Role of ROS, Soluble Guanylate Cyclase and cGMP in Mouse Lung Development During Hyperoxia

Bronchopulmonary dysplasia (BPD) is characterized by disruption of newborn lung alveolar and vascular development. Administration of supplemental O 2 predisposes to BPD by inducing oxidant stress in multiple subcellular compartments by augmenting reactive oxygen species (ROS) production. We studied the role of subcellular ROS in lung cGMP signaling, and its relationship to lung development in cells, embryonic lung explants, and newborn mice. Embryonic lung explants demonstrated increased mitochondrial ROS during hyperoxia. In hyperoxic HEK293T cells, ROS in the mitochondrial matrix, cytosol, and intermembrane space (IMS) increased. Those cells demonstrated impaired sGC-cGMP responsiveness to an NO donor, a response prevented by the cytosolic glutathione mimetic ebselen as well as by the sGC activator, cinaciguat, but not by mitochondrial matrix-targeted ebselen or by expression of an H 2 O 2 scavenger in the mitochondrial intermembrane space (IMS-Prdx5). Neonatal mice exposed to 75% O 2 for 2 weeks exhibited alveolar simplification and pulmonary artery (PA) wall thickening that were not rescued by cinaciguat or the sGC stimulator, riociguat. However, previous work demonstrated that mitochondria-targeted antioxidants prevent hyperoxia-mediated inhibition of lung alveolar development. Collectively these studies demonstrate that separate mechanisms underlie the effects of hyperoxia on cGMP signaling and alveolarization in the newborn lung, with cytosolic oxidant stress responsible for impairing cGMP signaling and mitochondrial matrix ROS mediating the hyperoxia-induced impairment in lung alveolar development. Hence, the impairments in cGMP signaling and lung alveolar development during hyperoxia involve oxidant stress in distinct subcellular compartments and occur through independent mechanisms.