Protective and damaging effects of platelets in acute cholestatic liver injury revealed by depletion and inhibition strategies.

Toxicological Sciences : an Official Journal of the Society of Toxicology
Bradley P SullivanJames P Luyendyk

Abstract

Alpha-naphthylisothiocyanate (ANIT) causes cholestatic hepatitis characterized by intrahepatic bile duct epithelial cell injury and periportal hepatocellular necrosis. The progression of ANIT-induced hepatocyte injury is reported to involve extrahepatic cells including platelets. We showed recently that the procoagulant protein tissue factor (TF) is essential for ANIT-induced coagulation and contributes to ANIT-induced liver necrosis. Platelets have been shown to express TF and can contribute to coagulation cascade activation. To this end, we tested the hypothesis that platelet-dependent coagulation contributes to ANIT-induced liver injury. In ANIT (60 mg/kg)-treated mice, activation of the coagulation cascade occurred prior to a decrease of platelets in the blood. Immunostaining for glycoprotein IIb (CD41) revealed platelet accumulation along the borders of necrotic foci in livers of ANIT-treated mice. Antibody-mediated platelet depletion did not affect coagulation but markedly affected liver histopathology in ANIT-treated mice. Platelet depletion induced marked pooling of blood within necrotic lesions consistent with parenchymal-type peliosis as early as 24 h after ANIT treatment. In contrast, treatment with the P2Y(12) inhib...Continue Reading

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Citations

Oct 27, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·James P LuyendykBradley P Sullivan
Dec 22, 2012·American Journal of Physiology. Gastrointestinal and Liver Physiology·Patricia F LalorDavid H Adams
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Apr 4, 2021·International Journal of Molecular Sciences·Marion MussbacherAlice Assinger
Mar 29, 2021·Journal of Thrombosis and Haemostasis : JTH·Dafna J GroeneveldJames P Luyendyk

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