Chemioxyexcitation (Delta pO(2)/ROS)-dependent release of IL-1 beta, IL-6 and TNF-alpha: Evidence of cytokines as oxygen-sensitive mediators in the alveolar epithelium

The signalling mechanisms in oxidative stress mediated by cytokines in the perinatal alveolar epithelium are not well known. In an in vitro model of f etal alveolar type II epithelial cells, we investigated the profile of cyto kines in response to ascending Delta pO(2) regimen (oxyexcitation). The pea k of TNF-alpha (4 h) preceded IL-1 beta and IL-6 (6-9 h), indicating a posi tive feedback autocrine loop confirmed by exogenous rmTNF-alpha. Reactive o xygen species (ROS) induced a dose-dependent release of cytokines, an effec t specifically obliterated by selective antioxidants of the hydroxyl radica l ((OH)-O-.) and superoxide anion (O-2(-)). Actinomycin and cycloheximide b locked the induced production of cytokines, implicating transcriptional and translational control. Whilst the dismutating enzymes superoxide dismutase (SOD) and catalase were ineffective in reducing ROS-induced cytokines, MnP , a cell-permeating SOD mimetic, abrogated xanthine/xanthine oxidase-depend ent cytokine release. Desferrioxamine mesylate, which inhibits the iron-cat alysed generation of OH via the Fenton reaction, exhibited a mild effect on the release of cytokines. Dynamic variation in alveolar pO(2) constitutes a potential signalling mechanism within the perinatal lung allowing upregul ation of cytokines in an ROS-dependent manner. (C) 2001 Academic Press.