Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
Copyright 2016, American College of Chest Physicians. All Rights Reserved.
SESSION TITLE: Asthma III
SESSION TYPE: Original Investigation Poster
PRESENTED ON: Saturday, April 16, 2016 at 11:45 AM - 12:45 PM
PURPOSE: Asthmatic inflammation is dominated either by eosinophil or neutrophil accumulation in airways. Resolution of these inflammatory cells is the key to disease alleviation. It is well accepted that eosinophilic airway inflammation is responsive to corticosteroid treatment, while neutrophilic inflammation contributes to most of the corticosteroid-insensitive severe asthma and increases the burden of global health care. Here, we explored a new strategy of effective treatment against corticosteroid-insensitive neutrophilic asthma by small molecule inhibitors against anti-apoptotic protein Bcl-2.
METHODS: Expression of Bcl-2 on inflammatory cells and inflamed tissues were detected. Resolution of airway inflammation in allergen-challenged Bcl-2 transgenic mice was analyzed. Mouse eosinophils and neutrophils from bronchoalveolar lavage (BAL) fluid in response to ABT-737 was detected by flow cytometry. Eosinophilic and neutrophilic airway inflammation model were treated with ABT-737 or ABT-199, the apoptosis of inflammatory cells and cytokines level were analyzed and airway hyperresponsiveness to aerosolized methacholine was measured.
RESULTS: Significantly higher viability and prolonged lifespan of eosinophils and neutrophils were observed in BAL fluid from allergen-induced airway inflammation mouse model showed. This was probably due to elevated expression levels of Bcl-2 protein in these inflammatory cells. It was striking that inflammatory response induced by allergen dramatically aggravated and persisted in vav-Bcl-2 transgenic mice, where nucleated hematopoietic cells were resistant to apoptosis. Based on these above observations, Bcl-2 inhibitors, ABT-737 or ABT-199, were shown to play efficient roles in alleviation of either eosinophilic or neutrophilic allergen-induced airway inflammation.
CONCLUSIONS: ABT-737 or ABT-199 may be promising drugs for the treatment against airway inflammation, especially corticosteroid-insensitive neutrophilic airway inflammation.
CLINICAL IMPLICATIONS: It is well-accepted that eosinophilic airway inflammation is responsive to corticosteroid treatment, while neutrophilic inflammation contributes to most of the corticosteroid-insensitive severe asthma. We have provided a new strategy to inhibit allergic airway inflammation, especially the neutrophil-dominated and corticosteroid insensitive airway inflammation, by promoting the death of inflammatory cell with the antagonist of anti-apoptotic proteins Bcl-2 termed ABT-737 or ABT-199.
DISCLOSURE: The following authors have nothing to disclose: Bao-ping Tian, Li-xia Xia, Zhengqiang Bao, Wen Li, Zhihua Chen, Songmin Ying, Huahao Shen
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