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Nitric oxide as a noninvasive biomarker of lipopolysaccharide-induced airway inflammation: possible role in lung neutrophilia.

Abstract
Lipopolysaccharide (LPS) is known to generate nitric oxide (NO) in the airway through the activation of nitric-oxide synthase (NOS). The functional consequences of this on the inflammatory response are not clear, with conflicting data published. In the clinic, exhaled NO (ex-NO) is used as a noninvasive biomarker to assess the extent of airway inflammation. It is proposed that monitoring levels of ex-NO could be a useful guide to determining the effectiveness of disease modifying therapies. The aim was, using pharmacological tools, to determine the role of NO in an aerosolized LPS-driven animal model of airway inflammation by assessment of ex-NO, neutrophilia, and inflammatory biomarkers, using a nonselective NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), and a selective inducible NOS (iNOS) inhibitor, N-3 (aminomethyl)benzyl)acetamidine (1400W). Real-time mRNA analysis of the lung tissue indicated an increased gene expression of iNOS following LPS challenge with minimal impact on constitutive NOS isoforms. LPS induced an increase in ex-NO, which appeared to correlate with the increase in iNOS gene expression and airway neutrophilia. Treatment with l-NAME and 1400W resulted in comparable reductions in ex-NO, a reduction in airway neutrophilia, but had little impact on a range of inflammatory biomarkers. This study indicates that the LPS-induced rise in ex-NO is due to enhanced iNOS activity and that NO has a role in airway neutrophilia. Additionally, it appears using ex-NO as a guide to monitoring airway inflammation may have some use, but data should be interpreted with caution when assessing therapies that may directly impact on NO formation.
AuthorsKerryn McCluskie, Mark A Birrell, Sissie Wong, Maria G Belvisi
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 311 Issue 2 Pg. 625-33 (Nov 2004) ISSN: 0022-3565 [Print] United States
PMID15226380 (Publication Type: Journal Article)
Chemical References
  • Amidines
  • Benzylamines
  • Biomarkers
  • Lipopolysaccharides
  • N-(3-(aminomethyl)benzyl)acetamidine
  • Nitric Oxide
  • Dexamethasone
  • Nitric Oxide Synthase
  • NG-Nitroarginine Methyl Ester
Topics
  • Amidines (pharmacology)
  • Animals
  • Benzylamines (pharmacology)
  • Biomarkers
  • Bronchial Diseases (chemically induced, diagnosis, pathology)
  • Dexamethasone (pharmacology)
  • Drug Interactions
  • Gene Expression (drug effects)
  • Inflammation (chemically induced)
  • Lipopolysaccharides
  • Lung (drug effects, pathology)
  • Male
  • NG-Nitroarginine Methyl Ester (pharmacology)
  • Neutrophils (pathology)
  • Nitric Oxide (analysis)
  • Nitric Oxide Synthase (metabolism)
  • Rats
  • Rats, Wistar
  • Time Factors

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