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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017537-05
Application #
8474754
Study Section
Special Emphasis Panel (ZES1-JAB-G (R3))
Program Officer
Shreffler, Carol K
Project Start
2009-09-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$345,202
Indirect Cost
$116,591
Name
Michigan State University
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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
Lopez, Michelle; Kopec, Anna K; Joshi, Nikita et al. (2014) Fas-induced apoptosis increases hepatocyte tissue factor procoagulant activity in vitro and in vivo. Toxicol Sci 141:453-64
Kopec, Anna K; Luyendyk, James P (2014) Coagulation in liver toxicity and disease: role of hepatocyte tissue factor. Thromb Res 133 Suppl 1:S57-9
Joshi, Nikita; Kopec, Anna K; Towery, Keara et al. (2014) The antifibrinolytic drug tranexamic acid reduces liver injury and fibrosis in a mouse model of chronic bile duct injury. J Pharmacol Exp Ther 349:383-92
Kopec, Anna K; Joshi, Nikita; Towery, Keara L et al. (2014) Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice. J Pharmacol Exp Ther 351:288-97
Mochizuki, Akie; Pace, Aaron; Rockwell, Cheryl E et al. (2014) Hepatic stellate cells orchestrate clearance of necrotic cells in a hypoxia-inducible factor-1?-dependent manner by modulating macrophage phenotype in mice. J Immunol 192:3847-57
O'Brien, Kate M; Allen, Katryn M; Rockwell, Cheryl E et al. (2013) IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis. Am J Pathol 183:1498-507
Sullivan, Bradley P; Kopec, Anna K; Joshi, Nikita et al. (2013) Hepatocyte tissue factor activates the coagulation cascade in mice. Blood 121:1868-74
Sullivan, Bradley P; Kassel, Karen M; Jone, Alice et al. (2012) Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury. Am J Pathol 180:2321-9

Showing the most recent 10 out of 18 publications