Thiol regulation of pro-inflammatory cytokines reveals a novel immunopharmacological potential of glutathione in the alveolar epithelium

The therapeutic immunopharmacological potential of glutathione in the alveo lar epithelium is not well characterized. We developed an in vitro model of fetal alveolar type II epithelial cells to investigate the effect of redox disequilibrium on chemioxyexcitation (Delta pO(2)/ROS) induced up-regulati on of pro-inflammatory cytokines. Buthionine sulfoximine, an irreversible i nhibitor of gamma -glutamylcysteine synthetase, the rate-limiting enzyme in glutathione (GSH) biosynthesis, induced intracellular reactive oxygen spec ies (ROS) and the release of interleukin-1 beta (IL-1 beta), IL-6, and tumo r necrosis factor-alpha. Chloroethyl nitrosourea, which blocks the NADPH-de pendent recycling of oxidized glutathione (GSSG), reduced ROS-induced cytok ine production, similar to pyrrolidine dithiocarbamate, an antioxidant/pro- oxidant thiuram, which elevates GSSG. The antioxidant and GSH precursor, ac etylcysteine, abrogated cytokine release concomitant with suppression of RO S, an effect mimicked by gamma -glutamylcysteinyl- ethyl ester, a cell perm eant GSH. Cysteine, the rate-limiting amino acid in the de novo synthesis o f GSH, administered as oxothiazolidine carboxylate and adenosylmethionine, mitigated the chemioxyexcitation-dependent cytokine release. Ebselen, an an ti-inflammatory antioxidant, which mimics the effect of glutathione peroxid ase, neutralized ROS by the GSH-peroxidase-coupled reaction, thereby blocki ng the pathway to cytokine enhancement. Our results indicate that modulatin g redox equilibrium by pharmacological thiols exhibits differential regulat ion on pro-inflammatory cytokines, thus bearing clinical consequences for t he therapeutic treatment of pediatric distresses in pathophysiology.