Published ahead of print on May 3, 2007, doi:10.1164/rccm.200605-662OC Am. J. Respir. Crit. Care Med., Volume 176, Number 3, August 2007, 291-299 A more recent version of this article appeared on August 1, 2007
Submitted on May 16, 2006 Inhaled Ethyl Nitrite Prevents Hyperoxia-Impaired Postnatal Alveolar Development in Newborn RatsRichard L Auten1*,1 Neonatal-Perinatal Research Institute, Division of Neonatal Medicine, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA, 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA, 3 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA; Department of Biochemistry, Duke University Medical Center, Durham, NC, USA * To whom correspondence should be addressed. E-mail: auten{at}duke.edu.
Rationale: Inhaled nitric oxide has been used to prevent bronchopulmonary dysplasia, but with variable results. Ethyl nitrite forms S nitrosothiols more readily than nitric oxide and resists higher-order nitrogen oxide formation. Because S-nitrosylation is a key pathway mediating many nitric oxide biological effects, treatment with inhaled ethyl nitrite may better protect postnatal lung development from oxidative stress than nitric oxide. Objective and Methods: To compare inhaled nitric oxide and inhaled ethyl nitrite, we treated newborn rats beginning at birth to air or 95% O2 ± ethyl nitrite 0.2-20 ppm x 8 days, or to nitric oxide 10 ppm x 8 days. Pups treated with the optimum ethyl nitrite dose, 10 ppm, and pups treated with nitric oxide 10 ppm were recovered in room air for six more days. Measurements and Main Results: Ethyl nitrite and nitric oxide partly prevented 95% O2-induced airway neutrophil influx in lavage, but ethyl nitrite > nitric oxide prevented lung myeloperoxidase accumulation, and expression of cytokine-induced neutrophil chemoattractant-1. Treatment with ethyl nitrite but not nitric oxide 10 ppm x 8 days followed by recovery in air x 6 days prevented 95% O2 -induced impairments of body weight, lung compliance, and alveolar development. Conclusions: Inhaled ethyl nitrite > nitric oxide protected against hyperoxia-induced inflammation. Ethyl nitrite prevented hyperoxia impairments of lung compliance and post-natal alveolar development in newborn rats. Key words: bronchopulmonary dysplasia, O-nitrosoethanol, S-nitrosylation, S-nitrosothiols, nitric oxide
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