Inhibition of PAR-4 and P2Y12 receptor-mediated platelet activation produces distinct hepatic pathologies in experimental xenobiotic-induced cholestatic liver disease. (15th July 2016)

• Record Type: Journal Article
• Authors: Joshi, Nikita; Kopec, Anna K.; Ray, Jessica L.; Luyendyk, James P.
• Is Part Of: Toxicology. Volume 365(2016)
• Page Start: 9
• Page End: 16
• Publication Date: 2016-07-15
• Subjects: ANIT alpha-naphthylisothiocyanate -- ADP adenosine diphosphate -- PAR protease activated receptor -- H&E hematoxylin and eosin -- CK-19 cytokeratin-19 -- ALT alanine aminotransferase -- TGFβ transforming growth factor beta -- COL1A1 type I collagen -- ITGβ6 integrin beta 6 -- TIMP1 tissue inhibitor of matrix metalloproteinase 1 -- αIIbβ3 alphaIIbbetaIIIintegrin -- αVβ6 alphaVbeta6 integrin; Platelets -- Liver disease -- Fibrosis -- Bile ducts; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2016.07.021
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Role and importance of specific platelet activation pathways in control of experimental xenobiotic-induced cholestatic liver injury and fibrosis. Abstract: Emerging evidence supports a protective effect of platelets in experimental cholestatic liver injury and cholangiofibrosis. Coagulation-mediated platelet activation has been shown to inhibit experimental chronic cholestatic liver necrosis and biliary fibrosis. This occurs through thrombin-mediated activation of protease activated receptor-4 (PAR-4) in mice. However, it is not known whether other pathways of platelet activation, such as adenosine diphosphate (ADP)-mediated receptor P2Y12 activation is also protective. We tested the hypothesis that inhibition of P2Y12 -mediated platelet activation exacerbates hepatic injury and cholangiofibrosis, and examined the impact of P2Y12 inhibition in both the presence and absence of PAR-4. Treatment of wild-type mice with the P2Y12 receptor antagonist clopidogrel increased biliary hyperplasia and cholangiofibrosis in wild-type mice exposed to the xenobiotic alpha-naphthylisothiocyanate (ANIT) for 4 weeks compared to vehicle-treated mice exposed to ANIT. Interestingly, this effect of clopidogrel occurred without a corresponding increase in hepatocellular necrosis. Whereas biliary hyperplasia and cholangiofibrosis were increased in PAR-4 −/− mice, clopidogrel treatment failed to further increase these pathologies in PAR-4 −/− mice. The results indicate that inhibition of receptor P2Y12 -mediated platelet activation exacerbates bile duct fibrosis in ANIT-exposed mice, independent of hepatocellular necrosis. Moreover, the lack of an added effect of clopidogrel administration on the exaggerated pathology in ANIT-exposed PAR-4 −/− mice reinforces the prevailing importance of coagulation-mediated platelet activation in limiting this unique liver pathology.