| First Author | Joshi N | Year | 2015 |
| Journal | J Thromb Haemost | Volume | 13 |
| Issue | 1 | Pages | 57-71 |
| PubMed ID | 25353084 | Mgi Jnum | J:299364 |
| Mgi Id | MGI:6492006 | Doi | 10.1111/jth.12770 |
| Citation | Joshi N, et al. (2015) Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice. J Thromb Haemost 13(1):57-71 |
| abstractText | BACKGROUND: The coagulation cascade has been shown to participate in chronic liver injury and fibrosis, but the contribution of various thrombin targets, such as protease activated receptors (PARs) and fibrin(ogen), has not been fully described. Emerging evidence suggests that in some experimental settings of chronic liver injury, platelets can promote liver repair and inhibit liver fibrosis. However, the precise mechanisms linking coagulation and platelet function to hepatic tissue changes following injury remain poorly defined. OBJECTIVES: To determine the role of PAR-4, a key thrombin receptor on mouse platelets, and fibrin(ogen) engagement of the platelet alphaII b beta3 integrin (alphaIIb beta3 ) in a model of cholestatic liver injury and fibrosis. METHODS: Biliary and hepatic injury was characterized following 4 week administration of the bile duct toxicant alpha-naphthylisothiocyanate (ANIT) (0.025%) in PAR-4-deficient mice, mice expressing a mutant form of fibrin(ogen) incapable of binding integrin alphaII b beta3 (Fibgamma(Delta5) ), and wild-type mice. RESULTS: Elevated plasma thrombin-antithrombin and serotonin levels, hepatic fibrin deposition, and platelet accumulation in liver accompanied hepatocellular injury and fibrosis in ANIT-treated wild-type mice. PAR-4 deficiency reduced plasma serotonin levels, increased serum bile acid concentration, and exacerbated ANIT-induced hepatocellular injury and peribiliary fibrosis. Compared with PAR-4-deficient mice, ANIT-treated Fibgamma(Delta5) mice displayed more widespread hepatocellular necrosis accompanied by marked inflammation, robust fibroblast activation, and extensive liver fibrosis. CONCLUSIONS: Collectively, the results indicate that PAR-4 and fibrin-alphaII b beta3 integrin engagement, pathways coupling coagulation to platelet activation, each exert hepatoprotective effects during chronic cholestasis. |
