Mechanisms of xenobiotic-induced biliary inflammation and fibrosis

Summary

Principal Investigator: James Luyendyk
Affiliation: University of Kansas Medical Center
Country: USA
Abstract: Abstract 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.
Funding Period: ----------------2009 - ---------------2014-
more information: NIH RePORT

Top Publications

  1. pmc Tissue factor-dependent coagulation contributes to alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice
    James P Luyendyk
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
    Am J Physiol Gastrointest Liver Physiol 296:G840-9. 2009
  2. pmc Coagulation in liver toxicity and disease: role of hepatocyte tissue factor
    Anna K Kopec
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824
    Thromb Res 133:S57-9. 2014
  3. pmc The antifibrinolytic drug tranexamic acid reduces liver injury and fibrosis in a mouse model of chronic bile duct injury
    Nikita Joshi
    Department of Pathobiology and Diagnostic Investigation A K K, K T, K J W, J P L, Department of Pharmacology and Toxicology N J, and Center for Integrative Toxicology N J, A K K, J P L, Michigan State University, East Lansing, Michigan
    J Pharmacol Exp Ther 349:383-92. 2014
  4. pmc IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis
    Kate M O'Brien
    Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
    Am J Pathol 183:1498-507. 2013
  5. pmc Hepatocyte tissue factor activates the coagulation cascade in mice
    Bradley P Sullivan
    Department of Pathobiology and Diagnostic Investigation, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA
    Blood 121:1868-74. 2013
  6. pmc Therapeutic administration of the direct thrombin inhibitor argatroban reduces hepatic inflammation in mice with established fatty liver disease
    Karen M Kassel
    Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA
    Am J Pathol 181:1287-95. 2012
  7. pmc Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy
    Hong Min Ni
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, United States
    J Hepatol 61:617-25. 2014
  8. pmc The coagulation system contributes to alphaVbeta6 integrin expression and liver fibrosis induced by cholestasis
    Bradley P Sullivan
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
    Am J Pathol 177:2837-49. 2010
  9. pmc Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes
    Shuang Mei
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center MS 1018, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
    J Pharmacol Exp Ther 339:487-98. 2011
  10. pmc Role of fibrinogen and protease-activated receptors in acute xenobiotic-induced cholestatic liver injury
    James P Luyendyk
    Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Toxicol Sci 119:233-43. 2011

Scientific Experts

  • James Luyendyk
  • Bradley P Sullivan
  • Karen M Kassel
  • Anna K Kopec
  • Bryan L Copple
  • Nikita Joshi
  • Hong Min Ni
  • Wei Cui
  • Keara Towery
  • Kate M O'Brien
  • Wen Xing Ding
  • Cheryl E Rockwell
  • Nigel Mackman
  • Shuang Mei
  • Sharon Manley
  • BRYAN COPPLE
  • Hartmut Jaeschke
  • Kurt J Williams
  • Jessica Williams
  • Benjamin L Woolbright
  • Stephanie C Bishop
  • CHERYL ROCKWELL
  • Holly Cline
  • Juliette A Brown
  • Katryn M Allen
  • Matthew J Flick
  • Alice Jone
  • Ruipeng Wang
  • A Phillip Owens
  • Grace L Guo
  • Alyson K Baker
  • Ossama Tawfik
  • Abigail Bockus
  • Guodong Li
  • Paul H Weinreb
  • Shelia M Violette

