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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/L984    most recent 00420.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Demchenko, I. T. Articles by Allen, B. W. Search for Related Content PubMed PubMed Citation Articles by Demchenko, I. T. Articles by Allen, B. W.

Contributions of nitric oxide synthase isoforms to pulmonary oxygen toxicity, local vs. mediated effects

¹Center for Hyperbaric Medicine and Environmental Physiology, ²Department of Anesthesiology, and ³Division of Pulmonary Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina; ⁴Cardiology Division, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; and ⁵Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

Submitted 10 October 2007 ; accepted in final form 4 March 2008

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.

normobaric oxygen toxicity; hyperbaric oxygen toxicity; superoxide dismutase; glutathione peroxidase 1; neurogenic pulmonary oxygen toxicity