Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
J Allergy Clin Immunol. 2017 Jul;140(1):190-203.e5. doi: 10.1016/j.jaci.2016.09.045. Epub 2016 Nov 16.
Type 2 airway inflammation plays a central role in the pathogenesis of allergen-induced asthma, but the underlying mechanisms remain poorly understood. Recently, we demonstrated that reduced mucociliary clearance, a characteristic feature of asthma, produces spontaneous type 2 airway inflammation in juvenile β-epithelial Na channel (Scnn1b)-transgenic (Tg) mice.
We sought to determine the role of impaired mucus clearance in the pathogenesis of allergen-induced type 2 airway inflammation and identify cellular sources of the signature cytokine IL-13.
We challenged juvenile Scnn1b-Tg and wild-type mice with Aspergillus fumigatus and house dust mite allergen and compared the effects on airway eosinophilia, type 2 cytokine levels, goblet cell metaplasia, and airway hyperresponsiveness. Furthermore, we determined cellular sources of IL-13 and effects of genetic deletion of the key type 2 signal-transducing molecule signal transducer and activator of transcription 6 (STAT6) and evaluated the effects of therapeutic improvement of mucus clearance.
Reduced mucociliary allergen clearance exacerbated Stat6-dependent secretion of type 2 cytokines, airway eosinophilia, and airway hyperresponsiveness in juvenile Scnn1b-Tg mice. IL-13 levels were increased in airway epithelial cells, macrophages, type 2 innate lymphoid cells, and T2 cells along with increased Il33 expression in the airway epithelium of Scnn1b-Tg mice. Treatment with the epithelial Na channel blocker amiloride, improving airway surface hydration and mucus clearance, reduced allergen-induced inflammation in Scnn1b-Tg mice.
Our data support that impaired clearance of inhaled allergens triggering IL-13 production by multiple cell types in the airways plays an important role in the pathogenesis of type 2 airway inflammation and suggests therapeutic improvement of mucociliary clearance as a novel treatment strategy for children with allergen-induced asthma.
2 型气道炎症在变应原诱导性哮喘的发病机制中起核心作用，但潜在机制仍知之甚少。最近，我们证明，黏液纤毛清除功能降低（哮喘的一个特征性特征）会导致幼年β-上皮钠离子通道（Scnn1b）转基因（Tg）小鼠自发出现 2 型气道炎症。
我们旨在确定黏液清除功能受损在变应原诱导的 2 型气道炎症发病机制中的作用，并确定标志性细胞因子 IL-13 的细胞来源。
我们用烟曲霉和屋尘螨变应原对幼年 Scnn1b-Tg 和野生型小鼠进行了挑战，并比较了它们对气道嗜酸性粒细胞增多、2 型细胞因子水平、杯状细胞化生和气道高反应性的影响。此外，我们确定了 IL-13 的细胞来源，以及关键 2 型信号转导分子信号转导和转录激活因子 6（STAT6）的基因缺失的影响，并评估了改善黏液清除的治疗效果。
减少黏液纤毛清除功能加剧了 Scnn1b-Tg 小鼠中 Stat6 依赖性 2 型细胞因子的分泌、气道嗜酸性粒细胞增多和气道高反应性。Scnn1b-Tg 小鼠的气道上皮细胞、巨噬细胞、2 型先天淋巴细胞和 T2 细胞中 IL-13 水平升高，气道上皮细胞中 Il33 表达增加。上皮钠离子通道阻滞剂阿米洛利治疗可改善气道表面水化和黏液清除，减少 Scnn1b-Tg 小鼠的变应原诱导性炎症。
我们的数据支持吸入过敏原触发气道中多种细胞类型产生 IL-13 的清除功能受损在 2 型气道炎症发病机制中起重要作用，并提示改善黏液纤毛清除作为一种新的治疗策略，用于治疗变应原诱导性哮喘的儿童。
