PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation

Hepatology. 2004 Feb;39(2):365-75. doi: 10.1002/hep.20054.


In fibroblasts, thrombin induces collagen deposition through activation of a G-protein-coupled receptor, proteinase-activated receptor 1 (PAR(1)). In the current study, we examined whether PAR(1) antagonism inhibits hepatic stellate cell (HSC) activation in vitro and whether it protects against fibrosis development in a rodent model of cirrhosis. A rat HSC line was used for in vitro studies whereas cirrhosis was induced by bile duct ligation (BDL). The current results demonstrated that HSCs express PAR(1), as well as proteinase-activated receptors 2 (PAR(2)) and 4 (PAR(4)), and that all three PARs were up-regulated in response to exposure to growth factor in vitro. Exposure to thrombin and to SFLLRN-(SF)-NH(2), a PAR(1) agonist, and GYPGKF (GY)-NH(2), a PAR(4) agonist, triggered HSC proliferation and contraction, as well as monocyte chemotactic protein-1 (MCP-1) production and collagen I synthesis and release. These effects were inhibited by the PAR(1) antagonist. Administration of this antagonist, 1.5 mg/kg/d, to BDL rats reduced liver type I collagen messenger RNA (mRNA) expression and surface collagen by 63%, as measured by quantitative morphometric analysis. Similarly, hepatic and urinary excretion of hydroxyproline was reduced significantly by the PAR(1) antagonist. In conclusion, PAR(s) regulates HSC activity; development of PAR antagonists might be a feasible therapeutic strategy for protecting against fibrosis in patients with chronic liver diseases.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Bile Ducts
  • Cell Line, Transformed
  • Collagen Type I / biosynthesis
  • GRB2 Adaptor Protein
  • Gene Expression
  • Hemostatics / pharmacology*
  • Ligation
  • Liver / cytology
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / physiopathology
  • Liver Cirrhosis / prevention & control*
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • Oligopeptides / pharmacology
  • Peptide Fragments / pharmacology
  • Proteins / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, PAR-1 / antagonists & inhibitors*
  • Receptor, PAR-1 / genetics
  • Receptor, PAR-2 / genetics
  • Receptors, Thrombin / genetics
  • Thrombin / pharmacology*


  • Adaptor Proteins, Signal Transducing
  • Collagen Type I
  • GRB2 Adaptor Protein
  • GYPGKF-NH(2)
  • Grb2 protein, rat
  • Hemostatics
  • Oligopeptides
  • Peptide Fragments
  • Proteins
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Receptors, Thrombin
  • thrombin receptor peptide (42-47)
  • Mitogen-Activated Protein Kinases
  • Thrombin
  • protease-activated receptor 4