Thiol Regulation of Pro-Inflammatory Cytokines Reveals a Novel Immunopharmacological Potential of Glutathione in the Alveolar Epithelium

摘要

The therapeutic immunopharmacological potential of glutathi- one in the alveolar 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 chemi- oxyexcitation {llpO2/ROS) induced up-regulation of pro-inflam-matory cytokines. Buthionine sulfoximine, an irreversible inhib- itor of 'Y-glutamylcysteine synthetase, the rate-Iimiting enzyme in glutathione {GSH) biosynthesis, induced intracellular reactive oxygen species {ROS) and the release of interleukin-1f3 {IL-1f3), IL-6, and tumor necrosis factor-a. Chloroethyl nitrosourea, which blocks the NADPH-dependent recycling of oxidized glu- tathione {GSSG), reduced ROS-induced cytokine production, similar to pyrrolidine dithiocarbamate, an antioxidanVpro-oxi- dant thiuram, which elevates GSSG. The antioxidant and GSH precursor, acetylcysteine, abrogated cytokine release concom- itant with suppression of ROS, an effect mimicked by 'Y-glu- tamylcysteinyl-ethyl ester, a cell permeant GSH. Cysteine, the rate-Iimiting amino acid in the de novo synthesis of GSH, ad- ministered as oxothiazolidine carboxylate and adenosylmethi- onine, mitigated the chemioxyexcitation-dependent cytokine release. Ebselen, an anti-inflammatory antioxidant, which mim- ics the effect of glutathione peroxidase, neutralized ROS by the GSH-peroxidase-coupled reaction, thereby blocking the path- way to cytokine enhancement. Our results indicate that modu- lating redox equilibrium by pharmacological thiols exhibits dif- ferential regulation on pro-inflammatory cytokines, thus bearing clinical consequences for th~ therapeutic treatment of pediatric distresses in pathophysiology.