title: Inhibition of PAR-4 and P2Y12 receptor-mediated platelet activation produces distinct hepatic pathologies in experimental xenobiotic-induced cholestatic liver disease.
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.
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, United States; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Nikita
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, United States; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kopec
authors.affiliation: Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Ray
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, United States; Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, United States; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States. Electronic address: luyendyk@cvm.msu.edu.
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
mesh_terms: D015058:1-Naphthylisothiocyanate; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D002779:Cholestasis / Q000139:chemically induced / Q000473:pathology*; D000077144:Clopidogrel; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D044462:Receptors, Proteinase-Activated / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012701:Serotonin / Q000097:blood; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015262:Xenobiotics
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D044462:Receptors, Proteinase-Activated; D015262:Xenobiotics; C481942:protease-activated receptor 4, mouse; D012701:Serotonin; D015058:1-Naphthylisothiocyanate; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Bile ducts; Fibrosis; Liver disease; Platelets