Mouse lung development and NOX1 induction during hyperoxia are developmentally regulated and mitochondrial ROS dependent

Abstract

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.

Mitochondria in lung disease

“…The exact source of mROS may change with the mitochondrial stressor and particular disease state, but investigations into the source of mROS in many lung diseases is limited by the lack of highly specific in vivo mROS-sensing agents (103). That said, there is compelling evidence for a role of mROS in the pathogenesis of a number of lung diseases, including PF (54), COPD (20,50), asthma (104), CF (105), lung cancer (106), BPD (107), and PH (108).…”

Mitochondrial dysfunction in inflammatory responses and cellular senescence: pathogenesis and pharmacological targets for chronic lung diseases

“…Indeed, the transmission of mtDNA mutations occurs in one in every 200 newborns, which potentially may cause disease or increase disease susceptibility (Elliott et al , ). Treatment with a mitochondria‐specific antioxidant, mitoTEMPO, during early post‐natal hyperoxia protected against compromised alveolarization (Datta et al , ), which suggests that targeted antioxidant therapy could be used to prevent or treat BPD. Hyperoxic exposure induces UCP2 expression in pulmonary macrophages and enhanced UCP3 levels in skeletal muscles in mice (Flandin et al , ; Steer et al , ), which may be compensatory responses to increased oxidative stress and mtROS.…”

Hyperoxia-Induced Proliferative Retinopathy: Early Interruption of Retinal Vascular Development with Severe and Irreversible Neurovascular Disruption

“…We have previously shown that mice exposed to this model have evidence of increased oxidative stress and that a mitochondrially-targeted antioxidant can prevent end organ damage in the lung and cardiovascular system [16, 81]. The NOX family is considered an important source of ROS in blood vessels and has been shown to be important in the pathogenesis of retinal angiogenesis and ischemic retinopathies [27].…”