Tissue levels of glutathione (GSH) play an important role in the protection of the lung against injury by hyperoxia, but little information is available about factors that regulate the synthesis of lung GSH. Gamma-Glu-Cys-synthetase and Gamma-Glu-transpeptidase are enzymes known to be important in GSH synthesis in general. We have found that Gamma-Glu-transpeptidase, but not Gamma-Glu-Cys-synthetase, is stimulated in lungs of rats exposed to hyperoxia and plan to investigate the correlation of the stimulation of this enzymatic activity with increases in lung GSH. The bovine pulmonary artery endothelial cell in culture will be tested for induction of Gamma-Glu-transpeptidase by hyperoxia, and these results will be correlated with our observed elevation of GSH in endothelial cells exposed to hyperoxia. Factors that may regulate Gamma-Glu-transpeptidase and, thereby, GSH will be evaluated in the perfused rat lung and in calf pulmonary artery endothelial cells in culture. The delivery of Gamma-Glu-Cys, a dipeptide precursor of GSH, to lungs and endothelial cells in culture will be assessed for its ability to elevate levels of tissue and cellular GSH and for protection against hyperoxia. Liposomes will be used as one method to deliver the Gamma-Glu-Cys. Modification of levels of GSH with diethylmaleate, buthionine sulfoximine and nutritional alterations will be studied in our experimental systems and will be evaluated for changes in sensitivity to hyperoxia. We anticipate that these studies will provide a broader assessment of modification of lung GSH and will make available new insights for protection of the lung against hyperoxia and other injurious oxidants.
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