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

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.

Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-β Receptor Signaling Pathways Contributes to Renal Fibrosis

“…Evidence suggests that PAR2 plays an important role in tissue fibrosis (12)(13)(14), but the molecular mechanism is undefined. In this study, we show that PAR2 contributes to early fibrosis in a murine experimental model of renal injury.…”

“…A recent study showed that PAR2 deficiency protected liver from the progression of fibrosis. A PAR2 agonist had a profibrogenic effect on hepatic stellate cells suggesting that PAR2 activation augments TGF␤ and other profibrotic genes, which in turn promote hepatic fibrosis in both in vivo and in vitro (12). In addition, an important role for PAR2 has been suggested in pulmonary fibrosis in vivo and fibroblast proliferation in vitro (13,14).…”

Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

“…The role of matriptase on AEC type II cells is obviously of interest in these future studies. Furthermore, CM is efficient in experimental models of fibrosis affecting other organs where PAR-2 is instrumental (40,53,54). Thus, further studies aimed at elucidating the role of matriptase in these diseases are warranted.…”

Human hepatic stellate cell isolation and characterization

“…They have also been shown to inactivate and acquire a quiescent-like phenotype, which might help with regression of liver fibrosis [114,115]. As well, blockage of certain proteins in HSC activation pathways might prove to have therapeutic implication in human diseases [98,[116][117][118]. Mouse model studies and advanced HSC isolation techniques have contributed to the elucidation of this cell's functions.…”