Potential conflict of interest: Nothing to report.
Liver Failure/Cirrhosis/Portal Hypertension
Article first published online: 12 JAN 2012
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 3, pages 879–887, March 2012
How to Cite
Knight, V., Tchongue, J., Lourensz, D., Tipping, P. and Sievert, W. (2012), Protease-activated receptor 2 promotes experimental liver fibrosis in mice and activates human hepatic stellate cells. Hepatology, 55: 879–887. doi: 10.1002/hep.24784
This work was supported by grants from the National Health and Medical Research Council of Australia.
- Issue published online: 23 FEB 2012
- Article first published online: 12 JAN 2012
- Accepted manuscript online: 16 NOV 2011 09:46AM EST
- Manuscript Accepted: 11 OCT 2011
- Manuscript Received: 4 MAR 2011
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)