinician|NNS|O .|.|.|O 
Thus|thus|RB|O ,|,|,|O a|a|DT|O large|large|JJ|O part|part|NN|O of|of|IN|O research|research|NN|O in|in|IN|O the|the|DT|O area|area|NN|O has|have|VBZ|O focused|focus|VBN|O on|on|IN|O the|the|DT|O pathogenesis|pathogenesis|NN|O on|on|IN|O IPF|IPF|NN|O .|.|.|O 
Characteristic|characteristic|JJ|O features|feature|NNS|O in|in|IN|O IPF|IPF|NN|O include|include|VBP|O fibrotic|fibrotic|JJ|O lesions|lesion|NNS|O devoid|devoid|JJ|O of|of|IN|O inflammatory|inflammatory|JJ|O cell|cell|NN|O infiltrates|infiltrate|NNS|O .|.|.|O 
There|there|EX|O are|be|VBP|O experimental|experimental|JJ|O models|model|NNS|O of|of|IN|O lung|lung|NN|O fibrosis|fibrosis|NN|O (|(|(|O e.g.|e.g.|FW|O ,|,|,|O bleomycin-induced|bleomycin-induced|JJ|O fibrosis|fibrosis|NN|O )|)|)|O ,|,|,|O but|but|CC|O they|they|PRP|O typically|typical|RB|O contain|contain|VBP|O a|a|DT|O prominent|prominent|JJ|O inflammatory|inflammatory|JJ|O pattern|pattern|NN|O in|in|IN|O the|the|DT|O lung|lung|NN|O ,|,|,|O which|which|WDT|O leads|lead|VBZ|O to|to|TO|O relatively|relative|RB|O diffuse|diffuse|JJ|O lung|lung|NN|O fibrosis|fibrosis|NN|O .|.|.|O 
Nonetheless|nonetheless|RB|O ,|,|,|O experimental|experimental|JJ|O models|model|NNS|O have|have|VBP|O provided|provide|VBN|O important|important|JJ|O information|information|NN|O about|about|IN|O the|the|DT|O progression|progression|NN|O and|and|CC|O pathways|pathway|NNS|O contributing|contribute|VBG|O to|to|TO|O the|the|DT|O lung|lung|NN|O fibrosis|fibrosis|NN|O ,|,|,|O including|include|VBG|O activation|activation|NN|O of|of|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta|beta|NN|GENE (|(|(|O TGF-beta|TGF-beta|NN|GENE )|)|)|O .|.|.|O 
Both|both|DT|O patient|patient|NN|O material|material|NN|O and|and|CC|O experimental|experimental|JJ|O models|model|NNS|O of|of|IN|O lung|lung|NN|O fibrosis|fibrosis|NN|O have|have|VBP|O displayed|display|VBN|O marked|marked|JJ|O elevation|elevation|NN|O of|of|IN|O several|several|JJ|O markers|marker|NNS|O of|of|IN|O oxidant|oxidant|JJ|O burden|burden|NN|O and|and|CC|O signs|sign|NNS|O for|for|IN|O disturbed|disturbed|JJ|O antioxidant/oxidant|antioxidant/oxidant|JJ|O balance|balance|NN|O .|.|.|O 
Several|several|JJ|O studies|study|NNS|O also|also|RB|O suggest|suggest|VBP|O that|that|IN|O reactive|reactive|JJ|O oxygen|oxygen|NN|O species|specie|NNS|O can|can|MD|O cause|cause|VB|O activation|activation|NN|O of|of|IN|O growth-regulatory|growth-regulatory|JJ|O cytokines|cytokine|NNS|O ,|,|,|O including|include|VBG|O TGF-beta|TGF-beta|NN|GENE .|.|.|O 
In|in|IN|O addition|addition|NN|O ,|,|,|O there|there|EX|O are|be|VBP|O indications|indication|NNS|O that|that|WDT|O endogenous|endogenous|JJ|O and|and|CC|O exogenous|exogenous|JJ|O antioxidants/redox|antioxidants/redox|JJ|O modulators|modulator|NNS|O can|can|MD|O influence|influence|VB|O fibrogenesis|fibrogenesis|NN|O ,|,|,|O protect|protect|VBP|O the|the|DT|O lung|lung|NN|O against|against|IN|O fibrosis|fibrosis|NN|O ,|,|,|O and|and|CC|O prevent|prevent|VB|O its|its|PRP$|O progression|progression|NN|O .|.|.|O 
Factors|factor|NNS|O that|that|WDT|O restore|restore|VBP|O the|the|DT|O antioxidant|antioxidant|JJ|O capacity|capacity|NN|O and|and|CC|O prevent|prevent|VB|O sustained|sustained|JJ|O activation|activation|NN|O of|of|IN|O growth-regulatory|growth-regulatory|JJ|O cytokines|cytokine|NNS|O may|may|MD|O have|have|VB|O a|a|DT|O therapeutic|therapeutic|JJ|O role|role|NN|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
Transgelin|transgelin|NNP|O is|be|VBZ|O a|a|DT|O direct|direct|JJ|O target|target|NN|O of|of|IN|O TGF-beta/Smad3-dependent|TGF-beta/Smad3-dependent|JJ|O epithelial|epithelial|JJ|O cell|cell|NN|O migration|migration|NN|O in|in|IN|O lung|lung|NN|O fibrosis|fibrosis|NN|O .|.|.|O 
Enhanced|enhance|VBN|O transforming|transform|VBG|O growth|growth|NN|O factor|factor|NN|O (|(|(|O TGF|tgf|NN|O )|)|)|O -|-|:|O beta|beta|NN|O signaling|signaling|NN|O contributes|contribute|VBZ|O to|to|TO|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O ,|,|,|O a|a|DT|O progressive|progressive|JJ|O and|and|CC|O fatal|fatal|JJ|O disease|disease|NN|O characterized|characterize|VBN|O by|by|IN|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O type|type|NN|O II|II|CD|O (|(|(|O ATII|ATII|NN|O )|)|)|O cell|cell|NN|O hyperplasia|hyperplasia|NN|O ,|,|,|O (|(|(|O myo|Myo|NN|O )|)|)|O fibroblast|fibroblast|NN|O accumulation|accumulation|NN|O ,|,|,|O and|and|CC|O excessive|excessive|JJ|O extracellular|extracellular|JJ|O matrix|matrix|NN|O deposition|deposition|NN|O .|.|.|O 
TGF-beta|TGF-beta|NN|GENE is|be|VBZ|O a|a|DT|O potent|potent|JJ|O inducer|inducer|NN|O of|of|IN|O lung|lung|NN|O fibrosis|fibrosis|NN|O ,|,|,|O and|and|CC|O it|it|PRP|O regulates|regulate|VBZ|O the|the|DT|O ATII|ATII|NN|O cell|cell|NN|O phenotype|phenotype|NN|O ;|;|:|O however|however|RB|O ,|,|,|O direct|direct|JJ|O TGF-beta|TGF-beta|NN|GENE target|target|NN|O genes|gene|NNS|O controlling|control|VBG|O the|the|DT|O ATII|ATII|NN|O cell|cell|NN|O phenotype|phenotype|NN|O remain|remain|VBP|O elusive|elusive|JJ|O .|.|.|O 
Here|here|RB|O ,|,|,|O we|we|PRP|O identified|identify|VBD|O the|the|DT|O transgelin|transgelin|NN|GENE (|(|(|O tagln|TAGLN|NN|GENE )|)|)|O gene|gene|NN|O as|as|IN|O a|a|DT|O novel|novel|JJ|O immediate|immediate|JJ|O target|target|NN|O of|of|IN|O TGF-beta/Smad3-dependent|TGF-beta/Smad3-dependent|JJ|O gene|gene|NN|O expression|expression|NN|O in|in|IN|O ATII|ATII|NN|O cells|cell|NNS|O using|use|VBG|O a|a|DT|O Smad3|Smad3|NN|GENE chromatin|chromatin|NN|O immunoprecipitation|immunoprecipitation|NN|O (|(|(|O ChIP|chip|NN|O )|)|)|O screen|screen|NN|O .|.|.|O 
Direct|direct|JJ|O ChIP|chip|NN|O confirmed|confirm|VBD|O the|the|DT|O rapid|rapid|JJ|O and|and|CC|O specific|specific|JJ|O binding|binding|NN|O of|of|IN|O Smad3|Smad3|NN|GENE to|to|TO|O the|the|DT|O tagln|TAGLN|NN|GENE promoter|promoter|NN|O .|.|.|O 
Luciferase|luciferase|NN|O assays|assay|NNS|O demonstrated|demonstrate|VBD|O transactivation|transactivation|NN|O of|of|IN|O the|the|DT|O tagln|TAGLN|NN|GENE promoter|promoter|NN|O by|by|IN|O activin-like|activin-like|JJ|O kinase|kinase|NN|O (|(|(|O Alk|ALK|NN|O )|)|)|O 5-mediated|5-mediated|JJ|O TGF-beta|TGF-beta|NN|GENE signaling|signaling|NN|O .|.|.|O 
TGF-beta|TGF-beta|NN|GENE treatment|treatment|NN|O resulted|result|VBD|O in|in|IN|O rapid|rapid|JJ|O up-regulation|up-regulation|NN|O of|of|IN|O tagln|TAGLN|NN|GENE ,|,|,|O but|but|CC|O not|not|RB|O tagln2|tagln2|NN|O ,|,|,|O mRNA|mRNA|NN|O and|and|CC|O protein|protein|NN|O expression|expression|NN|O ,|,|,|O assessed|assess|VBN|O by|by|IN|O reverse|reverse|JJ|O transcription-polymerase|transcription-polymerase|JJ|O chain|chain|NN|O reaction|reaction|NN|O (|(|(|O RT-PCR|rt-pcr|NN|O )|)|)|O ,|,|,|O Western|western|NN|O blotting|blotting|NN|O ,|,|,|O and|and|CC|O immunofluorescence|immunofluorescence|NN|O .|.|.|O 
In|in|FW|O vivo|vivo|FW|O ,|,|,|O tagln|TAGLN|NN|GENE expression|expression|NN|O was|be|VBD|O significantly|significant|RB|O increased|increase|VBN|O in|in|IN|O ATII|ATII|NN|O cells|cell|NNS|O of|of|IN|O mice|mouse|NNS|O during|during|IN|O bleomycin-induced|bleomycin-induced|JJ|O lung|lung|NN|O fibrosis|fibrosis|NN|O ,|,|,|O as|as|RB|O well|well|RB|O as|as|IN|O in|in|IN|O lung|lung|NN|O specimen|specimen|NN|O obtained|obtain|VBN|O from|from|IN|O IPF|IPF|NN|O patients|patient|NNS|O ,|,|,|O as|as|IN|O assessed|assess|VBN|O by|by|IN|O RT-PCR|rt-pcr|NN|O and|and|CC|O immunohistochemistry|immunohistochemistry|NN|O .|.|.|O 
Knockdown|knockdown|NNP|O of|of|IN|O tagln|TAGLN|NN|GENE using|use|VBG|O siRNA|siRNA|NN|O inhibited|inhibit|VBD|O TGF-beta-induced|tgf-beta-induced|JJ|O migration|migration|NN|O of|of|IN|O lung|lung|NN|O epithelial|epithelial|JJ|O A549|A549|NN|O cells|cell|NNS|O ,|,|,|O as|as|RB|O well|well|RB|O as|as|IN|O primary|primary|JJ|O ATII|ATII|NN|O cells|cell|NNS|O .|.|.|O 
We|we|PRP|O thus|thus|RB|O identified|identify|VBD|O tagln|TAGLN|NN|GENE as|as|IN|O a|a|DT|O novel|novel|JJ|O target|target|NN|O of|of|IN|O TGF-beta/Smad3-dependent|TGF-beta/Smad3-dependent|JJ|O gene|gene|NN|O expression|expression|NN|O in|in|IN|O ATII|ATII|NN|O cells|cell|NNS|O .|.|.|O 
Increased|increase|VBN|O ATII|ATII|NN|O cell|cell|NN|O expression|expression|NN|O of|of|IN|O tagln|TAGLN|NN|GENE in|in|IN|O experimental|experimental|JJ|O and|and|CC|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O may|may|MD|O contribute|contribute|VB|O to|to|TO|O TGF-beta-dependent|tgf-beta-dependent|JJ|O ATII|ATII|NN|O cell|cell|NN|O injury|injury|NN|O ,|,|,|O repair|repair|NN|O ,|,|,|O and|and|CC|O migration|migration|NN|O in|in|IN|O lung|lung|NN|O fibrosis|fibrosis|NN|O .|.|.|O 
Overexpression|overexpression|NN|O of|of|IN|O squamous|squamous|JJ|O cell|cell|NN|O carcinoma|carcinoma|NN|O antigen|antigen|NN|O in|in|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O :|:|:|O clinicopathological|clinicopathological|JJ|O correlations|correlation|NNS|O .|.|.|O 
BACKGROUND|background|NN|O :|:|:|O Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O chronic|chronic|JJ|O progressive|progressive|JJ|O disorder|disorder|NN|O with|with|IN|O a|a|DT|O poor|poor|JJ|O prognosis|prognosis|NN|O .|.|.|O 
Epithelial|epithelial|JJ|O instability|instability|NN|O is|be|VBZ|O a|a|DT|O crucial|crucial|JJ|O step|step|NN|O in|in|IN|O the|the|DT|O development|development|NN|O and|and|CC|O progression|progression|NN|O of|of|IN|O the|the|DT|O disease|disease|NN|O ,|,|,|O including|include|VBG|O neoplastic|neoplastic|JJ|O transformation|transformation|NN|O .|.|.|O 
Few|few|JJ|O tissue|tissue|NN|O markers|marker|NNS|O for|for|IN|O epithelial|epithelial|JJ|O instability|instability|NN|O have|have|VBP|O been|be|VBN|O reported|report|VBN|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
Squamous|squamous|JJ|O cell|cell|NN|O carcinoma|carcinoma|NN|O antigen|antigen|NN|O (|(|(|O SCCA|SCCA|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O serine|serine|NN|GENE protease|protease|NN|GENE inhibitor|inhibitor|NN|O typically|typical|RB|O expressed|express|VBN|O by|by|IN|O dysplastic|dysplastic|JJ|O and|and|CC|O neoplastic|neoplastic|JJ|O cells|cell|NNS|O of|of|IN|O epithelial|epithelial|JJ|O origin|origin|NN|O ,|,|,|O more|much|RBR|O often|often|RB|O in|in|IN|O squamous|squamous|JJ|O cell|cell|NN|O tumours|tumour|NNS|O .|.|.|O 
At|at|IN|O present|present|JJ|O ,|,|,|O no|no|DT|O information|information|NN|O is|be|VBZ|O available|available|JJ|O on|on|IN|O its|its|PRP$|O expression|expression|NN|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
METHODS|method|NNS|O :|:|:|O SCCA|SCCA|NN|O and|and|CC|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta|beta|NN|GENE (|(|(|O TGFbeta|TGFbeta|NN|GENE )|)|)|O expression|expression|NN|O in|in|IN|O surgical|surgical|JJ|O lung|lung|NN|O biopsies|biopsy|NNS|O from|from|IN|O 22|22|CD|O patients|patient|NNS|O with|with|IN|O IPF|IPF|NN|O and|and|CC|O 20|20|CD|O control|control|NN|O cases|case|NNS|O was|be|VBD|O examined|examine|VBN|O .|.|.|O 
An|a|DT|O in|in|FW|O vitro|vitro|FW|O study|study|NN|O using|use|VBG|O A549|A549|NN|O pneumocytes|pneumocyte|NNS|O was|be|VBD|O also|also|RB|O conducted|conduct|VBN|O to|to|TO|O investigate|investigate|VB|O the|the|DT|O relationship|relationship|NN|O between|between|IN|O SCCA|SCCA|NNP|O and|and|CC|O TGFbeta|TGFbeta|NN|GENE expression|expression|NN|O .|.|.|O 
SCCA|SCCA|NN|O and|and|CC|O TGFbeta|TGFbeta|NN|GENE epithelial|epithelial|JJ|O expression|expression|NN|O was|be|VBD|O evaluated|evaluate|VBN|O by|by|IN|O immunohistochemistry|immunohistochemistry|NN|O and|and|CC|O reverse|reverse|VB|O transcription-PCR|transcription-PCR|NN|O (|(|(|O RT-PCR|rt-pcr|NN|O )|)|)|O .|.|.|O 
SCCA|SCCA|NN|O values|value|NNS|O were|be|VBD|O correlated|correlate|VBN|O with|with|IN|O different|different|JJ|O pathological|pathological|JJ|O and|and|CC|O clinical|clinical|JJ|O parameters|parameter|NNS|O .|.|.|O 
Time|time|NNP|O course|course|NN|O analysis|analysis|NN|O of|of|IN|O TGFbeta|TGFbeta|NN|GENE expression|expression|NN|O in|in|IN|O A549|A549|NN|O pneumocytes|pneumocyte|NNS|O incubated|incubate|VBN|O with|with|IN|O different|different|JJ|O SCCA|SCCA|NN|O concentrations|concentration|NNS|O was|be|VBD|O assessed|assess|VBN|O by|by|IN|O real|real|JJ|O time|time|NN|O RT-PCR|rt-pcr|NN|O .|.|.|O 
RESULTS|result|NNS|O :|:|:|O SCCA|SCCA|NN|O was|be|VBD|O expressed|express|VBN|O in|in|IN|O many|many|JJ|O metaplastic|metaplastic|JJ|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O in|in|IN|O all|all|DT|O IPF|IPF|NN|O cases|case|NNS|O with|with|IN|O a|a|DT|O mean|mean|JJ|O value|value|NN|O of|of|IN|O 24.9|24.9|CD|O %|%|NN|O while|while|IN|O it|it|PRP|O was|be|VBD|O seen|see|VBN|O in|in|IN|O only|only|RB|O two|two|CD|O control|control|NN|O patients|patient|NNS|O in|in|IN|O up|up|RB|O to|to|TO|O 5|5|CD|O %|%|NN|O of|of|IN|O metaplastic|metaplastic|JJ|O cells|cell|NNS|O .|.|.|O 
In|in|IN|O patients|patient|NNS|O with|with|IN|O IPF|IPF|NN|O ,|,|,|O SCCA|SCCA|NNP|O correlated|correlate|VBD|O positively|positive|RB|O with|with|IN|O extension|extension|NN|O of|of|IN|O fibroblastic|fibroblastic|JJ|O foci|focus|NNS|O (|(|(|O r|r|NN|O =|=|JJ|O 0.49|0.49|CD|O ,|,|,|O p|p|NN|O =|=|JJ|O 0.02|0.02|CD|O )|)|)|O ,|,|,|O expression|expression|NN|O of|of|IN|O TGFbeta|TGFbeta|NN|GENE (|(|(|O r|r|NN|O =|=|JJ|O 0.78|0.78|CD|O ,|,|,|O p|p|NN|O <|<|JJR|O 0.0001|0.0001|CD|O )|)|)|O and|and|CC|O with|with|IN|O carbon|carbon|NN|O monoxide|monoxide|NN|O transfer|transfer|NN|O factor|factor|NN|O decline|decline|NN|O after|after|IN|O 9|9|CD|O months|month|NNS|O of|of|IN|O follow-up|follow-up|NN|O (|(|(|O r|r|NN|O =|=|JJ|O 0.59|0.59|CD|O ,|,|,|O p|p|NN|O =|=|JJ|O 0.01|0.01|CD|O )|)|)|O .|.|.|O 
In|in|FW|O vitro|vitro|FW|O experiments|experiment|NNS|O showed|show|VBD|O that|that|IN|O incubation|incubation|NN|O of|of|IN|O cultured|culture|VBN|O cells|cell|NNS|O with|with|IN|O SCCA|SCCA|NN|O induced|induce|VBD|O TGFbeta|TGFbeta|NN|GENE expression|expression|NN|O ,|,|,|O with|with|IN|O a|a|DT|O peak|peak|NN|O at|at|IN|O 24|24|CD|O h.|H.|NN|O CONCLUSION|conclusion|NN|O :|:|:|O Our|our|PRP$|O findings|finding|NNS|O provide|provide|VBP|O for|for|IN|O the|the|DT|O first|first|JJ|O time|time|NN|O a|a|DT|O potential|potential|JJ|O mechanism|mechanism|NN|O by|by|IN|O which|which|WDT|O SCCA|SCCA|NN|O secreted|secrete|VBN|O from|from|IN|O metaplastic|metaplastic|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O may|may|MD|O exert|exert|VB|O a|a|DT|O profibrotic|profibrotic|JJ|O effect|effect|NN|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
SCCA|SCCA|NNP|O could|can|MD|O be|be|VB|O an|a|DT|O important|important|JJ|O biomarker|biomarker|NN|O in|in|IN|O this|this|DT|O incurable|incurable|JJ|O disease|disease|NN|O .|.|.|O 
Hyper-responsiveness|Hyper-responsiveness|NN|O of|of|IN|O IPF/UIP|IPF/UIP|NN|O fibroblasts|fibroblast|NNS|O :|:|:|O interplay|interplay|NN|O between|between|IN|O TGFbeta1|TGFbeta1|NN|GENE ,|,|,|O IL-13|IL-13|NN|GENE and|and|CC|O CCL2|CCL2|NN|GENE .|.|.|O 
One|one|CD|O of|of|IN|O the|the|DT|O hallmarks|hallmark|NNS|O of|of|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O with|with|IN|O a|a|DT|O usual|usual|JJ|O interstitial|interstitial|JJ|O pneumonia|pneumonia|NN|O histological|histological|JJ|O pathology|pathology|NN|O (|(|(|O IPF/UIP|IPF/UIP|NN|O )|)|)|O is|be|VBZ|O excess|excess|JJ|O collagen|collagen|NN|O deposition|deposition|NN|O ,|,|,|O due|due|JJ|O to|to|TO|O enhanced|enhance|VBN|O fibroblast|fibroblast|NN|O extracellular|extracellular|JJ|O matrix|matrix|NN|O synthetic|synthetic|JJ|O activity|activity|NN|O .|.|.|O 
Studies|study|NNS|O using|use|VBG|O murine|murine|JJ|O models|model|NNS|O of|of|IN|O lung|lung|NN|O fibrosis|fibrosis|NN|O have|have|VBP|O elucidated|elucidate|VBN|O a|a|DT|O pro-fibrotic|pro-fibrotic|JJ|O pathway|pathway|NN|O involving|involve|VBG|O IL-13|IL-13|NN|GENE driving|drive|VBG|O CCL2|CCL2|NN|GENE ,|,|,|O which|which|WDT|O in|in|IN|O turn|turn|NN|O drives|drive|NNS|O TGFbeta1|TGFbeta1|NN|GENE in|in|IN|O lung|lung|NN|O fibroblasts|fibroblast|NNS|O .|.|.|O 
Therefore|therefore|RB|O ,|,|,|O we|we|PRP|O sought|seek|VBD|O to|to|TO|O determine|determine|VB|O whether|whether|IN|O this|this|DT|O pathway|pathway|NN|O exists|exist|VBZ|O in|in|IN|O the|the|DT|O human|human|JJ|O fibrotic|fibrotic|JJ|O setting|setting|NN|O by|by|IN|O evaluating|evaluate|VBG|O human|human|JJ|O IPF/UIP|IPF/UIP|NN|O fibroblasts|fibroblast|NNS|O .|.|.|O 
IPF/UIP|IPF/UIP|NN|O fibroblasts|fibroblast|NNS|O have|have|VBP|O an|a|DT|O increased|increase|VBN|O baseline|baseline|NN|O fibrotic|fibrotic|JJ|O phenotype|phenotype|NN|O compared|compare|VBN|O to|to|TO|O non-fibrotic|non-fibrotic|JJ|O fibroblasts|fibroblast|NNS|O .|.|.|O 
Interestingly|interesting|RB|O ,|,|,|O non-fibrotic|non-fibrotic|JJ|O fibroblasts|fibroblast|NNS|O responded|respond|VBD|O in|in|IN|O a|a|DT|O pro-fibrotic|pro-fibrotic|JJ|O manner|manner|NN|O to|to|TO|O TGFbeta1|TGFbeta1|NN|GENE but|but|CC|O were|be|VBD|O relatively|relative|RB|O non-responsive|non-responsive|JJ|O to|to|TO|O IL-13|IL-13|NN|GENE or|or|CC|O CCL2|CCL2|NN|GENE ,|,|,|O whereas|whereas|IN|O ,|,|,|O IPF/UIP|IPF/UIP|NN|O cells|cell|NNS|O were|be|VBD|O hyper-responsive|hyper-responsive|JJ|O to|to|TO|O TGFbeta1|TGFbeta1|NN|GENE ,|,|,|O IL-13|IL-13|NN|GENE and|and|CC|O CCL2|CCL2|NN|GENE .|.|.|O 
Interestingly|interesting|RB|O ,|,|,|O TGFbeta1|TGFbeta1|NN|GENE ,|,|,|O CCL2|CCL2|NN|GENE and|and|CC|O IL-13|IL-13|NN|GENE all|all|DT|O upregulated|upregulate|VBN|O TGFbeta|TGFbeta|NN|GENE receptor|receptor|NN|O and|and|CC|O IL-13|IL-13|NN|GENE receptor|receptor|NN|O expression|expression|NN|O ,|,|,|O suggesting|suggest|VBG|O an|a|DT|O ability|ability|NN|O of|of|IN|O the|the|DT|O mediators|mediator|NNS|O to|to|TO|O modulate|modulate|VB|O the|the|DT|O function|function|NN|O of|of|IN|O each|each|DT|O other|other|JJ|O .|.|.|O 
