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Role of TNF-receptors (TNFR) in carbon tetrachloride-induced liver toxicity.

Authors
Simeonova-PP; Flood-L; Komminemi-C; Luster-MI
Source
Toxicologist 1998 Mar; 42(1-S):271-272
NIOSHTIC No.
20025156
Abstract
Carbon tetrachloride (CCI4), a classical hepatotoxicant, causes acute, reversible liver injury characterized by centrilobular necrosis, fat accumulation, influx of neutrophils followed by hepatic regeneration and tissue repair. Although. TNF-a appears to be an important mediator in the pathogenesis of these processes, the role and the mechanisms responsible are still not well understood. TNF-a. a pleiotropic and multifunctional cytokine, transduces regulatory abilities by two distinct cell surface receptors of 55 kd (TNFRp55) and 75 kd (TNFRp75) with most of the known cellular TNF responses attributed to TNFRp55 activation. We used TNFR-deficient mice to characterized the contributions of these receptors in chemical-induced liver toxicity. Single injections of CCl(4) in double knockout mice dose dependently induced larger centrilobular necrosis, prominent destruction of the surrounding hepatocytes and minimal inflammatory response comparing to the same exposure in the background control mice. Liver regeneration, measured as PCNA staining, was impaired in TNFR deficient mice particularly at exposures to high doses of CCl(4). TNFRp55 is sufficient for mediating TNF effects in this model since mice deficient for this receptor demonstrated liver toxicity with similar characteristics as the double TNFR deficient mice. The protective role of TNF-a in CCl(4) -induced liver toxicity may be associated with activation of several transcription factors including NF-kB and AP-1 and generation of secondary inflammatory mediators such as C-C chemokines.
Keywords
Carbonates; Hepatotoxins; Hepatotoxicity; Liver-damage; Liver-disorders; Liver-function; Pathogenesis; Animals; Animal-studies; Laboratory-animals; Liver-tissue
CAS No.
56-23-5
Publication Date
19980301
Document Type
Abstract
Fiscal Year
1998
NTIS Accession No.
NTIS Price
ISSN
1096-6080
NIOSH Division
DBBS
Source Name
The Toxicologist. Society of Toxicology 37th Annual Meeting, March 1-5,1998, Seattle, Washington
State
OH; WA
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