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Protease-activated receptor 2 promotes experimental liver fibrosis in mice and activates human hepatic stellate cells

Authors

  • Virginia Knight,

    1. Center for Inflammatory Diseases, Monash University Monash University, Melbourne, Victoria, Australia
    2. Gastroenterology and Hepatology Unit, Monash Medical Center, Melbourne, Victoria, Australia
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  • Jorge Tchongue,

    1. Center for Inflammatory Diseases, Monash University Monash University, Melbourne, Victoria, Australia
    2. Gastroenterology and Hepatology Unit, Monash Medical Center, Melbourne, Victoria, Australia
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  • Dinushka Lourensz,

    1. Center for Inflammatory Diseases, Monash University Monash University, Melbourne, Victoria, Australia
    2. Gastroenterology and Hepatology Unit, Monash Medical Center, Melbourne, Victoria, Australia
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  • Peter Tipping,

    1. Center for Inflammatory Diseases, Monash University Monash University, Melbourne, Victoria, Australia
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  • William Sievert

    Corresponding author
    1. Center for Inflammatory Diseases, Monash University Monash University, Melbourne, Victoria, Australia
    2. Gastroenterology and Hepatology Unit, Monash Medical Center, Melbourne, Victoria, Australia
    • Gastroenterology and Hepatology Unit, Monash Medical Center, 246 Clayton Road, Melbourne, Victoria 3168, Australia fax: 613 9594 6250
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  • Potential conflict of interest: Nothing to report.

  • This work was supported by grants from the National Health and Medical Research Council of Australia.

Abstract

Protease-activated receptor (PAR) 2 is a G-protein–coupled receptor that is activated after proteolytic cleavage by serine proteases, including mast cell tryptase and activated coagulation factors. PAR-2 activation augments inflammatory and profibrotic pathways through the induction of genes encoding proinflammatory cytokines and extracellular 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 (HSCs), endothelial cells, and hepatic macrophages; however, its role in liver fibrosis has not been previously examined. We studied the development of CCl4-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 transforming growth factor beta (TGFβ) gene and protein expression and decreased matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinase 1 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 profibrogenic 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 profibrogenic phenotype in human HSCs. 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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