Furthermore|furthermore|RB|O ,|,|,|O in|in|FW|O vivo|vivo|FW|O ,|,|,|O neutralization|neutralization|NN|O of|of|IN|O both|both|CC|O JE|JE|NN|O and|and|CC|O MCP5|MCP5|NN|O ,|,|,|O the|the|DT|O two|two|CD|O functional|functional|JJ|O orthologs|ortholog|NNS|O of|of|IN|O CCL2|CCL2|NN|GENE ,|,|,|O during|during|IN|O bleomycin-induced|bleomycin-induced|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O significantly|significant|RB|O reduced|reduce|VBD|O collagen|collagen|NN|O deposition|deposition|NN|O as|as|RB|O well|well|RB|O as|as|IN|O JE|JE|NN|O and|and|CC|O CCR2|CCR2|NN|GENE expression|expression|NN|O .|.|.|O 
Also|also|RB|O in|in|IN|O the|the|DT|O bleomycin|bleomycin|NN|O model|model|NN|O ,|,|,|O CTGF|Ctgf|NN|GENE ,|,|,|O which|which|WDT|O is|be|VBZ|O highly|high|RB|O induced|induce|VBN|O following|follow|VBG|O TGFbeta|TGFbeta|NN|GENE stimulation|stimulation|NN|O ,|,|,|O was|be|VBD|O attenuated|attenuate|VBN|O with|with|IN|O anti-JE/anti-MCP|anti-JE/anti-MCP|JJ|O 5|5|CD|O treatment|treatment|NN|O .|.|.|O 
Overall|overall|RB|O this|this|DT|O study|study|NN|O demonstrates|demonstrate|VBZ|O an|a|DT|O interplay|interplay|NN|O between|between|IN|O TGFbeta1|TGFbeta1|NN|GENE ,|,|,|O IL-13|IL-13|NN|GENE and|and|CC|O CCL2|CCL2|NN|GENE in|in|IN|O IPF/UIP|IPF/UIP|NN|O ,|,|,|O where|where|WRB|O these|these|DT|O three|three|CD|O mediators|mediator|NNS|O feedback|feedback|NN|O on|on|IN|O each|each|DT|O other|other|JJ|O ,|,|,|O promoting|promote|VBG|O the|the|DT|O fibrotic|fibrotic|JJ|O response|response|NN|O .|.|.|O 
Comparison|comparison|NN|O between|between|IN|O conventional|conventional|JJ|O and|and|CC|O ``|``|``|O clinical|clinical|JJ|O ''|''|''|O assessment|assessment|NN|O of|of|IN|O experimental|experimental|JJ|O lung|lung|NN|O fibrosis|fibrosis|NN|O .|.|.|O 
BACKGROUND|background|NN|O :|:|:|O Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O treatment|treatment|NN|O resistant|resistant|JJ|O disease|disease|NN|O with|with|IN|O poor|poor|JJ|O prognosis|prognosis|NN|O .|.|.|O 
Numerous|numerous|JJ|O compounds|compound|NNS|O have|have|VBP|O been|be|VBN|O demonstrated|demonstrate|VBN|O to|to|TO|O efficiently|efficient|RB|O prevent|prevent|VB|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O PF|pf|NN|O )|)|)|O in|in|IN|O animal|animal|NN|O models|model|NNS|O but|but|CC|O only|only|RB|O a|a|DT|O few|few|JJ|O were|be|VBD|O successful|successful|JJ|O when|when|WRB|O given|give|VBN|O to|to|TO|O animals|animal|NNS|O with|with|IN|O established|established|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Major|major|JJ|O concerns|concern|NNS|O of|of|IN|O current|current|JJ|O PF|pf|NN|O models|model|NNS|O are|be|VBP|O spontaneous|spontaneous|JJ|O resolution|resolution|NN|O and|and|CC|O high|high|JJ|O variability|variability|NN|O of|of|IN|O fibrosis|fibrosis|NN|O ,|,|,|O and|and|CC|O the|the|DT|O lack|lack|NN|O of|of|IN|O assessment|assessment|NN|O methods|method|NNS|O that|that|WDT|O can|can|MD|O allow|allow|VB|O to|to|TO|O monitor|monitor|VB|O the|the|DT|O effect|effect|NN|O of|of|IN|O drugs|drug|NNS|O in|in|IN|O individual|individual|JJ|O animals|animal|NNS|O over|over|IN|O time|time|NN|O .|.|.|O 
We|we|PRP|O used|use|VBD|O a|a|DT|O model|model|NN|O of|of|IN|O experimental|experimental|JJ|O PF|pf|NN|O in|in|IN|O rats|rat|NNS|O and|and|CC|O compare|compare|VB|O parameters|parameter|NNS|O obtained|obtain|VBN|O in|in|IN|O living|live|VBG|O animals|animal|NNS|O with|with|IN|O conventional|conventional|JJ|O assessment|assessment|NN|O tools|tool|NNS|O that|that|WDT|O require|require|VBP|O removal|removal|NN|O of|of|IN|O the|the|DT|O lungs|lung|NNS|O .|.|.|O 
METHODS|method|NNS|O :|:|:|O PF|pf|NN|O was|be|VBD|O induced|induce|VBN|O in|in|IN|O rats|rat|NNS|O by|by|IN|O adenoviral|adenoviral|JJ|O gene|gene|NN|O transfer|transfer|NN|O of|of|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta|beta|NN|GENE .|.|.|O 
Morphological|morphological|JJ|O and|and|CC|O functional|functional|JJ|O changes|change|NNS|O were|be|VBD|O assessed|assess|VBN|O for|for|IN|O up|up|RB|O to|to|TO|O 56|56|CD|O days|day|NNS|O by|by|IN|O micro-CT|micro-CT|NN|O ,|,|,|O lung|lung|NN|O compliance|compliance|NN|O (|(|(|O measured|measure|VBN|O via|via|IN|O a|a|DT|O mechanical|mechanical|JJ|O ventilator|ventilator|NN|O )|)|)|O and|and|CC|O VO2max|VO2max|NN|O and|and|CC|O compared|compare|VBN|O to|to|TO|O histomorphometry|histomorphometry|NN|O and|and|CC|O hydroxyproline|hydroxyproline|NN|O content|content|NN|O .|.|.|O 
RESULTS|result|NNS|O :|:|:|O Standard|standard|NNP|O histological|histological|JJ|O and|and|CC|O collagen|collagen|NN|O assessment|assessment|NN|O confirmed|confirm|VBD|O the|the|DT|O persistent|persistent|JJ|O fibrotic|fibrotic|JJ|O phenotype|phenotype|NN|O as|as|IN|O described|describe|VBN|O before|before|IN|O .|.|.|O 
The|the|DT|O histomorphological|histomorphological|JJ|O scores|score|NNS|O correlated|correlate|VBD|O both|both|DT|O to|to|TO|O radiological|radiological|JJ|O (|(|(|O r2|r2|NN|O =|=|JJ|O 0.29|0.29|CD|O ,|,|,|O p|p|NN|O <|<|JJR|O 0.01|0.01|CD|O )|)|)|O and|and|CC|O functional|functional|JJ|O changes|change|NNS|O (|(|(|O r2|r2|NN|O =|=|JJ|O 0.51|0.51|CD|O ,|,|,|O p|p|NN|O <|<|JJR|O 0.0001|0.0001|CD|O )|)|)|O .|.|.|O 
VO2max|VO2max|NN|O did|do|VBD|O not|not|RB|O correlate|correlate|VB|O with|with|IN|O fibrosis|fibrosis|NN|O .|.|.|O 
CONCLUSION|conclusion|NN|O :|:|:|O The|the|DT|O progression|progression|NN|O of|of|IN|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O can|can|MD|O be|be|VB|O reliably|reliable|RB|O assessed|assess|VBN|O and|and|CC|O followed|follow|VBN|O in|in|IN|O living|live|VBG|O animals|animal|NNS|O over|over|IN|O time|time|NN|O using|use|VBG|O invasive|invasive|JJ|O ,|,|,|O non-terminal|non-terminal|JJ|O compliance|compliance|NN|O measurements|measurement|NNS|O and|and|CC|O micro-CT|micro-CT|NN|O .|.|.|O 
This|this|DT|O approach|approach|NN|O directly|direct|RB|O translates|translate|VBZ|O to|to|TO|O the|the|DT|O management|management|NN|O of|of|IN|O patients|patient|NNS|O with|with|IN|O IPF|IPF|NN|O and|and|CC|O allows|allow|VBZ|O to|to|TO|O monitor|monitor|VB|O therapeutic|therapeutic|JJ|O effects|effect|NNS|O in|in|IN|O drug|drug|NN|O intervention|intervention|NN|O studies|study|NNS|O .|.|.|O 
The|the|DT|O latent|latent|JJ|O form|form|NN|O of|of|IN|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O is|be|VBZ|O induced|induce|VBN|O by|by|IN|O TNFalpha|TNFalpha|NN|GENE through|through|IN|O an|a|DT|O ERK|erk|NN|GENE specific|specific|JJ|O pathway|pathway|NN|O and|and|CC|O is|be|VBZ|O activated|activate|VBN|O by|by|IN|O asbestos-derived|asbestos-derived|JJ|O reactive|reactive|JJ|O oxygen|oxygen|NN|O species|specie|NNS|O in|in|FW|O vitro|vitro|FW|O and|and|CC|O in|in|FW|O vivo|vivo|FW|O .|.|.|O 
Tumor|Tumor|NN|GENE necrosis|necrosis|NN|GENE factor|factor|NN|GENE alpha|alpha|NN|GENE (|(|(|O TNFalpha|TNFalpha|NN|GENE )|)|)|O and|and|CC|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta|beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O (|(|(|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O )|)|)|O are|be|VBP|O potent|potent|JJ|O peptide|peptide|NN|O growth|growth|NN|O factors|factor|NNS|O that|that|WDT|O are|be|VBP|O likely|likely|JJ|O to|to|TO|O play|play|VB|O important|important|JJ|O roles|role|NNS|O in|in|IN|O the|the|DT|O development|development|NN|O of|of|IN|O interstitial|interstitial|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O .|.|.|O 
Previously|previous|RB|O we|we|PRP|O showed|show|VBD|O that|that|IN|O TNFalpha|TNFalpha|NN|GENE and|and|CC|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O are|be|VBP|O up-regulated|upregulate|VBN|O in|in|IN|O macrophages|macrophage|NNS|O ,|,|,|O epithelial|epithelial|JJ|O and|and|CC|O mesenchymal|mesenchymal|JJ|O cells|cell|NNS|O early|early|RB|O after|after|IN|O exposure|exposure|NN|O to|to|TO|O chrysotile|chrysotile|NN|O asbestos|asbestos|NN|O ,|,|,|O particularly|particular|RB|O at|at|IN|O sites|site|NNS|O of|of|IN|O fiber|fiber|NN|O deposition|deposition|NN|O in|in|FW|O vivo|vivo|FW|O .|.|.|O 
We|we|PRP|O also|also|RB|O showed|show|VBD|O that|that|IN|O TNFalpha|TNFalpha|NN|GENE receptor|receptor|NN|O knockout|knockout|NN|O mice|mouse|NNS|O are|be|VBP|O resistant|resistant|JJ|O to|to|TO|O asbestos-induced|asbestos-induced|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Importantly|important|RB|O ,|,|,|O vectors|vector|NNS|O that|that|WDT|O over-express|overexpress|VBP|O TNFalpha|TNFalpha|NN|GENE cause|cause|NN|O inflammation|inflammation|NN|O and|and|CC|O fibrogenesis|fibrogenesis|NN|O along|along|IN|O with|with|IN|O increased|increase|VBN|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O production|production|NN|O in|in|IN|O C57Bl/6|C57Bl/6|NN|O mice|mouse|NNS|O .|.|.|O 
Recently|recent|RB|O we|we|PRP|O reported|report|VBD|O that|that|IN|O TNFalpha|TNFalpha|NN|GENE activates|activate|VBZ|O the|the|DT|O extracellular|extracellular|JJ|O regulated|regulated|JJ|O kinase|kinase|NN|O pathway|pathway|NN|O in|in|IN|O fibroblasts|fibroblast|NNS|O leading|lead|VBG|O to|to|TO|O a|a|DT|O 200-400|200-400|CD|O %|%|NN|O increase|increase|NN|O in|in|IN|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O mRNA|mRNA|NN|O and|and|CC|O protein|protein|NN|O .|.|.|O 
The|the|DT|O mechanism|mechanism|NN|O of|of|IN|O TNFalpha|TNFalpha|NN|GENE induction|induction|NN|O of|of|IN|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O expression|expression|NN|O appears|appear|VBZ|O to|to|TO|O be|be|VB|O complex|complex|JJ|O ,|,|,|O involving|involve|VBG|O both|both|CC|O transcriptional|transcriptional|JJ|O and|and|CC|O post-transcriptional|post-transcriptional|JJ|O mechanisms|mechanism|NNS|O .|.|.|O 
In|in|IN|O asbestos-exposed|asbestos-exposed|JJ|O animals|animal|NNS|O ,|,|,|O this|this|DT|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O is|be|VBZ|O produced|produce|VBN|O on|on|IN|O alveolar|alveolar|JJ|O surfaces|surface|NNS|O in|in|IN|O a|a|DT|O latent|latent|JJ|O form|form|NN|O (|(|(|O controlled|control|VBN|O by|by|IN|O binding|binding|NN|O of|of|IN|O a|a|DT|O latent|latent|JJ|O associated|associate|VBN|O peptide|peptide|NN|O [|[|(|O LAP|lap|NN|O ]|]|)|O )|)|)|O that|that|WDT|O must|must|MD|O be|be|VB|O activated|activate|VBN|O for|for|IN|O the|the|DT|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O to|to|TO|O bind|bind|VB|O to|to|TO|O its|its|PRP$|O receptors|receptor|NNS|O and|and|CC|O induce|induce|VB|O its|its|PRP$|O multiple|multiple|JJ|O biological|biological|JJ|O effects|effect|NNS|O .|.|.|O 
Thus|thus|RB|O ,|,|,|O we|we|PRP|O recently|recent|RB|O reported|report|VBD|O that|that|IN|O ,|,|,|O in|in|FW|O vitro|vitro|FW|O ,|,|,|O reactive|reactive|JJ|O oxygen|oxygen|NN|O species|specie|NNS|O (|(|(|O ROS|ros|NN|O )|)|)|O derived|derive|VBN|O from|from|IN|O chrysotile|chrysotile|NN|O and|and|CC|O crocidolite|crocidolite|NN|O asbestos|asbestos|NN|O activate|activate|VBP|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O by|by|IN|O oxidation|oxidation|NN|O of|of|IN|O the|the|DT|O LAP|lap|NN|O .|.|.|O 
Now|now|RB|O ,|,|,|O in|in|IN|O preliminary|preliminary|JJ|O findings|finding|NNS|O ,|,|,|O we|we|PRP|O have|have|VBP|O shown|show|VBN|O that|that|IN|O over-expression|over-expression|NN|O of|of|IN|O latent|latent|JJ|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O prior|prior|RB|O to|to|TO|O asbestos|asbestos|NN|O exposure|exposure|NN|O of|of|IN|O fibrogenic-resistant|fibrogenic-resistant|JJ|O TNFalpha|TNFalpha|NN|GENE receptor|receptor|NN|O knockout|knockout|NN|O mice|mouse|NNS|O produces|produce|VBZ|O asbestos|asbestos|NN|O lesions|lesion|NNS|O with|with|IN|O the|the|DT|O same|same|JJ|O severity|severity|NN|O as|as|IN|O seen|see|VBN|O in|in|IN|O normal|normal|JJ|O C57/Bl6|C57/Bl6|NN|O mice|mouse|NNS|O .|.|.|O 
This|this|DT|O finding|finding|NN|O plus|plus|IN|O the|the|DT|O demonstration|demonstration|NN|O of|of|IN|O increased|increase|VBN|O amounts|amount|NNS|O of|of|IN|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O ,|,|,|O increased|increase|VBD|O Smad|SMAD|NN|O activation|activation|NN|O and|and|CC|O amelioration|amelioration|NN|O of|of|IN|O the|the|DT|O developing|develop|VBG|O disease|disease|NN|O by|by|IN|O treating|treat|VBG|O the|the|DT|O mice|mouse|NNS|O with|with|IN|O an|a|DT|O anti-oxidant|anti-oxidant|JJ|O all|all|DT|O support|support|VBP|O the|the|DT|O concept|concept|NN|O that|that|IN|O ,|,|,|O in|in|FW|O vivo|vivo|FW|O ,|,|,|O latent|latent|JJ|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O is|be|VBZ|O activated|activate|VBN|O by|by|IN|O asbestos-generated|asbestos-generated|JJ|O oxygen|oxygen|NN|O radicals|radical|NNS|O and|and|CC|O consequently|consequent|RB|O mediates|mediate|VBZ|O at|at|IN|O least|little|JJS|O a|a|DT|O component|component|NN|O of|of|IN|O the|the|DT|O consequent|consequent|JJ|O fibrogenesis|fibrogenesis|NN|O .|.|.|O 
Taken|take|VBN|O together|together|RB|O ,|,|,|O these|these|DT|O findings|finding|NNS|O support|support|VBP|O the|the|DT|O postulate|postulate|VBP|O that|that|IN|O TNFalpha|TNFalpha|NN|GENE controls|control|NNS|O fibrogenesis|fibrogenesis|NN|O by|by|IN|O regulating|regulate|VBG|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O expression|expression|NN|O and|and|CC|O that|that|IN|O one|one|CD|O mechanism|mechanism|NN|O through|through|IN|O which|which|WDT|O ROS|ros|NN|O induce|induce|VBP|O lung|lung|NN|O fibrosis|fibrosis|NN|O is|be|VBZ|O by|by|IN|O activating|activate|VBG|O latent|latent|JJ|O TGFbeta|TGFbeta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O .|.|.|O 
Alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cell|cell|NN|O injury|injury|NN|O with|with|IN|O Epstein-Barr|epstein-barr|JJ|O virus|virus|NN|O upregulates|upregulate|VBZ|O TGFbeta1|TGFbeta1|NN|GENE expression|expression|NN|O .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O refractory|refractory|JJ|O and|and|CC|O lethal|lethal|JJ|O interstitial|interstitial|JJ|O lung|lung|NN|O disease|disease|NN|O characterized|characterize|VBN|O by|by|IN|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O apoptosis|apoptosis|NN|O ,|,|,|O fibroblast|fibroblast|NN|O proliferation|proliferation|NN|O ,|,|,|O and|and|CC|O ECM|ecm|NN|O protein|protein|NN|O deposition|deposition|NN|O .|.|.|O 
Epstein-Barr|epstein-barr|JJ|O virus|virus|NN|O (|(|(|O EBV|EBV|NN|O )|)|)|O has|have|VBZ|O previously|previous|RB|O been|be|VBN|O localized|localized|JJ|O to|to|TO|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O of|of|IN|O IPF|IPF|NN|O patients|patient|NNS|O and|and|CC|O is|be|VBZ|O associated|associate|VBN|O with|with|IN|O a|a|DT|O poor|poor|JJ|O prognosis|prognosis|NN|O .|.|.|O 
In|in|IN|O this|this|DT|O study|study|NN|O ,|,|,|O we|we|PRP|O utilized|utilize|VBD|O a|a|DT|O microarray-based|microarray-based|JJ|O differential|differential|JJ|O gene|gene|NN|O expression|expression|NN|O analysis|analysis|NN|O strategy|strategy|NN|O to|to|TO|O identify|identify|VB|O molecular|molecular|JJ|O drivers|driver|NNS|O of|of|IN|O EBV-associated|ebv-associated|JJ|O lung|lung|NN|O fibrosis|fibrosis|NN|O .|.|.|O 
Two|two|CD|O cell|cell|NN|O lines|line|NNS|O ,|,|,|O primary|primary|JJ|O human|human|JJ|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O type|type|NN|O 2|2|CD|O and|and|CC|O A549|A549|NN|O cells|cell|NNS|O ,|,|,|O were|be|VBD|O infected|infect|VBN|O with|with|IN|O EBV|EBV|NN|O .|.|.|O 
EBV|EBV|NN|O lytic|lytic|JJ|O phase|phase|NN|O induction|induction|NN|O increased|increase|VBD|O active|active|JJ|O and|and|CC|O total|total|JJ|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta1|beta1|NN|GENE (|(|(|O TGFbeta1|TGFbeta1|NN|GENE )|)|)|O transcript|transcript|NN|O expression|expression|NN|O in|in|IN|O association|association|NN|O with|with|IN|O reduced|reduce|VBN|O cell|cell|NN|O proliferation|proliferation|NN|O and|and|CC|O increased|increase|VBD|O caspase|caspase|NN|O 3/7|3/7|CD|O activity|activity|NN|O .|.|.|O 
Exposing|expose|VBG|O EBV-infected|ebv-infected|JJ|O cells|cell|NNS|O to|to|TO|O ganciclovir|ganciclovir|NN|O resulted|result|VBD|O in|in|IN|O TGFbeta1|TGFbeta1|NN|GENE deregulation|deregulation|NN|O and|and|CC|O reduced|reduce|VBN|O expression|expression|NN|O of|of|IN|O EBV|EBV|NN|O early|early|JJ|O response|response|NN|O genes|gene|NNS|O ,|,|,|O BRLF1|BRLF1|NN|O and|and|CC|O BZLF1|BZLF1|NN|O .|.|.|O 
We|we|PRP|O targeted|target|VBD|O the|the|DT|O BRLF1|BRLF1|NN|O and|and|CC|O BZLF1|BZLF1|NN|O gene|gene|NN|O products|product|NNS|O ,|,|,|O Rta|RTA|NN|O and|and|CC|O Zta|Zta|NN|O ,|,|,|O by|by|IN|O silencing|silencing|NN|O RNA|rna|NN|O ,|,|,|O and|and|CC|O this|this|DT|O resulted|result|VBD|O in|in|IN|O the|the|DT|O normalization|normalization|NN|O of|of|IN|O TGFbeta1|TGFbeta1|NN|GENE transcript|transcript|NN|O and|and|CC|O cell|cell|NN|O proliferation|proliferation|NN|O levels|level|NNS|O .|.|.|O 
Our|our|PRP$|O study|study|NN|O using|use|VBG|O a|a|DT|O viral|viral|JJ|O cell|cell|NN|O line|line|NN|O model|model|NN|O complements|complement|VBZ|O existing|exist|VBG|O human|human|JJ|O and|and|CC|O animal|animal|JJ|O model|model|NN|O data|datum|NNS|O and|and|CC|O further|further|JJ|O provides|provide|VBZ|O evidence|evidence|NN|O to|to|TO|O suggest|suggest|VB|O that|that|IN|O viral|viral|JJ|O epithelial|epithelial|JJ|O cell|cell|NN|O injury|injury|NN|O may|may|MD|O play|play|VB|O a|a|DT|O role|role|NN|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
Fibrotic|fibrotic|JJ|O myofibroblasts|myofibroblast|NNS|O manifest|manifest|VBP|O genome-wide|genome-wide|JJ|O derangements|derangement|NNS|O of|of|IN|O translational|translational|JJ|O control|control|NN|O .|.|.|O 
