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

Ivan T. Demchenko, Dmitriy N. Atochin, Diana R. Gutsaeva, Ryan R. Godfrey, Paul L. Huang, Claude A. Piantadosi, Barry W. Allen

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume294
Issue number5
DOIs
Publication statusPublished - May 2008
Externally publishedYes

Keywords

  • Glutathione peroxidase 1
  • Hyperbaric oxygen toxicity
  • Neurogenic pulmonary oxygen toxicity
  • Normobaric oxygen toxicity
  • Superoxide dismutase

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

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