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

Experimental & Molecular Medicine, Sep 2010

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.

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

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. Introduction The development of asthma is linked not only with respiratory allergen sensitization but also with viral respiratory tract infections in early childhood (Sigurs et al., 2005; Thomsen et al., 2009). The respiratory tract is commonly infected by a range of viruses, and double-stranded (ds) RNA is a pathogen-associated molecular pattern (PAMP) expressed by many viruses during their replicative cycles (Yang et al., 1995; Guillot et al., 2005). Antiviral immune responses have innate and adaptive components; dsRNA stimulates innate immune responses via pattern-recognition receptors (PRRs), including Toll-like receptor 3 (TLR3), which result in the production of pro-inflammatory and immunomodulatory mediators, such as type I interferons (e.g., IFN-α and IFN-β), IFN-γ, and IL-12 (Alexopoulou et al., 2001; Kulka et al., 2004; Kato et al., 2006). Recently, we developed a novel asthma model that mimics virus-associated asthma; this model is characterized by neutrophilic inflammation induced by sensitization with allergens and dsRNA and is in part dependent upon type I helper T (Th1) cell response (Jeon et al., 2007b). There is increasing evidence that neutrophilic inflammation contributes to the pathophysiology of asthma exacerbation associated with viral infections (Jatakanon et al., 1999). Therefore, it is worthwhile to elucidate the precise molecular mechanisms underlying the development of virus-associated asthma exacerbation and to discover therapeutic targets. Mild and moderate asthma are related to eosinophilic inflammation, whereas severe asthma is associated with neutrophilic (or non-eosinophilic) inflammation (Busse and Lemanske, 2001; Kim et al., 2007; Bateman et al., 2008). Eosinophilic inflammation represents Th2 cell response, whereas neutrophilic inflammation may be related to Th1 or Th17 cell responses (Kim et al., 2007, 2009). However, the precise immunologic mechanisms of neutrophilic inflammation seen in asthma exacerbation during respiratory viral infections are controversial. Nitric oxide (NO) is a reactive, free radical gas that is produced by diverse cells via the activation of nitric oxide synthases (NOSs). All three known NOS isoforms are expressed within airways and mediate various functions, including innate host defense (Karupiah et al., 1993). In general, endothelial NOS (eNOS) and neuronal NOS (nNOS) are expressed under physiologic conditions, whereas inducible NOS (iNOS) is upregulated in the presence of pro-inflammatory factors, such as IFN-γ, VEGF, and TNF-α (Chesrown et al., 1994; Dembinska-Kiec et al., 1997). The NO levels in the airways are increased in asthma animal models, as well as in patients with asthma (Kharitonov et al., 1995; Weicker et al., 2001). Measurement of exhaled NO has been suggested as being helpful in the monitoring of airway inflammation in asthma, especially in the case of exacerbated asthma (Harkins et al., 2004). However, the role of NO or NOS-mediated effects in the development of asthma exacerbation during viral infections remains controversial. In the present study, we hypothesized that both Th1 and Th17 cell responses are important in the development of virus-associated asthma exacerbation and that NOSs could be used as novel therapeutic targets against this condition. The evidence that viral respiratory tract inf (...truncated)


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Tae-Seop Shin, Byung-Jae Lee, You-Me Tae, You-Sun Kim, Seong Gyu Jeon, Yong Song Gho, Dong-Chull Choi, Yoon-Keun Kim. Role of inducible nitric oxide synthase on the development of virus-associated asthma exacerbation which is dependent on Th1 and Th17 cell responses, Experimental & Molecular Medicine, 2010, pp. 721-730, Issue: 42, DOI: 10.3858/emm.2010.42.10.072