Contribution of Nitric Oxide Synthases 1, 2, and 3 to Airway Hyperresponsiveness and Inflammation in a Murine Model of Asthma

Abstract

Asthma is a chronic disease characterized by increased airway responsiveness and airway inflammation. The functional role of nitric oxide (NO) and the various nitric oxide synthase (NOS) isoforms in human asthma is controversial. To investigate the role of NO in an established model of allergic asthma, mice with targeted deletions of the three known isoforms of NOS (NOS1, 2, and 3) were studied. Although the inducible (NOS2) isoform was significantly upregulated in the lungs of ovalbumin (OVA)-sensitized and -challenged (OVA/OVA) wild-type (WT) mice and was undetectable in similarly treated NOS2-deficient mice, airway responsiveness was not significantly different between these groups. OVA/OVA endothelial (NOS3)-deficient mice were significantly more responsive to methacholine challenge compared with similarly treated NOS1 and NOS1&3-deficient mice. Airway responsiveness in OVA/OVA neuronal (NOS1)-deficient and neuronal/endothelial (NOS1&3) double-deficient mice was significantly less than that observed in similarly treated NOS2 and WT groups. These findings demonstrate an important function for the nNOS isoform in controlling the inducibility of airway hyperresponsiveness in this model of allergic asthma.

Bacterial Lipopolysaccharide Signaling Through Toll-Like Receptor 4 Suppresses Asthma-Like Responses Via Nitric Oxide Synthase 2 Activity

“…In the same vein, it has been shown that acute inhibition of NOS2 activity either suppresses or exacerbates airway inflammation and chemokine expression (21,22). Our results and those of others (20) clearly indicate that airway inflammation is fully expressed in the absence of NOS2. Thus, the apparent conflict between studies that favor NO derived from NOS2 as a proinflammatory molecule with those that are opposed to this concept is likely due to differences in the immunization and challenge protocols, and to the concentration of NO produced.…”

“…However, the role of NOS2 in allergic inflammation is controversial. For instance, Xiong et al (19) showed that NOS2 Ϫ/Ϫ animals presented an inhibited airway inflammation while De Sanctis et al (20) found no significant differences in airway inflammation or cellular recruitment into the airway space between NOS2 Ϫ/Ϫ and WT animals. In the same vein, it has been shown that acute inhibition of NOS2 activity either suppresses or exacerbates airway inflammation and chemokine expression (21,22).…”

“…Whether NO production has a beneficial or deleterious effect in asthma is still controversial. Data from experimental asthma models, using gene inactivation of NOS isoforms, indicate that the induction of airway eosinophilic inflammation appears to be either dependent or independent of NOS2 activity, whereas NOS1, but not NOS2 expression, seems to be required for protection against AHR (19,20). In addition, conflicting results were also obtained in studies with drug-induced inhibition of NO production in which NOS2 inhibition has been shown to either exacerbate or attenuate allergen-induced airway inflammation and AHR (21,22).…”

Nitric oxide paradox in asthma

“…Strikingly, studies in mice with targeted deletions of the three isoforms of NOS also generated conflicting results. For instance, De Sanctis et al (1999) compared the asthmalike response of wild-type (WT) animals with those obtained in mice with NOS-deficiencies. The authors found that total NOS activity increased in sensitized and OVAchallenged WT animals as well as in NOS1 and 3 double KO animals, but not in NOS2-KO mice.…”

“…Controversial data was also generated in studies using NOS2 knockout mice. Xiong et al (1999), showed that NOS2 -/-animals presented a diminished airway inflammation while others clearly showed that airways inflammation is fully expressed in NOS2 -/-mice (De Sanctis et al 1999, Rodriguez et al 2003.…”