title: Contributions of nitric oxide synthase isoforms to pulmonary oxygen toxicity, local vs. mediated effects.
abstract: Reactive species of oxygen and nitrogen have been collectively implicated in pulmonary oxygen toxicity, but the contributions of specific molecules are unknown. Therefore, we assessed the roles of several reactive species, particularly nitric oxide, in pulmonary injury by exposing wild-type mice and seven groups of genetically altered mice to >98% O2 at 1, 3, or 4 atmospheres absolute. Genetically altered animals included knockouts lacking either neuronal nitric oxide synthase (nNOS(-/-)), endothelial nitric oxide synthase (eNOS(-/-)), inducible nitric oxide synthase (iNOS(-/-)), extracellular superoxide dismutase (SOD3(-/-)), or glutathione peroxidase 1 (GPx1(-/-)), as well as two transgenic variants (S1179A and S1179D) having altered eNOS activities. We confirmed our earlier finding that normobaric hyperoxia (NBO2) and hyperbaric hyperoxia (HBO2) result in at least two distinct but overlapping patterns of pulmonary injury. Our new findings are that the role of nitric oxide in the pulmonary pathophysiology of hyperoxia depends both on the specific NOS isozyme that is its source and on the level of hyperoxia. Thus, iNOS predominates in the etiology of lung injury in NBO2, and SOD3 provides an important defense. But in HBO2, nNOS is a major contributor to pulmonary injury, whereas eNOS is protective. In addition, we demonstrated that nitric oxide derived from nNOS is involved in a neurogenic mechanism of HBO2-induced lung injury that is linked to central nervous system oxygen toxicity through adrenergic/cholinergic pathways.
authors.affiliation: Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ivan T
authors.initials: IT
authors.lastname: Demchenko
authors.forename: Dmitriy N
authors.initials: DN
authors.lastname: Atochin
authors.forename: Diana R
authors.initials: DR
authors.lastname: Gutsaeva
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Godfrey
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.forename: Barry W
authors.initials: BW
authors.lastname: Allen
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D005979:Glutathione Peroxidase / Q000378:metabolism; D006931:Hyperbaric Oxygenation; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000201:enzymology; D008171:Lung Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen / Q000633:toxicity; D010108:Oxyhemoglobins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D010108:Oxyhemoglobins; D009569:Nitric Oxide; D005979:Glutathione Peroxidase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D010100:Oxygen; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse