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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

基本信息

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
项目类别：
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

项目摘要

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.

肺的粘液清除系统代表了保护气道表面的关键先天免疫系统防止持续暴露于吸入的传染性和有毒颗粒。然而，粘液的异常清除纤毛跳动和咳嗽是所谓的粘膜阻塞性疾病发病机制的重要因素。肺部疾病，包括囊性纤维化、哮喘和慢性支气管炎。尽管减少了清除率粘液在粘液阻塞性肺疾病患者中的作用，我们对如何发挥作用的知识存在很大的空白，异常粘液产生这种粘液淤滞。为了了解病理的根本原因，要想获得治疗这些疾病的有效疗法，就必须了解其基本机制在调节健康的粘液清除和了解它是如何受到疾病的影响。因此，这一目标该项目的目的是回答一些关于粘液清除系统的未解决的问题。在第一个具体的目的是，我们试图了解气道粘蛋白的作用，这种大的生物聚合物使粘液呈凝胶状，特性，在促进健康中的有效粘液清除中发挥作用。在这里，我们将使用新的体外纤毛-和咳嗽- 介导的清除测定，以测试气道粘蛋白对于有效的粘液清除至关重要的假设，由于粘蛋白和气道细胞表面之间的相互作用，研究还将确定哪些粘蛋白结构域参与这种相互作用。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化，非常长的聚合物，是否需要有效的粘液运输。这个问题具有临床相关性，因为二硫键还原剂“切割”长链粘蛋白，降低粘液的弹性，已被提议作为肺部疾病的粘液溶解疗法。在这目的是，我们将测试这一假设，即粘蛋白聚合需要有效的纤毛和咳嗽介导的通过促进粘液运输穿过纤毛搏动差的气道区域的清除来促进粘液运输协调或缺乏纤毛细胞，由于与胃吸入、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/细胞表面因此，在与分泌的MUC 5AC粘蛋白的过度产生相关的疾病中， Th 2细胞因子信号传导。具体来说，我们将检验慢性IL-13介导的IL-13表达增加的假设。 MUC 5AC表达可以增加纤毛-粘液相互作用的强度，产生粘附性更强、更硬的粘附性。清除粘液层。为了评估疾病相关的MUC 5AC表达增加的影响，我们将利用量化粘液对气道表面的粘附的新型粘液粘附和摩擦测试装置和粘液推进的阻力。这些假设的测试将是至关重要的，以解决我们的许多差距，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/加速粘膜阻塞性肺病患者粘液清除方法的目标。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

DOI：
10.1016/j.coph.2022.102248
发表时间：
2022-08
期刊：
Current opinion in pharmacology
影响因子：
4
作者：
通讯作者：

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

DOI：
10.3389/fphys.2022.842592
发表时间：
2022
期刊：
Frontiers in physiology
影响因子：
4
作者：
Rogers TD;Button B;Kelada SNP;Ostrowski LE;Livraghi-Butrico A;Gutay MI;Esther CR Jr;Grubb BR
通讯作者：
Grubb BR

Mucociliary Clearance in Mice Measured by Tracking Trans-tracheal Fluorescence of Nasally Aerosolized Beads.

通过跟踪鼻雾化珠的经气管荧光测量小鼠的粘膜纤毛清除率。

DOI：
10.1038/s41598-018-33053-2
发表时间：
2018
期刊：
Scientific reports
影响因子：
4.6
作者：
Rogers,TroyD;Ostrowski,LawrenceE;Livraghi-Butrico,Alessandra;Button,Brian;Grubb,BarbaraR
通讯作者：
Grubb,BarbaraR

Airway Epithelial Nucleotide Release Contributes to Mucociliary Clearance.