TY - JOUR T1 - Nitric Oxide as a Noninvasive Biomarker of Lipopolysaccharide-Induced Airway Inflammation: Possible Role in Lung Neutrophilia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 625 LP - 633 DO - 10.1124/jpet.104.068890 VL - 311 IS - 2 AU - Kerryn McCluskie AU - Mark A. Birrell AU - Sissie Wong AU - Maria G. Belvisi Y1 - 2004/11/01 UR - http://jpet.aspetjournals.org/content/311/2/625.abstract N2 - 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, NG-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. The American Society for Pharmacology and Experimental Therapeutics ER -