Role of different nitric oxide synthase isoforms in a murine model of acute lung injury and sepsis

Matthias Lange, Yoshimitsu Nakano, Daniel L. Traber, Atsumori Hamahata, Aimalohi Esechie, Collette Jonkam, Kamna Bansal, Lillian D. Traber, Perenlei Enkhbaatar

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Excessive production of nitric oxide (NO) by NO synthase (NOS) with subsequent formation of peroxynitrite and poly(adenosine diphosphate ribose) is critically implemented in the pathophysiology of acute lung injury and sepsis. To elucidate the roles of different isoforms of NOS, we tested the effects of non-selective NOS inhibition and neuronal NOS (nNOS)- and inducible NOS (iNOS)-gene deficiency on the pulmonary oxidative and nitrosative stress reaction in a murine sepsis model. The injury was induced by four sets of cotton smoke using an inhalation chamber and subsequent intranasal administration of live Pseudomonas aeruginosa (3.2×107 colony-forming units). In wild type mice, the injury was associated with excessive releases of pro-inflammatory cytokines in the plasma, enhanced neutrophil accumulation, increased lipid peroxidation, and excessive formation of reactive nitrogen species and vascular endothelial growth factor in the lung. Both nNOS- and iNOS-gene deficiency led to significantly reduced oxidative and nitrosative stress markers in the lung, but failed to significantly improve survival. Treatment with a non-selective NOS inhibitor failed to reduce the oxidative and nitrosative stress reaction to the same extent and even tended to increase mortality. In conclusion, the current study demonstrates that both nNOS and iNOS are partially responsible for the pulmonary oxidative and nitrosative stress reaction in this model. Future studies should investigate the effects of specific pharmacological inhibition of nNOS and iNOS at different time points during the disease process.

Original languageEnglish (US)
Pages (from-to)286-291
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume399
Issue number2
DOIs
StatePublished - Aug 20 2010

Keywords

  • Mice
  • Neuronal nitric oxide synthase
  • Nitrosative stress
  • Oxidative stress
  • Smoke inhalation

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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