Bcl-2 Inhibitors Reduce Steroid-insensitive Airway Inflammation

Publication date: Available online 31 December 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Bao-ping Tian, Li-xia Xia, Zheng-qiang Bao, Hao Zhang, Zhi-wei Xu, Yuan-yuan Mao, Chao Cao, Luan-qing Che, Jin-kai Liu, Wen Li, Zhi-hua Chen, Songmin Ying, Hua-hao Shen
BackgroundAsthmatic inflammation is dominated either by eosinophil and/or neutrophil accumulation in airways. Disposal of these inflammatory cells is the key to disease control. Eosinophilic airway inflammation is responsive to corticosteroid treatment, while 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.ObjectiveWe thought 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.MethodsMouse models of either eosinophils-dominated or neutrophils-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, Bcl-2 inhibitors ABT-737 or ABT-199 –were tested for their therapeutic effects against eosinophilic or neutrophilic airway inflammation and airway hyperresponsiveness.ResultsOverexpression of Bcl-2 protein was found to be responsible for persistence of granulocytes in bronchoalveolar lavage fluid following allergic challenge. This was important as allergen-induced airway inflammation aggravated and persisted in vav-Bcl-2 transgenic mice, where nucleated hematopoietic cells were over-expressed with Bcl-2 and resistant to apoptosis. 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 cell, such as eosinophils, neutrophils, Th2, Th17 and dendritic cells. Moreover, these inhibitors were found to be more efficient than steroid to induce granulocytes apoptosis ex vivo from severe asthma patients.ConclusionApoptosis of inflammatory cells is essential for the clearance of allergen-induced airway inflammation. Bcl-2 inhibitors ABT-737 or ABT-199 may be promising drugs for the treatment against airway inflammation, especially for corticosteroid-insensitive neutrophilic airway inflammation.

Teaser

Bcl-2 inhibitors may be promising drugs for the treatment against corticosteroid-insensitive neutrophilic airway inflammation.


http://ift.tt/2hGolv0