Role of cilia, mucus, and airway surface liquid in mucociliary dysfunction: Lessons from mouse models
Role of cilia, mucus, and airway surface liquid in mucociliary dysfunction: Lessons from mouse models
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DOI：
10.1089/jamp.2007.0659
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发表时间：
2008-03-01
影响因子：
3.4
通讯作者：
Mall, Marcus A.
中科院分区：
文献类型：
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作者：
Mall, Marcus A.
粘膜纤毛清除是一种重要的主要先天防御机制，可保护肺部免受吸入污染物、过敏原和病原体的有害影响。粘膜纤毛功能障碍是人类慢性气道疾病的常见特征。粘膜纤毛器由三个功能部件组成，即纤毛、保护性粘液层和气道表面液体（ASL）层，它们协同工作以从肺中去除吸入的颗粒。对囊性纤维化、原发性纤毛运动障碍、哮喘和慢性支气管炎患者的临床和病理学观察结果进行了概述，结果表明，粘液纤毛系统各隔室的异常可影响粘液清除并导致慢性气道疾病。然而，导致粘液清除不足的机制仍然不完全清楚。黏膜纤毛器单个元件缺陷的基因工程小鼠是研究体内黏膜纤毛功能障碍发病机制的有力工具。在这篇简明的综述中，我评估了小鼠模型的肺表型，这些小鼠模型在纤毛结构/功能、粘液产生和ASL调节方面具有遗传学定义的异常，并讨论了这些动物研究的结果，这些动物研究的背景是目前的粘液纤毛功能障碍的发病机制假设。这些动物研究的最新数据表明ASL脱水在粘膜纤毛功能障碍和慢性气道疾病的发病机制中起关键作用。在具有上皮Na+通道（ENaQ，其构成从气道表面吸收盐和水的限速途径）的气道特异性过表达的小鼠中，ASL消耗引起粘液清除减少，以及具有粘液阻塞、杯状细胞化生、慢性炎症、细菌清除减少和高肺死亡率的自发性慢性气道疾病。这种粘膜纤毛功能障碍的小鼠模型将允许设计用于改善粘膜纤毛清除的新型治疗策略的体内评价，并且将有助于慢性气道疾病的新型疗法的临床前开发。
Mucociliary clearance is an important primary innate defense mechanism that protects the lungs from deleterious effects of inhaled pollutants, allergens, and pathogens. Mucociliary dysfunction is a common feature of chronic airway diseases in humans. The mucociliary apparatus consists of three functional comp artments, that is, the cilia, a protective mucus layer, and an airway surface liquid (ASL) layer, which work in concert to remove inhaled particles from the lung. A synopsis of clinical and pathological observations in patients with cystic fibrosis, primary ciliary dyskinesia, asthma, and chronic bronchitis indicates that abnormalities in each compartment of the mucociliary system can com ' promise mucus clearance and cause chronic airway disease. Howe * ver, the mechanisms-that lead to deficient mucus clearance are still incompletely understood. Genetically engineered mice with defects in individual elements of the mucociliary apparatus are powerful tools to study the pathogenesis of mucociliary dysfunction in vivo. In this concise review, I assess the pulmonary phenotypes of mouse models with genetically defined abnormalities in ciliary structure/function, mucus production, and ASL regulation, and discuss the results of these animal studies in the context of current pathogenetic hypotheses for mucociliary dysfunction. Recent data driven from.these animal studies point to a critical role of ASL dehydration in the pathogenesis of mucociliary dysfunction and chronic airway disease. In mice with airway-specific overexpression of epithelial Na' channels (ENaQ, which constitute a.rate limiting pathway for absorption of salt and water from airway surfaces, ASL depletion caused reduced mucus clearance, and a spontaneous chronic airway disease with mucus obstruction, goblet cell metaplasia, chronic inflammation, reduced bacterial clearance, and high pulmonary mortality. This mouse model of mucociliary dysfunction will allow an in vivo evaluation of novel therapeutic strategies designed to improve mucociliary clearance, and will aid the preclinical development of novel therapies for chronic airway diseases.