Thioredoxin protects fetal type II epithelial cells from hyperoxia-induced injury.

Oxygen toxicity is known to be one of the major contributors to bronchopulmonary dysplasia, a chronic lung disease in premature infants. Thioredoxin (Trx) is an antioxidant that prevents oxidative stress-induced cell death, suggesting a potential therapeutic role in bronchopulmonary dysplasia. The aim of this study was to determine the role of Trx in the pathogenesis of hyperoxia-induced alveolar epithelial cell injury. Alveolar type II epithelial cells from fetal rat lung were exposed to hyperoxia in vitro in the presence or absence of recombinant human Trx (rhTrx 2 µg/ml). Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Apoptosis and levels of reactive oxygen species (ROS) were measured by flow cytometry. Activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathways were detected by Western blotting. We also investigated the effects of rhTrx on the following antioxidants (superoxide dismutase, catalase, and glutathione peroxidase). Trx significantly reduced hyperoxia-induced cell death and increased cell viability. In addition, ROS generation in type II cells was inhibited by rhTrx under hyperoxic conditions. We demonstrated that rhTrx protected type II cells against hyperoxic injury via sustaining the extracellular signal regulated kinase and PI3K activation, and decreasing of c-Jun N-terminal protein kinase and p38 activation. The results also showed manganese superoxide dismutase and glutathione peroxidase activities were increased by rhTrx in type II cells exposed to hyperoxia.Taken together, these results demonstrate that rhTrx administration markedly attenuates hyperoxia-induced type II cell injury through reduction of ROS generation, elevation of antioxidant activities and regulation of both MAPK and PI3K-Akt signaling pathways.