Glutathione protects signal transduction in type II cells under oxidant stress

Brief exposure of type II cells to 100 microM t-butyl hydroperoxide (tBOOH) inhibits agonist-induced surfactant secretion and second messenger generation presumably through the oxidation of membrane lipids. Since glutathione (GSH) reduces lipid peroxides and protects type II cells from oxidant injury as determined by crude indicators, then GSH should also protect signal transduction. In the current study, tBOOH inhibited ATP-induced adenosine 3',5'-cyclic monophosphate and inositol trisphosphate generation and surfactant secretion. Stimulation of surfactant secretion by forskolin or phorbol acetate was also inhibited by tBOOH. Pretreatment with GSH (1 mM) blocked the tBOOH inhibition. This protection occurred in the presence of gamma-glutamyl transferase and gamma-glutamylcysteine synthetase inhibitors and suggested GSH was transported as an intact molecule. GSH protection was blocked by gamma-L-glutamyl-L-glutamate, an agent that blocks GSH transport. Protection of surfactant secretion and signal transduction was also provided by the constitutive amino acids but not if GSH synthesis was blocked. In the cultured type II cell model, GSH transport and synthesis protected signal transduction and, subsequently, surfactant secretion against oxidant injury.