BACKGROUND|background|NN|O :|:|:|O As|as|IN|O a|a|DT|O group|group|NN|O ,|,|,|O fibroproliferative|fibroproliferative|JJ|O disorders|disorder|NNS|O of|of|IN|O the|the|DT|O lung|lung|NN|O ,|,|,|O liver|liver|NN|O ,|,|,|O kidney|kidney|NN|O ,|,|,|O heart|heart|NN|O ,|,|,|O vasculature|vasculature|NN|O and|and|CC|O integument|integument|NN|O are|be|VBP|O common|common|JJ|O ,|,|,|O progressive|progressive|JJ|O and|and|CC|O refractory|refractory|JJ|O to|to|TO|O therapy|therapy|NN|O .|.|.|O 
They|they|PRP|O can|can|MD|O emerge|emerge|VB|O following|follow|VBG|O toxic|toxic|JJ|O insults|insult|NNS|O ,|,|,|O but|but|CC|O are|be|VBP|O frequently|frequent|RB|O idiopathic|idiopathic|JJ|O .|.|.|O 
Their|their|PRP$|O enigmatic|enigmatic|JJ|O propensity|propensity|NN|O to|to|TO|O resist|resist|VB|O therapy|therapy|NN|O and|and|CC|O progress|progress|NN|O to|to|TO|O organ|organ|NN|O failure|failure|NN|O has|have|VBZ|O focused|focus|VBN|O attention|attention|NN|O on|on|IN|O the|the|DT|O myofibroblast-the|myofibroblast-the|JJ|O primary|primary|JJ|O effector|effector|NN|O of|of|IN|O the|the|DT|O fibroproliferative|fibroproliferative|JJ|O response|response|NN|O .|.|.|O 
We|we|PRP|O have|have|VBP|O recently|recent|RB|O shown|show|VBN|O that|that|IN|O aberrant|aberrant|JJ|O beta|beta|NN|GENE 1|1|NN|GENE integrin|integrin|NN|GENE signaling|signaling|NN|O in|in|IN|O fibrotic|fibrotic|JJ|O fibroblasts|fibroblast|NNS|O results|result|VBZ|O in|in|IN|O defective|defective|JJ|O PTEN|PTEN|NN|GENE function|function|NN|O ,|,|,|O unrestrained|unrestrained|JJ|O Akt|akt|NN|GENE signaling|signaling|NN|O and|and|CC|O subsequent|subsequent|JJ|O activation|activation|NN|O of|of|IN|O the|the|DT|O translation|translation|NN|O initiation|initiation|NN|O machinery|machinery|NN|O .|.|.|O 
How|how|WRB|O this|this|DT|O pathological|pathological|JJ|O integrin|integrin|NN|O signaling|signaling|NN|O alters|alter|VBZ|O the|the|DT|O gene|gene|NN|O expression|expression|NN|O pathway|pathway|NN|O has|have|VBZ|O not|not|RB|O been|be|VBN|O elucidated|elucidate|VBN|O .|.|.|O 
RESULTS|result|NNS|O :|:|:|O Using|use|VBG|O a|a|DT|O systems|system|NNS|O approach|approach|VBP|O to|to|TO|O study|study|VB|O this|this|DT|O question|question|NN|O in|in|IN|O a|a|DT|O prototype|prototype|NN|O fibrotic|fibrotic|JJ|O disease|disease|NN|O ,|,|,|O Idiopathic|idiopathic|JJ|O Pulmonary|pulmonary|JJ|O Fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O ;|;|:|O here|here|RB|O we|we|PRP|O show|show|VBP|O organized|organize|VBN|O changes|change|NNS|O in|in|IN|O the|the|DT|O gene|gene|NN|O expression|expression|NN|O pathway|pathway|NN|O of|of|IN|O primary|primary|JJ|O lung|lung|NN|O myofibroblasts|myofibroblast|NNS|O that|that|WDT|O persist|persist|VBP|O for|for|IN|O up|up|RB|O to|to|TO|O 9|9|CD|O sub-cultivations|sub-cultivation|NNS|O in|in|FW|O vitro|vitro|FW|O .|.|.|O 
When|when|WRB|O comparing|compare|VBG|O IPF|IPF|NN|O and|and|CC|O control|control|NN|O myofibroblasts|myofibroblast|NNS|O in|in|IN|O a|a|DT|O 3-dimensional|3-dimensional|JJ|O type|type|NN|O I|i|CD|O collagen|collagen|NN|O matrix|matrix|NN|O ,|,|,|O more|many|JJR|O genes|gene|NNS|O differed|differ|VBD|O at|at|IN|O the|the|DT|O level|level|NN|O of|of|IN|O ribosome|ribosome|NN|O recruitment|recruitment|NN|O than|than|IN|O at|at|IN|O the|the|DT|O level|level|NN|O of|of|IN|O transcript|transcript|NN|O abundance|abundance|NN|O ,|,|,|O indicating|indicate|VBG|O pathological|pathological|JJ|O translational|translational|JJ|O control|control|NN|O as|as|IN|O a|a|DT|O major|major|JJ|O characteristic|characteristic|NN|O of|of|IN|O IPF|IPF|NN|O myofibroblasts|myofibroblast|NNS|O .|.|.|O 
To|to|TO|O determine|determine|VB|O the|the|DT|O effect|effect|NN|O of|of|IN|O matrix|matrix|NN|O state|state|NN|O on|on|IN|O translational|translational|JJ|O control|control|NN|O ,|,|,|O myofibroblasts|myofibroblast|NNS|O were|be|VBD|O permitted|permit|VBN|O to|to|TO|O contract|contract|VB|O the|the|DT|O matrix|matrix|NN|O .|.|.|O 
Ribosome|ribosome|NN|O recruitment|recruitment|NN|O in|in|IN|O control|control|NN|O myofibroblasts|myofibroblast|NNS|O was|be|VBD|O relatively|relative|RB|O stable|stable|JJ|O .|.|.|O 
In|in|IN|O contrast|contrast|NN|O ,|,|,|O IPF|IPF|NN|O cells|cell|NNS|O manifested|manifest|VBN|O large|large|JJ|O alterations|alteration|NNS|O in|in|IN|O the|the|DT|O ribosome|ribosome|NN|O recruitment|recruitment|NN|O pattern|pattern|NN|O .|.|.|O 
Pathological|pathological|JJ|O studies|study|NNS|O suggest|suggest|VBP|O an|a|DT|O epithelial|epithelial|JJ|O origin|origin|NN|O for|for|IN|O IPF|IPF|NN|O myofibroblasts|myofibroblast|NNS|O through|through|IN|O the|the|DT|O epithelial|epithelial|JJ|O to|to|TO|O mesenchymal|mesenchymal|JJ|O transition|transition|NN|O (|(|(|O EMT|emt|NN|GENE )|)|)|O .|.|.|O 
In|in|IN|O accord|accord|NN|O with|with|IN|O this|this|DT|O ,|,|,|O we|we|PRP|O found|find|VBD|O systems-level|systems-level|JJ|O indications|indication|NNS|O for|for|IN|O TGF-beta|TGF-beta|NN|GENE -|-|:|O driven|drive|VBN|O EMT|emt|NNP|GENE as|as|IN|O one|one|CD|O source|source|NN|O of|of|IN|O IPF|IPF|NN|O myofibroblasts|myofibroblast|NNS|O .|.|.|O 
CONCLUSIONS|conclusion|NNS|O :|:|:|O These|these|DT|O findings|finding|NNS|O establish|establish|VBP|O the|the|DT|O power|power|NN|O of|of|IN|O systems|system|NNS|O level|level|NN|O genome-wide|genome-wide|JJ|O analysis|analysis|NN|O to|to|TO|O provide|provide|VB|O mechanistic|mechanistic|JJ|O insights|insight|NNS|O into|into|IN|O fibrotic|fibrotic|JJ|O disorders|disorder|NNS|O such|such|JJ|O as|as|IN|O IPF|IPF|NN|O .|.|.|O 
Our|our|PRP$|O data|datum|NNS|O point|point|VBP|O to|to|TO|O derangements|derangement|NNS|O of|of|IN|O translational|translational|JJ|O control|control|NN|O downstream|downstream|RB|O of|of|IN|O aberrant|aberrant|JJ|O beta|beta|NN|GENE 1|1|NN|GENE integrin|integrin|NN|GENE signaling|signaling|NN|O as|as|IN|O a|a|DT|O fundamental|fundamental|JJ|O component|component|NN|O of|of|IN|O IPF|IPF|NN|O pathobiology|pathobiology|NN|O and|and|CC|O indicates|indicate|VBZ|O that|that|IN|O TGF-beta|TGF-beta|NN|GENE -|-|:|O driven|drive|VBN|O EMT|emt|NNP|GENE is|be|VBZ|O one|one|CD|O source|source|NN|O for|for|IN|O IPF|IPF|NN|O myofibroblasts|myofibroblast|NNS|O .|.|.|O 
Role|role|NN|O for|for|IN|O alpha3|alpha3|NN|O integrin|integrin|NN|O in|in|IN|O EMT|emt|NNP|GENE and|and|CC|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O characterized|characterize|VBN|O by|by|IN|O progressive|progressive|JJ|O (|(|(|O myo|Myo|NN|O )|)|)|O fibroblast|fibroblast|NN|O accumulation|accumulation|NN|O and|and|CC|O collagen|collagen|NN|O deposition|deposition|NN|O .|.|.|O 
One|one|CD|O possible|possible|JJ|O source|source|NN|O of|of|IN|O (|(|(|O myo|Myo|NN|O )|)|)|O fibroblasts|fibroblast|NNS|O is|be|VBZ|O epithelial|epithelial|JJ|O cells|cell|NNS|O that|that|WDT|O undergo|undergo|VBP|O epithelial-mesenchymal|epithelial-mesenchymal|JJ|O transition|transition|NN|O (|(|(|O EMT|emt|NN|GENE )|)|)|O ,|,|,|O a|a|DT|O process|process|NN|O frequently|frequent|RB|O mediated|mediate|VBN|O by|by|IN|O TGF-beta|TGF-beta|NN|GENE .|.|.|O 
In|in|IN|O this|this|DT|O issue|issue|NN|O of|of|IN|O the|the|DT|O JCI|JCI|NNP|O ,|,|,|O Kim|Kim|NNP|O et|et|FW|O al.|al.|FW|O report|report|NN|O that|that|IN|O epithelial|epithelial|JJ|O cell-specific|cell-specific|JJ|O deletion|deletion|NN|O of|of|IN|O alpha3|alpha3|NN|O integrin|integrin|NN|O prevents|prevent|VBZ|O EMT|emt|NNP|GENE in|in|IN|O mice|mouse|NNS|O ,|,|,|O thereby|thereby|RB|O protecting|protect|VBG|O against|against|IN|O bleomycin-induced|bleomycin-induced|JJ|O fibrosis|fibrosis|NN|O (|(|(|O see|see|VB|O the|the|DT|O related|related|JJ|O article|article|NN|O beginning|beginning|NN|O on|on|IN|O page|page|NN|O 213|213|CD|O )|)|)|O .|.|.|O 
The|the|DT|O authors|author|NNS|O propose|propose|VBP|O a|a|DT|O novel|novel|JJ|O mechanism|mechanism|NN|O linking|link|VBG|O TGF-beta|TGF-beta|NN|GENE and|and|CC|O beta-catenin|beta-catenin|NN|GENE signaling|signaling|NN|O in|in|IN|O EMT|emt|NN|GENE through|through|IN|O integrin-dependent|integrin-dependent|JJ|O association|association|NN|O of|of|IN|O tyrosine-phosphorylated|tyrosine-phosphorylated|JJ|O beta-catenin|beta-catenin|NN|GENE and|and|CC|O pSmad2|pSmad2|NN|O and|and|CC|O suggest|suggest|VBP|O targeted|target|VBN|O disruption|disruption|NN|O of|of|IN|O this|this|DT|O interaction|interaction|NN|O as|as|IN|O a|a|DT|O potential|potential|JJ|O therapeutic|therapeutic|JJ|O approach|approach|NN|O .|.|.|O 
Epithelial|epithelial|JJ|O cell|cell|NN|O alpha3beta1|alpha3beta1|NN|O integrin|integrin|NN|O links|link|NNS|O beta-catenin|beta-catenin|NN|GENE and|and|CC|O Smad|SMAD|NN|O signaling|signaling|NN|O to|to|TO|O promote|promote|VB|O myofibroblast|myofibroblast|NN|O formation|formation|NN|O and|and|CC|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O ,|,|,|O in|in|IN|O particular|particular|JJ|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O ,|,|,|O results|result|VBZ|O from|from|IN|O aberrant|aberrant|JJ|O wound|wound|NN|O healing|healing|NN|O and|and|CC|O scarification|scarification|NN|O .|.|.|O 
One|one|CD|O population|population|NN|O of|of|IN|O fibroblasts|fibroblast|NNS|O involved|involve|VBN|O in|in|IN|O the|the|DT|O fibrotic|fibrotic|JJ|O process|process|NN|O is|be|VBZ|O thought|think|VBN|O to|to|TO|O originate|originate|VB|O from|from|IN|O lung|lung|NN|O epithelial|epithelial|JJ|O cells|cell|NNS|O via|via|IN|O epithelial-mesenchymal|epithelial-mesenchymal|JJ|O transition|transition|NN|O (|(|(|O EMT|emt|NN|GENE )|)|)|O .|.|.|O 
Indeed|indeed|RB|O ,|,|,|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O (|(|(|O AECs|aec|NNS|O )|)|)|O undergo|undergo|VBP|O EMT|emt|NN|GENE in|in|FW|O vivo|vivo|FW|O during|during|IN|O experimental|experimental|JJ|O fibrosis|fibrosis|NN|O and|and|CC|O ex|ex|FW|O vivo|vivo|FW|O in|in|IN|O response|response|NN|O to|to|TO|O TGF-beta1|TGF-beta1|NN|GENE .|.|.|O 
As|as|IN|O the|the|DT|O ECM|ecm|NNP|O critically|critical|RB|O regulates|regulate|VBZ|O AEC|aec|NN|O responses|response|NNS|O to|to|TO|O TGF-beta1|TGF-beta1|NN|GENE ,|,|,|O we|we|PRP|O explored|explore|VBD|O the|the|DT|O role|role|NN|O of|of|IN|O the|the|DT|O prominent|prominent|JJ|O epithelial|epithelial|JJ|O integrin|integrin|NN|O alpha3beta1|alpha3beta1|NN|O in|in|IN|O experimental|experimental|JJ|O fibrosis|fibrosis|NN|O by|by|IN|O generating|generate|VBG|O mice|mouse|NNS|O with|with|IN|O lung|lung|NN|O epithelial|epithelial|JJ|O cell-specific|cell-specific|JJ|O loss|loss|NN|O of|of|IN|O alpha3|alpha3|NN|O integrin|integrin|NN|O expression|expression|NN|O .|.|.|O 
These|these|DT|O mice|mouse|NNS|O had|have|VBD|O a|a|DT|O normal|normal|JJ|O acute|acute|JJ|O response|response|NN|O to|to|TO|O bleomycin|bleomycin|NN|O injury|injury|NN|O ,|,|,|O but|but|CC|O they|they|PRP|O exhibited|exhibit|VBD|O markedly|marked|RB|O decreased|decrease|VBN|O accumulation|accumulation|NN|O of|of|IN|O lung|lung|NN|O myofibroblasts|myofibroblast|NNS|O and|and|CC|O type|type|NN|O I|i|CD|O collagen|collagen|NN|O and|and|CC|O did|do|VBD|O not|not|RB|O progress|progress|VB|O to|to|TO|O fibrosis|fibrosis|NN|O .|.|.|O 
Signaling|signaling|NN|O through|through|IN|O beta-catenin|beta-catenin|NN|GENE has|have|VBZ|O been|be|VBN|O implicated|implicate|VBN|O in|in|IN|O EMT|emt|NN|GENE ;|;|:|O we|we|PRP|O found|find|VBD|O that|that|IN|O in|in|IN|O primary|primary|JJ|O AECs|aec|NNS|O ,|,|,|O alpha3|alpha3|NN|O integrin|integrin|NN|O was|be|VBD|O required|require|VBN|O for|for|IN|O beta-catenin|beta-catenin|NN|GENE phosphorylation|phosphorylation|NN|O at|at|IN|O tyrosine|tyrosine|NN|O residue|residue|NN|O 654|654|CD|O (|(|(|O Y654|Y654|NN|O )|)|)|O ,|,|,|O formation|formation|NN|O of|of|IN|O the|the|DT|O pY654-beta-catenin/pSmad2|pY654-beta-catenin/pSmad2|NN|O complex|complex|NN|O ,|,|,|O and|and|CC|O initiation|initiation|NN|O of|of|IN|O EMT|emt|NNP|GENE ,|,|,|O both|both|DT|O in|in|FW|O vitro|vitro|FW|O and|and|CC|O in|in|FW|O vivo|vivo|FW|O during|during|IN|O the|the|DT|O fibrotic|fibrotic|JJ|O phase|phase|NN|O following|follow|VBG|O bleomycin|bleomycin|NN|O injury|injury|NN|O .|.|.|O 
Finally|final|RB|O ,|,|,|O analysis|analysis|NN|O of|of|IN|O lung|lung|NN|O tissue|tissue|NN|O from|from|IN|O IPF|IPF|NN|O patients|patient|NNS|O revealed|reveal|VBD|O the|the|DT|O presence|presence|NN|O of|of|IN|O pY654-beta-catenin/pSmad2|pY654-beta-catenin/pSmad2|NN|O complexes|complex|NNS|O and|and|CC|O showed|show|VBD|O accumulation|accumulation|NN|O of|of|IN|O pY654-beta-catenin|pY654-beta-catenin|NN|O in|in|IN|O myofibroblasts|myofibroblast|NNS|O .|.|.|O 
These|these|DT|O findings|finding|NNS|O demonstrate|demonstrate|VBP|O epithelial|epithelial|JJ|O integrin-dependent|integrin-dependent|JJ|O profibrotic|profibrotic|JJ|O crosstalk|crosstalk|NN|O between|between|IN|O beta-catenin|beta-catenin|NN|GENE and|and|CC|O Smad|SMAD|NN|O signaling|signaling|NN|O and|and|CC|O support|support|VBP|O the|the|DT|O hypothesis|hypothesis|NN|O that|that|IN|O EMT|emt|NN|GENE is|be|VBZ|O an|a|DT|O important|important|JJ|O contributor|contributor|NN|O to|to|TO|O pathologic|pathologic|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Reduced|reduce|VBN|O transcription|transcription|NN|O of|of|IN|O the|the|DT|O Smad4|Smad4|NN|GENE gene|gene|NN|O during|during|IN|O pulmonary|pulmonary|JJ|O carcinogenesis|carcinogenesis|NN|O in|in|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Patients|patient|NNS|O with|with|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O have|have|VBP|O an|a|DT|O increased|increase|VBN|O risk|risk|NN|O of|of|IN|O developing|develop|VBG|O lung|lung|NN|O cancer|cancer|NN|O .|.|.|O 
To|to|TO|O identify|identify|VB|O key|key|JJ|O molecules|molecule|NNS|O involved|involve|VBN|O in|in|IN|O malignant|malignant|JJ|O transformation|transformation|NN|O in|in|IN|O IPF|IPF|NNP|O ,|,|,|O we|we|PRP|O analyzed|analyse|VBD|O the|the|DT|O expression|expression|NN|O profiles|profile|NNS|O of|of|IN|O lung|lung|NN|O and|and|CC|O lung|lung|NN|O tumor|tumor|NN|O tissue|tissue|NN|O from|from|IN|O patients|patient|NNS|O with|with|IN|O lung|lung|NN|O cancer|cancer|NN|O and|and|CC|O IPF|IPF|NN|O (|(|(|O lung|lung|NN|O cancer/IPF|cancer/IPF|NN|O )|)|)|O using|use|VBG|O cDNA|cDNA|NN|O arrays|array|NNS|O and|and|CC|O real-time|real-time|JJ|O quantitative|quantitative|JJ|O reverse|reverse|JJ|O transcriptase-polymerase|transcriptase-polymerase|NN|O chain|chain|NN|O reaction|reaction|NN|O (|(|(|O RT-PCR|rt-pcr|NN|O )|)|)|O .|.|.|O 
Reduced|reduce|VBN|O expression|expression|NN|O of|of|IN|O the|the|DT|O Smad4|Smad4|NN|GENE gene|gene|NN|O was|be|VBD|O identified|identify|VBN|O in|in|IN|O all|all|DT|O eight|eight|CD|O tumor|tumor|NN|O samples|sample|NNS|O from|from|IN|O the|the|DT|O lung|lung|NN|O cancer/IPF|cancer/IPF|NN|O patients|patient|NNS|O using|use|VBG|O real-time|real-time|JJ|O RT-PCR|rt-pcr|NN|O .|.|.|O 
Expression|expression|NN|O levels|level|NNS|O of|of|IN|O Smad4|Smad4|NN|GENE were|be|VBD|O significantly|significant|RB|O lower|low|JJR|O in|in|IN|O tumors|tumor|NNS|O from|from|IN|O lung|lung|NN|O cancer/IPF|cancer/IPF|NN|O patients|patient|NNS|O than|than|IN|O in|in|IN|O those|those|DT|O from|from|IN|O lung|lung|NN|O cancer|cancer|NN|O patients|patient|NNS|O without|without|IN|O IPF|IPF|NN|O or|or|CC|O in|in|IN|O lung|lung|NN|O cancer|cancer|NN|O cell|cell|NN|O lines|line|NNS|O (|(|(|O p|p|NN|O <|<|JJR|O 0.01|0.01|CD|O )|)|)|O .|.|.|O 
Mutational|mutational|JJ|O analysis|analysis|NN|O of|of|IN|O TGF-b|TGF-b|NN|GENE type|type|NN|O II|II|CD|O receptor|receptor|NN|O and|and|CC|O Smad4|Smad4|NN|GENE was|be|VBD|O performed|perform|VBN|O using|use|VBG|O polymerase|polymerase|NN|O chain|chain|NN|O reaction-single|reaction-single|JJ|O strand|strand|NN|O conformation|conformation|NN|O polymorphism|polymorphism|NN|O (|(|(|O PCR-SSCP|PCR-SSCP|NN|O )|)|)|O .|.|.|O 
The|the|DT|O methylation|methylation|NN|O status|status|NN|O of|of|IN|O the|the|DT|O Smad4|Smad4|NN|GENE promoter|promoter|NN|O was|be|VBD|O analyzed|analyse|VBN|O using|use|VBG|O methylation-specific|methylation-specific|JJ|O PCR|pcr|NN|O with|with|IN|O subsequent|subsequent|JJ|O sequence|sequence|NN|O analysis|analysis|NN|O .|.|.|O 
No|no|DT|O mutations|mutation|NNS|O were|be|VBD|O detected|detect|VBN|O in|in|IN|O the|the|DT|O eight|eight|CD|O tumor|tumor|NN|O samples|sample|NNS|O ,|,|,|O but|but|CC|O hypermethylated|hypermethylate|VBN|O regions|region|NNS|O were|be|VBD|O detected|detect|VBN|O in|in|IN|O the|the|DT|O Smad4|Smad4|NN|GENE promoter|promoter|NN|O in|in|IN|O two|two|CD|O of|of|IN|O the|the|DT|O eight|eight|CD|O tumors|tumor|NNS|O with|with|IN|O reduced|reduce|VBN|O Smad4|Smad4|NN|GENE expression|expression|NN|O .|.|.|O 
Promoter|promoter|NN|O reporter|reporter|NN|O assays|assay|NNS|O showed|show|VBD|O that|that|IN|O the|the|DT|O activity|activity|NN|O of|of|IN|O the|the|DT|O Smad4|Smad4|NN|GENE promoter|promoter|NN|O containing|contain|VBG|O the|the|DT|O sequence|sequence|NN|O of|of|IN|O the|the|DT|O methylated|methylate|VBN|O region|region|NN|O was|be|VBD|O significantly|significant|RB|O stronger|strong|JJR|O than|than|IN|O that|that|DT|O of|of|IN|O the|the|DT|O Smad4|Smad4|NN|GENE promoter|promoter|NN|O with|with|IN|O a|a|DT|O deleted|delete|VBN|O methylated|methylate|VBN|O region|region|NN|O (|(|(|O p|p|NN|O <|<|JJR|O 0.002|0.002|CD|O )|)|)|O .|.|.|O 
Our|our|PRP$|O findings|finding|NNS|O indicate|indicate|VBP|O that|that|IN|O the|the|DT|O loss|loss|NN|O of|of|IN|O the|the|DT|O growth|growth|NN|O inhibitory|inhibitory|JJ|O response|response|NN|O to|to|TO|O TGF-b|TGF-b|NN|GENE signaling|signaling|NN|O may|may|MD|O be|be|VB|O crucial|crucial|JJ|O in|in|IN|O pulmonary|pulmonary|JJ|O carcinogensis|carcinogensis|NN|O or|or|CC|O in|in|IN|O the|the|DT|O progression|progression|NN|O of|of|IN|O lung|lung|NN|O cancer|cancer|NN|O in|in|IN|O IPF|IPF|NN|O patients|patient|NNS|O in|in|IN|O whom|who|WP|O TGF-b|TGF-b|NNP|GENE is|be|VBZ|O overexpressed|overexpress|VBN|O ;|;|:|O hypermethylation|hypermethylation|NN|O of|of|IN|O the|the|DT|O Smad4|Smad4|NN|GENE promoter|promoter|NN|O region|region|NN|O may|may|MD|O be|be|VB|O one|one|CD|O mechanism|mechanism|NN|O by|by|IN|O which|which|WDT|O this|this|DT|O occurs|occur|VBZ|O .|.|.|O 
These|these|DT|O findings|finding|NNS|O are|be|VBP|O useful|useful|JJ|O for|for|IN|O the|the|DT|O development|development|NN|O of|of|IN|O preventive|preventive|JJ|O measures|measure|NNS|O or|or|CC|O treatment|treatment|NN|O for|for|IN|O lung|lung|NN|O cancer|cancer|NN|O patients|patient|NNS|O with|with|IN|O IPF|IPF|NN|O .|.|.|O 
Cytokine|cytokine|NN|O gene|gene|NN|O polymorphisms|polymorphism|NNS|O and|and|CC|O BALF|BALF|NN|O cytokine|cytokine|NN|O levels|level|NNS|O in|in|IN|O interstitial|interstitial|JJ|O lung|lung|NN|O diseases|disease|NNS|O .|.|.|O 
BACKGROUND|background|NN|O :|:|:|O The|the|DT|O aim|aim|NN|O of|of|IN|O our|our|PRP$|O study|study|NN|O is|be|VBZ|O to|to|TO|O investigate|investigate|VB|O correlations|correlation|NNS|O of|of|IN|O T|T|NN|O (|(|(|O H|h|NN|O )|)|)|O 1/T|1/T|NN|O (|(|(|O H|h|NN|O )|)|)|O 2|2|CD|O cytokine|cytokine|NN|O gene|gene|NN|O polymorphisms|polymorphism|NNS|O and|and|CC|O bronchoalveolar|bronchoalveolar|JJ|O lavage|lavage|NN|O fluid|fluid|NN|O (|(|(|O BALF|BALF|NN|O )|)|)|O cytokine|cytokine|NN|O values|value|NNS|O in|in|IN|O interstitial|interstitial|JJ|O lung|lung|NN|O diseases|disease|NNS|O (|(|(|O ILD|ild|NNS|O )|)|)|O .|.|.|O 
METHODS|method|NNS|O :|:|:|O In|in|IN|O 16|16|CD|O sarcoidosis|sarcoidosis|NN|O ,|,|,|O 7|7|CD|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O and|and|CC|O 8|8|CD|O hypersensitivity|hypersensitivity|NN|O pneumonitis|pneumonitis|NN|O (|(|(|O HP|hp|NNP|O )|)|)|O patients|patient|NNS|O we|we|PRP|O evaluated|evaluate|VBD|O IL-1|IL-1|NN|O alpha|alpha|NN|O ,|,|,|O -1|-1|CD|O R|r|NN|O ,|,|,|O -1|-1|CD|O RA|ra|NN|O ,|,|,|O -2|-2|CD|O ,|,|,|O -4|-4|CD|O ,|,|,|O -4|-4|CD|O R|r|NN|O alpha|alpha|NN|O ,|,|,|O -6|-6|CD|O ,|,|,|O -10|-10|CD|O ,|,|,|O -12|-12|CD|O ,|,|,|O IFN-gamma|IFN-gamma|NN|GENE ,|,|,|O TGF-beta1|TGF-beta1|NN|GENE and|and|CC|O TNF-alpha|TNF-alpha|NN|GENE gene|gene|NN|O polymorphisms|polymorphism|NNS|O in|in|IN|O peripheral|peripheral|JJ|O blood|blood|NN|O ,|,|,|O and|and|CC|O MCP-1|MCP-1|NN|GENE ,|,|,|O MIP-1|MIP-1|NN|O alpha|alpha|NN|O ,|,|,|O MIP-1|MIP-1|NN|O beta|beta|NN|O ,|,|,|O RANTES|RANTES|NN|GENE ,|,|,|O ENA-78|ENA-78|NN|O ,|,|,|O FGF|FGF|NN|O ,|,|,|O G-CSF|G-CSF|NN|O ,|,|,|O GM-CSF|gm-csf|NN|O ,|,|,|O IFN-gamma|IFN-gamma|NN|GENE ,|,|,|O IL-1|IL-1|NN|O alpha|alpha|NN|O ,|,|,|O IL-1RA|IL-1RA|NN|O ,|,|,|O IL-1|IL-1|NN|O beta|beta|NN|O ,|,|,|O -2|-2|CD|O ,|,|,|O -4|-4|CD|O ,|,|,|O -5|-5|CD|O ,|,|,|O -6|-6|CD|O ,|,|,|O -8|-8|CD|O ,|,|,|O -10|-10|CD|O ,|,|,|O -17|-17|CD|O ,|,|,|O TNF-alpha|TNF-alpha|NN|GENE ,|,|,|O Tpo|tpo|NN|O and|and|CC|O VEGF|vegf|NN|GENE values|value|NNS|O in|in|IN|O BALF|BALF|NN|O .|.|.|O 
RESULTS|result|NNS|O :|:|:|O We|we|PRP|O found|find|VBD|O higher|high|JJR|O TNF-alpha|TNF-alpha|NN|GENE values|value|NNS|O in|in|IN|O IL-1R|IL-1R|NN|O pst|pst|NN|O 1970|1970|CD|O TT|tt|NN|O homozygotes|homozygote|NNS|O regardless|regardless|RB|O of|of|IN|O diagnosis|diagnosis|NN|O (|(|(|O p|p|NN|O =|=|JJ|O 0.0126|0.0126|CD|O )|)|)|O .|.|.|O 
In|in|IN|O the|the|DT|O sarcoidosis|sarcoidosis|NN|O group|group|NN|O IL-4R|IL-4R|NN|O alpha|alpha|NN|O (|(|(|O +1902|+1902|CD|O )|)|)|O AA|aa|NN|O and|and|CC|O IL-10|IL-10|NN|GENE (|(|(|O -1082|-1082|CD|O )|)|)|O G|g|NN|O allele|allele|NN|O correlated|correlate|VBD|O with|with|IN|O higher|high|JJR|O BALF|BALF|NN|O ENA-78|ENA-78|NN|O levels|level|NNS|O (|(|(|O p|p|NN|O =|=|JJ|O 0.0258|0.0258|CD|O ,|,|,|O p|p|NN|O =|=|JJ|O 0.0230|0.0230|CD|O )|)|)|O .|.|.|O 
In|in|IN|O the|the|DT|O HP|hp|NNP|O group|group|NN|O the|the|DT|O IL-6|IL-6|NN|GENE (|(|(|O -174|-174|CD|O )|)|)|O CG|cg|NN|O and|and|CC|O IL-6|IL-6|NN|GENE (|(|(|O nt565|nt565|NN|O )|)|)|O AG|ag|NNP|O correlated|correlate|VBD|O with|with|IN|O higher|high|JJR|O ENA-78|ENA-78|NN|O BALF|BALF|NN|O levels|level|NNS|O (|(|(|O p|p|NN|O =|=|JJ|O 0.0253|0.0253|CD|O )|)|)|O .|.|.|O 
In|in|IN|O the|the|DT|O IPF|IPF|NN|O group|group|NN|O the|the|DT|O IL-1|IL-1|NN|O beta|beta|NN|O +3962|+3962|CD|O CC|cc|NN|O homozygotes|homozygote|NNS|O had|have|VBD|O lower|low|JJR|O IL-1RA|IL-1RA|NN|O BALF|BALF|NN|O values|value|NNS|O (|(|(|O p|p|NN|O =|=|JJ|O 0.046|0.046|CD|O )|)|)|O .|.|.|O 
BALF|BALF|NN|O chemokine|chemokine|NN|O values|value|NNS|O did|do|VBD|O not|not|RB|O differ|differ|VB|O between|between|IN|O ILD|ILD|NNP|O subgroups|subgroup|NNS|O ,|,|,|O except|except|IN|O for|for|IN|O IL-8|IL-8|NN|GENE ,|,|,|O which|which|WDT|O was|be|VBD|O higher|high|JJR|O in|in|IN|O stage|stage|NN|O III|III|CD|O sarcoidosis|sarcoidosis|NN|O patients|patient|NNS|O compared|compare|VBN|O to|to|TO|O stage|stage|NN|O I.|I.|NN|O CONCLUSION|conclusion|NN|O :|:|:|O Our|our|PRP$|O results|result|NNS|O show|show|VBP|O a|a|DT|O probable|probable|JJ|O influence|influence|NN|O of|of|IN|O gene|gene|NN|O polymorphisms|polymorphism|NNS|O ,|,|,|O namely|namely|RB|O IL-4R|IL-4R|NN|O alpha|alpha|NN|O and|and|CC|O IL-10|IL-10|NN|GENE on|on|IN|O ENA-78|ENA-78|NN|O BALF|BALF|NN|O levels|level|NNS|O in|in|IN|O sarcoidosis|sarcoidosis|NN|O ,|,|,|O IL-6|IL-6|NN|GENE on|on|IN|O ENA-78|ENA-78|NN|O BALF|BALF|NN|O levels|level|NNS|O in|in|IN|O HP|hp|NNP|O and|and|CC|O IL-1-beta|IL-1-beta|NN|O on|on|IN|O IL-1RA|IL-1RA|NN|O BALF|BALF|NN|O values|value|NNS|O in|in|IN|O the|the|DT|O IPF|IPF|NN|O group|group|NN|O .|.|.|O 
The|the|DT|O TNF-alpha|TNF-alpha|NN|GENE BALF|BALF|NN|O values|value|NNS|O correlated|correlate|VBD|O with|with|IN|O IL-1R|IL-1R|NN|O pst|pst|NN|O 1970|1970|CD|O gene|gene|NN|O polymorphisms|polymorphism|NNS|O .|.|.|O 
Pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O :|:|:|O pathogenesis|pathogenesis|NN|O ,|,|,|O etiology|etiology|NN|O and|and|CC|O regulation|regulation|NN|O .|.|.|O 
Pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O and|and|CC|O architectural|architectural|JJ|O remodeling|remodeling|NN|O of|of|IN|O tissues|tissue|NNS|O can|can|MD|O severely|severe|RB|O disrupt|disrupt|VB|O lung|lung|NN|O function|function|NN|O ,|,|,|O often|often|RB|O with|with|IN|O fatal|fatal|JJ|O consequences|consequence|NNS|O .|.|.|O 
The|the|DT|O etiology|etiology|NN|O of|of|IN|O pulmonary|pulmonary|JJ|O fibrotic|fibrotic|JJ|O diseases|disease|NNS|O is|be|VBZ|O varied|vary|VBN|O ,|,|,|O with|with|IN|O an|a|DT|O array|array|NN|O of|of|IN|O triggers|trigger|NNS|O including|include|VBG|O allergens|allergen|NNS|O ,|,|,|O chemicals|chemical|NNS|O ,|,|,|O radiation|radiation|NN|O and|and|CC|O environmental|environmental|JJ|O particles|particle|NNS|O .|.|.|O 
However|however|RB|O ,|,|,|O the|the|DT|O cause|cause|NN|O of|of|IN|O one|one|CD|O of|of|IN|O the|the|DT|O most|much|RBS|O common|common|JJ|O pulmonary|pulmonary|JJ|O fibrotic|fibrotic|JJ|O conditions|condition|NNS|O ,|,|,|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O ,|,|,|O is|be|VBZ|O still|still|RB|O unclear|unclear|JJ|O .|.|.|O 
This|this|DT|O review|review|NN|O examines|examine|VBZ|O common|common|JJ|O mechanisms|mechanism|NNS|O of|of|IN|O pulmonary|pulmonary|JJ|O wound-healing|wound-healing|JJ|O responses|response|NNS|O following|follow|VBG|O lung|lung|NN|O injury|injury|NN|O ,|,|,|O and|and|CC|O highlights|highlight|VBZ|O the|the|DT|O pathogenesis|pathogenesis|NN|O of|of|IN|O some|some|DT|O of|of|IN|O the|the|DT|O most|much|RBS|O widespread|widespread|JJ|O pulmonary|pulmonary|JJ|O fibrotic|fibrotic|JJ|O diseases|disease|NNS|O .|.|.|O 
A|a|DT|O three|three|CD|O phase|phase|NN|O model|model|NN|O of|of|IN|O wound|wound|NN|O repair|repair|NN|O is|be|VBZ|O reviewed|review|VBN|O that|that|IN|O includes|include|VBZ|O ;|;|:|O (|(|(|O 1|1|LS|O )|)|)|O injury|injury|NN|O ;|;|:|O (|(|(|O 2|2|LS|O )|)|)|O inflammation|inflammation|NN|O ;|;|:|O and|and|CC|O (|(|(|O 3|3|LS|O )|)|)|O repair|repair|NN|O .|.|.|O 
In|in|IN|O most|many|JJS|O pulmonary|pulmonary|JJ|O fibrotic|fibrotic|JJ|O conditions|condition|NNS|O dysregulation|dysregulation|NN|O at|at|IN|O one|one|CD|O or|or|CC|O more|many|JJR|O of|of|IN|O these|these|DT|O phases|phase|NNS|O has|have|VBZ|O been|be|VBN|O reported|report|VBN|O .|.|.|O 
Chronic|chronic|JJ|O inflammation|inflammation|NN|O can|can|MD|O lead|lead|VB|O to|to|TO|O an|a|DT|O imbalance|imbalance|NN|O in|in|IN|O the|the|DT|O production|production|NN|O of|of|IN|O chemokines|chemokine|NNS|O ,|,|,|O cytokines|cytokine|NNS|O ,|,|,|O growth|growth|NN|O factors|factor|NNS|O ,|,|,|O and|and|CC|O disrupt|disrupt|VB|O cellular|cellular|JJ|O recruitment|recruitment|NN|O .|.|.|O 
These|these|DT|O changes|change|NNS|O coupled|couple|VBN|O with|with|IN|O excessive|excessive|JJ|O pro-fibrotic|pro-fibrotic|JJ|O IL-13|IL-13|NN|GENE and/or|and/or|CC|O TGFbeta1|TGFbeta1|NN|GENE production|production|NN|O can|can|MD|O turn|turn|VB|O a|a|DT|O well-controlled|well-controlled|JJ|O healing|healing|NN|O response|response|NN|O into|into|IN|O a|a|DT|O pathogenic|pathogenic|JJ|O fibrotic|fibrotic|JJ|O response|response|NN|O .|.|.|O 
Endogenous|endogenous|JJ|O regulatory|regulatory|JJ|O mechanisms|mechanism|NNS|O are|be|VBP|O discussed|discuss|VBN|O including|include|VBG|O novel|novel|JJ|O areas|area|NNS|O of|of|IN|O therapeutic|therapeutic|JJ|O intervention|intervention|NN|O .|.|.|O 
Restoring|restore|VBG|O homeostasis|homeostasis|NN|O to|to|TO|O these|these|DT|O dysregulated|dysregulate|VBN|O healing|healing|NN|O responses|response|NNS|O ,|,|,|O or|or|CC|O simply|simple|RB|O neutralizing|neutralize|VBG|O the|the|DT|O key|key|JJ|O pro-fibrotic|pro-fibrotic|JJ|O mediators|mediator|NNS|O may|may|MD|O prevent|prevent|VB|O or|or|CC|O slow|slow|VB|O the|the|DT|O progression|progression|NN|O of|of|IN|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Recent|recent|JJ|O advances|advance|NNS|O in|in|IN|O molecular|molecular|JJ|O targets|target|NNS|O and|and|CC|O treatment|treatment|NN|O of|of|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O :|:|:|O focus|focus|VB|O on|on|IN|O TGFbeta|TGFbeta|NN|GENE signaling|signaling|NN|O and|and|CC|O the|the|DT|O myofibroblast|myofibroblast|NN|O .|.|.|O 
Idiopathic|idiopathic|JJ|O Pulmonary|pulmonary|JJ|O Fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O characterized|characterize|VBN|O by|by|IN|O injury|injury|NN|O and|and|CC|O loss|loss|NN|O of|of|IN|O lung|lung|NN|O epithelial|epithelial|JJ|O cells|cell|NNS|O ,|,|,|O accumulation|accumulation|NN|O of|of|IN|O fibroblasts/myofibroblasts|fibroblasts/myofibroblasts|NNS|O and|and|CC|O abnormal|abnormal|JJ|O remodeling|remodeling|NN|O of|of|IN|O the|the|DT|O lung|lung|NN|O parenchyma|parenchyma|NN|O .|.|.|O 
The|the|DT|O prognosis|prognosis|NN|O for|for|IN|O IPF|IPF|NN|O patients|patient|NNS|O is|be|VBZ|O poor|poor|JJ|O and|and|CC|O current|current|JJ|O therapies|therapy|NNS|O are|be|VBP|O largely|large|RB|O ineffective|ineffective|JJ|O in|in|IN|O preventing|prevent|VBG|O respiratory|respiratory|JJ|O failure|failure|NN|O .|.|.|O 
Current|current|JJ|O therapeutic|therapeutic|JJ|O approaches|approach|NNS|O target|target|VBP|O epithelial|epithelial|JJ|O cell|cell|NN|O replacement|replacement|NN|O ,|,|,|O manipulation|manipulation|NN|O of|of|IN|O fibroblasts/myofibroblasts|fibroblasts/myofibroblasts|NNS|O ,|,|,|O modulation|modulation|NN|O of|of|IN|O procoagulant/fibrinolytic|procoagulant/fibrinolytic|JJ|O activities|activity|NNS|O ,|,|,|O cytokine|cytokine|NN|O and|and|CC|O growth|growth|NN|O factor|factor|NN|O production|production|NN|O ,|,|,|O angiogenesis|angiogenesis|NN|O ,|,|,|O and|and|CC|O reduction|reduction|NN|O of|of|IN|O oxidative|oxidative|JJ|O stress|stress|NN|O .|.|.|O 
Myofibroblasts|myofibroblast|NNS|O are|be|VBP|O the|the|DT|O primary|primary|JJ|O effector|effector|NN|O cells|cell|NNS|O in|in|IN|O fibrosis|fibrosis|NN|O .|.|.|O 
These|these|DT|O cells|cell|NNS|O may|may|MD|O be|be|VB|O derived|derive|VBN|O by|by|IN|O the|the|DT|O activation|activation|NN|O and|and|CC|O proliferation|proliferation|NN|O of|of|IN|O resident|resident|JJ|O lung|lung|NN|O fibroblasts|fibroblast|NNS|O ,|,|,|O from|from|IN|O epithelial-mesenchymal|epithelial-mesenchymal|JJ|O transition|transition|NN|O (|(|(|O EMT|emt|NN|GENE )|)|)|O ,|,|,|O or|or|CC|O through|through|IN|O recruitment|recruitment|NN|O of|of|IN|O circulating|circulate|VBG|O fibrocytes|fibrocyte|NNS|O .|.|.|O 
Transforming|Transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta|beta|NN|GENE (|(|(|O TGFbeta|TGFbeta|NN|GENE )|)|)|O is|be|VBZ|O a|a|DT|O profibrotic|profibrotic|JJ|O factor|factor|NN|O that|that|WDT|O increases|increase|VBZ|O fibroblast|fibroblast|NN|O proliferation|proliferation|NN|O ,|,|,|O stimulates|stimulate|VBZ|O the|the|DT|O synthesis|synthesis|NN|O and|and|CC|O deposition|deposition|NN|O of|of|IN|O connective|connective|JJ|O tissue|tissue|NN|O ,|,|,|O and|and|CC|O inhibits|inhibit|VBZ|O connective|connective|JJ|O tissue|tissue|NN|O breakdown|breakdown|NN|O .|.|.|O 
TGFbeta|TGFbeta|NN|GENE acts|act|VBZ|O through|through|IN|O the|the|DT|O promoter|promoter|NN|O of|of|IN|O the|the|DT|O type|type|NN|O 1|1|CD|O collagen|collagen|NN|O gene|gene|NN|O causing|cause|VBG|O increased|increase|VBN|O collagen|collagen|NN|O synthesis|synthesis|NN|O .|.|.|O 
In|in|IN|O addition|addition|NN|O ,|,|,|O TGFbeta|TGFbeta|NN|GENE induces|induce|VBZ|O EMT|emt|NNP|GENE in|in|IN|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O (|(|(|O AECs|aec|NNS|O )|)|)|O in|in|FW|O vitro|vitro|FW|O and|and|CC|O in|in|FW|O vivo|vivo|FW|O .|.|.|O 
AECs|aec|NNS|O exhibit|exhibit|VBP|O substantial|substantial|JJ|O plasticity|plasticity|NN|O and|and|CC|O may|may|MD|O serve|serve|VB|O as|as|IN|O a|a|DT|O source|source|NN|O of|of|IN|O fibroblasts|fibroblast|NNS|O and/or|and/or|CC|O myofibroblasts|myofibroblast|NNS|O in|in|IN|O lung|lung|NN|O fibrosis|fibrosis|NN|O .|.|.|O 
Therapeutic|therapeutic|JJ|O interventions|intervention|NNS|O interfering|interfere|VBG|O with|with|IN|O the|the|DT|O pathways|pathway|NNS|O that|that|WDT|O lead|lead|VBP|O to|to|TO|O myofibroblast|myofibroblast|JJ|O expansion|expansion|NN|O and|and|CC|O AEC|aec|NN|O apoptosis|apoptosis|NN|O should|shall|MD|O be|be|VB|O of|of|IN|O considerable|considerable|JJ|O benefit|benefit|NN|O in|in|IN|O the|the|DT|O treatment|treatment|NN|O of|of|IN|O IPF|IPF|NN|O .|.|.|O 
This|this|DT|O review|review|NN|O will|will|MD|O focus|focus|VB|O on|on|IN|O the|the|DT|O critical|critical|JJ|O role|role|NN|O of|of|IN|O TGFbeta|TGFbeta|NN|GENE on|on|IN|O AECs|aec|NNS|O EMT|emt|NN|GENE and|and|CC|O myofibroblasts|myofibroblast|NNS|O in|in|IN|O the|the|DT|O development|development|NN|O of|of|IN|O fibrosis|fibrosis|NN|O .|.|.|O 
CUX1/Wnt|CUX1/Wnt|NN|O signaling|signaling|NN|O regulates|regulate|VBZ|O epithelial|epithelial|JJ|O mesenchymal|mesenchymal|JJ|O transition|transition|NN|O in|in|IN|O EBV|EBV|NN|O infected|infected|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O refractory|refractory|JJ|O and|and|CC|O lethal|lethal|JJ|O interstitial|interstitial|JJ|O lung|lung|NN|O disease|disease|NN|O characterized|characterize|VBN|O by|by|IN|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O apoptosis|apoptosis|NN|O ,|,|,|O fibroblast|fibroblast|NN|O proliferation|proliferation|NN|O and|and|CC|O extra-cellular|extra-cellular|JJ|O matrix|matrix|NN|O protein|protein|NN|O deposition|deposition|NN|O .|.|.|O 
EBV|EBV|NN|O ,|,|,|O localised|localised|JJ|O to|to|TO|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O of|of|IN|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O patients|patient|NNS|O is|be|VBZ|O associated|associate|VBN|O with|with|IN|O a|a|DT|O poor|poor|JJ|O prognosis|prognosis|NN|O .|.|.|O 
A|a|DT|O strategy|strategy|NN|O based|base|VBN|O on|on|IN|O microarray-differential|microarray-differential|JJ|O gene|gene|NN|O expression|expression|NN|O analysis|analysis|NN|O to|to|TO|O identify|identify|VB|O molecular|molecular|JJ|O drivers|driver|NNS|O of|of|IN|O EBV-associated|ebv-associated|JJ|O lung|lung|NN|O fibrosis|fibrosis|NN|O was|be|VBD|O utilized|utilize|VBN|O .|.|.|O 
Alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O were|be|VBD|O infected|infect|VBN|O with|with|IN|O EBV|EBV|NN|O to|to|TO|O identify|identify|VB|O genes|gene|NNS|O whose|who|WP$|O expression|expression|NN|O was|be|VBD|O altered|alter|VBN|O following|follow|VBG|O TGFbeta1-mediated|tgfbeta1-mediated|JJ|O lytic|lytic|JJ|O phase|phase|NN|O .|.|.|O 
EBV|EBV|NN|O lytic|lytic|JJ|O reactivation|reactivation|NN|O by|by|IN|O TGFbeta1|TGFbeta1|NN|GENE drives|drive|VBZ|O a|a|DT|O selective|selective|JJ|O alteration|alteration|NN|O in|in|IN|O CUX1|CUX1|NN|GENE variant|variant|NN|O (|(|(|O a|a|DT|O )|)|)|O (|(|(|O NCBI|NCBI|NN|O accession|accession|NN|O number|number|NN|O NM|NN|181552|O )|)|)|O expression|expression|NN|O ,|,|,|O inducing|induce|VBG|O activation|activation|NN|O of|of|IN|O non-canonical|non-canonical|JJ|O Wnt|Wnt|NN|O pathway|pathway|NN|O mediators|mediator|NNS|O ,|,|,|O implicating|implicate|VBG|O it|it|PRP|O in|in|IN|O Epithelial|epithelial|JJ|O Mesenchymal|mesenchymal|JJ|O Transition|transition|NN|O (|(|(|O EMT|emt|NN|GENE )|)|)|O ,|,|,|O the|the|DT|O molecular|molecular|JJ|O event|event|NN|O underpinning|underpinning|NN|O scar|scar|NN|O production|production|NN|O in|in|IN|O tissue|tissue|NN|O fibrosis|fibrosis|NN|O .|.|.|O 
The|the|DT|O role|role|NN|O of|of|IN|O EBV|EBV|NN|O in|in|IN|O EMT|emt|NNP|GENE can|can|MD|O be|be|VB|O attenuated|attenuate|VBN|O by|by|IN|O antiviral|antiviral|JJ|O strategies|strategy|NNS|O and|and|CC|O inhibition|inhibition|NN|O of|of|IN|O Wnt|Wnt|NN|O signaling|signaling|NN|O by|by|IN|O using|use|VBG|O All-Trans|All-Trans|NNP|O Retinoic|retinoic|JJ|O Acids|acid|NNS|O (|(|(|O ATRA|ATRA|NN|O )|)|)|O .|.|.|O 
