Damage to bile duct epithelial cells causes cholestatic liver disease. The broad, long term goal of this proposal is to elucidate the mechanism whereby xenobiotic-induced cholestasis causes inflammation and fibrosis. Epidemiological studies link human exposure to environmental xenobiotics and cholestatic liver disease. Xenobiotic exposure can cause bile duct injury and chronic cholestasis. The pathologic consequences of cholestasis include liver parenchymal cell injury, inflammation and fibrosis, all of which contribute to liver- related morbidity and mortality in patients with cholestatic liver disease. Determining mechanisms of xenobiotic-induced cholestasis, inflammation and fibrosis could identify novel strategies to limit the progression of cholestatic liver disease. Our preliminary studies indicate that tissue factor (TF), the primary activator of the coagulation cascade, is expressed by bile duct epithelial cells. We found that TF-dependent coagulation contributed to the progression of acute, xenobiotic-induced cholestatic liver injury. To determine whether TF contributes to biliary fibrosis, we established a mouse model of chronic xenobiotic-induced biliary inflammation and fibrosis. Mice were fed a diet containing 0.1% alpha-naphthylisothiocyanate, a xenobiotic for which unique hepatic metabolism causes selective bile duct epithelial cell injury. Cellular and histopathological changes in livers of mice fed the ANIT diet resembled primary biliary cirrhosis. Our preliminary studies indicate that systemic hypercoagulability in mice fed the ANIT diet is TF-dependent. Neutrophil activation, bile duct injury and collagen deposition were significantly reduced in low TF mice, which express 1% of normal TF levels. These results form the basis of this proposal, which will test the hypothesis that TF expressed by bile duct epithelial cells generates coagulation proteases that promote inflammation and fibrosis in xenobiotic-induced cholestasis by activating protease activated receptors. This hypothesis will be tested utilizing various genetic strategies, bone marrow transplantation, and a combination of in vivo and in vitro approaches. The apparent hypercoagulability of patients with cholestatic liver disease is consistent with the observation that TF is expressed by the bile duct epithelial cells. To this end, a greater understanding of the mechanisms whereby TF-dependent coagulation contributes to inflammation and fibrosis in xenobiotic-induced cholestasis could lead to novel strategies to treat patients with cholestatic liver disease.

Public Health Relevance

Certain liver diseases are associated with excessive activity of blood clotting factors. The progression of liver disease is linked to environmental chemical exposure. The purpose of this project is to determine the role of the blood clotting system in the progression of liver disease caused by chemical exposure.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZES1-JAB-G (R3))
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Shreffler, Carol K
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Michigan State University
Schools of Veterinary Medicine
East Lansing
United States
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Kopec, A K; Joshi, N; Luyendyk, J P (2016) Role of hemostatic factors in hepatic injury and disease: animal models de-liver. J Thromb Haemost 14:1337-49
Joshi, Nikita; Kopec, Anna K; Ray, Jessica L et al. (2016) Inhibition of PAR-4 and P2Y12 receptor-mediated platelet activation produces distinct hepatic pathologies in experimental xenobiotic-induced cholestatic liver disease. Toxicology 365:9-16
Joshi, Nikita; Kopec, Anna K; Ray, Jessica L et al. (2016) Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism. Blood 127:2751-62
Rautou, Pierre-Emmanuel; Tatsumi, Kohei; Antoniak, Silvio et al. (2016) Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury. J Hepatol 64:53-9
Kopec, Anna K; Luyendyk, James P (2016) Role of Fibrin(ogen) in Progression of Liver Disease: Guilt by Association? Semin Thromb Hemost :
Ellery, Paul E R; Maroney, Susan A; Cooley, Brian C et al. (2015) A balance between TFPI and thrombin-mediated platelet activation is required for murine embryonic development. Blood 125:4078-84
Joshi, N; Kopec, A K; O'Brien, K M et al. (2015) Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice. J Thromb Haemost 13:57-71
Ni, Hong-Min; Woolbright, Benjamin L; Williams, Jessica et al. (2014) Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. J Hepatol 61:617-25
Kopec, Anna K; Sullivan, Bradley P; Kassel, Karen M et al. (2014) Toxicogenomic analysis reveals profibrogenic effects of trichloroethylene in autoimmune-mediated cholangitis in mice. Toxicol Sci 141:515-23
Rautou, Pierre-Emmanuel; Vion, Anne-Clémence; Luyendyk, James P et al. (2014) Circulating microparticle tissue factor activity is increased in patients with cirrhosis. Hepatology 60:1793-5

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