Bcl-2 inhibitors reduce steroid-insensitive airway inflammation
Authors: Yuan-Yuan Mao
Zheng-Qiang Bao
Bao-Ping Tian
Luan-Qing Che
Zhi-Wei Xu
Jin-Kai Liu
Wen Li
Chao Cao
Li-Xia Xia
Songmin Ying
Zhi-Hua Chen
Hua-Hao Shen
Hao Zhang
Journal: Journal of Allergy and Clinical Immunology (2017)
Discipline: IMMUNOLOGY
Keywords: Airway inflammation; Bcl-2; apoptosis; eosinophil; neutrophil
Affiliations: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China., Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China., Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China; Department of Critical Care Medicine, Ningbo Medical Center, Lihuili Hospital, Ningbo University, Ningbo, China., Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: ., Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China; State Key Laboratory of Respiratory Diseases, Guangzhou, China. Electronic address: .

Abstract:  Background: Asthmatic inflammation is dominated by accumulation of either eosinophils, neutrophils, or both in the airways. Disposal of these inflammatory cells is the key to disease control. Eosinophilic airway inflammation is responsive to corticosteroid treatment, whereas neutrophilic inflammation is resistant and increases the burden of global health care. Corticosteroid-resistant neutrophilic asthma remains mechanistically poorly understood and requires novel effective therapeutic strategies. Objective: We sought to explore the underlying mechanisms of airway inflammation persistence, as well as corticosteroid resistance, and to investigate a new strategy of effective treatment against corticosteroid-insensitive neutrophilic asthma. Methods: Mouse models of either eosinophil-dominated or neutrophil-dominated airway inflammation were used in this study to test corticosteroid sensitivity in vivo and in vitro. We also used vav-Bcl-2 transgenic mice to confirm the importance of granulocytes apoptosis in the clearance of airway inflammation. Finally, the Bcl-2 inhibitors ABT-737 or ABT-199 were tested for their therapeutic effects against eosinophilic or neutrophilic airway inflammation and airway hyperresponsiveness. Results: Overexpression of Bcl-2 protein was found to be responsible for persistence of granulocytes in bronchoalveolar lavage fluid after allergic challenge. This was important because allergen-induced airway inflammation aggravated and persisted in vav-Bcl-2 transgenic mice, in which nucleated hematopoietic cells were overexpressed with Bcl-2 and resistant to apoptosis. The Bcl-2 inhibitors ABT-737 or ABT-199 play efficient roles in alleviation of either eosinophilic or corticosteroid-resistant neutrophilic airway inflammation by inducing apoptosis of immune cells, such as eosinophils, neutrophils, TH2 cells, TH17 cells, and dendritic cells. Moreover, these inhibitors were found to be more efficient than steroids to induce granulocyte apoptosis ex vivo from patients with severe asthma. Conclusion: Apoptosis of inflammatory cells is essential for clearance of allergen-induced airway inflammation. The Bcl-2 inhibitors ABT-737 or ABT-199 might be promising drugs for the treatment of airway inflammation, especially for corticosteroid-insensitive neutrophilic airway inflammation. 

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