Inhaled nitric oxide prevents 3-nitrotyrosine formation in the lungs of neonatal mice exposed to >95% oxygen

Michael R. Stenger, Melissa J. Rose, Mandar S. Joshi, Lynette K. Rogers, Louis G. Chicoine, John Anthony Bauer, Leif D. Nelin

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Inhaled nitric oxide is being evaluated as a preventative therapy for patients at risk for bronchopulmonary dysplasia (BPD). Nitric oxide (NO), in the presence of superoxide, forms peroxynitrite, which reacts with tyrosine residues on proteins to form 3-nitrotyrosine (3-NT). However, NO can also act as an antioxidant and was recently found to improve the oxidative balance in preterm infants. Thus, we tested the hypothesis that the addition of a therapeutically relevant concentration (10 ppm) of NO to a hyperoxic exposure would lead to decreased 3-NT formation in the lung. FVB mouse pups were exposed to either room air (21% O2) or >95% O2 with or without 0 ppm NO within 24 h of birth. In the first set of studies, body weights and survival were monitored for 7 days, and xposure to >95% O2 resulted in impaired weight gain and near 100% mortality by 7 days. However, the mortality ccurred earlier in pups exposed to >95% O2 ? NO than in pups exposed to >95% O2 alone. In a second set of studies, lungs were harvested at 72 h. Immunohistochemistry of the lungs at 72 h revealed that the addition of NO decreased alveolar, bronchial, and vascular 3-NT staining in pups exposed to both room air and hyperoxia. The lung nitrite levels were higher in animals exposed to >95% oxygen ? NO than in animals exposed to >95% oxygen alone. The protein levels of myeloperoxidase, monocyte chemotactic protein-1, and intracellular adhesion molecule- 1 were assessed after 72 h of exposure and found to be greatest in the lungs of pups exposed to >95% O 2. This hyperoxia-induced protein expression was significantly attenuated by the addition of 10 ppm NO. We propose that in the presence of >95% O2, peroxynitrite formation results in protein nitration; however, adding excess NO to the >95% O2 exposure prevents 3-NT formation by NO reacting with peroxynitrite to produce nitrite and NO 2. We speculate that the decreased protein nitration observed with the addition of NO may be a potential mechanism limiting hyperoxic lung injury.

Original languageEnglish
Pages (from-to)217-227
Number of pages11
JournalLung
Volume188
Issue number3
DOIs
StatePublished - Jun 2010

Bibliographical note

Funding Information:
We thank Dionna Hatch and T. J. Calvert for excellent technical assistance. We also thank Ikaria for providing the NO gas and the AeroNOx delivery system. This study was supported by National Heart Lung and Blood Institute Grant HL-075261.

Keywords

  • Lung injury
  • Oxygen toxicity
  • Peroxynitrite
  • Protein nitration

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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