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Inhaled Ethyl Nitrite Prevents Hyperoxia-impaired Postnatal Alveolar Development in Newborn Rats

¹ Division of Neonatal Medicine, Department of Pediatrics, Neonatal–Perinatal Research Institute; ² Division of Pulmonary and Critical Care Medicine, Department of Medicine; and ³ Department of Biochemistry, Duke University Medical Center, Durham, North Carolina

Correspondence and requests for reprints should be addressed to Richard L. Auten, M.D., DUMC Box 3373, Duke University Medical Center, Durham, NC 27710. E-mail: auten{at}duke.edu

Rationale: Inhaled nitric oxide (NO) has been used to prevent bronchopulmonary dysplasia, but with variable results. Ethyl nitrite (ENO) forms S-nitrosothiols more readily than does NO, and resists higher-order nitrogen oxide formation. Because S-nitrosylation is a key pathway mediating many NO biological effects, treatment with inhaled ENO may better protect postnatal lung development from oxidative stress than NO.

Objectives: To compare inhaled NO and ENO on hyperoxia-impaired postnatal lung development.

Methods: We treated newborn rats beginning at birth to air or 95% O₂ ± 0.2–20.0 ppm ENO for 8 days, or to 10 ppm NO for 8 days. Pups treated with the optimum ENO dose, 10 ppm, and pups treated with 10 ppm NO were recovered in room air for 6 more days.

Measurements and Main Results: ENO and NO partly prevented 95% O₂–induced airway neutrophil influx in lavage, but ENO had a greater effect than did NO in prevention of lung myeloperoxidase accumulation, and in expression of cytokine-induced neutrophil chemoattractant-1. Treatment with 10 ppm ENO, but not NO, for 8 days followed by recovery in air for 6 days prevented 95% O₂–induced impairments of body weight, lung compliance, and alveolar development.

Conclusions: Inhaled ENO conferred protection superior to inhaled NO against hyperoxia-induced inflammation. ENO prevented hyperoxia impairments of lung compliance and postnatal alveolar development in newborn rats.

Key Words: bronchopulmonary dysplasia • O-nitrosoethanol • S-nitrosylation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject S-nitrosylation may affect a broad number of regulatory cell responses, such as inflammation. Inhaled agents that promote S-nitrosylation may provide targeted protection from inflammation. What This Study Adds to the Field Inhaled ethyl nitrite dose-dependently prevents hyperoxia-induced lung inflammation in newborn rats, and, at an equivalent dose, afforded better protection of postnatal lung function and development than nitric oxide.

 

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