Bcl-2 inhibitors reduce steroid-insensitive airway inflammation
Bcl-2 inhibitors reduce steroid-insensitive airway inflammation
复制标题
Bcl-2 抑制剂可减少类固醇不敏感的气道炎症。
DOI：
10.1016/j.jaci.2016.11.027
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发表时间：
2017-08-01
影响因子：
14.2
通讯作者：
Shen, Hua-hao
中科院分区：
文献类型：
--
作者：
Tian, Bao-ping;Xia, Li-xia;Shen, Hua-hao
背景：哮喘炎症主要由嗜酸性粒细胞、中性粒细胞或两者在气道中的积聚引起。处理这些炎症细胞是疾病控制的关键。嗜酸性粒细胞性气道炎症对皮质类固醇治疗有反应，而嗜酸性粒细胞性炎症具有抵抗性，增加了全球卫生保健的负担。皮质类固醇抵抗的嗜酸性粒细胞性哮喘的机制仍然知之甚少，需要新的有效治疗策略。目的：我们试图探索气道炎症持续存在的潜在机制，以及皮质类固醇抵抗，方法：采用小鼠嗜酸性粒细胞为主气道炎症模型和嗜酸性粒细胞为主气道炎症模型，在体内外检测激素敏感性。我们还使用vav-Bcl-2转基因小鼠来证实粒细胞凋亡在清除气道炎症中的重要性。最后，Bcl-2抑制剂ABT-737或ABT-199测试其对嗜酸性粒细胞或嗜酸性粒细胞的气道炎症和气道高反应性的治疗效果。这一点很重要，因为过敏原诱导的气道炎症在vav-Bcl-2转基因小鼠中加重并持续存在，其中有核造血细胞过度表达Bcl-2并抵抗凋亡。Bcl-2抑制剂ABT-737或ABT-199通过诱导免疫细胞（如嗜酸性粒细胞、中性粒细胞、TH 2细胞、T（H）17细胞和树突状细胞）凋亡，在减轻嗜酸性粒细胞或皮质类固醇抵抗的嗜酸性粒细胞气道炎症中发挥有效作用。此外，这些抑制剂被认为是更有效的比类固醇诱导粒细胞凋亡离体从重度asthene.Conclusion患者：炎症细胞的凋亡是必不可少的过敏原诱导的气道炎症的清除。Bcl-2抑制剂ABT-737或ABT-199可能是治疗气道炎症，特别是激素不敏感的嗜酸性气道炎症的有希望的药物。
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, T(H)17 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.