Activation|activation|NN|O of|of|IN|O non-canonical|non-canonical|JJ|O Wnt|Wnt|NN|O signaling|signaling|NN|O pathway|pathway|NN|O by|by|IN|O EBV|EBV|NN|O in|in|IN|O epithelial|epithelial|JJ|O cells|cell|NNS|O suggests|suggest|VBZ|O a|a|DT|O novel|novel|JJ|O mechanism|mechanism|NN|O of|of|IN|O EMT|emt|NNP|GENE via|via|IN|O CUX1|CUX1|NN|GENE signaling|signaling|NN|O .|.|.|O 
These|these|DT|O data|datum|NNS|O present|present|VBP|O a|a|DT|O framework|framework|NN|O for|for|IN|O further|further|JJ|O description|description|NN|O of|of|IN|O the|the|DT|O link|link|NN|O between|between|IN|O infectious|infectious|JJ|O agents|agent|NNS|O and|and|CC|O fibrosis|fibrosis|NN|O ,|,|,|O a|a|DT|O significant|significant|JJ|O disease|disease|NN|O burden|burden|NN|O .|.|.|O 
VEGF|vegf|NN|GENE ameliorates|ameliorate|VBZ|O pulmonary|pulmonary|JJ|O hypertension|hypertension|NN|O through|through|IN|O inhibition|inhibition|NN|O of|of|IN|O endothelial|endothelial|JJ|O apoptosis|apoptosis|NN|O in|in|IN|O experimental|experimental|JJ|O lung|lung|NN|O fibrosis|fibrosis|NN|O in|in|IN|O rats|rat|NNS|O .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O can|can|MD|O lead|lead|VB|O to|to|TO|O the|the|DT|O development|development|NN|O of|of|IN|O secondary|secondary|JJ|O pulmonary|pulmonary|JJ|O hypertension|hypertension|NN|O (|(|(|O PH|ph|NN|O )|)|)|O and|and|CC|O ultimately|ultimate|RB|O death|death|NN|O .|.|.|O 
Despite|despite|IN|O this|this|DT|O known|known|JJ|O association|association|NN|O ,|,|,|O the|the|DT|O precise|precise|JJ|O mechanism|mechanism|NN|O of|of|IN|O disease|disease|NN|O remains|remain|VBZ|O unknown|unknown|JJ|O .|.|.|O 
Using|use|VBG|O a|a|DT|O rat|rat|NN|O model|model|NN|O of|of|IN|O IPF|IPF|NN|O ,|,|,|O we|we|PRP|O explored|explore|VBD|O the|the|DT|O role|role|NN|O of|of|IN|O the|the|DT|O proangiogenic|proangiogenic|JJ|O and|and|CC|O antiapoptotic|antiapoptotic|JJ|O growth|growth|NN|O factor|factor|NN|O VEGF|vegf|NN|GENE in|in|IN|O the|the|DT|O vascular|vascular|JJ|O remodeling|remodeling|NN|O that|that|WDT|O underlies|underlie|VBZ|O PH.|PH.|NNP|O In|in|IN|O this|this|DT|O model|model|NN|O ,|,|,|O adenoviral|adenoviral|JJ|O delivery|delivery|NN|O of|of|IN|O active|active|JJ|O TGF-beta1|TGF-beta1|NN|GENE induces|induce|VBZ|O pulmonary|pulmonary|JJ|O arterial|arterial|JJ|O remodeling|remodeling|NN|O ,|,|,|O loss|loss|NN|O of|of|IN|O the|the|DT|O microvasculature|microvasculature|NN|O in|in|IN|O fibrotic|fibrotic|JJ|O areas|area|NNS|O ,|,|,|O and|and|CC|O increased|increase|VBD|O pulmonary|pulmonary|JJ|O arterial|arterial|JJ|O pressure|pressure|NN|O (|(|(|O PAP|pap|NNP|O )|)|)|O .|.|.|O 
Immunohistochemistry|immunohistochemistry|NN|O and|and|CC|O mRNA|mRNA|NN|O analysis|analysis|NN|O revealed|reveal|VBD|O decreased|decrease|VBN|O levels|level|NNS|O of|of|IN|O VEGF|vegf|NN|GENE and|and|CC|O its|its|PRP$|O receptor|receptor|NN|O ,|,|,|O which|which|WDT|O were|be|VBD|O inversely|inverse|RB|O correlated|correlate|VBN|O with|with|IN|O PAP|pap|NNP|O and|and|CC|O endothelial|endothelial|JJ|O cell|cell|NN|O apoptosis|apoptosis|NN|O in|in|IN|O both|both|CC|O the|the|DT|O micro|micro|JJ|O -|-|:|O and|and|CC|O macrovasculature|macrovasculature|NN|O .|.|.|O 
Treatment|treatment|NN|O of|of|IN|O IPF|IPF|NNP|O rats|rat|NNS|O with|with|IN|O adenoviral|adenoviral|JJ|O delivery|delivery|NN|O of|of|IN|O VEGF|vegf|NN|GENE resulted|result|VBD|O in|in|IN|O reduced|reduce|VBN|O endothelial|endothelial|JJ|O apoptosis|apoptosis|NN|O ,|,|,|O increased|increase|VBD|O vascularization|vascularization|NN|O ,|,|,|O and|and|CC|O improved|improve|VBD|O PAP|pap|NNP|O due|due|JJ|O to|to|TO|O reduced|reduce|VBN|O remodeling|remodeling|NN|O but|but|CC|O worsened|worsen|VBD|O PF|pf|NN|O .|.|.|O 
These|these|DT|O data|datum|NNS|O show|show|VBP|O that|that|IN|O experimental|experimental|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O PF|pf|NN|O )|)|)|O leads|lead|VBZ|O to|to|TO|O loss|loss|NN|O of|of|IN|O the|the|DT|O microvasculature|microvasculature|NN|O through|through|IN|O increased|increase|VBN|O apoptosis|apoptosis|NN|O and|and|CC|O to|to|TO|O remodeling|remodeling|NN|O of|of|IN|O the|the|DT|O pulmonary|pulmonary|JJ|O arteries|artery|NNS|O ,|,|,|O with|with|IN|O both|both|DT|O processes|process|NNS|O resulting|result|VBG|O in|in|IN|O PH.|PH.|NNP|O As|as|IN|O administration|administration|NN|O of|of|IN|O VEGF|vegf|NN|GENE ameliorated|ameliorate|VBD|O the|the|DT|O PH|ph|NN|O in|in|IN|O this|this|DT|O model|model|NN|O but|but|CC|O concomitantly|concomitant|RB|O aggravated|aggravate|VBD|O the|the|DT|O fibrogenic|fibrogenic|JJ|O process|process|NN|O ,|,|,|O VEGF-based|vegf-based|JJ|O therapies|therapy|NNS|O should|shall|MD|O be|be|VB|O used|use|VBN|O with|with|IN|O caution|caution|NN|O .|.|.|O 
N-acetyl-L-cysteine|N-acetyl-L-cysteine|NN|O inhibits|inhibit|VBZ|O TGF-beta1-induced|tgf-beta1-induced|JJ|O profibrotic|profibrotic|JJ|O responses|response|NNS|O in|in|IN|O fibroblasts|fibroblast|NNS|O .|.|.|O 
BACKGROUND|background|NN|O :|:|:|O Excessive|excessive|JJ|O production|production|NN|O of|of|IN|O TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O plays|play|VBZ|O a|a|DT|O key|key|JJ|O role|role|NN|O in|in|IN|O the|the|DT|O tissue|tissue|NN|O remodeling|remodeling|NN|O or|or|CC|O fibrotic|fibrotic|JJ|O process|process|NN|O observed|observe|VBN|O in|in|IN|O bronchial|bronchial|JJ|O asthma|asthma|NN|O ,|,|,|O chronic|chronic|JJ|O pulmonary|pulmonary|JJ|O disease|disease|NN|O (|(|(|O COPD|copd|NN|O )|)|)|O ,|,|,|O and|and|CC|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O .|.|.|O 
TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O has|have|VBZ|O been|be|VBN|O reported|report|VBN|O to|to|TO|O decrease|decrease|VB|O the|the|DT|O intracellular|intracellular|JJ|O glutathione|glutathione|NN|O level|level|NN|O and|and|CC|O stimulate|stimulate|VBP|O the|the|DT|O production|production|NN|O of|of|IN|O reactive|reactive|JJ|O oxygen|oxygen|NN|O species|specie|NNS|O .|.|.|O 
OBJECTIVES|objective|NNS|O :|:|:|O The|the|DT|O aim|aim|NN|O of|of|IN|O this|this|DT|O study|study|NN|O was|be|VBD|O to|to|TO|O evaluate|evaluate|VB|O whether|whether|IN|O the|the|DT|O antioxidant|antioxidant|JJ|O N-acetyl-l-cysteine|N-acetyl-l-cysteine|NN|O (|(|(|O NAC|nac|NN|O )|)|)|O can|can|MD|O affect|affect|VB|O TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O -|-|:|O mediated|mediate|VBN|O tissue|tissue|NN|O remodeling|remodeling|NN|O in|in|IN|O fibroblasts|fibroblast|NNS|O or|or|CC|O modulate|modulate|VB|O the|the|DT|O production|production|NN|O of|of|IN|O fibronectin|fibronectin|NN|GENE and|and|CC|O vascular|vascular|NN|GENE endothelial|endothelial|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE (|(|(|O VEGF|vegf|NN|GENE )|)|)|O which|which|WDT|O are|be|VBP|O believed|believe|VBN|O to|to|TO|O be|be|VB|O important|important|JJ|O mediators|mediator|NNS|O of|of|IN|O tissue|tissue|NN|O repair|repair|NN|O and|and|CC|O remodeling|remodeling|NN|O .|.|.|O 
METHODS|method|NNS|O :|:|:|O To|to|TO|O accomplish|accomplish|VB|O this|this|DT|O ,|,|,|O human|human|JJ|O fetal|fetal|JJ|O lung|lung|NN|O fibroblasts|fibroblast|NNS|O (|(|(|O HFL-1|HFL-1|NN|O )|)|)|O were|be|VBD|O used|use|VBN|O to|to|TO|O assess|assess|VB|O the|the|DT|O effect|effect|NN|O of|of|IN|O NAC|nac|NN|O on|on|IN|O the|the|DT|O TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O -|-|:|O mediated|mediate|VBN|O contraction|contraction|NN|O of|of|IN|O floating|float|VBG|O gels|gel|NNS|O and|and|CC|O the|the|DT|O TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O -|-|:|O induced|induce|VBN|O mediator|mediator|NN|O production|production|NN|O .|.|.|O 
In|in|IN|O addition|addition|NN|O ,|,|,|O the|the|DT|O effect|effect|NN|O of|of|IN|O NAC|nac|NN|O on|on|IN|O the|the|DT|O TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O -|-|:|O induced|induce|VBD|O differentiation|differentiation|NN|O to|to|TO|O myofibroblasts|myofibroblast|NNS|O was|be|VBD|O evaluated|evaluate|VBN|O by|by|IN|O assessing|assess|VBG|O alpha-smooth-muscle-actin|alpha-smooth-muscle-actin|NN|GENE (|(|(|O alpha-SMA|alpha-SMA|NN|GENE )|)|)|O expression|expression|NN|O .|.|.|O 
RESULTS|result|NNS|O :|:|:|O NAC|nac|NN|O significantly|significant|RB|O abolished|abolish|VBD|O the|the|DT|O TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O -|-|:|O augmented|augment|VBD|O gel|gel|NN|O contraction|contraction|NN|O (|(|(|O at|at|IN|O 3mM|3mM|NN|O ,|,|,|O gel|gel|NN|O size|size|NN|O 63.4|63.4|CD|O +|+|CC|O /|/|:|O -2.6|-2.6|CD|O %|%|NN|O vs.|vs.|CC|O 39.1|39.1|CD|O +|+|CC|O /|/|:|O -4.1|-4.1|CD|O %|%|NN|O ;|;|:|O p|p|NN|O <|<|JJR|O 0.01|0.01|CD|O )|)|)|O compared|compare|VBN|O with|with|IN|O control|control|NN|O in|in|IN|O a|a|DT|O concentration-dependent|concentration-dependent|JJ|O manner|manner|NN|O .|.|.|O 
NAC|nac|NN|O also|also|RB|O significantly|significant|RB|O inhibited|inhibit|VBD|O the|the|DT|O TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O -|-|:|O augmented|augment|VBD|O fibronectin|fibronectin|NN|GENE (|(|(|O p|p|NN|O <|<|JJR|O 0.01|0.01|CD|O )|)|)|O and|and|CC|O VEGF|vegf|NN|GENE (|(|(|O p|p|NN|O <|<|JJR|O 0.01|0.01|CD|O )|)|)|O production|production|NN|O in|in|IN|O the|the|DT|O media|medium|NNS|O of|of|IN|O both|both|CC|O the|the|DT|O three-dimensional|three-dimensional|JJ|O gel|gel|NN|O and|and|CC|O monolayer|monolayer|NN|O culture|culture|NN|O .|.|.|O 
Furthermore|furthermore|RB|O ,|,|,|O NAC|nac|NN|O reversed|reverse|VBD|O the|the|DT|O TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O -|-|:|O stimulated|stimulate|VBN|O alpha-SMA|alpha-SMA|NN|GENE expression|expression|NN|O (|(|(|O p|p|NN|O <|<|JJR|O 0.01|0.01|CD|O )|)|)|O .|.|.|O 
CONCLUSION|conclusion|NN|O :|:|:|O These|these|DT|O results|result|NNS|O suggest|suggest|VBP|O that|that|IN|O NAC|nac|NN|O can|can|MD|O affect|affect|VB|O the|the|DT|O TGF-beta|TGF-beta|NN|GENE (|(|(|O 1|1|CD|O )|)|)|O -|-|:|O induced|induce|VBN|O tissue|tissue|NN|O remodeling|remodeling|NN|O or|or|CC|O fibrotic|fibrotic|JJ|O process|process|NN|O in|in|FW|O vitro|vitro|FW|O .|.|.|O 
Pleural|pleural|JJ|O mesothelial|mesothelial|JJ|O cell|cell|NN|O transformation|transformation|NN|O into|into|IN|O myofibroblasts|myofibroblast|NNS|O and|and|CC|O haptotactic|haptotactic|JJ|O migration|migration|NN|O in|in|IN|O response|response|NN|O to|to|TO|O TGF-beta1|TGF-beta1|NN|GENE in|in|FW|O vitro|vitro|FW|O .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O disease|disease|NN|O of|of|IN|O unknown|unknown|JJ|O etiology|etiology|NN|O characterized|characterize|VBN|O by|by|IN|O the|the|DT|O development|development|NN|O of|of|IN|O subpleural|subpleural|JJ|O foci|focus|NNS|O of|of|IN|O myofibroblasts|myofibroblast|NNS|O that|that|WDT|O contribute|contribute|VBP|O to|to|TO|O the|the|DT|O exuberant|exuberant|JJ|O fibrosis|fibrosis|NN|O noted|note|VBD|O in|in|IN|O the|the|DT|O pulmonary|pulmonary|JJ|O parenchyma|parenchyma|NN|O .|.|.|O 
Pleural|pleural|JJ|O mesothelial|mesothelial|JJ|O cells|cell|NNS|O (|(|(|O PMC|PMC|NN|O )|)|)|O are|be|VBP|O metabolically|metabolic|RB|O dynamic|dynamic|JJ|O cells|cell|NNS|O that|that|WDT|O cover|cover|VBP|O the|the|DT|O lung|lung|NN|O and|and|CC|O chest|chest|NN|O wall|wall|NN|O as|as|IN|O a|a|DT|O monolayer|monolayer|NN|O and|and|CC|O are|be|VBP|O in|in|IN|O intimate|intimate|JJ|O proximity|proximity|NN|O to|to|TO|O the|the|DT|O underlying|underlie|VBG|O lung|lung|NN|O parenchyma|parenchyma|NN|O .|.|.|O 
The|the|DT|O precise|precise|JJ|O role|role|NN|O of|of|IN|O PMC|PMC|NN|O in|in|IN|O the|the|DT|O pathogenesis|pathogenesis|NN|O of|of|IN|O pulmonary|pulmonary|JJ|O parenchymal|parenchymal|JJ|O fibrosis|fibrosis|NN|O remains|remain|VBZ|O to|to|TO|O be|be|VB|O identified|identify|VBN|O .|.|.|O 
Transforming|transform|VBG|O growth|growth|NN|O factor|factor|NN|O (|(|(|O TGF|tgf|NN|O )|)|)|O -|-|:|O beta1|beta1|NN|O ,|,|,|O a|a|DT|O cytokine|cytokine|NN|O known|know|VBN|O for|for|IN|O its|its|PRP$|O capacity|capacity|NN|O to|to|TO|O induce|induce|VB|O proliferative|proliferative|JJ|O and|and|CC|O transformative|transformative|JJ|O changes|change|NNS|O in|in|IN|O lung|lung|NN|O cells|cell|NNS|O ,|,|,|O is|be|VBZ|O found|find|VBN|O in|in|IN|O significantly|significant|RB|O higher|high|JJR|O quantities|quantity|NNS|O in|in|IN|O the|the|DT|O lungs|lung|NNS|O of|of|IN|O patients|patient|NNS|O with|with|IN|O IPF|IPF|NN|O .|.|.|O 
High|high|JJ|O levels|level|NNS|O of|of|IN|O TGF-beta1|TGF-beta1|NN|GENE in|in|IN|O the|the|DT|O subpleural|subpleural|JJ|O milieu|milieu|NN|O may|may|MD|O play|play|VB|O a|a|DT|O key|key|JJ|O role|role|NN|O in|in|IN|O the|the|DT|O transition|transition|NN|O of|of|IN|O normal|normal|JJ|O PMC|PMC|NN|O to|to|TO|O myofibroblasts|myofibroblast|NNS|O .|.|.|O 
Here|here|RB|O we|we|PRP|O demonstrate|demonstrate|VBP|O that|that|IN|O PMC|PMC|NN|O activated|activate|VBN|O by|by|IN|O TGF-beta1|TGF-beta1|NN|GENE undergo|undergo|VBP|O epithelial-mesenchymal|epithelial-mesenchymal|JJ|O transition|transition|NN|O (|(|(|O EMT|emt|NN|GENE )|)|)|O and|and|CC|O respond|respond|VBP|O with|with|IN|O haptotactic|haptotactic|JJ|O migration|migration|NN|O to|to|TO|O a|a|DT|O gradient|gradient|NN|O of|of|IN|O TGF-beta1|TGF-beta1|NN|GENE and|and|CC|O that|that|IN|O the|the|DT|O transition|transition|NN|O of|of|IN|O PMC|PMC|NN|O to|to|TO|O myofibroblasts|myofibroblast|NNS|O is|be|VBZ|O dependent|dependent|JJ|O on|on|IN|O smad-2|smad-2|NN|O signaling|signaling|NN|O .|.|.|O 
The|the|DT|O EMT|emt|NN|GENE of|of|IN|O PMC|PMC|NN|O was|be|VBD|O marked|mark|VBN|O by|by|IN|O upregulation|upregulation|NN|O of|of|IN|O alpha-smooth-muscle-actin|alpha-smooth-muscle-actin|NN|GENE (|(|(|O alpha-SMA|alpha-SMA|NN|GENE )|)|)|O ,|,|,|O fibroblast|fibroblast|NN|O specific|specific|JJ|O protein-1|protein-1|NN|O (|(|(|O FSP-1|FSP-1|NN|O )|)|)|O ,|,|,|O and|and|CC|O collagen|collagen|NN|O type|type|NN|O I|i|CD|O expression|expression|NN|O .|.|.|O 
Cytokeratin-8|Cytokeratin-8|NN|O and|and|CC|O E-cadherin|e-cadherin|NN|GENE expression|expression|NN|O decreased|decrease|VBD|O whereas|whereas|IN|O vimentin|vimentin|NN|GENE remained|remain|VBD|O unchanged|unchanged|JJ|O over|over|IN|O time|time|NN|O in|in|IN|O transforming|transform|VBG|O PMC|PMC|NNP|O .|.|.|O 
Knockdown|knockdown|NNP|O of|of|IN|O smad-2|smad-2|NN|O gene|gene|NN|O by|by|IN|O silencing|silencing|NN|O small|small|JJ|O interfering|interfere|VBG|O RNA|rna|NN|O significantly|significant|RB|O suppressed|suppress|VBD|O the|the|DT|O transition|transition|NN|O of|of|IN|O PMC|PMC|NN|O to|to|TO|O myofibroblasts|myofibroblast|NNS|O and|and|CC|O significantly|significant|RB|O inhibited|inhibit|VBD|O the|the|DT|O PMC|PMC|NN|O haptotaxis|haptotaxis|NN|O .|.|.|O 
We|we|PRP|O conclude|conclude|VBP|O that|that|IN|O PMC|PMC|NN|O undergo|undergo|VBP|O EMT|emt|NN|GENE when|when|WRB|O exposed|expose|VBN|O to|to|TO|O TGF-beta1|TGF-beta1|NN|GENE ,|,|,|O involving|involve|VBG|O smad-2|smad-2|NN|O signaling|signaling|NN|O ,|,|,|O and|and|CC|O PMC|PMC|NN|O may|may|MD|O be|be|VB|O a|a|DT|O possible|possible|JJ|O source|source|NN|O of|of|IN|O myofibroblasts|myofibroblast|NNS|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
Effects|effect|NNS|O of|of|IN|O a|a|DT|O leukotriene|leukotriene|NN|O B4|B4|NN|O receptor|receptor|NN|O antagonist|antagonist|NN|O on|on|IN|O bleomycin-induced|bleomycin-induced|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O devastating|devastating|JJ|O disease|disease|NN|O with|with|IN|O poor|poor|JJ|O prognosis|prognosis|NN|O .|.|.|O 
Leukotrienes|leukotriene|NNS|O play|play|VBP|O an|a|DT|O important|important|JJ|O role|role|NN|O in|in|IN|O IPF|IPF|NNP|O ,|,|,|O and|and|CC|O leukotriene|leukotriene|NN|O (|(|(|O LT|lt|NN|O )|)|)|O B|b|NN|O (|(|(|O 4|4|CD|O )|)|)|O is|be|VBZ|O one|one|CD|O of|of|IN|O the|the|DT|O key|key|JJ|O eicosanoids|eicosanoid|NNS|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
In|in|IN|O this|this|DT|O study|study|NN|O ,|,|,|O we|we|PRP|O investigated|investigate|VBD|O whether|whether|IN|O ONO-4057|ONO-4057|NN|O ,|,|,|O a|a|DT|O LTB|ltb|NN|O (|(|(|O 4|4|CD|O )|)|)|O receptor|receptor|NN|O (|(|(|O BLTR|BLTR|NN|O )|)|)|O antagonist|antagonist|NN|O is|be|VBZ|O capable|capable|JJ|O of|of|IN|O preventing|prevent|VBG|O bleomycin-induced|bleomycin-induced|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
On|on|IN|O day|day|NN|O 1|1|CD|O ,|,|,|O C57BL/6|C57BL/6|NN|O male|male|NN|O mice|mouse|NNS|O were|be|VBD|O given|give|VBN|O a|a|DT|O single|single|JJ|O intratracheal|intratracheal|JJ|O injection|injection|NN|O of|of|IN|O bleomycin|bleomycin|NN|O (|(|(|O 2.5|2.5|CD|O mg|mg|NN|O x|x|CC|O kg|kg|NN|O (|(|(|O -1|-1|CD|O )|)|)|O )|)|)|O ,|,|,|O and|and|CC|O ONO-4057|ONO-4057|NN|O (|(|(|O 1.0|1.0|CD|O mg|mg|NN|O x|x|CC|O kg|kg|NN|O (|(|(|O -1|-1|CD|O )|)|)|O )|)|)|O or|or|CC|O vehicle|vehicle|NN|O alone|alone|RB|O ,|,|,|O administered|administer|VBN|O by|by|IN|O intraperitoneal|intraperitoneal|JJ|O injection|injection|NN|O on|on|IN|O days|day|NNS|O 1-5|1-5|CD|O each|each|DT|O week|week|NN|O for|for|IN|O 3|3|CD|O weeks|week|NNS|O after|after|IN|O the|the|DT|O bleomycin|bleomycin|NN|O injection|injection|NN|O .|.|.|O 
ONO-4057|ONO-4057|NN|O reduced|reduce|VBD|O the|the|DT|O total|total|JJ|O cell|cell|NN|O count|count|NN|O in|in|IN|O bronchoalveolar|bronchoalveolar|JJ|O lavage|lavage|NN|O fluid|fluid|NN|O (|(|(|O BALF|BALF|NN|O )|)|)|O on|on|IN|O days|day|NNS|O 7|7|CD|O ,|,|,|O 14|14|CD|O and|and|CC|O 21|21|CD|O and|and|CC|O the|the|DT|O Ashcroft|Ashcroft|NNP|O score|score|NN|O and|and|CC|O the|the|DT|O lung|lung|NN|O hydroxyproline|hydroxyproline|NN|O content|content|NN|O on|on|IN|O days|day|NNS|O 14|14|CD|O and|and|CC|O 21|21|CD|O .|.|.|O 
