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

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.

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Similar but not the same: normobaric and hyperbaric pulmonary oxygen toxicity, the role of nitric oxide

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00450.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L229-L238 ◽

Cited By ~ 44

Author(s):

Ivan T. Demchenko ◽

Karen E. Welty-Wolf ◽

Barry W. Allen ◽

Claude A. Piantadosi

Keyword(s):

Nitric Oxide ◽

Lung Injury ◽

Oxygen Toxicity ◽

Selective Inhibition ◽

Lung Pathology ◽

Pulmonary Injury ◽

Autonomic Pathways ◽

Pulmonary Manifestations ◽

Pulmonary Damage ◽

Oxide Synthase

Pulmonary manifestations of oxygen toxicity were studied and quantified in rats breathing >98% O2 at 1, 1.5, 2, 2.5, and 3 ATA to test our hypothesis that different patterns of pulmonary injury would emerge, reflecting a role for central nervous system (CNS) excitation by hyperbaric oxygen. At 1.5 atmosphere absolute (ATA) and below, the well-recognized pattern of diffuse pulmonary damage developed slowly with an extensive inflammatory response and destruction of the alveolar-capillary barrier leading to edema, impaired gas exchange, respiratory failure, and death; the severity of these effects increased with time over the 56-h period of observation. At higher inspired O2 pressures, 2–3 ATA, pulmonary injury was greatly accelerated but less inflammatory in character, and events in the brain were a prelude to a distinct lung pathology. The CNS-mediated component of this lung injury could be attenuated by selective inhibition of neuronal nitric oxide synthase (nNOS) or by unilateral transection of the vagus nerve. We propose that extrapulmonary, neurogenic events predominate in the pathogenesis of acute pulmonary oxygen toxicity in hyperbaric oxygenation, as nNOS activity drives lung injury by modulating the output of central autonomic pathways.

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Increased cardiac microvascular permeability and activation of cardiac endothelial nitric oxide synthase in high tidal volume ventilation-induced lung injury

Asian Biomedicine ◽

10.2478/abm-2010-0004 ◽

2010 ◽

Vol 4 (1) ◽

pp. 27-36

Author(s):

Ming-Jui Hung ◽

Ming-Yow Hung ◽

Wen-Jin Cherng ◽

Li-Fu Li

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Lung Injury ◽

Tidal Volume ◽

Endothelial Nitric Oxide Synthase ◽

Microvascular Permeability ◽

Akt Phosphorylation ◽

Enos Phosphorylation ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Abstract Background: Positive pressure ventilation with large tidal volumes has been shown to cause lung injury via the serine/threonine kinase-protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS)-pathways. However, the effects of high tidal volume (VT) ventilation on the heart are unclear. Objectives: Evaluate the effect of VT ventilation on the cardiac vascular permeability and intracellular Akt and eNOS signaling pathway. Methods: C57BL/6 and Akt knock-out (heterozygotes, +/−) mice were exposed to high VT (30 mL/kg) mechanical ventilation with room air for one and/or five hours. Results: High VT ventilation increased cardiac microvascular permeability and eNOS phosphorylation in a timedependent manner. Serum cardiac troponin I was increased after one hour of high VT ventilation. Cardiac Akt phosphorylation was accentuated after one hour and attenuated after five hours of high VT ventilation. Pharmacological inhibition of Akt with LY294002 and high VT ventilation of Akt+/− mice attenuated cardiac Akt phosphorylation, but not eNOS phosphorylation. Conclusion: High VT ventilation increased cardiac myocardial injury, microvascular permeability, and eNOS phosphorylation. Involvement of cardiac Akt in high VT ventilation was transient.

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