ATTENUATION OF HYPEROXIA-INDUCED CELL DEATH WITH MITOCHONDRIAL ALDEHYDE DEHYDROGENASE

摘要

Oxygen toxicity is one of the major risk factors in Jhe development of the chronic lung disease or bronchopulmonary dysplasia in premature infants. Using proteoraic analysis, we discovered mitochondria! aldehyde dehydrogenase (mtALDR or ALDB2) was down-regulated in neonatal rat lung after hyperoxic exposure. To study the role of mtALDH in hyperoxie lung injury, we overexpressed ratALDH in human lung epithelial ceils (A549) and found thai 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 ratALDH-A549 cells after hyperoxic exposure were significantly lowered compared to Neo-A549 cells. mtALDH overexpreasion significantly stimulated extracellular signal regulated kinase (HRK) phosphorylation, under nontoxic and hyperoxic conditions. inhibition of ERK phosphorylation partially eliminated the protective effect of mtALDH in hyperoxia-induced cell death, suggesting ERK activation by ratALDH conferred cellular resistance to hyperoxia. mtALDH overexpresaion augmented Akt phosphorylation and maintained She total Akt level in mt ALDH- A549 cells under.nonnoxie and hyperoxic conditions. Inhibition of FBK activation by LY294002 in miALüH-A549 cells significantly increased necrotic cell death after hyperoxic exposure, indicating that. POKVAkt activation by mtALDH played an important role in cell survival after hyperoxia. Taken together, these data demonstrate that puALDH overexpression attenuates hyperøxia-induced cell death in lung epithelial cells through reduction of ROS, activation of ERK/MAPK and PBK/Akt cell survival signaling pathways.