Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma

Asthma is a chronic disease characterized by increased airway responsivenes s and airway inflammation. The functional role of nitric oxide (NO) and the various nitric oxide synthase (NOS) isoforms in human asthma is controvers ial. To investigate the role of NO in an established model of allergic asth ma, mice with targeted deletions of the three known isoforms of NOS (NOS1, 2, and 3) were studied. Although the inducible (NOS2) isoform was significa ntly upregulated in the lungs of ovalbumin (OVA)-sensitized and -challenged (OVA/OVA) wild-type (WT) mice and was undetectable in similarly treated NO S2-deficient mice, airway responsiveness was not significantly different be tween these groups. OVA/OVA endothelial (NOS3)-deficient mice were signific antly more responsive to methacholine challenge compared with similarly tre ated NOS1 and NOS1&3-deficient mice. Airway responsiveness in OVA/OVA neuro nal (NOS1)-deficient and neuronal/endothelial (NOS1&3) double-deficient mic e was signifcantly less than that observed in similarly treated NOS2 and WT groups. These findings demonstrate an important function for the nNOS isof orm in controlling the inducibility of airway hyperresponsiveness in this m odel of allergic asthma.