A number of mechanisms have been proposed to explain the hepatic damage following the administration of the volatile anesthetic, halothane. Although explanations for this hepatotoxicity range from peroxidation, endotoxemia or hypoxia to hyperthyroidism or hypersensitivity, the pathogenetic mechanisms for halothane-induced liver damage are still not well understood. The goal of this study is to demonstrate the presence of and role for an immune component in modulating halothane-induced hepatoxicity. This goal will be accomplished through the following specific aims: (1) To establish the presence of a modified self component in the liver which has been altered by the metabolism of halothane. This modified self component could serve as a potential immunogen in the generation of an immune hypersensitivity response. (2) To detect in halothane-exposed animals the presence of a humoral immune response which cross reacts with synthetic halothane reactive intermediate conjugated proteins. (3) To determine if this humoral immune response plays a role in exacerbating halothane hepatotoxicity. (4) To assess """"""""halothane hepatitis"""""""" patients for the presence of a circulating antibody which cross reacts with halothane reactive intermediate conjugated proteins and (5) To extend this model of hypersensitivity in halothane hepatitis to other volatile anesthetics. The methodology in these investigations will include (1) an enzyme linked immunosorbent assay to detect specific antibodies to modified self or synthetics antigens; (2) indirect immunofluorescence, indirect immunoperoxidase, and complement mediated cytotoxicity to determine the presence of halothane reactive intermediate-modified liver tissue and/or hepatocytes; (3) existing in vivo models of halothane hepatotoxicity to examine the development of a halothane reactive intermediate-induced immune response and any subsequent potentiation of the liver injury by this immune response; (4) collaborative ties with anesthesiologists within and outside the United States to expedite access to """"""""halothane hepatitis"""""""" patient sera. Ultimately, this project will determine if a hypersensitivity immune response is instrumental in the pathogenetic mechanisms of halothane hepatotoxicity.
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