title: Tissue factor-dependent coagulation contributes to alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice.
abstract: 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 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.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Blvd., MS-1018, Kansas City, KS 66160, USA. jluyendyk@kumc.edu
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Cantor
authors.forename: Daniel
authors.initials: D
authors.lastname: Kirchhofer
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Copple
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Wang
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D002779:Cholestasis / Q000139:chemically induced*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015058:1-Naphthylisothiocyanate; D013925:Thromboplastin