| First Author | Sullivan BP | Year | 2010 |
| Journal | Am J Pathol | Volume | 177 |
| Issue | 6 | Pages | 2837-49 |
| PubMed ID | 21037076 | Mgi Jnum | J:167636 |
| Mgi Id | MGI:4868664 | Doi | 10.2353/ajpath.2010.100425 |
| Citation | Sullivan BP, et al. (2010) The coagulation system contributes to alphaVbeta6 integrin expression and liver fibrosis induced by cholestasis. Am J Pathol 177(6):2837-49 |
| abstractText | 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. |
