The lung tissue is one of the main targets of oxidative stress due to external sources and respiratory activity. In our previous work we have demonstrated in that O3 exposure alters the Cl- current-voltage relationship, with the appearance of a large outward rectifier component mainly sustained by ORCCs (Outward Rectifier Chloride Channel) in human lung epithelial cells (A549 line). In the present study we have performed patch clamp experiments, in order to identify which one of the O3 byproducts (4hydroxynonenal (HNE) and/or H2 O2 ) was responsible for chloride current change. While 4HNE exposition (up to 25μM for 30' before electrophysiological analysis) did not reproduce O3 effect, H2 O2 produced by Glucose Oxidase 10mU for 24h before electrophysiological analysis, mimicked O3 response. This result was confirmed treating the cell with catalase (CAT) before O3 exposure (1000 U/ml for 2h): CAT was able to rescue Cl- current alteration. Since CAT is regulated by Nrf2 transcription factor, we pre-treated the cells with the Nrf2 activators, Resveratrol and tBHQ. Immunochemical and immunocytochemical results showed Nrf2 activation with both substances that lead to prevent OS effect on Cl- current. These data bring new insights on the mechanisms involved in OS induced lung tissue damage , pointing out the role of H2 O2 in chloride current alteration and the ability of Nfr2 activation in preventing this effect. This article is protected by copyright. All rights reserved.