Submitted on November 5, 2008
Revised on January 9, 2009
Accepted on January 22, 2009
Tissue factor-dependent coagulation contributes to alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice
James P Luyendyk1*, Glenn H Cantor2, Daniel Kirchhofer3, Nigel Mackman4, Bryan L Copple1, and Ruipeng Wang1
1 University of Kansas Medical Center
2 Bristol-Myers Squibb
3 Genentech, Inc.
4 University of North Carolina-Chapel Hill
* To whom correspondence should be addressed. E-mail: jluyendyk{at}kumc.edu.
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 co-immunostaining, 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 alpha-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.
