TOXICOLOGICAL IMPORTANCE OF LIVER GLUTATHIONE

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DESCRIPTION: (Adapted from the Investigator's Abstract) The major objective of this proposal is to study the central role of reactive oxygen released by liver macrophages and neutrophils in the pathogenesisof endotoxin-induced liver injury and to test the hypothesis that the enhancedrelease of glutathione (GSH) from hepatocytes functions asan endogenous defense system of the liver to scavenge reactive oxygen species. Established models of endotoxin- induced liver injury will be used to investigate the temporal relationship between the oxidant stress, neutrophil localization in the liver and liver injury in vivo. Extracellular and intracellular reactive oxygen formation will be quantified in vivo through measurements of oxidized glutathione and, after isolation of macrophages and neutrophils from the liver, the cellular source and the nature ofthe oxidant stress will be identified. Alterations of the number and priming status of liver macrophages with various pretreatments or blocking of neutrophil adhesion and functions through newly developed monoclonalantibodies directed against the beta2- integrins on neutrophils (CD11/CD18 family) and ICAM on hepatocytes will be used to investigate the role of reactive oxygen in the pathogenesis. The protective role of GSH will be tested by manipulation of the hepatocellular glutathione content and plasma GSH concentrations. The mechanism of neutrophil-induced parenchymal cell injury, particularly the role of adhesion molecules on neutrophils and hepatocytes will be studied in isolated cells using flow cytometric and fluorescence imaging techniques. Theinformation from this study will give insight into the role of tissue macrophages and neutrophils in endotoxin-induced liver injury and the potential therapeutic value of glutathione.