The role of mucus and pulmonary surface interactions in lung defense

粘液和肺表面相互作用在肺防御中的作用

• 批准号: 10204086
• 负责人: BRIAN M BUTTON
• 金额: $ 38.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-03 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204086
• 关键词: Address; Adherence; Adhesions; Affect; Asthma; Binding; Biochemical; Biological Assay; Biological Models; Biophysics; Biopolymers; Cause of Death; Cell surface; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cilia; Cleaved cell; Confusion; Coughing; Cystic Fibrosis; Cytokine Signaling; Data; Defect; Defense Mechanisms; Devices; Disease; Epithelial; Event; Exhibits; Exposure to; Filament; Force of Gravity; Friction; Gel; Goals; Health; Higher Order Chromatin Structure; In Vitro; Infectious Agent; Inhalation; Innate Immune System; Interleukin-13; Knowledge; Length; Liquid substance; Lung; Lung diseases; MUC5AC gene; MUC5B gene; Mediating; Modeling; Molecular Weight; Mucins; Mucociliary Clearance; Mucolytics; Mucous body substance; Particulate; Pathogenesis; Pathology; Patients; Persons; Plant Roots; Play; Polymers; Production; Property; Proteins; Reducing Agents; Resistance; Role; Safety; Stomach; Surface; System; Testing; Virus Diseases; base; biophysical properties; cigarette smoking; clinically relevant; cytokine; disulfide bond; effective therapy; hydrodynamic flow; in vitro Model; mucus clearance; mucus-associated lung diseases; novel; novel strategies; overexpression; particle; pathogen; physical property; polymerization; targeted agent; targeted treatment

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.

肺的粘液间隙系统代表了保护气道表面的关键先天免疫系统 反对不断暴露于吸入感染和有害颗粒。但是，粘液的异常清除率 由Cilia Beating和Coug代表了所谓的粘膜粘结性发病机理的重要贡献 肺部疾病，包括囊性纤维化，哮喘和慢性支气管炎。尽管作用降低了间隙 粘液刺激性肺部疾病患者的粘液发挥作用，我们知道如何了解如何 异常粘液会产生这种粘液性。为了了解病理的根本原因并发展 有效治疗此类疾病的疗法有必要了解所涉及的基本机制 在调节健康方面的粘液清除并了解疾病的影响如何。因此，目标的目标 项目是回答有关粘液清除系统的许多未解决的问题。在第一个特定 目的，我们试图了解气道粘蛋白的角色，大型生物聚合物，使粘液类似于凝胶 属性，可促进健康中有效的粘液清除率。在这里，我们将使用新颖的体外纤毛和coug- 介导的清除率ASS测试气道粘蛋白对于有效粘液清除至关重要的假设 肺部与气道细胞表面之间的相互作用。研究还将确定哪个 粘蛋白结构域参与了这种相互作用。在第二个目标中，我们将解决另一个杰出问题 有效的粘液转运是否需要粘蛋白的高阶多层化（对很长的聚合物）。 这个问题与二硫键还原剂具有临床相关性，该蛋白质降低了长链粘蛋白和“裂解” 已经提出了减少粘液的弹性特性作为肺部疾病的粘液溶解疗法。在这个 目的，我们将检验以下假设：有效的纤毛和咳嗽介导的粘蛋白聚合需要 粘液运输通过支撑跨气道地区的粘液运输的清除，而纤毛较差 由于与胃抽吸有关的气道损害，香烟的配位或没有纤毛细胞 吸烟和某些病毒感染。在第三个目标中，我们将测试粘蛋白/细胞表面的假设 结果，与分泌的MUC5AC粘蛋白超生产有关的疾病异常是异常的 Th2细胞因子信号传导。具体而言，我们将检验以下假设：慢性IL-13介导的增加 MUC5AC表达可以增加纤毛 - 糖相互作用的强度，从而产生更坚固，硬的强度 清除粘液层。为了评估与疾病相关的增加MUC5AC表达的影响，我们将利用 新型的粘液粘合剂和摩擦测试设备，可量化粘液对气道表面的粘附 和粘液推进的抗性。这些假设的检验对于解决我们的许多差距至关重要 有关粘液清除系统在健康中起作用的知识，为什么在疾病中功能失调，并确定 在患有粘液刺激性肺部疾病的人中恢复/加速粘液清除方法的方法。