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PAR 1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation
Author(s) -
Fiorucci Stefano,
Antonelli Elisabetta,
Distrutti Eleonora,
Severino Beatrice,
Fiorentina Roviezzo,
Baldoni Monia,
Caliendo Giuseppe,
Santagada Vincenzo,
Morelli Antonio,
Cirino Giuseppe
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20054
Subject(s) - hepatic stellate cell , receptor , medicine , endocrinology , agonist , biology , cirrhosis , hepatic fibrosis , thrombin , chemistry , platelet
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. (H EPATOLOGY 2004;39:365–375.)