| Protease-activated receptor 2 promotes experimental liver fibrosis and activates human hepatic stellate cells. | |
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MedLine Citation:
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PMID: 22095855 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Protease-activated receptor (PAR) 2 is a G protein coupled receptor that is activated following proteolytic cleavage by serine proteases including mast cell tryptase and activated coagulation factors. PAR-2 activation augments inflammatory and pro-fibrotic pathways through the induction of genes encoding proinflammatory cytokines and extra-cellular matrix proteins. Thus PAR-2 represents an important interface linking coagulation and inflammation. PAR-2 is widely expressed in cells of the gastrointestinal tract including hepatic stellate cells, endothelial cells and hepatic macrophages; however its role in liver fibrosis has not been previously examined. We studied the development of carbon tetrachloride induced liver fibrosis in PAR-2 knockout mice and showed that PAR-2 deficiency reduced the progression of liver fibrosis, hepatic collagen gene expression and hydroxyproline content. Reduced fibrosis was associated with decreased TGFβ gene and protein expression and decreased MMP2 and TIMP1 gene expression. In addition, PAR-2 stimulated activation, proliferation, collagen production and TGFβ protein production by human stellate cells, indicating that hepatic PAR-2 activation increases pro-fibrogenic cytokines and collagen production both in vivo and in vitro. Conclusion: Our findings demonstrate the capacity of PAR-2 activation to augment TGFβ production and promote hepatic fibrosis in mice and to induce a pro-fibrogenic phenotype in human hepatic stellate cells. PAR-2 antagonists have recently been developed and may represent a novel therapeutic approach in preventing fibrosis in patients with chronic liver disease. (HEPATOLOGY 2011.). |
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Authors:
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Virginia Knight; Jorge Tchongue; Dinushka Lourensz; Peter Tipping; William Sievert |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-16 |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: - ISSN: 1527-3350 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 American Association for the Study of Liver Diseases. |
Affiliation:
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Centre for Inflammatory Diseases, Monash University, Melbourne, Australia; Gastroenterology and Hepatology Unit, Monash Medical Centre, Melbourne, Australia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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