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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/4/G840    most recent 90639.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Luyendyk, J. P. Articles by Wang, R. Search for Related Content PubMed PubMed Citation Articles by Luyendyk, J. P. Articles by Wang, R.

LIVER AND BILIARY TRACT

Tissue factor-dependent coagulation contributes to -naphthylisothiocyanate-induced cholestatic liver injury in mice

¹Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas; ²Discovery Toxicology, Bristol-Myers Squibb, Princeton, New Jersey; ³Department of Protein Engineering, Genentech, South San Francisco, California; and ⁴Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina

Submitted 5 November 2008 ; accepted in final form 22 January 2009

Separation of concentrated bile acids from hepatic parenchymal cells is a key function of the bile duct epithelial cells (BDECs) that form intrahepatic bile ducts. Using coimmunostaining, we found that tissue factor (TF), the principal activator of coagulation, colocalized with cytokeratin 19, a marker of BDECs in the adult mouse liver. BDEC injury induced by xenobiotics such as -naphthylisothiocyanate (ANIT) causes cholestasis, inflammation, and hepatocellular injury. We tested the hypothesis that acute ANIT-induced cholestatic hepatitis is associated with TF-dependent activation of coagulation and determined the role of TF in ANIT hepatotoxicity. Treatment of mice with ANIT (60 mg/kg) caused multifocal hepatic necrosis and significantly increased serum biomarkers of cholestasis and hepatic parenchymal cell injury. ANIT treatment also significantly increased liver TF expression and activity. ANIT-induced activation of the coagulation cascade was shown by increased plasma thrombin-antithrombin levels and significant deposition of fibrin within the necrotic foci. ANIT-induced coagulation and liver injury were reduced in low-TF mice, which express 1% of normal TF levels. The results indicate that ANIT-induced liver injury is accompanied by TF-dependent activation of the coagulation cascade and that TF contributes to the progression of injury during acute cholestatic hepatitis.

cholestasis; -naphthylisothiocyanate