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PAR1 Antagonism Protects Against Experimental Liver Fibrosis. Role of Proteinase Receptors in Stellate Cell Activation

PAR1 Antagonism Protects Against Experimental Liver Fibrosis. Role of Proteinase Receptors in Stellate Cell Activation

Stefano Fiorucci, Elisabetta Antonelli, Eleonora Distrutti, Beatrice Severino, Roviezzo Fiorentina, Monia Baldoni, Giuseppe Caliendo, Vincenzo Santagada, Antonio Morelli, Giuseppe Cirino

Hepatology. 2004 Feb;39(2):365-75.

PMID: 14767989

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4249365	PAR-2 Agonist I			Price

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