Immunological mechanisms of alcohol-exacerbated asthma
Bouchard, Jacqueline Claire
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Despite numerous therapeutic options, asthma remains a significant inflammatory disease causing substantial patient and economic burdens. Identifying stimuli that exacerbate asthma will help control disease morbidity and possibly circumvent the need for therapeutic intervention. Asthma is triggered by multiple mediators including allergen-lgE cross linking and non-lgE mechanisms. Several clinical studies have shown that acute ethanol consumption exacerbates asthma. The study presented here investigated the basic mechanisms of alcohol-exacerbated asthma in mild cockroach-allergen induced asthma in mice. This model demonstrates that a single exposure to oral alcohol is sufficient to trigger immediate asthmatic responses. Within 30 minutes of alcohol gavage to cockroach-allergen sensitized mice, substantial asthmatic responses were identified, including increased mucin production, alveolar eosinophil infiltration, eosinophil chemokine and Th2 cytokine production, and indications of respiratory distress and dysfunction. Significant mast cell degranulation was also observed, yet mast cell stabilizers failed to improve ethanol-triggered inflammatory events, suggesting that these rapid responses are not mediated through mast cell granule release. IL-13 neutralizing antibodies were utilized to investigate the role of IL-13 in the ethanol-triggered mucin production. IL-13 neutralization failed to decrease mucin production, but did result in an unexpected increase in lung inflammation, suggesting that endogenous IL-13 production may serve to dampen the ethanol-triggered asthmatic response. Lastly, this work provided evidence that concurrent ethanol and allergen exposures push mice with mild asthma towards more severe responses, in a process mediated by ethanol-induced overproduction of chemokines. In this model, ethanol caused respiratory function decline, including increased airways hyperreactivity and mucin plug formation with pulmonary obstructions. Ethanol induced significant elevations in pro-inflammatory proteins, including increased CXC chemokines, eotaxins and TNFα, with greater and sustained neutrophil and eosinophil inflammation. Administration of chemokine-neutralizing antibodies prevented acute ethanol-induced bronchoalveolar cellular infiltration and eliminated airways hyperreactivity, providing evidence for the role of chemokines in ethanol-mediated exacerbations. Together these investigations support the clinical findings that acute alcohol can worsen asthma, and provide novel insights into the basic mechanisms through which this occurs, namely through mucin production and subsequent respiratory obstructions, respiratory dysfunction and airways hyperreactivity, lung inflammatory cell recruitment, and orchestration of several responses via protein inflammatory mediators.
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