The role of mucus and pulmonary surface interactions in lung defense

肺的粘液清除系统是保护呼吸道表面的关键先天免疫系统。 防止持续暴露在吸入的传染性和有毒颗粒物中。然而，粘液的异常清除 纤毛跳动和咳嗽是所谓的粘液阻塞性疾病的重要致病因素。 肺部疾病，包括囊性纤维化、哮喘和慢性支气管炎。尽管减少了通关的作用 粘液在粘液阻塞性肺疾病患者中的作用，我们对其如何发挥作用的认识存在很大差距。 异常粘液会产生这种粘液抑制作用。为了了解本病的根本原因并发展起来 要有效治疗这类疾病，有必要了解其中涉及的基本机制。 在调节健康的粘液清除方面，并了解它是如何受到疾病的影响的。因此，这一目标是 该项目将回答有关粘液清除系统的一些悬而未决的问题。在第一个具体的 目的，我们试图了解呼吸道粘蛋白是什么作用，这种大的生物聚合物使粘液呈凝胶状。 特性，在促进有效的粘液清除健康方面发挥了作用。在这里，我们将使用新型的体外纤毛-和咳嗽- 用介导性清除试验来检验呼吸道粘蛋白对有效清除粘液至关重要的假设 由于粘蛋白和呼吸道细胞表面之间的相互作用，导致了对肺的损伤。研究还将确定哪些 粘蛋白结构域参与了这种相互作用。在第二个目标中，我们将解决另一个悬而未决的问题 粘蛋白的高阶多聚体是否为有效的粘液运输所必需的。 这个问题作为二硫键还原剂具有临床意义，它可以“裂解”长链粘蛋白和 降低粘液的弹性，已被认为是一种肺部疾病的粘液溶解疗法。在这 目的：我们将验证一种假设，即有效的纤毛和咳嗽调节需要粘蛋白聚合。 通过促进粘液跨纤毛节拍较差的呼吸道区域的粘液传输而实现的粘液传输 与胃吸入相关的呼吸道损伤导致的纤毛细胞协调或缺失，香烟 吸烟和某些病毒感染。在第三个目标中，我们将检验粘蛋白/细胞表面的假设 因此，在与分泌的MUC5AC粘蛋白过度产生相关的疾病中，相互作用是异常的 Th2细胞因子信号转导。具体地说，我们将测试这一假设，即慢性IL-13介导的 MUC5AC的表达可以增加纤毛-粘液相互作用的强度，产生更多的黏附、坚硬 要清除粘液层。为了评估与疾病相关的MUC5AC表达增加的影响，我们将利用 新型黏液黏附和摩擦测试装置，用于量化黏液对呼吸道表面的黏附 以及粘液推进的阻力。对这些假设的测试将是解决我们的许多差距的关键 了解粘液清除系统在健康中的功能，为什么它在疾病中功能失调，并确定 恢复/加速粘液阻塞性肺病患者粘液清除的方法的目标。

The mucus clearance system of the lung represents a key innate immune system that protects the airway surface against constant exposure to inhaled infectious and noxious particles. However, abnormal clearance of mucus by cilia beating and cough represents a significant contributor to the pathogenesis in so-called muco-obstructive lung diseases, including cystic fibrosis, asthma, and chronic bronchitis. Despite the role that reduced clearance of mucus plays in patients with muco-obstructive lung diseases, there are large gaps in our knowledge of how abnormal mucus produces such mucostasis. In order to understand the root causes of the pathology and develop effective therapies to treat such diseases, it is necessary to understand the fundamental mechanisms involved in regulating mucus clearance in health and understand how is it affected by disease. Therefore, the goal of this project is to answer a number of unresolved questions regarding the mucus clearance system. In the first specific aim, we seek to understand what role airway mucins, the large biopolymers which give mucus its gel-like properties, play in facilitating efficient mucus clearance in health. Here, we will use novel in vitro cilia- and cough- mediated clearance assays to test the hypothesis that airway mucins are vital for efficient mucus clearance out of the lung, as a result of interactions between mucins and the airway cell surface. Studies will also identify which mucin domains are involved in this interaction. In the second aim, we will address another outstanding question of whether higher-order multimerization of mucins, to very long polymers, is required for efficient mucus transport. This question has clinical relevance as disulfide bond reducing agents, which “cleave” long-chain mucins and reduce the elastic properties of mucus, have been proposed as a mucolytic therapy for lung diseases. In this aim, we will test the hypothesis that mucin polymerization is required for efficient cilia- and cough-mediated mucus transport by facilitating the clearance of mucus transport across regions of the airways with poor cilia beat coordination or devoid of ciliated cells, as a result of airway damage associated with gastric aspiration, cigarette smoking, and certain viral infections. In the third aim, we will test the hypothesis that mucin/cell surface interactions are abnormal in diseases associated with hyperproduction of secreted MUC5AC mucin, as a result of Th2 cytokine signaling. Specifically, we will test the hypothesis that chronic IL-13-mediated increases in MUC5AC expression can increase the strength of the cilia-mucus interactions, generating a more adherent, hard to clear, mucus layer. To assess the impact of disease-related increases in MUC5AC expression we will utilize novel mucus adhesion and friction testing devices which quantifies the adherence of mucus to the airway surface and resistance of mucus propulsion. The testing of these hypotheses will be critical to address many gaps in our knowledge about mucus clearance system functions in health, why it is dysfunctional in disease, and to identify targets for approaches to restore/accelerate mucus clearance in persons with muco-obstructive lung diseases.