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Coagulation driven platelet activation reduces injury and fibrosis in chronic liver disease (144.3)
Author(s) -
Joshi Nikita,
Kopec Anna,
Towery Keara,
Cline Holly,
Williams Kurt,
Flick Matthew,
Luyendyk James
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.144.3
Subject(s) - cholestasis , fibrin , fibrosis , platelet , liver injury , platelet activation , chemistry , endocrinology , medicine , thrombin , chronic liver disease , inflammation , platelet adhesiveness , immunology , cirrhosis , platelet aggregation
Previous studies suggest that platelets and fibrin(ogen), components of the hemostatic system, reduce hepatocellular injury and inhibit liver fibrosis in models of cholestasis. However, the molecular pathways linking fibrin polymerization and platelet activation to liver injury during cholestasis are not known. We hypothesized that platelet activation by thrombin‐mediated protease activated receptor (PAR)‐4 signaling and fibrin engagement of the αIIBβ3 integrin on platelets are key events linked to inhibition of hepatic injury and fibrosis in a mouse model of cholestasis. To test this hypothesis, mice expressing a mutant form of fibrin(ogen) incapable of binding αIIBβ3 (FibγΔ5), mice lacking PAR‐4 and wild‐type (WT) mice were fed a diet containing the bile duct toxicant alpha‐naphthylisothiocyanate (ANIT) (0.025%), or control diet (AIN‐93M) for four weeks. Consistent with our hypothesis, PAR‐4 deficiency significantly increased portal inflammation and peribiliary fibrosis in mice fed ANIT diet, but did not increase liver necrosis. Hepatocellular necrosis increased significantly in FibγΔ5 mice fed ANIT diet compared to WT mice. The enhanced necrosis was accompanied increased hepatic deposition of type 1 collagen protein. The results indicate that PAR‐4 dependent platelet activation and fibrin‐αIIBβ3 integrin engagement have hepatoprotective effects in a model of chronic biliary injury.