Detail Information

Publications18

  1. pmc Tissue factor-dependent coagulation contributes to alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice
    James P Luyendyk
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
    Am J Physiol Gastrointest Liver Physiol 296:G840-9. 2009
    ..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...
  2. pmc Coagulation in liver toxicity and disease: role of hepatocyte tissue factor
    Anna K Kopec
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824
    Thromb Res 133:S57-9. 2014
    ..This review will briefly cover the expression and regulation of TF by hepatocytes, the role of TF in coagulation triggered by liver toxicity, and the contribution of coagulation activity to the progression of liver disease. ..
  3. pmc The antifibrinolytic drug tranexamic acid reduces liver injury and fibrosis in a mouse model of chronic bile duct injury
    Nikita Joshi
    Department of Pathobiology and Diagnostic Investigation A K K, K T, K J W, J P L, Department of Pharmacology and Toxicology N J, and Center for Integrative Toxicology N J, A K K, J P L, Michigan State University, East Lansing, Michigan
    J Pharmacol Exp Ther 349:383-92. 2014
    ..In addition, these proof-of-principle studies suggest the possibility that therapeutic intervention with an antifibrinolytic drug could form a novel strategy to prevent or reduce liver injury and fibrosis in patients with liver disease. ..
  4. pmc IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis
    Kate M O'Brien
    Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
    Am J Pathol 183:1498-507. 2013
    ....
  5. pmc Hepatocyte tissue factor activates the coagulation cascade in mice
    Bradley P Sullivan
    Department of Pathobiology and Diagnostic Investigation, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA
    Blood 121:1868-74. 2013
    ..These results suggest that mouse HPCs constitutively express cell surface TF that mediates activation of coagulation during hepatocellular injury...
  6. pmc Therapeutic administration of the direct thrombin inhibitor argatroban reduces hepatic inflammation in mice with established fatty liver disease
    Karen M Kassel
    Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA
    Am J Pathol 181:1287-95. 2012
    ..This study indicates that therapeutic intervention with a thrombin inhibitor attenuates hepatic inflammation and several profibrogenic changes in mice fed a Western diet...
  7. pmc Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy
    Hong Min Ni
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, United States
    J Hepatol 61:617-25. 2014
    ..The purpose of the present study was to investigate the mechanism(s) by which the loss of hepatic autophagy leads to liver inflammation, fibrosis and tumorigenesis...
  8. pmc The coagulation system contributes to alphaVbeta6 integrin expression and liver fibrosis induced by cholestasis
    Bradley P Sullivan
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
    Am J Pathol 177:2837-49. 2010
    ..These results indicate that a TF-PAR-1 pathway contributes to liver fibrosis induced by chronic cholestasis by increasing expression of the αVβ6 integrin, an important regulator of transforming growth factor-β1 activation...
  9. pmc Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes
    Shuang Mei
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center MS 1018, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
    J Pharmacol Exp Ther 339:487-98. 2011
    ..Potential modulation of autophagy may be a novel approach that has therapeutic benefits for obesity-induced steatosis and liver injury...
  10. pmc Role of fibrinogen and protease-activated receptors in acute xenobiotic-induced cholestatic liver injury
    James P Luyendyk
    Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Toxicol Sci 119:233-43. 2011
    ..Moreover, the data suggest a dual role for PAR-4 in ANIT hepatotoxicity, both mediating an early protection against peliosis and contributing to the progression of hepatocellular necrosis...
  11. pmc Tissue factor contributes to neutrophil CD11b expression in alpha-naphthylisothiocyanate-treated mice
    James P Luyendyk
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 250:256-62. 2011
    ....
  12. pmc Regulation of transforming growth factor-β1-dependent integrin β6 expression by p38 mitogen-activated protein kinase in bile duct epithelial cells
    Bradley P Sullivan
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
    J Pharmacol Exp Ther 337:471-8. 2011
    ..Overall, the results suggest that p38 contributes to TGF-β1-induced Itgβ6 mRNA expression in MMNK-1 cells by regulating activation of both SMAD and AP-1 transcription factors...
  13. pmc Fibrinogen deficiency increases liver injury and early growth response-1 (Egr-1) expression in a model of chronic xenobiotic-induced cholestasis
    James P Luyendyk
    Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Am J Pathol 178:1117-25. 2011
    ..The results suggest that in this model of chronic cholestasis, fibrin constrains the release of bile constituents from injured intrahepatic bile ducts, thereby limiting the progression of hepatic inflammation and hepatocellular injury...
  14. pmc Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury
    Bradley P Sullivan
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Am J Pathol 180:2321-9. 2012
    ..The results indicate that fibrin(ogen) does not contribute to development of APAP-induced liver injury and suggest rather that plasminogen activation contributes to APAP-induced liver injury...
  15. pmc Early growth response factor-1 limits biliary fibrosis in a model of xenobiotic-induced cholestasis in mice
    Bradley P Sullivan
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Toxicol Sci 126:267-74. 2012
    ..Rather, these studies indicate that Egr-1 deficiency worsens liver fibrosis in conjunction with enhanced expression of the profibrogenic Itgb6 gene...
  16. pmc Protease-activated receptor 1 and hematopoietic cell tissue factor are required for hepatic steatosis in mice fed a Western diet
    Karen M Kassel
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
    Am J Pathol 179:2278-89. 2011
    ..Moreover, hematopoietic cell TF deficiency reduced hepatic fibrin deposition. These studies indicate that PAR-1 and hematopoietic cell TF are required for liver inflammation and steatosis in mice fed a Western diet...
  17. pmc Lipopolysaccharide enhances transforming growth factor β1-induced platelet-derived growth factor-B expression in bile duct epithelial cells
    Karen M Kassel
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    J Gastroenterol Hepatol 27:714-21. 2012
    ..Transforming growth factor β (TGFβ) and lipopolysaccharide (LPS) also contribute to the profibrogenic response after bile duct ligation. We tested the hypothesis that LPS and TGFβ1 synergistically induce PDGF-B expression in BDECs...