| First Author | Joshi N | Year | 2016 |
| Journal | Blood | Volume | 127 |
| Issue | 22 | Pages | 2751-62 |
| PubMed ID | 26921287 | Mgi Jnum | J:234730 |
| Mgi Id | MGI:5790752 | Doi | 10.1182/blood-2015-09-670703 |
| Citation | Joshi N, et al. (2016) Fibrin deposition following bile duct injury limits fibrosis through an alphaMbeta2-dependent mechanism. Blood 127(22):2751-62 |
| abstractText | Coagulation cascade activation and fibrin deposits have been implicated or observed in diverse forms of liver damage. Given that fibrin amplifies pathological inflammation in several diseases through the integrin receptor alphaMbeta2, we tested the hypothesis that disruption of the fibrin(ogen)-alphaMbeta2 interaction in Fibgamma(390-396A) mice would reduce hepatic inflammation and fibrosis in an experimental setting of chemical liver injury. Contrary to our hypothesis, alpha-naphthylisothiocyanate (ANIT)-induced liver fibrosis increased in Fibgamma(390-396A) mice, whereas inflammatory cytokine expression and hepatic necrosis were similar to ANIT-challenged wild-type (WT) mice. Increased fibrosis in Fibgamma(390-396A) mice appeared to be independent of coagulation factor 13 (FXIII) transglutaminase, as ANIT challenge in FXIII-deficient mice resulted in a distinct pathological phenotype characterized by increased hepatic necrosis. Rather, bile duct proliferation underpinned the increased fibrosis in ANIT-exposed Fibgamma(390-396A) mice. The mechanism of fibrin-mediated fibrosis was linked to interferon (IFN)gamma induction of inducible nitric oxide synthase (iNOS), a gene linked to bile duct hyperplasia and liver fibrosis. Expression of iNOS messenger RNA was significantly increased in livers of ANIT-exposed Fibgamma(390-396A) mice. Fibrin(ogen)-alphaMbeta2 interaction inhibited iNOS induction in macrophages stimulated with IFNgamma in vitro and ANIT-challenged IFNgamma-deficient mice had reduced iNOS induction, bile duct hyperplasia, and liver fibrosis. Further, ANIT-induced iNOS expression, liver fibrosis, and bile duct hyperplasia were significantly reduced in WT mice administered leukadherin-1, a small molecule that allosterically enhances alphaMbeta2-dependent cell adhesion to fibrin. These studies characterize a novel mechanism whereby the fibrin(ogen)-integrin-alphaMbeta2 interaction reduces biliary fibrosis and suggests a novel putative therapeutic target for this difficult-to-treat fibrotic disease. |
