Exp Mol Med.  2010 Oct;42(10):721-730. 10.3858/emm.2010.42.10.072.

Role of inducible nitric oxide synthase on the development of virus-associated asthma exacerbation which is dependent on Th1 and Th17 cell responses

• Shin TS
• Lee BJ
• Tae YM
• Kim YS
• Jeon SG
• Gho YS
• Choi DC
• Kim YK

• KMID: 964667
• DOI: http://doi.org/10.3858/emm.2010.42.10.072

Abstract

Asthma is characterized by airway inflammation induced by immune dysfunction to inhaled antigens. Although respiratory viral infections are the most common cause of asthma exacerbation, immunologic mechanisms underlying virus-associated asthma exacerbation are controversial. Clinical evidence indicates that nitric oxide (NO) levels in exhaled air are increased in exacerbated asthma patients compared to stable patients. Here, we evaluated the immunologic mechanisms and the role of NO synthases (NOSs) in the development of virus-associated asthma exacerbation. A murine model of virus-associated asthma exacerbation was established using intranasal challenge with ovalbumin (OVA) plus dsRNA for 4 weeks in mice sensitized with OVA plus dsRNA. Lung infiltration of inflammatory cells, especially neutrophils, was increased by repeated challenge with OVA plus dsRNA, as compared to OVA alone. The neutrophilic inflammation enhanced by dsRNA was partly abolished in the absence of IFN-gamma or IL-17 gene expression, whereas unaffected in the absence of IL-13. In terms of the roles of NOSs, dsRNA-enhanced neutrophilic inflammation was significantly decreased in inducible NOS (iNOS)-deficient mice compared to wild type controls; in addition, this phenotype was inhibited by treatment with a non-specific NOS inhibitor (L-NAME) or an specific inhibitor (1400 W), but not with a specific endothelial NOS inhibitor (AP-CAV peptide). Taken together, these findings suggest that iNOS pathway is important in the development of virus-associated exacerbation of neutrophilic inflammation, which is dependent on both Th1 and Th17 cell responses.

Keyword

asthma; interferon-gamma; interleukin-17; neutrophils; nitric oxide synthase type II; RNA viruses; Th1 cells

MeSH Terms

Animals
Asthma/*immunology/virology
Imines/pharmacology
Mice
Mice, Inbred BALB C
NG-Nitroarginine Methyl Ester/pharmacology
Nitric Oxide Synthase Type II/antagonists & inhibitors/*metabolism
RNA, Double-Stranded/metabolism
Th1 Cells/*immunology
Th17 Cells/*immunology