title: 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 CCl(4) -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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Inflammatory Diseases, Monash University, Melbourne, Victoria, Australia.
authors.forename: Virginia
authors.initials: V
authors.lastname: Knight
authors.forename: Jorge
authors.initials: J
authors.lastname: Tchongue
authors.forename: Dinushka
authors.initials: D
authors.lastname: Lourensz
authors.forename: Peter
authors.initials: P
authors.lastname: Tipping
authors.forename: William
authors.initials: W
authors.lastname: Sievert
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000503:physiopathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016207:Cytokines; D009842:Oligopeptides; D044464:Receptor, PAR-2; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; C109968:seryl-leucyl-isoleucyl--glycyl-lysyl-valine; D003094:Collagen; D002251:Carbon Tetrachloride; D020778:Matrix Metalloproteinase 2; D006909:Hydroxyproline