Exposure of animals to
hyperoxia results in
respiratory failure and death within 72 h. Histologic evaluation of the lungs of these animals demonstrates epithelial apoptosis and
necrosis. Although the generation of
reactive oxygen species (ROS) is widely thought to be responsible for the cell death observed following exposure to
hyperoxia, it is not clear whether they act upstream of activation of the cell death pathway or whether they are generated as a result of mitochondrial membrane permeabilization and
caspase activation. We hypothesized that the generation of ROS was required for
hyperoxia-induced cell death upstream of Bax activation. In primary rat alveolar epithelial cells, we found that exposure to
hyperoxia resulted in the generation of ROS that was completely prevented by the administration of the combined
superoxide dismutase/
catalase mimetic
EUK-134 (Eukarion, Inc., Bedford, MA). Exposure to
hyperoxia resulted in the activation of Bax at the mitochondrial membrane,
cytochrome c release, and cell death. The administration of
EUK-134 prevented Bax activation,
cytochrome c release, and cell death. In a mouse lung epithelial cell line (MLE-12), the overexpression of Bcl-XL protected cells against
hyperoxia by preventing the activation of Bax at the mitochondrial membrane. We conclude that exposure to
hyperoxia results in Bax activation at the mitochondrial membrane and subsequent
cytochrome c release. Bax activation at the mitochondrial membrane requires the generation of ROS and can be prevented by the overexpression of Bcl-XL.