Forkhead Transcription Factor FOXO3a Protects Alveolar Epithelial Cells from Oxidative Stress

Abstract

Acute lung injury (ALI) is a devastating clinical problem involving the key events of inflammation and alveolar epithelial cell death. The fundamental mechanism of this serious condition evolves from an imbalance between pro- inflammatory and anti-inflammatory cytokines finally resulting in oxidative stress induced cell death. FOXO transcription factors are important regulators of cell survival in response to a variety of stress stimuli, among which are oxidative stress, DNA damage, and nutrient deprivation. However, the role of FOXO3a in acute lung injury and epithelial cell death is not known. It was hypothesized that FOXO3a protects alveolar epithelial cells from H2O2 induced cell death. To test this hypothesis, the effects of H2O2 on subconfluent human alveolar epithelial cell (A549) cultures were tested. A549 cells were transfected with vector containing wild type FOXO3a cDNA (FOXO3a- WT) or vector containing mutant FOXO3a cDNA (FOXO3a-M) and treated with or without H2O2 (1hour) to induce oxidative stress. The results showed that H2O2 induced a significant alveolar epithelial cell necrosis and apoptosis. In contrast epithelial cells transfected with FOXO3a –WT inhibited H2O2 induced cell necrosis and apoptosis. However cells transfected with a mutant, FOXO3a-M did not alter H2O2 mediated epithelial cell apoptosis and necrosis. Together these results suggest that FOXO3a protects alveolar epithelial cells from oxidative stress induced cell death. This work was supported by T32-HL007874 and American Heart Association National Scientist Development Grant 09SDG2260957 to N.K.