Inhibition of PAR-4 and P2Y₁₂ receptor-mediated platelet activation produces distinct hepatic pathologies in experimental xenobiotic-induced cholestatic liver disease

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• 作者：Nikita Joshi^a ; ^c ; Anna K. Kopec^b ; ^c ; Jessica L. Ray^b ; James P. Luyendyk^a ; ^b ; ^c ; ^{luyendyk@cvm.msu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：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
• 刊名：Toxicology
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：365
• 期：Complete
• 页码：9-16
• 全文大小：2282 K

文摘

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.