Specific inhibition of nitric oxide synthases at different time points in a murine model of pulmonary sepsis

Matthias Lange, Atsumori Hamahata, Daniel L. Traber, Yoshimitsu Nakano, Lillian D. Traber, Perenlei Enkhbaatar

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Excessive production of nitric oxide (NO) by NO synthase (NOS) and a subsequent oxidative stress reaction are thought to be critically involved in the pathophysiology of sepsis. Previous studies suggested that NO production by neuronal NOS (nNOS) and inducible NOS (iNOS) is implemented in the disease process at different time points after the injury. Here we tested the roles of selective pharmacological inhibition of nNOS and iNOS at different time points in a murine model of pulmonary sepsis. The injury was induced by intranasal administration of live Pseudomonas aeruginosa (3.2×107 colony-forming units) in C57BL/6 wild-type mice. The animals received no treatment (control) or treatment with a specific nNOS inhibitor (4 or 8h), iNOS inhibitor (4 or 8h), or non-specific NOS inhibitor (4 or 8h). In controls, the injury was associated with excessive releases of pro-inflammatory cytokines in the plasma, enhanced tissue lipid peroxidation, and decreased survival. Non-specific NOS inhibition at either time point did not influence survival and was not further investigated. While nNOS inhibition at 4h was associated with a trend toward improved survival and significantly reduced contents of lung nitrite/nitrate (NOx) and liver malondialdehyde, the blockade of nNOS at 8h had no effect on these parameters. In contrast, early iNOS inhibition was associated with a trend toward decreased survival and no effects on lung NOx and liver malondialdehyde contents, whereas later iNOS blockade was associated with decreased malondialdehyde content in liver homogenates. In conclusion, pulmonary sepsis in mice may be beneficially influenced by specific pharmacological nNOS inhibition at an earlier time point and iNOS inhibition at a later time points post-injury. Future investigations should identify the time changes of the expression and activation of NOS isoforms.

Original languageEnglish (US)
Pages (from-to)877-881
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume404
Issue number3
DOIs
StatePublished - Jan 21 2011

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Keywords

  • Malondialdehyde
  • Mice
  • Neuronal nitric oxide synthase
  • Oxidative stress
  • Survival

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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