Abstract
BackgroundChronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice.MethodsBALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge.ResultsMice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice.ConclusionThese data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil- and eosinophil-dominant phases of the response to secondary allergen challenge.
Highlights
Chronic asthma is often associated with neutrophilic infiltration in the airways
We evaluated the role of neutrophil elastase in allergen-induced inflammation and airway hyperresponsiveness (AHR) on a background of previously established disease, provoked by secondary challenge
When mice were treated with sivelestat, AHR were significantly reduced compared to vehicle saline-treated mice (Figure 1A)
Summary
Chronic asthma is often associated with neutrophilic infiltration in the airways. We have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice. Bronchial asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyperresponsiveness (AHR) [1]. In the pathogenesis of asthma, various inflammatory cells contribute to the development of AHR and allergic airway inflammation. A common theory is that the disease results from chronic airway inflammation leading to AHR and reversible airway obstruction [2]. Neutrophils are one of the pro-inflammatory cell types whose role in the pathology of asthma has been emphasized recently. Acute severe asthma has been shown to be associated with neutrophilic infiltration of the airways [4,5]. The specific role of neutrophils in the pathogenesis of asthma has not been clarified
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