期刊
TOXICOLOGICAL SCIENCES
卷 154, 期 2, 页码 381-391出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfw175
关键词
TCDD; Coagulation; PAR-1; Fibrosis; NAFLD
类别
资金
- National Institutes of Health [NIH R01 ES017537]
- National Institute of Environmental Health Sciences Superfund Research Program [NIEHS SRP P42ES04911]
- AgBioResearch at MSU
- MSU Barnett Rosenberg Endowed Assistantship and Integrative Training in the Pharmacological Sciences grant [NIH 5T32GM092715]
- Canadian Institutes of Health Research (CIHR) Doctoral Foreign Study Award [DFS-140386]
Emerging evidence supports a role for environmental chemical exposure in the pathology of non-alcoholic fatty liver disease (NAFLD), a disease process tightly linked to increased activity of the blood coagulation cascade. Exposure of C57BL/6 mice to the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) recapitulates features of the NAFLD spectrum, including steatosis, hepatic injury, inflammation, and fibrosis. We assessed coagulation cascade activation, and determined the role of the thrombin receptor protease activated receptor-1 (PAR-1) in experimental TCDDelicited NAFLD. Chronic exposure to TCDD (30 mu g/kg every 4 days for 28 days) was associated with intrahepatic coagulation, indicated by increased plasma thrombin-antithrombin levels and hepatic fibrin(ogen) deposition. PAR-1 deficiency diminished TCDD-elicited body weight loss and relative liver weight was reduced in TCDD-exposed PAR-1(-/-) mice compared with TCDD-exposed wild-type mice. PAR-1 deficiency did not affect TCDD-induced hepatic steatosis or hepatocellular injury, as indicated by serum alanine aminotransferase activity. Despite a lack of effect on these 2 features of NAFLD pathology, PAR-1 deficiency was associated with a reduction in hepatic inflammation evident in liver histopathology, and reflected by a reduction in serum levels of the proinflammatory cytokine interleukin-6. Moreover, TCDD-driven hepatic collagen deposition was markedly reduced in PAR-1-deficient mice. These results indicate that experimental TCDD-elicited steatohepatitis is associated with coagulation cascade activation and PAR-1-driven hepatic inflammation and fibrosis.
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