The|the|DT|O LTB|ltb|NN|O (|(|(|O 4|4|CD|O )|)|)|O ,|,|,|O interleukin|interleukin|NN|O (|(|(|O IL|IL|NN|O )|)|)|O -6|-6|CD|O ,|,|,|O IL-13|IL-13|NN|GENE ,|,|,|O transforming|transform|VBG|O growth|growth|NN|O factor|factor|NN|O (|(|(|O TGF|tgf|NN|O )|)|)|O -|-|:|O beta|beta|NN|O levels|level|NNS|O in|in|IN|O BALF|BALF|NN|O and|and|CC|O the|the|DT|O TGF-beta|TGF-beta|NN|GENE expression|expression|NN|O in|in|IN|O lung|lung|NN|O tissue|tissue|NN|O ,|,|,|O assessed|assess|VBN|O by|by|IN|O immunohistochemistry|immunohistochemistry|NN|O were|be|VBD|O decreased|decrease|VBN|O on|on|IN|O day|day|NN|O 7|7|CD|O ,|,|,|O whereas|whereas|IN|O interferon|interferon|NN|O (|(|(|O IFN|IFN|NN|O )|)|)|O -|-|:|O gamma|gamma|NN|O level|level|NN|O in|in|IN|O BALF|BALF|NN|O was|be|VBD|O increased|increase|VBN|O on|on|IN|O day|day|NN|O 14|14|CD|O .|.|.|O 
The|the|DT|O results|result|NNS|O of|of|IN|O this|this|DT|O study|study|NN|O indicated|indicate|VBD|O that|that|IN|O the|the|DT|O BLTR|BLTR|NN|O antagonist|antagonist|NN|O inhibited|inhibit|VBD|O the|the|DT|O development|development|NN|O of|of|IN|O bleomycin-induced|bleomycin-induced|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O in|in|IN|O mice|mouse|NNS|O by|by|IN|O decreasing|decrease|VBG|O inflammation|inflammation|NN|O and|and|CC|O altering|alter|VBG|O TGF-beta|TGF-beta|NN|GENE ,|,|,|O IL-6|IL-6|NN|GENE ,|,|,|O IL-13|IL-13|NN|GENE and|and|CC|O IFN-gamma|IFN-gamma|NN|GENE .|.|.|O 
Defective|defective|JJ|O histone|histone|NN|O acetylation|acetylation|NN|O is|be|VBZ|O responsible|responsible|JJ|O for|for|IN|O the|the|DT|O diminished|diminish|VBN|O expression|expression|NN|O of|of|IN|O cyclooxygenase|cyclooxygenase|NN|GENE 2|2|NN|GENE in|in|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Diminished|diminish|VBN|O cyclooxygenase|cyclooxygenase|NN|GENE 2|2|NN|GENE (|(|(|O COX-2|COX-2|NN|GENE )|)|)|O expression|expression|NN|O in|in|IN|O fibroblasts|fibroblast|NNS|O ,|,|,|O with|with|IN|O a|a|DT|O resultant|resultant|JJ|O defect|defect|NN|O in|in|IN|O the|the|DT|O production|production|NN|O of|of|IN|O the|the|DT|O antifibrotic|antifibrotic|JJ|O mediator|mediator|NN|O prostaglandin|prostaglandin|NN|O E|e|NN|O (|(|(|O 2|2|CD|O )|)|)|O ,|,|,|O plays|play|VBZ|O a|a|DT|O key|key|JJ|O role|role|NN|O in|in|IN|O the|the|DT|O pathogenesis|pathogenesis|NN|O of|of|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O .|.|.|O 
Here|here|RB|O ,|,|,|O we|we|PRP|O have|have|VBP|O characterized|characterize|VBN|O the|the|DT|O molecular|molecular|JJ|O mechanism|mechanism|NN|O .|.|.|O 
We|we|PRP|O found|find|VBD|O that|that|IN|O COX-2|COX-2|NN|GENE mRNA|mRNA|NN|O levels|level|NNS|O in|in|IN|O fibroblasts|fibroblast|NNS|O from|from|IN|O patients|patient|NNS|O with|with|IN|O IPF|IPF|NN|O (|(|(|O F-IPF|F-IPF|NN|O )|)|)|O were|be|VBD|O significantly|significant|RB|O lower|low|JJR|O than|than|IN|O those|those|DT|O in|in|IN|O fibroblasts|fibroblast|NNS|O from|from|IN|O nonfibrotic|nonfibrotic|JJ|O lungs|lung|NNS|O (|(|(|O F-NL|F-NL|NN|O )|)|)|O after|after|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta1|beta1|NN|GENE and|and|CC|O interleukin-1beta|interleukin-1beta|NN|GENE treatment|treatment|NN|O but|but|CC|O that|that|IN|O COX-2|COX-2|NN|GENE mRNA|mRNA|NN|O degradation|degradation|NN|O rates|rate|NNS|O were|be|VBD|O similar|similar|JJ|O ,|,|,|O suggesting|suggest|VBG|O defective|defective|JJ|O transcription|transcription|NN|O .|.|.|O 
A|a|DT|O reporter|reporter|NN|O gene|gene|NN|O assay|assay|NN|O showed|show|VBD|O that|that|IN|O there|there|EX|O were|be|VBD|O no|no|DT|O clear|clear|JJ|O differences|difference|NNS|O between|between|IN|O F-IPF|F-IPF|NN|O and|and|CC|O F-NL|F-NL|NN|O in|in|IN|O transcription|transcription|NN|O factor|factor|NN|O involvement|involvement|NN|O and|and|CC|O activation|activation|NN|O in|in|IN|O COX-2|COX-2|NN|GENE gene|gene|NN|O transcription|transcription|NN|O .|.|.|O 
However|however|RB|O ,|,|,|O a|a|DT|O chromatin|chromatin|NN|O immunoprecipitation|immunoprecipitation|NN|O assay|assay|NN|O revealed|reveal|VBD|O that|that|IN|O transcription|transcription|NN|O factor|factor|NN|O binding|binding|NN|O to|to|TO|O the|the|DT|O COX-2|COX-2|NN|GENE promoter|promoter|NN|O in|in|IN|O F-IPF|F-IPF|NN|O was|be|VBD|O reduced|reduce|VBN|O compared|compare|VBN|O to|to|TO|O that|that|DT|O in|in|IN|O F-NL|F-NL|NN|O ,|,|,|O an|a|DT|O effect|effect|NN|O that|that|WDT|O was|be|VBD|O dynamically|dynamical|RB|O linked|link|VBN|O to|to|TO|O reduced|reduce|VBN|O histone|histone|NN|O H3|H3|NN|O and|and|CC|O H4|H4|NN|O acetylation|acetylation|NN|O due|due|JJ|O to|to|TO|O decreased|decrease|VBN|O recruitment|recruitment|NN|O of|of|IN|O histone|histone|NN|O acetyltransferases|acetyltransferase|NNS|O (|(|(|O HATs|hat|NNS|O )|)|)|O and|and|CC|O increased|increase|VBD|O recruitment|recruitment|NN|O of|of|IN|O transcriptional|transcriptional|JJ|O corepressor|corepressor|NN|O complexes|complex|NNS|O to|to|TO|O the|the|DT|O COX-2|COX-2|NN|GENE promoter|promoter|NN|O .|.|.|O 
The|the|DT|O treatment|treatment|NN|O of|of|IN|O F-IPF|F-IPF|NN|O with|with|IN|O histone|histone|NN|GENE deacetylase|deacetylase|NN|GENE (|(|(|O HDAC|HDAC|NN|O )|)|)|O inhibitors|inhibitor|NNS|O together|together|RB|O with|with|IN|O cytokines|cytokine|NNS|O increased|increase|VBD|O histone|histone|NN|O H3|H3|NN|O and|and|CC|O H4|H4|NN|O acetylation|acetylation|NN|O .|.|.|O 
Both|both|DT|O HDAC|HDAC|NN|O inhibitors|inhibitor|NNS|O and|and|CC|O the|the|DT|O overexpression|overexpression|NN|O of|of|IN|O HATs|hat|NNS|O restored|restore|VBD|O cytokine-induced|cytokine-induced|JJ|O COX-2|COX-2|NN|GENE mRNA|mRNA|NN|O and|and|CC|O protein|protein|NN|O expression|expression|NN|O in|in|IN|O F-IPF|F-IPF|NN|O .|.|.|O 
The|the|DT|O results|result|NNS|O demonstrate|demonstrate|VBP|O that|that|IN|O epigenetic|epigenetic|JJ|O abnormality|abnormality|NN|O in|in|IN|O the|the|DT|O form|form|NN|O of|of|IN|O histone|histone|NN|O hypoacetylation|hypoacetylation|NN|O is|be|VBZ|O responsible|responsible|JJ|O for|for|IN|O diminished|diminish|VBN|O COX-2|COX-2|NN|GENE expression|expression|NN|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
MS80|MS80|NN|O ,|,|,|O a|a|DT|O novel|novel|JJ|O sulfated|sulfated|JJ|O oligosaccharide|oligosaccharide|NN|O ,|,|,|O inhibits|inhibit|VBZ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O by|by|IN|O targeting|target|VBG|O TGF-beta1|TGF-beta1|NN|GENE both|both|CC|O in|in|FW|O vitro|vitro|FW|O and|and|CC|O in|in|FW|O vivo|vivo|FW|O .|.|.|O 
AIM|aim|NN|O :|:|:|O The|the|DT|O pro-fibrogenic|pro-fibrogenic|JJ|O cytokine|cytokine|NN|O transforming-growth-factor-beta-1|transforming-growth-factor-beta-1|NN|GENE (|(|(|O TGF-beta1|TGF-beta1|NN|GENE )|)|)|O has|have|VBZ|O attracted|attract|VBN|O much|much|JJ|O attention|attention|NN|O for|for|IN|O its|its|PRP$|O potential|potential|JJ|O role|role|NN|O in|in|IN|O the|the|DT|O etiology|etiology|NN|O of|of|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O .|.|.|O 
Here|here|RB|O ,|,|,|O we|we|PRP|O demonstrate|demonstrate|VBP|O that|that|IN|O MS80|MS80|NN|O ,|,|,|O a|a|DT|O novel|novel|JJ|O sulfated|sulfated|JJ|O oligosaccharide|oligosaccharide|NN|O extracted|extract|VBN|O from|from|IN|O seaweed|seaweed|NN|O ,|,|,|O can|can|MD|O bind|bind|VB|O TGF-beta1|TGF-beta1|NN|GENE .|.|.|O 
The|the|DT|O aim|aim|NN|O of|of|IN|O the|the|DT|O present|present|JJ|O study|study|NN|O was|be|VBD|O to|to|TO|O determine|determine|VB|O whether|whether|IN|O MS80|MS80|NN|O is|be|VBZ|O capable|capable|JJ|O of|of|IN|O combating|combat|VBG|O TGF-beta1-mediated|tgf-beta1-mediated|JJ|O pulmonary|pulmonary|JJ|O fibrotic|fibrotic|JJ|O events|event|NNS|O both|both|CC|O in|in|FW|O vitro|vitro|FW|O and|and|CC|O in|in|FW|O vivo|vivo|FW|O ,|,|,|O and|and|CC|O to|to|TO|O investigate|investigate|VB|O the|the|DT|O possible|possible|JJ|O underlying|underlying|JJ|O mechanisms|mechanism|NNS|O .|.|.|O 
METHODS|method|NNS|O :|:|:|O Surface|surface|NN|O plasmon|plasmon|NNS|O resonance|resonance|NN|O was|be|VBD|O used|use|VBN|O to|to|TO|O uncover|uncover|VB|O the|the|DT|O binding|binding|NN|O profiles|profile|NNS|O between|between|IN|O the|the|DT|O compound|compound|NN|O and|and|CC|O TGF-beta|TGF-beta|NN|GENE .|.|.|O 
MTT|MTT|NNP|O assay|assay|NN|O ,|,|,|O flow|flow|NN|O cytometry|cytometry|NN|O ,|,|,|O Western|western|NN|O blot|blot|NN|O analysis|analysis|NN|O ,|,|,|O BCA|Bca|NN|O protein|protein|NN|O assay|assay|NN|O and|and|CC|O SDS-PAGE|sds-page|NN|O gelatin|gelatin|NN|O zymography|zymography|NN|O were|be|VBD|O used|use|VBN|O to|to|TO|O probe|probe|VB|O the|the|DT|O antifibrotic|antifibrotic|JJ|O mechanisms|mechanism|NNS|O of|of|IN|O MS80|MS80|NN|O .|.|.|O 
The|the|DT|O in|in|FW|O vivo|vivo|FW|O fibrotic|fibrotic|JJ|O efficacy|efficacy|NN|O was|be|VBD|O evaluated|evaluate|VBN|O in|in|IN|O a|a|DT|O bleomycin|bleomycin|NN|O instillation-induced|instillation-induced|JJ|O rat|rat|NN|O model|model|NN|O .|.|.|O 
RESULTS|result|NNS|O :|:|:|O We|we|PRP|O report|report|VBP|O that|that|IN|O MS80|MS80|NN|O ,|,|,|O a|a|DT|O new|new|JJ|O kind|kind|NN|O of|of|IN|O sulfated|sulfated|JJ|O oligosaccharide|oligosaccharide|NN|O extracted|extract|VBN|O from|from|IN|O seaweed|seaweed|NN|O ,|,|,|O inhibits|inhibit|VBZ|O TGF-beta1-induced|tgf-beta1-induced|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O in|in|FW|O vitro|vitro|FW|O and|and|CC|O bleomycin-induced|bleomycin-induced|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O in|in|FW|O vivo|vivo|FW|O .|.|.|O 
Our|our|PRP$|O results|result|NNS|O indicated|indicate|VBD|O that|that|IN|O MS80|MS80|NN|O competitively|competitive|RB|O inhibited|inhibit|VBD|O heparin/HS-TGF-beta|heparin/HS-TGF-beta|NN|O 1|1|CD|O interaction|interaction|NN|O through|through|IN|O its|its|PRP$|O high|high|JJ|O binding|binding|NN|O affinity|affinity|NN|O for|for|IN|O TGF-beta1|TGF-beta1|NN|GENE .|.|.|O 
Moreover|moreover|RB|O ,|,|,|O MS80|MS80|NN|O arrested|arrest|VBN|O TGF-beta1-induced|tgf-beta1-induced|JJ|O human|human|JJ|O embryo|embryo|NN|O pulmonary|pulmonary|JJ|O fibroblast|fibroblast|NN|O (|(|(|O HEPF|HEPF|NN|O )|)|)|O cell|cell|NN|O proliferation|proliferation|NN|O ,|,|,|O collagen|collagen|NN|O deposition|deposition|NN|O and|and|CC|O matrix|matrix|NN|O metalloproteinase|metalloproteinase|NN|O (|(|(|O MMP|MMP|NN|O )|)|)|O activity|activity|NN|O .|.|.|O 
Intriguingly|intriguing|RB|O ,|,|,|O MS80|MS80|NN|O deactivated|deactivate|VBD|O both|both|CC|O the|the|DT|O ERK|erk|NN|GENE and|and|CC|O p38|p38|NN|GENE signaling|signaling|NN|O pathways|pathway|NNS|O .|.|.|O 
MS80|MS80|NN|O was|be|VBD|O also|also|RB|O a|a|DT|O potent|potent|JJ|O suppressor|suppressor|NN|O of|of|IN|O bleomycin-induced|bleomycin-induced|JJ|O rat|rat|NN|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O in|in|FW|O vivo|vivo|FW|O ,|,|,|O as|as|IN|O evidenced|evidence|VBN|O by|by|IN|O improved|improve|VBN|O pathological|pathological|JJ|O settings|setting|NNS|O and|and|CC|O decreased|decrease|VBD|O lung|lung|NN|O collagen|collagen|NN|O contents|content|NNS|O .|.|.|O 
CONCLUSION|conclusion|NN|O :|:|:|O MS80|MS80|NN|O in|in|IN|O particular|particular|JJ|O ,|,|,|O and|and|CC|O perhaps|perhaps|RB|O oligosaccharide|oligosaccharide|NN|O in|in|IN|O general|general|JJ|O ,|,|,|O offer|offer|VB|O better|good|JJR|O pharmacological|pharmacological|JJ|O profiles|profile|NNS|O with|with|IN|O appreciably|appreciable|RB|O few|few|JJ|O side|side|JJ|O effects|effect|NNS|O and|and|CC|O represent|represent|VBP|O a|a|DT|O promising|promising|JJ|O class|class|NN|O of|of|IN|O drug|drug|NN|O candidates|candidate|NNS|O for|for|IN|O IPF|IPF|NN|O therapy.Acta|therapy.Acta|NN|O Pharmacologica|Pharmacologica|NNP|O Sinica|Sinica|NNP|O (|(|(|O 2009|2009|CD|O )|)|)|O 30|30|CD|O :|:|:|O 973-979|973-979|CD|O ;|;|:|O doi|doi|FW|O :|:|:|O 10.1038|10.1038|CD|O /|/|:|O aps|APS|NNS|O .2009.86|.2009.86|CD|O ;|;|:|O published|publish|VBN|O online|online|NN|O 22|22|CD|O June|june|NNP|O 2009|2009|CD|O .|.|.|O 
Transcription|transcription|NN|O factor|factor|NN|O GATA-6|GATA-6|NN|O is|be|VBZ|O expressed|express|VBN|O in|in|IN|O quiescent|quiescent|JJ|O myofibroblasts|myofibroblast|NNS|O in|in|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O (|(|(|O histopathology|histopathology|NN|O of|of|IN|O usual|usual|JJ|O interstitial|interstitial|JJ|O pneumonia|pneumonia|NN|O [|[|(|O UIP|UIP|NN|O ]|]|)|O )|)|)|O is|be|VBZ|O a|a|DT|O progressive|progressive|JJ|O disease|disease|NN|O with|with|IN|O poor|poor|JJ|O prognosis|prognosis|NN|O .|.|.|O 
Characteristic|characteristic|JJ|O features|feature|NNS|O of|of|IN|O IPF/UIP|IPF/UIP|NN|O include|include|VBP|O fibroblastic|fibroblastic|JJ|O foci|focus|NNS|O ,|,|,|O which|which|WDT|O are|be|VBP|O patchy|patchy|JJ|O lesions|lesion|NNS|O of|of|IN|O focal|focal|JJ|O ,|,|,|O disarranged|disarranged|JJ|O myofibroblasts|myofibroblast|NNS|O .|.|.|O 
GATA-6|GATA-6|NN|O is|be|VBZ|O a|a|DT|O transcription|transcription|NN|O factor|factor|NN|O linked|link|VBN|O with|with|IN|O cell|cell|NN|O differentiation|differentiation|NN|O .|.|.|O 
Its|its|PRP$|O role|role|NN|O in|in|IN|O the|the|DT|O development|development|NN|O of|of|IN|O IPF|IPF|NN|O has|have|VBZ|O not|not|RB|O previously|previous|RB|O been|be|VBN|O investigated|investigate|VBN|O .|.|.|O 
We|we|PRP|O hypothesized|hypothesise|VBD|O that|that|IN|O GATA-6|GATA-6|NN|O participates|participate|VBZ|O in|in|IN|O the|the|DT|O differentiation|differentiation|NN|O of|of|IN|O fibroblasts|fibroblast|NNS|O into|into|IN|O myofibroblasts|myofibroblast|NNS|O in|in|IN|O IPF/UIP|IPF/UIP|NN|O lungs|lung|NNS|O .|.|.|O 
The|the|DT|O expression|expression|NN|O patterns|pattern|NNS|O of|of|IN|O GATA-6|GATA-6|NN|O ,|,|,|O the|the|DT|O mesenchymal|mesenchymal|JJ|O marker|marker|NN|O alpha-smooth-muscle-actin|alpha-smooth-muscle-actin|NN|GENE (|(|(|O alpha-SMA|alpha-SMA|NN|GENE )|)|)|O ,|,|,|O and|and|CC|O markers|marker|NNS|O for|for|IN|O proliferation|proliferation|NN|O (|(|(|O Ki67|Ki67|NN|O )|)|)|O and|and|CC|O apoptosis|apoptosis|NN|O (|(|(|O caspase-3|caspase-3|NN|GENE )|)|)|O were|be|VBD|O analyzed|analyse|VBN|O in|in|IN|O human|human|JJ|O IPF/UIP|IPF/UIP|NN|O tissue|tissue|NN|O samples|sample|NNS|O .|.|.|O 
The|the|DT|O effects|effect|NNS|O of|of|IN|O GATA-6|GATA-6|NN|O overexpression|overexpression|NN|O and|and|CC|O silencing|silencing|NN|O were|be|VBD|O studied|study|VBN|O in|in|IN|O cell|cell|NN|O cultures|culture|NNS|O .|.|.|O 
The|the|DT|O results|result|NNS|O show|show|VBP|O that|that|IN|O the|the|DT|O alpha-SMA-positive|alpha-sma-positive|JJ|O fibroblastic|fibroblastic|JJ|O foci|focus|NNS|O in|in|IN|O IPF/UIP|IPF/UIP|NN|O lungs|lung|NNS|O are|be|VBP|O positive|positive|JJ|O for|for|IN|O GATA-6|GATA-6|NN|O ,|,|,|O but|but|CC|O negative|negative|JJ|O for|for|IN|O Ki67|Ki67|NN|O and|and|CC|O caspase-3|caspase-3|NN|GENE .|.|.|O 
Cultured|culture|VBN|O human|human|JJ|O IPF/UIP|IPF/UIP|NN|O fibroblasts|fibroblast|NNS|O expressed|express|VBD|O GATA-6|GATA-6|NN|O mRNA|mRNA|NN|O ,|,|,|O whereas|whereas|IN|O cells|cell|NNS|O from|from|IN|O the|the|DT|O normal|normal|JJ|O adult|adult|JJ|O lung|lung|NN|O did|do|VBD|O not|not|RB|O .|.|.|O 
In|in|IN|O cultured|culture|VBN|O A549|A549|NN|O lung|lung|NN|O epithelial|epithelial|JJ|O cells|cell|NNS|O ,|,|,|O the|the|DT|O induction|induction|NN|O of|of|IN|O GATA-6|GATA-6|NN|O by|by|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta1|beta1|NN|GENE resulted|result|VBD|O in|in|IN|O simultaneous|simultaneous|JJ|O expression|expression|NN|O of|of|IN|O alpha-SMA|alpha-SMA|NN|GENE and|and|CC|O decrease|decrease|NN|O of|of|IN|O E-cadherin|e-cadherin|NN|GENE .|.|.|O 
The|the|DT|O inhibition|inhibition|NN|O of|of|IN|O GATA-6|GATA-6|NN|O expression|expression|NN|O in|in|IN|O fibroblasts|fibroblast|NNS|O showed|show|VBD|O that|that|IN|O GATA-6|GATA-6|NN|O mediates|mediate|VBZ|O the|the|DT|O alpha-SMA-inducing|alpha-sma-inducing|JJ|O signal|signal|NN|O of|of|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta1|beta1|NN|GENE .|.|.|O 
In|in|IN|O conclusion|conclusion|NN|O ,|,|,|O the|the|DT|O hallmark|hallmark|NN|O of|of|IN|O IPF/UIP|IPF/UIP|NN|O histopathology|histopathology|NN|O ,|,|,|O the|the|DT|O fibroblast|fibroblast|NN|O focus|focus|NN|O ,|,|,|O consists|consist|VBZ|O of|of|IN|O differentiated|differentiate|VBN|O ,|,|,|O quiescent|quiescent|JJ|O cells|cell|NNS|O that|that|WDT|O prominently|prominent|RB|O express|express|VBP|O GATA-6|GATA-6|NN|O .|.|.|O 
Role|role|NN|O of|of|IN|O integrin-mediated|integrin-mediated|JJ|O TGFbeta|TGFbeta|NN|GENE activation|activation|NN|O in|in|IN|O the|the|DT|O pathogenesis|pathogenesis|NN|O of|of|IN|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
IPF|IPF|NN|O (|(|(|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O chronic|chronic|JJ|O progressive|progressive|JJ|O disease|disease|NN|O of|of|IN|O unknown|unknown|JJ|O aetiology|aetiology|NN|O without|without|IN|O effective|effective|JJ|O treatment|treatment|NN|O .|.|.|O 
IPF|IPF|NN|O is|be|VBZ|O characterized|characterize|VBN|O by|by|IN|O excessive|excessive|JJ|O collagen|collagen|NN|O deposition|deposition|NN|O within|within|IN|O the|the|DT|O lung|lung|NN|O .|.|.|O 
Recent|recent|JJ|O evidence|evidence|NN|O suggests|suggest|VBZ|O that|that|IN|O the|the|DT|O lung|lung|NN|O epithelium|epithelium|NN|O plays|play|VBZ|O a|a|DT|O key|key|JJ|O role|role|NN|O in|in|IN|O driving|drive|VBG|O the|the|DT|O fibrotic|fibrotic|JJ|O response|response|NN|O .|.|.|O 
The|the|DT|O current|current|JJ|O paradigm|paradigm|NN|O suggests|suggest|VBZ|O that|that|IN|O ,|,|,|O after|after|IN|O epithelial|epithelial|JJ|O injury|injury|NN|O ,|,|,|O there|there|EX|O is|be|VBZ|O impaired|impaired|JJ|O epithelial|epithelial|JJ|O proliferation|proliferation|NN|O and|and|CC|O enhanced|enhance|VBD|O epithelial|epithelial|JJ|O apoptosis|apoptosis|NN|O .|.|.|O 
