{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:53:39Z","timestamp":1791176019640,"version":"4.1.0"},"reference-count":58,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2009,4]]},"abstract":"<jats:p>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 \u03b1-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.<\/jats:p>","DOI":"10.1152\/ajpgi.90639.2008","type":"journal-article","created":{"date-parts":[[2009,1,30]],"date-time":"2009-01-30T02:44:24Z","timestamp":1233283464000},"page":"G840-G849","source":"Crossref","is-referenced-by-count":38,"title":["Tissue factor-dependent coagulation contributes to \u03b1-naphthylisothiocyanate-induced cholestatic liver injury in mice"],"prefix":"10.1152","volume":"296","author":[{"given":"James P.","family":"Luyendyk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn H.","family":"Cantor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kirchhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Mackman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan L.","family":"Copple","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruipeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1989.257.1.G124"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1016\/0049-3848(95)00157-M"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1994.1245"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00372.2007"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20665"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(65)90125-0"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.161026"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(91)90353-7"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.046391"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2006.05.016"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1006\/taap.2002.9394"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.20.11023"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17564"},{"key":"R14","doi-asserted-by":"crossref","unstructured":"Dahm LJ, Schultze AE, Roth RA.An antibody to neutrophils attenuates alpha-naphthylisothiocyanate-induced liver injury.J Pharmacol Exp Ther256: 412\u2013420, 1991.","DOI":"10.1016\/S0022-3565(25)23054-3"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1016\/0163-7258(91)90029-L"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-483X(01)00459-0"},{"key":"R17","unstructured":"Drake TA, Morrissey JH, Edgington TS.Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis.Am J Pathol134: 1087\u20131097, 1989."},{"key":"R18","unstructured":"Eliakim M, Eisner M, Ungar H.Experimental intrahepatic obstructive jaundice following ingestion of alphanaphthyl-iso-thiocyanate.Bull Res Counc Isr Sect E Exp Med8E: 7\u201317, 1959."},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1177\/153537020422901104"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1172\/JCI20741"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1007\/BF00269495"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1136\/gut.29.8.1103"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(01)00285-9"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21779"},{"key":"R25","unstructured":"Goldfarb S, Singer EJ, Popper H.Experimental cholangitis due to alpha-naphthyl-isothiocyanate (ANIT).Am J Pathol40: 685\u2013698, 1962."},{"key":"R26","doi-asserted-by":"crossref","unstructured":"Hansen CB, van Deurs B, Petersen LC, Rao LV.Discordant expression of tissue factor and its activity in polarized epithelial cells. Asymmetry in anionic phospholipid availability as a possible explanation.Blood94: 1657\u20131664, 1999.","DOI":"10.1182\/blood.V94.5.1657"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/47.1.118"},{"key":"R28","doi-asserted-by":"crossref","unstructured":"Huang ZF, Higuchi D, Lasky N, Broze GJ Jr.Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice.Blood90: 944\u2013951, 1997.","DOI":"10.1182\/blood.V90.3.944.944_944_951"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1038\/nm1317"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI10489"},{"key":"R31","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfi336"},{"key":"R32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI3011"},{"key":"R33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2005.01253.x"},{"key":"R34","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00458.2005"},{"key":"R35","doi-asserted-by":"publisher","DOI":"10.1006\/faat.1995.1074"},{"key":"R36","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.2001.281.1.G182"},{"key":"R37","unstructured":"Luther T, Fl\u00f6ssel C, Mackman N, Bierhaus A, Kasper M, Albrecht S, Sage EH, Iruela-Arispe L, Grossmann H, Str\u00f6hlein A, Zhang Y, Nawroth PP, Carmeliet P, Loskutoff DJ, M\u00fcller M.Tissue factor expression during human and mouse development.Am J Pathol149: 101\u2013113, 1996."},{"key":"R38","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.087981"},{"key":"R39","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000183884.06371.52"},{"key":"R40","unstructured":"Mackman N, Sawdey MS, Keeton MR, Loskutoff DJ.Murine tissue factor gene expression in vivo: tissue and cell specificity and regulation by lipopolysaccharide.Am J Pathol143: 76\u201384, 1993."},{"key":"R41","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-1345(01)02512-X"},{"key":"R42","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2004.06.001"},{"key":"R43","doi-asserted-by":"publisher","DOI":"10.1172\/JCI814"},{"key":"R44","doi-asserted-by":"crossref","unstructured":"Pearson JM, Schultze AE, Schwartz KA, Scott MA, Davis JM, Roth RA.The thrombin inhibitor, hirudin, attenuates lipopolysaccharide-induced liver injury in the rat.J Pharmacol Exp Ther278: 378\u2013383, 1996.","DOI":"10.1016\/S0022-3565(25)20145-8"},{"key":"R45","doi-asserted-by":"crossref","unstructured":"Plaa GL, Priestly BG.Intrahepatic cholestasis induced by drugs and chemicals.Pharmacol Rev28: 207\u2013273, 1976.","DOI":"10.1016\/S0031-6997(25)06713-4"},{"key":"R46","doi-asserted-by":"crossref","unstructured":"Reinhardt C, von Bruhl ML, Manukyan D, Grahl L, Lorenz M, Altmann B, Dlugai S, Hess S, Konrad I, Orschiedt L, Mackman N, Ruddock L, Massberg S, Engelmann B.Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation.J Clin Invest118: 1110\u20131122, 2008.","DOI":"10.1172\/JCI32376"},{"key":"R47","unstructured":"Rodriguez-Garay EA.Cholestasis: human disease and experimental animal models.Ann Hepatol2: 150\u2013158, 2003."},{"key":"R48","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfh078"},{"key":"R49","doi-asserted-by":"publisher","DOI":"10.3109\/03602539709037578"},{"key":"R50","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.3.2002"},{"key":"R51","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v12.i48.7725"},{"key":"R52","doi-asserted-by":"publisher","DOI":"10.1002\/lt.21128"},{"key":"R53","doi-asserted-by":"publisher","DOI":"10.1006\/abio.1997.2431"},{"key":"R54","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2006"},{"key":"R55","unstructured":"Willingham AK, Matschiner JT.The activation of factor X by hepatocyte plasma membranes.Cell Mol Biol35: 421\u2013429, 1989."},{"key":"R56","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-991516"},{"key":"R57","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-199901150-00007"},{"key":"R58","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfm131"}],"container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpgi.90639.2008","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T09:06:07Z","timestamp":1738919167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpgi.90639.2008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,4]]},"references-count":58,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2009,4]]}},"alternative-id":["10.1152\/ajpgi.90639.2008"],"URL":"https:\/\/doi.org\/10.1152\/ajpgi.90639.2008","relation":{},"ISSN":["0193-1857","1522-1547"],"issn-type":[{"value":"0193-1857","type":"print"},{"value":"1522-1547","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,4]]}}}