The role of tumor necrosis factor-alpha in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride.
Simeonova-PP; Gallucci-RM; Hulderman-T; Wilson-R; Kommineni-C; Rao-M; Luster-MI
Toxicol Appl Pharmacol 2001 Dec; 177(2):112-120
Hepatic expression of the proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) occurs in many acute and chronic liver diseases, as well as following exposure to hepatotoxic chemicals, and is believed to help influence both the damage and repair processes that occur following these insults by regulating additional mediators. We examined the role of TNFalpha in transgenic mice deficient in TNF receptors (TNFR) utilizing carbon tetrachloride (CCl(4)) as a model hepatotoxic agent that allowed for the evaluation of necrosis, inflammation, and fibrosis. Hepatocyte damage, as evident by local areas of liver necrosis and elevated levels of serum transaminase, occurred to a similar degree in wild-type and TNFR-deficient knockout (KO) mice following acute exposure to CCl(4). In contrast, the inflammatory response, manifested as an inflammatory cell influx, as well as induction of chemokines and adhesion molecules that occurred in wild-type mice following treatment with CCl(4), was not as evident in TNFR-KO mice. This response was associated primarily with type-1 (TNFR1) rather than type-2 (TNFR2) receptor responses. Liver fibrosis resulting from chronic CCl(4) exposure was also markedly dependent upon TNFalpha as demonstrated by almost a complete histological absence of fibrosis in TNFR-deficient mice. This was further supported by marked reductions in procollagen and transforming growth factor beta synthesis in TNFR-deficient mice. Taken together, these results indicate that TNFalpha is responsible for regulating products that induce inflammation and fibrosis but not direct hepatocyte damage in CCl(4)-induced hepatotoxicity.
Tumors; Fibrosis; Liver; Liver-disorders; Hepatotoxicity; Exposure-levels
Toxicology and Molecular Biology Branch, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, West Virginia 26505, USA
Toxicology and Applied Pharmacology