This|this|DT|O in|in|IN|O turn|turn|NN|O promotes|promote|VBZ|O lung|lung|NN|O fibrosis|fibrosis|NN|O through|through|IN|O impaired|impaired|JJ|O basement|basement|NN|O membrane|membrane|NN|O repair|repair|NN|O and|and|CC|O increased|increase|VBD|O epithelial-mesenchymal|epithelial-mesenchymal|JJ|O transition|transition|NN|O .|.|.|O 
Furthermore|furthermore|RB|O ,|,|,|O fibroblasts|fibroblast|NNS|O are|be|VBP|O recruited|recruit|VBN|O to|to|TO|O the|the|DT|O wounded|wound|VBN|O area|area|NN|O and|and|CC|O adopt|adopt|VB|O a|a|DT|O myofibroblast|myofibroblast|NN|O phenotype|phenotype|NN|O ,|,|,|O with|with|IN|O the|the|DT|O up-regulation|up-regulation|NN|O of|of|IN|O matrix-synthesizing|matrix-synthesizing|JJ|O genes|gene|NNS|O and|and|CC|O down-regulation|down-regulation|NN|O of|of|IN|O matrix-degradation|matrix-degradation|NN|O genes|gene|NNS|O .|.|.|O 
There|there|EX|O is|be|VBZ|O compelling|compelling|JJ|O evidence|evidence|NN|O that|that|IN|O the|the|DT|O cytokine|cytokine|NN|O TGFbeta|TGFbeta|NN|GENE (|(|(|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta|beta|NN|GENE )|)|)|O plays|play|VBZ|O a|a|DT|O central|central|JJ|O role|role|NN|O in|in|IN|O this|this|DT|O process|process|NN|O .|.|.|O 
In|in|IN|O normal|normal|JJ|O lung|lung|NN|O ,|,|,|O TGFbeta|TGFbeta|NN|GENE is|be|VBZ|O maintained|maintain|VBN|O in|in|IN|O an|a|DT|O inactive|inactive|JJ|O state|state|NN|O that|that|WDT|O is|be|VBZ|O tightly|tight|RB|O regulated|regulate|VBN|O temporally|temporal|RB|O and|and|CC|O spatially|spatial|RB|O .|.|.|O 
One|one|CD|O of|of|IN|O the|the|DT|O major|major|JJ|O TGFbeta-activation|TGFbeta-activation|NN|O pathways|pathway|NNS|O involves|involve|VBZ|O integrins|integrin|NNS|O ,|,|,|O and|and|CC|O the|the|DT|O role|role|NN|O of|of|IN|O the|the|DT|O (|(|(|O alpha|alpha|NN|O )|)|)|O vbeta6|vbeta6|NN|O integrin|integrin|NN|O has|have|VBZ|O been|be|VBN|O particularly|particular|RB|O well|well|RB|O described|describe|VBN|O in|in|IN|O the|the|DT|O pathogenesis|pathogenesis|NN|O of|of|IN|O IPF|IPF|NN|O .|.|.|O 
Owing|owe|VBG|O to|to|TO|O the|the|DT|O pleiotropic|pleiotropic|JJ|O nature|nature|NN|O of|of|IN|O TGFbeta|TGFbeta|NN|GENE ,|,|,|O strategies|strategy|NNS|O that|that|WDT|O inhibit|inhibit|VBP|O activation|activation|NN|O of|of|IN|O TGFbeta|TGFbeta|NN|GENE in|in|IN|O a|a|DT|O cell|cell|NN|O -|-|:|O or|or|CC|O disease-specific|disease-specific|JJ|O manner|manner|NN|O are|be|VBP|O attractive|attractive|JJ|O for|for|IN|O the|the|DT|O treatment|treatment|NN|O of|of|IN|O chronic|chronic|JJ|O fibrotic|fibrotic|JJ|O lung|lung|NN|O conditions|condition|NNS|O .|.|.|O 
Therefore|therefore|RB|O the|the|DT|O molecular|molecular|JJ|O pathways|pathway|NNS|O that|that|WDT|O lead|lead|VBP|O to|to|TO|O integrin-mediated|integrin-mediated|JJ|O TGFbeta|TGFbeta|NN|GENE activation|activation|NN|O must|must|MD|O be|be|VB|O precisely|precise|RB|O defined|define|VBN|O to|to|TO|O identify|identify|VB|O and|and|CC|O fully|full|RB|O exploit|exploit|VB|O novel|novel|JJ|O therapeutic|therapeutic|JJ|O targets|target|NNS|O that|that|WDT|O might|may|MD|O ultimately|ultimate|RB|O improve|improve|VB|O the|the|DT|O prognosis|prognosis|NN|O for|for|IN|O patients|patient|NNS|O with|with|IN|O IPF|IPF|NN|O .|.|.|O 
The|the|DT|O ability|ability|NN|O of|of|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta1|beta1|NN|GENE (|(|(|O TGF-beta1|TGF-beta1|NN|GENE )|)|)|O to|to|TO|O induce|induce|VB|O epithelial-mesenchymal|epithelial-mesenchymal|JJ|O transition|transition|NN|O (|(|(|O EMT|emt|NN|GENE )|)|)|O in|in|IN|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O (|(|(|O AEC|aec|NNS|O )|)|)|O in|in|FW|O vitro|vitro|FW|O and|and|CC|O in|in|FW|O vivo|vivo|FW|O ,|,|,|O together|together|RB|O with|with|IN|O the|the|DT|O demonstration|demonstration|NN|O of|of|IN|O EMT|emt|NN|GENE in|in|IN|O biopsies|biopsy|NNS|O of|of|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O patients|patient|NNS|O ,|,|,|O suggests|suggest|VBZ|O a|a|DT|O role|role|NN|O for|for|IN|O TGF-beta1-induced|tgf-beta1-induced|JJ|O EMT|emt|NN|GENE in|in|IN|O disease|disease|NN|O pathogenesis|pathogenesis|NN|O .|.|.|O 
We|we|PRP|O investigated|investigate|VBD|O the|the|DT|O effects|effect|NNS|O of|of|IN|O N-acetylcysteine|N-acetylcysteine|NN|O (|(|(|O NAC|nac|NN|O )|)|)|O on|on|IN|O TGF-beta1-induced|tgf-beta1-induced|JJ|O EMT|emt|NN|GENE in|in|IN|O a|a|DT|O rat|rat|NN|O epithelial|epithelial|JJ|O cell|cell|NN|O line|line|NN|O (|(|(|O RLE-6TN|RLE-6TN|NN|O )|)|)|O and|and|CC|O in|in|IN|O primary|primary|JJ|O rat|rat|NN|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O (|(|(|O AEC|aec|NNS|O )|)|)|O .|.|.|O 
RLE-6TN|RLE-6TN|NN|O cells|cell|NNS|O exposed|expose|VBN|O to|to|TO|O TGF-beta1|TGF-beta1|NN|GENE for|for|IN|O 5|5|CD|O days|day|NNS|O underwent|undergo|VBD|O EMT|emt|NNP|GENE as|as|IN|O evidenced|evidence|VBN|O by|by|IN|O acquisition|acquisition|NN|O of|of|IN|O a|a|DT|O fibroblast-like|fibroblast-like|JJ|O morphology|morphology|NN|O ,|,|,|O downregulation|downregulation|NN|O of|of|IN|O the|the|DT|O epithelial-specific|epithelial-specific|JJ|O protein|protein|NN|O zonula|zonula|NN|O occludens-1|occludens-1|NN|O ,|,|,|O and|and|CC|O induction|induction|NN|O of|of|IN|O the|the|DT|O mesenchymal-specific|mesenchymal-specific|JJ|O proteins|protein|NNS|O alpha-smooth-muscle-actin|alpha-smooth-muscle-actin|NN|GENE (|(|(|O alpha-SMA|alpha-SMA|NN|GENE )|)|)|O and|and|CC|O vimentin|vimentin|NN|GENE .|.|.|O 
These|these|DT|O changes|change|NNS|O were|be|VBD|O inhibited|inhibit|VBN|O by|by|IN|O NAC|nac|NN|O ,|,|,|O which|which|WDT|O also|also|RB|O prevented|prevent|VBD|O Smad3|Smad3|NN|GENE phosphorylation|phosphorylation|NN|O .|.|.|O 
Similarly|similar|RB|O ,|,|,|O primary|primary|JJ|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O type|type|NN|O II|II|CD|O cells|cell|NNS|O exposed|expose|VBN|O to|to|TO|O TGF-beta1|TGF-beta1|NN|GENE also|also|RB|O underwent|undergo|VBD|O EMT|emt|NNP|GENE that|that|WDT|O was|be|VBD|O prevented|prevent|VBN|O by|by|IN|O NAC|nac|NN|O .|.|.|O 
TGF-beta1|TGF-beta1|NN|GENE decreased|decrease|VBD|O cellular|cellular|JJ|O GSH|gsh|NN|O levels|level|NNS|O by|by|IN|O 50-80|50-80|CD|O %|%|NN|O ,|,|,|O whereas|whereas|IN|O NAC|nac|NN|O restored|restore|VBD|O them|they|PRP|O to|to|TO|O approximately|approximate|RB|O 150|150|CD|O %|%|NN|O of|of|IN|O those|those|DT|O found|find|VBN|O in|in|IN|O TGF-beta1-treated|tgf-beta1-treated|JJ|O cells|cell|NNS|O .|.|.|O 
Treatment|treatment|NN|O with|with|IN|O glutathione|glutathione|NN|O monoethyl|monoethyl|NN|O ester|ester|NN|O similarly|similar|RB|O prevented|prevent|VBD|O an|a|DT|O increase|increase|NN|O in|in|IN|O mesenchymal|mesenchymal|JJ|O marker|marker|NN|O expression|expression|NN|O .|.|.|O 
Consistent|consistent|JJ|O with|with|IN|O its|its|PRP$|O role|role|NN|O as|as|IN|O an|a|DT|O antioxidant|antioxidant|JJ|O and|and|CC|O cellular|cellular|JJ|O redox|redox|NN|O stabilizer|stabilizer|NN|O ,|,|,|O NAC|nac|NN|O dramatically|dramatic|RB|O reduced|reduce|VBD|O intracellular|intracellular|JJ|O reactive|reactive|JJ|O oxygen|oxygen|NN|O species|specie|NNS|O production|production|NN|O in|in|IN|O the|the|DT|O presence|presence|NN|O of|of|IN|O TGF-beta1|TGF-beta1|NN|GENE .|.|.|O 
Finally|final|RB|O ,|,|,|O inhibition|inhibition|NN|O of|of|IN|O intracellular|intracellular|JJ|O ROS|ros|NN|O generation|generation|NN|O during|during|IN|O TGF-beta1|TGF-beta1|NN|GENE treatment|treatment|NN|O prevented|prevent|VBD|O alveolar|alveolar|JJ|O EMT|emt|NN|GENE ,|,|,|O but|but|CC|O treatment|treatment|NN|O with|with|IN|O H2O2|H2O2|NN|O alone|alone|RB|O did|do|VBD|O not|not|RB|O induce|induce|VB|O EMT|emt|NN|GENE .|.|.|O 
We|we|PRP|O conclude|conclude|VBP|O that|that|IN|O NAC|nac|NN|O prevents|prevent|VBZ|O EMT|emt|NNP|GENE in|in|IN|O AEC|aec|NNP|O in|in|FW|O vitro|vitro|FW|O ,|,|,|O at|at|IN|O least|little|JJS|O in|in|IN|O part|part|NN|O through|through|IN|O replenishment|replenishment|NN|O of|of|IN|O intracellular|intracellular|JJ|O GSH|gsh|NN|O stores|store|NNS|O and|and|CC|O limitation|limitation|NN|O of|of|IN|O TGF-beta1-induced|tgf-beta1-induced|JJ|O intracellular|intracellular|JJ|O ROS|ros|NN|O generation|generation|NN|O .|.|.|O 
We|we|PRP|O speculate|speculate|VBP|O that|that|IN|O beneficial|beneficial|JJ|O effects|effect|NNS|O of|of|IN|O NAC|nac|NN|O on|on|IN|O pulmonary|pulmonary|JJ|O function|function|NN|O in|in|IN|O IPF|IPF|NN|O may|may|MD|O be|be|VB|O mediated|mediate|VBN|O by|by|IN|O inhibitory|inhibitory|JJ|O effects|effect|NNS|O on|on|IN|O alveolar|alveolar|JJ|O EMT|emt|NN|GENE .|.|.|O 
Abrogation|abrogation|NN|O of|of|IN|O TGF-beta1-induced|tgf-beta1-induced|JJ|O fibroblast-myofibroblast|fibroblast-myofibroblast|JJ|O differentiation|differentiation|NN|O by|by|IN|O histone|histone|NN|GENE deacetylase|deacetylase|NN|GENE inhibition|inhibition|NN|O .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O devastating|devastating|JJ|O disease|disease|NN|O with|with|IN|O no|no|DT|O known|known|JJ|O effective|effective|JJ|O pharmacological|pharmacological|JJ|O therapy|therapy|NN|O .|.|.|O 
The|the|DT|O fibroblastic|fibroblastic|JJ|O foci|focus|NNS|O of|of|IN|O IPF|IPF|NN|O contain|contain|VBP|O activated|activate|VBN|O myofibroblasts|myofibroblast|NNS|O that|that|WDT|O are|be|VBP|O the|the|DT|O major|major|JJ|O synthesizers|synthesizer|NNS|O of|of|IN|O type|type|NN|O I|i|CD|O collagen|collagen|NN|O .|.|.|O 
Transforming|transform|VBG|O growth|growth|NN|O factor|factor|NN|O (|(|(|O TGF|tgf|NN|O )|)|)|O -|-|:|O beta1|beta1|NN|O promotes|promote|VBZ|O differentiation|differentiation|NN|O of|of|IN|O fibroblasts|fibroblast|NNS|O into|into|IN|O myofibroblasts|myofibroblast|NNS|O in|in|FW|O vitro|vitro|FW|O and|and|CC|O in|in|FW|O vivo|vivo|FW|O .|.|.|O 
In|in|IN|O the|the|DT|O current|current|JJ|O study|study|NN|O ,|,|,|O we|we|PRP|O investigated|investigate|VBD|O the|the|DT|O molecular|molecular|JJ|O link|link|NN|O between|between|IN|O TGF-beta1-mediated|tgf-beta1-mediated|JJ|O myofibroblast|myofibroblast|NN|O differentiation|differentiation|NN|O and|and|CC|O histone|histone|NN|GENE deacetylase|deacetylase|NN|GENE (|(|(|O HDAC|HDAC|NN|O )|)|)|O activity|activity|NN|O .|.|.|O 
Treatment|treatment|NN|O of|of|IN|O normal|normal|JJ|O human|human|JJ|O lung|lung|NN|O fibroblasts|fibroblast|NNS|O (|(|(|O NHLFs|nhlf|NNS|O )|)|)|O with|with|IN|O the|the|DT|O pan-HDAC|pan-HDAC|NN|O inhibitor|inhibitor|NN|O trichostatin|trichostatin|NN|O A|a|NN|O (|(|(|O TSA|tsa|NN|O )|)|)|O inhibited|inhibit|VBD|O TGF-beta1-mediated|tgf-beta1-mediated|JJ|O alpha-smooth-muscle-actin|alpha-smooth-muscle-actin|NN|GENE (|(|(|O alpha-SMA|alpha-SMA|NN|GENE )|)|)|O and|and|CC|O alpha1|alpha1|NN|O type|type|NN|O I|i|CD|O collagen|collagen|NN|O mRNA|mRNA|NN|O induction|induction|NN|O .|.|.|O 
TSA|tsa|NNP|O also|also|RB|O blocked|block|VBD|O the|the|DT|O TGF-beta1-driven|tgf-beta1-driven|JJ|O contractile|contractile|NN|O response|response|NN|O in|in|IN|O NHLFs|nhlf|NNS|O .|.|.|O 
The|the|DT|O inhibition|inhibition|NN|O of|of|IN|O alpha-SMA|alpha-SMA|NN|GENE expression|expression|NN|O by|by|IN|O TSA|tsa|NN|O was|be|VBD|O associated|associate|VBN|O with|with|IN|O reduced|reduce|VBN|O phosphorylation|phosphorylation|NN|O of|of|IN|O Akt|akt|NN|GENE ,|,|,|O and|and|CC|O a|a|DT|O pharmacological|pharmacological|JJ|O inhibitor|inhibitor|NN|O of|of|IN|O Akt|akt|NN|GENE blocked|block|VBD|O TGF-beta1-mediated|tgf-beta1-mediated|JJ|O alpha-SMA|alpha-SMA|NN|GENE induction|induction|NN|O in|in|IN|O a|a|DT|O dose-dependent|dose-dependent|JJ|O manner|manner|NN|O .|.|.|O 
HDAC4|HDAC4|NN|O knockdown|knockdown|NN|O was|be|VBD|O effective|effective|JJ|O in|in|IN|O inhibiting|inhibit|VBG|O TGF-beta1-stimulated|tgf-beta1-stimulated|JJ|O alpha-SMA|alpha-SMA|NN|GENE expression|expression|NN|O as|as|RB|O well|well|RB|O as|as|IN|O the|the|DT|O phosphorylation|phosphorylation|NN|O of|of|IN|O Akt|akt|NN|GENE .|.|.|O 
Moreover|moreover|RB|O ,|,|,|O the|the|DT|O inhibitors|inhibitor|NNS|O of|of|IN|O protein|protein|NN|O phosphatase|phosphatase|NN|O 2A|2A|NN|O and|and|CC|O 1|1|CD|O (|(|(|O PP2A|PP2A|NN|O and|and|CC|O PP1|pp1|NN|O )|)|)|O rescued|rescue|VBD|O the|the|DT|O TGF-beta1-mediated|tgf-beta1-mediated|JJ|O alpha-SMA|alpha-SMA|NN|GENE induction|induction|NN|O from|from|IN|O the|the|DT|O inhibitory|inhibitory|JJ|O effect|effect|NN|O of|of|IN|O TSA|tsa|NNP|O .|.|.|O 
Together|together|RB|O ,|,|,|O these|these|DT|O data|datum|NNS|O demonstrate|demonstrate|VBP|O that|that|IN|O the|the|DT|O differentiation|differentiation|NN|O of|of|IN|O NHLFs|nhlf|NNS|O to|to|TO|O myofibroblasts|myofibroblast|NNS|O is|be|VBZ|O HDAC4|HDAC4|NN|O dependent|dependent|JJ|O and|and|CC|O requires|require|VBZ|O phosphorylation|phosphorylation|NN|O of|of|IN|O Akt|akt|NN|GENE .|.|.|O 
NADPH|NADPH|NN|O oxidase-4|oxidase-4|NN|O mediates|mediate|VBZ|O myofibroblast|myofibroblast|NN|O activation|activation|NN|O and|and|CC|O fibrogenic|fibrogenic|JJ|O responses|response|NNS|O to|to|TO|O lung|lung|NN|O injury|injury|NN|O .|.|.|O 
Members|member|NNS|O of|of|IN|O the|the|DT|O NADPH|NADPH|NN|O oxidase|oxidase|NN|O (|(|(|O NOX|nox|NN|O )|)|)|O family|family|NN|O of|of|IN|O enzymes|enzyme|NNS|O ,|,|,|O which|which|WDT|O catalyze|catalyze|VBP|O the|the|DT|O reduction|reduction|NN|O of|of|IN|O O|o|NN|O (|(|(|O 2|2|CD|O )|)|)|O to|to|TO|O reactive|reactive|JJ|O oxygen|oxygen|NN|O species|specie|NNS|O ,|,|,|O have|have|VBP|O increased|increase|VBN|O in|in|IN|O number|number|NN|O during|during|IN|O eukaryotic|eukaryotic|JJ|O evolution|evolution|NN|O .|.|.|O 
Seven|seven|CD|O isoforms|isoform|NNS|O of|of|IN|O the|the|DT|O NOX|nox|NN|O gene|gene|NN|O family|family|NN|O have|have|VBP|O been|be|VBN|O identified|identify|VBN|O in|in|IN|O mammals|mammal|NNS|O ;|;|:|O however|however|RB|O ,|,|,|O specific|specific|JJ|O roles|role|NNS|O of|of|IN|O NOX|nox|NN|O enzymes|enzyme|NNS|O in|in|IN|O mammalian|mammalian|JJ|O physiology|physiology|NN|O and|and|CC|O pathophysiology|pathophysiology|NN|O have|have|VBP|O not|not|RB|O been|be|VBN|O fully|full|RB|O elucidated|elucidate|VBN|O .|.|.|O 
The|the|DT|O best|good|JJS|O established|establish|VBN|O physiological|physiological|JJ|O role|role|NN|O of|of|IN|O NOX|nox|NN|O enzymes|enzyme|NNS|O is|be|VBZ|O in|in|IN|O host|host|NN|O defense|defense|NN|O against|against|IN|O pathogen|pathogen|NN|O invasion|invasion|NN|O in|in|IN|O diverse|diverse|JJ|O species|specie|NNS|O ,|,|,|O including|include|VBG|O plants|plant|NNS|O .|.|.|O 
The|the|DT|O prototypical|prototypical|JJ|O member|member|NN|O of|of|IN|O this|this|DT|O family|family|NN|O ,|,|,|O NOX-2|NOX-2|NN|GENE (|(|(|O gp91|gp91|NN|O (|(|(|O phox|phox|NN|O )|)|)|O )|)|)|O ,|,|,|O is|be|VBZ|O expressed|express|VBN|O in|in|IN|O phagocytic|phagocytic|JJ|O cells|cell|NNS|O and|and|CC|O mediates|mediate|VBZ|O microbicidal|microbicidal|JJ|O activities|activity|NNS|O .|.|.|O 
Here|here|RB|O we|we|PRP|O report|report|VBP|O a|a|DT|O role|role|NN|O for|for|IN|O the|the|DT|O NOX4|NOX4|NN|GENE isoform|isoform|NN|O in|in|IN|O tissue|tissue|NN|O repair|repair|NN|O functions|function|NNS|O of|of|IN|O myofibroblasts|myofibroblast|NNS|O and|and|CC|O fibrogenesis|fibrogenesis|NN|O .|.|.|O 
Transforming|Transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta1|beta1|NN|GENE (|(|(|O TGF-beta1|TGF-beta1|NN|GENE )|)|)|O induces|induce|VBZ|O NOX-4|NOX-4|NN|GENE expression|expression|NN|O in|in|IN|O lung|lung|NN|O mesenchymal|mesenchymal|JJ|O cells|cell|NNS|O via|via|IN|O SMAD-3|SMAD-3|NN|GENE ,|,|,|O a|a|DT|O receptor-regulated|receptor-regulated|JJ|O protein|protein|NN|O that|that|WDT|O modulates|modulate|VBZ|O gene|gene|NN|O transcription|transcription|NN|O .|.|.|O 
NOX-4-dependent|nox-4-dependent|JJ|O generation|generation|NN|O of|of|IN|O hydrogen|hydrogen|NN|O peroxide|peroxide|NN|O (|(|(|O H|h|NN|O (|(|(|O 2|2|CD|O )|)|)|O O|o|NN|O (|(|(|O 2|2|CD|O )|)|)|O )|)|)|O is|be|VBZ|O required|require|VBN|O for|for|IN|O TGF-beta1-induced|tgf-beta1-induced|JJ|O myofibroblast|myofibroblast|NN|O differentiation|differentiation|NN|O ,|,|,|O extracellular|extracellular|JJ|O matrix|matrix|NN|O (|(|(|O ECM|ecm|NN|O )|)|)|O production|production|NN|O and|and|CC|O contractility|contractility|NN|O .|.|.|O 
NOX-4|NOX-4|NN|GENE is|be|VBZ|O upregulated|upregulate|VBN|O in|in|IN|O lungs|lung|NNS|O of|of|IN|O mice|mouse|NNS|O subjected|subject|VBN|O to|to|TO|O noninfectious|noninfectious|JJ|O injury|injury|NN|O and|and|CC|O in|in|IN|O cases|case|NNS|O of|of|IN|O human|human|JJ|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O .|.|.|O 
Genetic|genetic|JJ|O or|or|CC|O pharmacologic|pharmacologic|JJ|O targeting|targeting|NN|O of|of|IN|O NOX-4|NOX-4|NN|GENE abrogates|abrogate|VBZ|O fibrogenesis|fibrogenesis|NN|O in|in|IN|O two|two|CD|O murine|murine|JJ|O models|model|NNS|O of|of|IN|O lung|lung|NN|O injury|injury|NN|O .|.|.|O 
These|these|DT|O studies|study|NNS|O support|support|VBP|O a|a|DT|O function|function|NN|O for|for|IN|O NOX4|NOX4|NN|GENE in|in|IN|O tissue|tissue|NN|O fibrogenesis|fibrogenesis|NN|O and|and|CC|O provide|provide|VB|O proof|proof|NN|O of|of|IN|O concept|concept|NN|O for|for|IN|O therapeutic|therapeutic|JJ|O targeting|targeting|NN|O of|of|IN|O NOX-4|NOX-4|NN|GENE in|in|IN|O recalcitrant|recalcitrant|JJ|O fibrotic|fibrotic|JJ|O disorders|disorder|NNS|O .|.|.|O 
SNAI|Snai|NN|O transcription|transcription|NN|O factors|factor|NNS|O mediate|mediate|VBP|O epithelial-mesenchymal|epithelial-mesenchymal|JJ|O transition|transition|NN|O in|in|IN|O lung|lung|NN|O fibrosis|fibrosis|NN|O .|.|.|O 
