Nitric oxide as a noninvasive biomarker of lipopolysaccharide-induced airway inflammation: possible role in lung neutrophilia.
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.
McCluskie
Kerryn
K
Head Respiratory Pharmacology Group, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK.
Birrell
Mark A
MA
Wong
Sissie
S
Belvisi
Maria G
MG
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D015415:Biomarkers; D001982:Bronchial Diseases / Q000139:chemically induced / Q000175:diagnosis* / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009504:Neutrophils / Q000473:pathology*; D009569:Nitric Oxide / Q000032:analysis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000578:Amidines; D001596:Benzylamines; D015415:Biomarkers; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009569:Nitric Oxide; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester