Animal models demonstrate that exposure to supraphysiological
oxygen during the neonatal period compromises both lung and pulmonary vascular development, resulting in a phenotype comparable to
bronchopulmonary dysplasia (BPD). Our prior work in murine models identified postnatal maturation of
antioxidant enzyme capacities as well as developmental regulation of mitochondrial oxidative stress in
hyperoxia. We hypothesize that consequences of
hyperoxia may also be developmentally regulated and mitochondrial
reactive oxygen species (ROS) dependent. To determine whether age of exposure impacts the effect of
hyperoxia, neonatal mice were placed in 75%
oxygen for 72 h at either postnatal day 0 (early postnatal) or day 4 (late postnatal). Mice exposed to early, but not late, postnatal
hyperoxia demonstrated decreased alveolarization and septation, increased muscularization of resistance pulmonary arteries, and
right ventricular hypertrophy (RVH) compared with normoxic controls. Treatment with a mitochondria-specific
antioxidant, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium
chloride (
mitoTEMPO), during early postnatal
hyperoxia protected against compromised alveolarization and RVH. In addition, early, but not late, postnatal
hyperoxia resulted in induction of NOX1 expression that was mitochondrial ROS dependent. Because early, but not late, exposure resulted in compromised lung and cardiovascular development, we conclude that the consequences of
hyperoxia are developmentally regulated and decrease with age. Attenuated disease in
mitoTEMPO-treated mice implicates mitochondrial ROS in the pathophysiology of neonatal hyperoxic
lung injury, with potential for amplification of ROS signaling through NOX1 induction. Furthermore, it suggests a potential role for targeted
antioxidant therapy in the prevention or treatment of BPD.