Extracellular glutathione peroxidase induction in asthmatic lungs: evidence for redox regulation of expression in human airway epithelial cells

A critical first-line antioxidant defense on the airway epithelial surface against reactive oxygen and nitrogen species (ROS and RNS) is extracellular glutathione peroxidase (eGPx). Little is known about the regulation of eGP x or its role in ROS-mediated lung diseases such as asthma. Here we show th at eGPx is increased in the asthmatic airway in comparison to healthy contr ols. Higher levels of eGPx mRNA in asthmatic airway epithelium verified bro nchial epithelial cells as the source for the increased eGPx, The eGPx mRNA in bronchial epithelial cells in vitro increased eightfold after exposure to ROS and glutathione, an essential cofactor for eGPx activity. Alteration s in intracellular and extracellular oxidized and reduced glutathione were temporally associated with eGPx induction, further supporting redox mechani sms in gene expression, Overexpression of superoxide dismutase, but not cat alase, inhibited induction and identified superoxide as a key intermediary. The eGPx mRNA half-life was not affected by ROS, suggesting a transcriptio nal mechanism for eGPx regulation. Fusion genes of deletion fragments of th e eGPx gene 5' flanking region driving a reporter gene conclusively identif ied the ROS-responsive region, which contained the consensus DNA binding si te for the redox-regulated transcription factor, activator protein 1.