The coagulation system contributes to alphaVbeta6 integrin expression and liver fibrosis induced by cholestasis.

摘要

Chronic injury to intrahepatic bile duct epithelial cells (BDECs) elicits expression of various mediators, including the alphaVbeta6 integrin, promoting liver fibrosis. We tested the hypothesis that tissue factor (TF)-dependent thrombin generation and protease activated receptor-1 (PAR-1) activation contribute to liver fibrosis induced by cholestasis via induction of alphaVbeta6 expression. To test this hypothesis, mice deficient in either TF or PAR-1 were fed a diet containing 0.025 alpha-naphthylisothiocyanate (ANIT), a BDEC-selective toxicant. In genetically modified mice with a 50 reduction in liver TF activity fed an ANIT diet, coagulation cascade activation and liver fibrosis were reduced. Similarly, liver fibrosis was significantly reduced in PAR-1(-/-) mice fed an ANIT diet. Hepatic integrin beta6 mRNA induction, expression of alphaVbeta6 protein by intrahepatic BDECs, and SMAD2 phosphorylation were reduced by TF deficiency and PAR-1 deficiency in mice fed the ANIT diet. Treatment with either an anti-alphaVbeta6 blocking antibody or soluble transforming growth factor-beta receptor type II reduced liver fibrosis in mice fed the ANIT diet. PAR-1 activation enhanced transforming growth factor-beta1-induced integrin beta6 mRNA expression in both transformed human BDECs and primary rat BDECs. Interestingly, TF and PAR-1 mRNA levels were increased in livers from patients with cholestatic liver disease. These results indicate that a TF-PAR-1 pathway contributes to liver fibrosis induced by chronic cholestasis by increasing expression of the alphaVbeta6 integrin, an important regulator of transforming growth factor-beta1 activation.