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.
J Allergy Clin Immunol. 2017 Aug;140(2):418-430. doi: 10.1016/j.jaci.2016.11.027. Epub 2016 Dec 31.
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.
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.
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.
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, T2 cells, T17 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.
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.
哮喘炎症主要表现为气道中嗜酸性粒细胞、中性粒细胞或两者的积聚。清除这些炎症细胞是控制疾病的关键。嗜酸性粒细胞性气道炎症对皮质类固醇治疗有反应，而中性粒细胞性炎症则具有抗性，并增加全球医疗保健负担。皮质类固醇抵抗性中性粒细胞性哮喘在机制上仍知之甚少，需要新的有效治疗策略。
我们试图探索气道炎症持续存在以及皮质类固醇抵抗的潜在机制，并研究一种针对皮质类固醇不敏感的中性粒细胞性哮喘的有效治疗新策略。
本研究使用嗜酸性粒细胞为主或中性粒细胞为主的气道炎症小鼠模型，在体内和体外测试皮质类固醇的敏感性。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，测试了 Bcl-2 抑制剂 ABT-737 或 ABT-199 对嗜酸性粒细胞或中性粒细胞性气道炎症和气道高反应性的治疗效果。
研究发现，Bcl-2 蛋白的过表达导致过敏挑战后支气管肺泡灌洗液中粒细胞的持续存在。这很重要，因为变应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，其中造血核细胞过表达 Bcl-2 且对凋亡有抗性。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、T2 细胞、T17 细胞和树突状细胞）的凋亡，在缓解嗜酸性粒细胞或皮质类固醇抵抗性中性粒细胞性气道炎症方面发挥了有效的作用。此外，与皮质类固醇相比，这些抑制剂在体外从严重哮喘患者中诱导粒细胞凋亡的效果更好。
炎症细胞的凋亡对于清除变应原诱导的气道炎症至关重要。Bcl-2 抑制剂 ABT-737 或 ABT-199 可能是治疗气道炎症的有前途的药物，特别是对于皮质类固醇不敏感的中性粒细胞性气道炎症。
