IMMUNE MECHANISMS IN HALOTHANE HEPATITIS

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.