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: 10656371
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656371
• 关键词: Acceleration; Address; Adherence; Adhesions; Affect; Asthma; Binding; Biochemical; Biological Assay; Biological Models; Biophysics; Biopolymers; Cause of Death; Cell surface; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Cilia; Confusion; Coughing; Cystic Fibrosis; Cytokine Signaling; Data; Defect; Defense Mechanisms; Devices; Disease; Elasticity; Epithelium; 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; Membrane; Modeling; Molecular Weight; Mucins; Mucociliary Clearance; Mucolytics; Mucous body substance; Particulate; Pathogenesis; Pathology; Patients; Persons; Play; Polymers; Production; Property; Proteins; Reducing Agents; Resistance; Role; Safety; Stomach; Surface; System; Testing; Virus Diseases; aspirate; biophysical properties; cigarette smoking; clinically relevant; cytokine; disulfide bond reduction; effective therapy; glycosylation; hydrodynamic flow; in vitro Model; lung health; muco-obstructive airway diseases; 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.

肺部的粘液清除系统是保护气道表面的关键先天免疫系统 防止持续接触吸入的传染性和有毒颗粒。然而，粘液清除异常。 纤毛跳动和咳嗽是所谓粘膜阻塞性疾病发病机制的重要贡献者 肺部疾病，包括囊性纤维化、哮喘和慢性支气管炎，尽管有降低清除率的作用。 粘液阻塞性肺病患者的粘液分泌情况，我们对于如何进行粘液分泌的了解还存在很大差距 异常的粘液会产生这种粘膜淤积，以便了解病理学的根本原因并进行发展。 治疗此类疾病的有效疗法，有必要了解所涉及的基本机制 调节健康中的粘液清除并了解它如何受到疾病的影响因此，这是本研究的目标。 该项目的目的是回答一些有关粘液清除系统的未解决的问题。 我们的目标是了解气道粘蛋白的作用，粘蛋白是一种大型生物聚合物，使粘液呈凝胶状 特性，在促进健康中有效的粘液清除方面发挥作用，在这里，我们将使用新型的体外纤毛和咳嗽。 介导的清除测定来检验气道粘蛋白对于有效清除粘液至关重要的假设 由于粘蛋白和气道细胞表面之间的相互作用，研究还将确定哪些因素会影响肺部。 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。 有效的粘液运输是否需要粘蛋白的高阶多聚化，形成很长的聚合物。 这个问题作为二硫键还原剂具有临床意义，它可以“裂解”长链粘蛋白并 降低粘液的弹性，已被提议作为肺部疾病的粘液溶解疗法。 目标，我们将测试粘蛋白聚合是有效纤毛和咳嗽介导所必需的假设 通过促进纤毛跳动较差的气道区域的粘液运输的清除来促进粘液运输 由于胃误吸、香烟引起的气道损伤，导致纤毛细胞协调或缺乏 在第三个目标中，我们将检验粘蛋白/细胞表面的假设。 在与分泌性 MUC5AC 粘蛋白过度产生相关的疾病中，相互作用是异常的，因此 具体来说，我们将测试以下假设：IL-13 介导的慢性增加。 MUC5AC 表达可以增加纤毛-粘液相互作用的强度，产生更粘附、更坚硬的纤维。 为了评估疾病相关的 MUC5AC 表达增加的影响，我们将利用 新型粘液粘附和摩擦测试装置，可量化粘液对气道表面的粘附力 这些假设的测试对于解决我们的许多差距至关重要。 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以及识别 恢复/加速粘液阻塞性肺病患者粘液清除方法的目标。

项目成果

Mucus-targeting therapies of defective mucus clearance for cystic fibrosis: A short review.

囊性纤维化粘液清除缺陷的粘液靶向治疗：简短回顾。

• 发表时间: 2022-08
• 影响因子: 4
• 作者: Figueira, Miriam Frankenthal;Ribeiro, Carla M P;Button, Brian
• 通讯作者: Button, Brian

Osmolytes and ion transport modulators: new strategies for airway surface rehydration.

渗透剂和离子传输调节剂：气道表面补液的新策略。

• 发表时间: 2010-06
• 影响因子: 4
• 作者: Goralski, Jennifer L;Boucher, Richard C;Button, Brian
• 通讯作者: Button, Brian

Regional Differences in Mucociliary Clearance in the Upper and Lower Airways.

上呼吸道和下呼吸道粘液纤毛清除的区域差异。

• 发表时间: 2022
• 作者: Rogers, Troy D;Button, Brian;Kelada, Samir N P;Ostrowski, Lawrence E;Livraghi;Gutay, Mark I;Esther Jr, Charles R;Grubb, Barbara R
• 通讯作者: Grubb, Barbara R

Airway Epithelial Nucleotide Release Contributes to Mucociliary Clearance.

气道上皮核苷酸释放有助于粘膜纤毛清除。

• 发表时间: 2021-05-11
• 作者: van Heusden, Catharina;Grubb, Barbara R;Button, Brian;Lazarowski, Eduardo R
• 通讯作者: Lazarowski, Eduardo R

Pathological mucus and impaired mucus clearance in cystic fibrosis patients result from increased concentration, not altered pH.

囊性纤维化患者的病理性粘液和粘液清除功能受损是由于浓度增加而不是 pH 值改变造成的。

• 发表时间: 2018
• 作者: Hill, David B;Long, Robert F;Kissner, William J;Atieh, Eyad;Garbarine, Ian C;Markovetz, Matthew R;Fontana, Nicholas C;Christy, Matthew;Habibpour, Mehdi;Tarran, Robert;Forest, M Gregory;Boucher, Richard C;Button, Brian
• 通讯作者: Button, Brian