BACKGROUND|background|NN|O :|:|:|O Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O fatal|fatal|JJ|O interstitial|interstitial|JJ|O lung|lung|NN|O disease|disease|NN|O characterised|characterize|VBN|O by|by|IN|O accumulation|accumulation|NN|O of|of|IN|O activated|activate|VBN|O (|(|(|O myo|Myo|NN|O )|)|)|O fibroblasts|fibroblast|NNS|O and|and|CC|O excessive|excessive|JJ|O extracellular|extracellular|JJ|O matrix|matrix|NN|O deposition|deposition|NN|O .|.|.|O 
The|the|DT|O enhanced|enhance|VBN|O accumulation|accumulation|NN|O of|of|IN|O (|(|(|O myo|Myo|NN|O )|)|)|O fibroblasts|fibroblast|NNS|O may|may|MD|O be|be|VB|O attributed|attribute|VBN|O ,|,|,|O in|in|IN|O part|part|NN|O ,|,|,|O to|to|TO|O the|the|DT|O process|process|NN|O of|of|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta1|beta1|NN|GENE (|(|(|O TGFbeta1|TGFbeta1|NN|GENE )|)|)|O -|-|:|O induced|induce|VBN|O epithelial-mesenchymal|epithelial-mesenchymal|JJ|O transition|transition|NN|O (|(|(|O EMT|emt|NN|GENE )|)|)|O ,|,|,|O the|the|DT|O phenotypic|phenotypic|JJ|O switching|switching|NN|O of|of|IN|O epithelial|epithelial|JJ|O to|to|TO|O fibroblast-like|fibroblast-like|JJ|O cells|cell|NNS|O .|.|.|O 
Although|although|IN|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O type|type|NN|O II|II|CD|O (|(|(|O ATII|ATII|NN|O )|)|)|O cells|cell|NNS|O have|have|VBP|O been|be|VBN|O shown|show|VBN|O to|to|TO|O undergo|undergo|VB|O EMT|emt|NN|GENE ,|,|,|O the|the|DT|O precise|precise|JJ|O mediators|mediator|NNS|O and|and|CC|O mechanisms|mechanism|NNS|O remain|remain|VBP|O to|to|TO|O be|be|VB|O resolved|resolve|VBN|O .|.|.|O 
The|the|DT|O objective|objective|NN|O of|of|IN|O this|this|DT|O study|study|NN|O is|be|VBZ|O to|to|TO|O investigate|investigate|VB|O the|the|DT|O role|role|NN|O of|of|IN|O SNAI|Snai|NN|O transcription|transcription|NN|O factors|factor|NNS|O in|in|IN|O the|the|DT|O process|process|NN|O of|of|IN|O EMT|emt|NN|GENE and|and|CC|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
METHODS|method|NNS|O :|:|:|O Using|use|VBG|O quantitative|quantitative|JJ|O reverse|reverse|NN|O transcription-PCR|transcription-PCR|NN|O (|(|(|O RT-PCR|rt-pcr|NN|O )|)|)|O ,|,|,|O immunofluorescence|immunofluorescence|NN|O ,|,|,|O immunohistochemistry|immunohistochemistry|NN|O ,|,|,|O western|western|NN|O blotting|blotting|NN|O ,|,|,|O as|as|RB|O well|well|RB|O as|as|IN|O gain|gain|NN|O -|-|:|O and|and|CC|O loss-of-function|loss-of-function|JJ|O studies|study|NNS|O and|and|CC|O functional|functional|JJ|O assays|assay|NNS|O ,|,|,|O the|the|DT|O role|role|NN|O of|of|IN|O SNAI1|SNAI1|NN|GENE and|and|CC|O SNAI2|SNAI2|NN|GENE in|in|IN|O TGFbeta1-induced|tgfbeta1-induced|JJ|O EMT|emt|NN|GENE in|in|IN|O ATII|ATII|NN|O cells|cell|NNS|O in|in|FW|O vitro|vitro|FW|O was|be|VBD|O assessed|assess|VBN|O ;|;|:|O and|and|CC|O the|the|DT|O expression|expression|NN|O of|of|IN|O SNAI|Snai|NN|O transcription|transcription|NN|O factors|factor|NNS|O was|be|VBD|O analysed|analyse|VBN|O in|in|IN|O experimental|experimental|JJ|O and|and|CC|O human|human|JJ|O IPF|IPF|NN|O in|in|FW|O vivo|vivo|FW|O .|.|.|O 
RESULTS|result|NNS|O :|:|:|O TGFbeta1|TGFbeta1|NN|GENE treatment|treatment|NN|O increased|increase|VBD|O the|the|DT|O expression|expression|NN|O and|and|CC|O nuclear|nuclear|JJ|O accumulation|accumulation|NN|O of|of|IN|O SNAI1|SNAI1|NN|GENE and|and|CC|O SNAI2|SNAI2|NN|GENE ,|,|,|O in|in|IN|O concert|concert|NN|O with|with|IN|O induction|induction|NN|O of|of|IN|O EMT|emt|NN|GENE in|in|IN|O ATII|ATII|NN|O cells|cell|NNS|O .|.|.|O 
SNAI|Snai|NN|O overexpression|overexpression|NN|O was|be|VBD|O sufficient|sufficient|JJ|O to|to|TO|O induce|induce|VB|O EMT|emt|NN|GENE ,|,|,|O and|and|CC|O small|small|JJ|O interfering|interfere|VBG|O RNA|rna|NN|O (|(|(|O siRNA|siRNA|NN|O )|)|)|O -|-|:|O mediated|mediate|VBN|O SNAI|Snai|NNP|O depletion|depletion|NN|O attenuated|attenuate|VBD|O TGFbeta1-induced|tgfbeta1-induced|JJ|O ATII|ATII|NN|O cell|cell|NN|O migration|migration|NN|O and|and|CC|O EMT|emt|NN|GENE .|.|.|O 
SNAI|Snai|NN|O expression|expression|NN|O was|be|VBD|O elevated|elevated|JJ|O in|in|IN|O experimental|experimental|JJ|O and|and|CC|O human|human|JJ|O IPF|IPF|NN|O and|and|CC|O localised|localised|JJ|O to|to|TO|O hyperplastic|hyperplastic|JJ|O ATII|ATII|NN|O cells|cell|NNS|O in|in|FW|O vivo|vivo|FW|O .|.|.|O 
CONCLUSIONS|conclusion|NNS|O :|:|:|O The|the|DT|O results|result|NNS|O demonstrate|demonstrate|VBP|O that|that|IN|O TGFbeta1-induced|tgfbeta1-induced|JJ|O EMT|emt|NN|GENE in|in|IN|O ATII|ATII|NN|O cells|cell|NNS|O is|be|VBZ|O essentially|essential|RB|O controlled|control|VBN|O by|by|IN|O the|the|DT|O expression|expression|NN|O and|and|CC|O nuclear|nuclear|JJ|O translocation|translocation|NN|O of|of|IN|O SNAI|Snai|NN|O transcription|transcription|NN|O factors|factor|NNS|O .|.|.|O 
Increased|increase|VBN|O SNAI1|SNAI1|NN|GENE and|and|CC|O SNAI2|SNAI2|NN|GENE expression|expression|NN|O in|in|IN|O experimental|experimental|JJ|O and|and|CC|O human|human|JJ|O IPF|IPF|NN|O in|in|FW|O vivo|vivo|FW|O suggests|suggest|VBZ|O that|that|IN|O SNAI-mediated|snai-mediated|JJ|O EMT|emt|NN|GENE may|may|MD|O contribute|contribute|VB|O to|to|TO|O the|the|DT|O fibroblast|fibroblast|NN|O pool|pool|NN|O in|in|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O .|.|.|O 
Effects|effect|NNS|O of|of|IN|O cigarette|cigarette|NN|O smoke|smoke|NN|O extract|extract|NN|O on|on|IN|O A549|A549|NN|O cells|cell|NNS|O and|and|CC|O human|human|JJ|O lung|lung|NN|O fibroblasts|fibroblast|NNS|O treated|treat|VBN|O with|with|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta1|beta1|NN|GENE in|in|IN|O a|a|DT|O coculture|coculture|NN|O system|system|NN|O .|.|.|O 
Smoking|smoking|NN|O is|be|VBZ|O a|a|DT|O risk|risk|NN|O factor|factor|NN|O for|for|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O ,|,|,|O but|but|CC|O the|the|DT|O mechanism|mechanism|NN|O of|of|IN|O the|the|DT|O association|association|NN|O remains|remain|VBZ|O unknown|unknown|JJ|O .|.|.|O 
The|the|DT|O aim|aim|NN|O of|of|IN|O this|this|DT|O study|study|NN|O was|be|VBD|O to|to|TO|O investigate|investigate|VB|O the|the|DT|O effects|effect|NNS|O of|of|IN|O cigarette|cigarette|NN|O smoke|smoke|NN|O extract|extract|NN|O (|(|(|O CSE|CSE|NN|O )|)|)|O on|on|IN|O A549|A549|NN|O cells|cell|NNS|O and|and|CC|O human|human|JJ|O lung|lung|NN|O fibroblasts|fibroblast|NNS|O treated|treat|VBN|O with|with|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta1|beta1|NN|GENE .|.|.|O 
A|a|DT|O transwell|transwell|NN|O two-chamber|two-chamber|JJ|O coculture|coculture|NN|O system|system|NN|O was|be|VBD|O used|use|VBN|O to|to|TO|O study|study|VB|O the|the|DT|O proliferation|proliferation|NN|O ,|,|,|O differentiation|differentiation|NN|O ,|,|,|O morphologic|morphologic|JJ|O changes|change|NNS|O and|and|CC|O soluble|soluble|JJ|O factors|factor|NNS|O production|production|NN|O of|of|IN|O A549|A549|NN|O cells|cell|NNS|O and|and|CC|O myofibroblasts|myofibroblast|NNS|O .|.|.|O 
Low|low|JJ|O concentrations|concentration|NNS|O of|of|IN|O CSE|CSE|NNP|O promoted|promote|VBD|O myofibroblasts|myofibroblast|NNS|O proliferation|proliferation|NN|O ;|;|:|O however|however|RB|O ,|,|,|O high|high|JJ|O concentrations|concentration|NNS|O of|of|IN|O CSE|CSE|NN|O inhibited|inhibit|VBD|O their|their|PRP$|O proliferation|proliferation|NN|O .|.|.|O 
Low|low|JJ|O concentrations|concentration|NNS|O of|of|IN|O CSE|CSE|NNP|O also|also|RB|O markedly|marked|RB|O increased|increase|VBD|O extracellular|extracellular|JJ|O secretion|secretion|NN|O of|of|IN|O hydrogen|hydrogen|NN|O peroxide|peroxide|NN|O ,|,|,|O inhibited|inhibit|VBD|O proliferation|proliferation|NN|O ,|,|,|O induced|induce|VBD|O apoptosis|apoptosis|NN|O and|and|CC|O produced|produce|VBD|O epithelial-mesenchymal|epithelial-mesenchymal|JJ|O transition|transition|NN|O (|(|(|O EMT|emt|NN|GENE )|)|)|O in|in|IN|O cocultured|coculture|VBN|O A549|A549|NN|O cells|cell|NNS|O .|.|.|O 
This|this|DT|O cigarette|cigarette|NN|O smoke-induced|smoke-induced|JJ|O A549|A549|NN|O cells|cell|NNS|O EMT|emt|NN|GENE may|may|MD|O become|become|VB|O a|a|DT|O new|new|JJ|O pathophysiological|pathophysiological|JJ|O concept|concept|NN|O in|in|IN|O the|the|DT|O development|development|NN|O of|of|IN|O IPF|IPF|NN|O .|.|.|O 
CSE|CSE|NNP|O possibly|possible|RB|O takes|take|VBZ|O part|part|NN|O in|in|IN|O the|the|DT|O development|development|NN|O and|and|CC|O progress|progress|NN|O of|of|IN|O IPF|IPF|NN|O by|by|IN|O increasing|increase|VBG|O oxidative|oxidative|JJ|O stress|stress|NN|O .|.|.|O 
Prostaglandin|prostaglandin|NN|O F|f|NN|O (|(|(|O 2alpha|2alpha|NN|O )|)|)|O receptor|receptor|NN|O signaling|signaling|NN|O facilitates|facilitate|VBZ|O bleomycin-induced|bleomycin-induced|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O independently|independent|RB|O of|of|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta|beta|NN|GENE .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O progressive|progressive|JJ|O disease|disease|NN|O characterized|characterize|VBN|O by|by|IN|O fibroblast|fibroblast|NN|O proliferation|proliferation|NN|O and|and|CC|O excess|excess|JJ|O deposition|deposition|NN|O of|of|IN|O collagen|collagen|NN|O and|and|CC|O other|other|JJ|O extracellular|extracellular|JJ|O matrix|matrix|NN|O (|(|(|O ECM|ecm|NN|O )|)|)|O proteins|protein|NNS|O ,|,|,|O which|which|WDT|O lead|lead|VBP|O to|to|TO|O distorted|distorted|JJ|O lung|lung|NN|O architecture|architecture|NN|O and|and|CC|O function|function|NN|O .|.|.|O 
Given|give|VBN|O that|that|IN|O anti-inflammatory|anti-inflammatory|JJ|O or|or|CC|O immunosuppressive|immunosuppressive|JJ|O therapy|therapy|NN|O currently|current|RB|O used|use|VBN|O for|for|IN|O IPF|IPF|NN|O does|do|VBZ|O not|not|RB|O improve|improve|VB|O disease|disease|NN|O progression|progression|NN|O therapies|therapy|NNS|O targeted|target|VBN|O to|to|TO|O blocking|block|VBG|O the|the|DT|O mechanisms|mechanism|NNS|O of|of|IN|O fibrogenesis|fibrogenesis|NN|O are|be|VBP|O needed|need|VBN|O .|.|.|O 
Although|although|IN|O transforming|transforming|NN|GENE growth|growth|NN|GENE factor|factor|NN|GENE beta|beta|NN|GENE (|(|(|O TGF-beta|TGF-beta|NN|GENE )|)|)|O functions|function|NNS|O are|be|VBP|O crucial|crucial|JJ|O in|in|IN|O fibrosis|fibrosis|NN|O ,|,|,|O antagonizing|antagonize|VBG|O this|this|DT|O pathway|pathway|NN|O in|in|IN|O bleomycin-induced|bleomycin-induced|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O ,|,|,|O an|a|DT|O animal|animal|NN|O model|model|NN|O of|of|IN|O IPF|IPF|NN|O ,|,|,|O does|do|VBZ|O not|not|RB|O prevent|prevent|VB|O fibrosis|fibrosis|NN|O completely|complete|RB|O ,|,|,|O indicating|indicate|VBG|O an|a|DT|O additional|additional|JJ|O pathway|pathway|NN|O also|also|RB|O has|have|VBZ|O a|a|DT|O key|key|JJ|O role|role|NN|O in|in|IN|O fibrogenesis|fibrogenesis|NN|O .|.|.|O 
Given|give|VBN|O that|that|IN|O the|the|DT|O loss|loss|NN|O of|of|IN|O cytosolic|cytosolic|JJ|O phospholipase|phospholipase|NN|O A|a|NN|O (|(|(|O 2|2|CD|O )|)|)|O (|(|(|O cPLA|cPLA|NN|O (|(|(|O 2|2|CD|O )|)|)|O )|)|)|O suppresses|suppress|VBZ|O bleomycin-induced|bleomycin-induced|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O ,|,|,|O we|we|PRP|O examined|examine|VBD|O the|the|DT|O roles|role|NNS|O of|of|IN|O prostaglandins|prostaglandin|NNS|O using|use|VBG|O mice|mouse|NNS|O lacking|lack|VBG|O each|each|DT|O prostoaglandin|prostoaglandin|NN|O receptor|receptor|NN|O .|.|.|O 
Here|here|RB|O we|we|PRP|O show|show|VBP|O that|that|IN|O loss|loss|NN|O of|of|IN|O prostaglandin|prostaglandin|NN|O F|f|NN|O (|(|(|O PGF|PGF|NN|O )|)|)|O receptor|receptor|NN|O (|(|(|O FP|fp|NN|O )|)|)|O selectively|selective|RB|O attenuates|attenuate|VBZ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O while|while|IN|O maintaining|maintain|VBG|O similar|similar|JJ|O levels|level|NNS|O of|of|IN|O alveolar|alveolar|JJ|O inflammation|inflammation|NN|O and|and|CC|O TGF-beta|TGF-beta|NN|GENE stimulation|stimulation|NN|O as|as|IN|O compared|compare|VBN|O to|to|TO|O wild-type|wild-type|JJ|O (|(|(|O WT|wt|JJ|O )|)|)|O mice|mouse|NNS|O ,|,|,|O and|and|CC|O that|that|IN|O FP|fp|NN|O deficiency|deficiency|NN|O and|and|CC|O inhibition|inhibition|NN|O of|of|IN|O TGF-beta|TGF-beta|NN|GENE signaling|signaling|NN|O additively|additive|RB|O decrease|decrease|VB|O fibrosis|fibrosis|NN|O .|.|.|O 
Furthermore|furthermore|RB|O ,|,|,|O PGF|PGF|NN|O (|(|(|O 2alpha|2alpha|NN|O )|)|)|O is|be|VBZ|O abundant|abundant|JJ|O in|in|IN|O bronchoalveolar|bronchoalveolar|JJ|O lavage|lavage|NN|O fluid|fluid|NN|O (|(|(|O BALF|BALF|NN|O )|)|)|O of|of|IN|O subjects|subject|NNS|O with|with|IN|O IPF|IPF|NN|O and|and|CC|O stimulates|stimulate|VBZ|O proliferation|proliferation|NN|O and|and|CC|O collagen|collagen|NN|O production|production|NN|O of|of|IN|O lung|lung|NN|O fibroblasts|fibroblast|NNS|O via|via|IN|O FP|fp|NN|O ,|,|,|O independently|independent|RB|O of|of|IN|O TGF-beta|TGF-beta|NN|GENE .|.|.|O 
These|these|DT|O findings|finding|NNS|O show|show|VBP|O that|that|IN|O PGF|PGF|NN|O (|(|(|O 2alpha|2alpha|NN|O )|)|)|O -|-|:|O FP|fp|NN|O signaling|signaling|NN|O facilitates|facilitate|VBZ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O independently|independent|RB|O of|of|IN|O TGF-beta|TGF-beta|NN|GENE and|and|CC|O suggests|suggest|VBZ|O this|this|DT|O signaling|signaling|NN|O pathway|pathway|NN|O as|as|IN|O a|a|DT|O therapeutic|therapeutic|JJ|O target|target|NN|O for|for|IN|O IPF|IPF|NN|O .|.|.|O 
SPARC|sparc|NNP|GENE suppresses|suppress|VBZ|O apoptosis|apoptosis|NN|O of|of|IN|O idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O fibroblasts|fibroblast|NNS|O through|through|IN|O constitutive|constitutive|JJ|O activation|activation|NN|O of|of|IN|O beta-catenin|beta-catenin|NN|GENE .|.|.|O 
Idiopathic|idiopathic|JJ|O pulmonary|pulmonary|JJ|O fibrosis|fibrosis|NN|O (|(|(|O IPF|IPF|NN|O )|)|)|O is|be|VBZ|O a|a|DT|O poorly|poor|RB|O understood|understand|VBN|O progressive|progressive|JJ|O disease|disease|NN|O characterized|characterize|VBN|O by|by|IN|O the|the|DT|O accumulation|accumulation|NN|O of|of|IN|O scar|scar|NN|O tissue|tissue|NN|O in|in|IN|O the|the|DT|O lung|lung|NN|O interstitium|interstitium|NN|O .|.|.|O 
A|a|DT|O hallmark|hallmark|NN|O of|of|IN|O the|the|DT|O disease|disease|NN|O is|be|VBZ|O areas|area|NNS|O of|of|IN|O injury|injury|NN|O to|to|TO|O type|type|NN|O II|II|CD|O alveolar|alveolar|JJ|O epithelial|epithelial|JJ|O cells|cell|NNS|O with|with|IN|O attendant|attendant|JJ|O accumulation|accumulation|NN|O of|of|IN|O fibroblasts|fibroblast|NNS|O in|in|IN|O areas|area|NNS|O called|call|VBN|O fibroblastic|fibroblastic|JJ|O foci|focus|NNS|O .|.|.|O 
In|in|IN|O an|a|DT|O effort|effort|NN|O to|to|TO|O better|well|RB|O characterize|characterize|VB|O the|the|DT|O lung|lung|NN|O fibroblast|fibroblast|NN|O phenotype|phenotype|NN|O in|in|IN|O IPF|IPF|NN|O patients|patient|NNS|O ,|,|,|O we|we|PRP|O isolated|isolate|VBD|O fibroblasts|fibroblast|NNS|O from|from|IN|O patients|patient|NNS|O with|with|IN|O IPF|IPF|NN|O and|and|CC|O looked|look|VBD|O for|for|IN|O activation|activation|NN|O of|of|IN|O signaling|signaling|NN|O proteins|protein|NNS|O ,|,|,|O which|which|WDT|O could|can|MD|O help|help|VB|O explain|explain|VB|O the|the|DT|O exaggerated|exaggerated|JJ|O fibrogenic|fibrogenic|JJ|O response|response|NN|O in|in|IN|O IPF|IPF|NN|O .|.|.|O 
We|we|PRP|O found|find|VBD|O that|that|IN|O IPF|IPF|NN|O fibroblasts|fibroblast|NNS|O constitutively|constitutive|RB|O expressed|express|VBD|O increased|increase|VBN|O basal|basal|JJ|O levels|level|NNS|O of|of|IN|O SPARC|sparc|NNP|GENE ,|,|,|O plasminogen|plasminogen|NN|GENE activator|activator|NN|GENE inhibitor|inhibitor|NN|GENE 1|1|NN|GENE (|(|(|O PAI-1|PAI-1|NN|GENE )|)|)|O ,|,|,|O and|and|CC|O active|active|JJ|O beta-catenin|beta-catenin|NN|GENE compared|compare|VBN|O with|with|IN|O control|control|NN|O cells|cell|NNS|O .|.|.|O 
Control|control|NN|O of|of|IN|O basal|basal|JJ|O PAI-1|PAI-1|NN|GENE expression|expression|NN|O in|in|IN|O IPF|IPF|NN|O fibroblasts|fibroblast|NNS|O was|be|VBD|O regulated|regulate|VBN|O by|by|IN|O SPARC-mediated|sparc-mediated|JJ|O activation|activation|NN|O of|of|IN|O Akt|akt|NN|GENE ,|,|,|O leading|lead|VBG|O to|to|TO|O inhibition|inhibition|NN|O of|of|IN|O glycogen|glycogen|NN|O synthase|synthase|NN|O kinase-3beta|kinase-3beta|NN|O and|and|CC|O activation|activation|NN|O of|of|IN|O beta-catenin|beta-catenin|NN|GENE .|.|.|O 
Additionally|additional|RB|O ,|,|,|O IPF|IPF|NN|O fibroblasts|fibroblast|NNS|O (|(|(|O but|but|CC|O not|not|RB|O control|control|JJ|O fibroblasts|fibroblast|NNS|O )|)|)|O were|be|VBD|O resistant|resistant|JJ|O to|to|TO|O plasminogen-induced|plasminogen-induced|JJ|O apoptosis|apoptosis|NN|O and|and|CC|O were|be|VBD|O sensitized|sensitise|VBN|O to|to|TO|O plasminogen-mediated|plasminogen-mediated|JJ|O apoptosis|apoptosis|NN|O by|by|IN|O inhibition|inhibition|NN|O of|of|IN|O SPARC|sparc|NNP|GENE or|or|CC|O beta-catenin|beta-catenin|NN|GENE .|.|.|O 
These|these|DT|O findings|finding|NNS|O uncover|uncover|VBP|O a|a|DT|O newly|new|RB|O discovered|discover|VBN|O regulatory|regulatory|JJ|O pathway|pathway|NN|O in|in|IN|O IPF|IPF|NN|O fibroblasts|fibroblast|NNS|O that|that|WDT|O is|be|VBZ|O characterized|characterize|VBN|O by|by|IN|O elevated|elevated|JJ|O SPARC|sparc|NNP|GENE ,|,|,|O giving|give|VBG|O rise|rise|NN|O to|to|TO|O activated|activate|VBN|O beta-catenin|beta-catenin|NN|GENE ,|,|,|O which|which|WDT|O regulates|regulate|VBZ|O expression|expression|NN|O of|of|IN|O downstream|downstream|JJ|O genes|gene|NNS|O ,|,|,|O such|such|JJ|O as|as|IN|O PAI-1|PAI-1|NN|GENE ,|,|,|O and|and|CC|O confers|confer|VBZ|O an|a|DT|O apoptosis-resistant|apoptosis-resistant|JJ|O phenotype|phenotype|NN|O .|.|.|O 
Disruption|disruption|NN|O of|of|IN|O this|this|DT|O pathway|pathway|NN|O may|may|MD|O represent|represent|VB|O a|a|DT|O novel|novel|JJ|O therapeutic|therapeutic|JJ|O target|target|NN|O in|in|IN|O IPF|IPF|NN|O .|.|.|O