Oxygen toxicity is one of the major risk factors in the development of the chronic
lung disease or
bronchopulmonary dysplasia in premature infants. Using proteomic analysis, we discovered mitochondrial
aldehyde dehydrogenase (mtALDH or ALDH2) was down-regulated in
neonatal rat lung after hyperoxic
exposure. To study the role of mtALDH in hyperoxic
lung injury, we overexpressed mtALDH in
human lung epithelial cells (A549) and found that mtALDH significantly reduced
hyperoxia-induced
cell death. Compared to control cells (Neo-A549), the
necrotic cell death in mtALDH overexpressing cells (mtALDH-A549) decreased from 25.3% to 6.5%, 50.5% to 9.1% and 52.4% to 15.06% after 24-, 48- and 72-hour hyperoxic
exposure, respectively. The levels of
intracellular and mitochondria-derived
reactive oxygen species (ROS) in mtALDH-A549 cells after hyperoxic
exposure were significantly lowered compared to Neo-A549 cells. mtALDH overexpression significantly stimulated
extracellular signal regulated
kinase (ERK)
phosphorylation under normoxic and hyperoxic conditions. Inhibition of ERK
phosphorylation partially eliminated the protective effect of mtALDH in
hyperoxia-induced
cell death, suggesting ERK activation by mtALDH conferred cellular resistance to
hyperoxia. mtALDH overexpression augmented Akt
phosphorylation and maintained the total Akt level in mtALDH-A549 cells under normoxic and hyperoxic conditions. Inhibition of PI3K activation by LY294002 in mtALDH-A549 cells significantly increased
necrotic cell death after hyperoxic exposure, indicating that PI3K / Akt activation by mtALDH played an important role in
cell survival after hyperoxia. Taken together, these data demonstrate that mtALDH overexpression attenuates hyperoxia-induced cell death in lung epithelial cells through reduction of ROS, activation of ERK / MAPK and PI3K / Akt
cell survival signaling pathways.