Project 1: Mechanism of action of mucolytics in improving mucus clearance in lung disease

项目1：粘液溶解剂改善肺部疾病粘液清除的作用机制

• 批准号: 9560889
• 负责人: Michael Rubinstein
• 金额: $ 34.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9560889
• 关键词: Adhesions; Adhesives; Affect; Airway Disease; Asthma; Biological Markers; Biophysics; Cell surface; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cilia; Clinic; Clinical; Coughing; Cystic Fibrosis; Data; Dehydration; Development; Disease; Doctor of Philosophy; Failure; Friction; Gel; Goals; Growth; Health; Hydration status; Inflammation; Inflammatory Response; Knowledge; Lead; Life; Lung; Lung diseases; MUC5AC gene; MUC5B gene; Mediating; Metabolic Clearance Rate; Methods; Molecular Weight; Mono-S; Mucins; Mucolytics; Mucous body substance; Obstruction; Obstructive Lung Diseases; Oxidants; Oxides; Pathogenesis; Pathogenicity; Patients; Persons; Phenotype; Property; Proteins; Public Health; Reducing Agents; Regimen; Research Personnel; Resistance; Rheology; Role; Structure; Sulfhydryl Compounds; System; Testing; Thick; Treatment Efficacy; Viscosity; base; biophysical properties; cohesion; crosslink; cystic fibrosis patients; design; disulfide bond; dithiol; improved; microorganism; molecular size; novel; oxidation; physical property; viscoelasticity

Patients with muco-obstructive lung diseases (CF, COPD, and asthma) suffer from reduced mucus clearability due to accumulation of sticky, adherent, mucus in their airways. In order to understand the pathogenesis of these diseases, it is necessary to understand both the mechanisms that mediate efficient mucus clearance in health and how alterations in this system leads to failed mucus clearance in each of these disorders. Our overarching hypothesis is that reduced mucus clearance in disease is a result of multiple alterations in the composition and physical properties of the airway mucus. Based on our preliminary data, such changes in mucus properties come as a result of: 1) disease-related increases in mucus concentration, 2) alteration in the ratio of MUC5AC (the dominant asthma mucin) vs. MUC5B (the dominant CF/COPD mucin), and/or 3) oxidation of mucins resulting in additional cross-links. We hypothesize that such alterations in the mucus layer will produce a more “sticky” (more viscous, adherent, tear-resistant) mucus that will be harder to be cleared by the action of cilia beating and coughing. There is currently a lack of knowledge of how such changes in the mucus alter the biophysics properties of the mucus and how such changes lead to reduced mucus clearance. To answer these questions, studies in Aim 1 are designed to test the effect of altering mucus concentration and MUC5AC:MUC5B ratio on mucus biophysical properties (rheology, adhesion and cohesion strength, and friction) and how such alterations affect the rate of mucus clearance by cough and cilia beating. Once it has been established how disease alters mucus clearance, our goal, in support of the tPPG clinical projects 3 & 4 is to determine how best to restore mucus clearance in patients with mucus obstructions. We hypothesize that there are two separate, but complementary, approaches to clear adherent mucus from the airways. The simplest is to reduce the mucus concentration, via hydration. The second is by breaking down the structure of mucus through reduction in mucin molecular weight using reducing agents. Importantly, we hypothesize that such approaches may be additive/synergistic. In Aim 2 we will test these hypotheses by correlating reducing agent-mediated changes in mucin molecular weight/size combined with hydration-mediated changes in mucus concentration on changes in mucus biophysical properties and assess the impact of these changes on stimulating both cilia- and cough-mediated mucus clearance. In Aim 3, we will assess the role of inflammation- mediated oxidation of mucus in the formation of a permeant, non-swellable, mucus gel, which can severely limit clearance from the airways. We will test the hypothesis that hydration method alone is not sufficient, but a combination of hydrator plus a reducing agent is required to restore the mucus clearance. Overall, the studies in Project 1 are expected to support other tPPG Projects by advancing our understanding of the mechanism(s) of defective mucus clearance in disease and identifying the most effective therapeutic combination of hydrating and reducing agents to maximally restore mucus clearance in patients with CF, COPD, and asthma.

粘膜肺癌疾病（CF，COPD和哮喘）患者的粘液可见性降低 由于其呼吸道中粘性，粘附，粘液的积累。为了了解 这些疾病，有必要了解介导有效粘液清除率的两种机制 健康以及该系统中的变化如何导致每种疾病中的粘液清除失败。我们的 总体假设是，疾病中粘液清除率降低是由于多次改变的结果 气道粘液的组成和物理特性。根据我们的初步数据，此类变化 粘液特性的结果是：1）粘液浓度与疾病相关的增加，2）改变 MUC5AC（主要哮喘粘蛋白）与MUC5B（主要CF/COPD粘蛋白）和/或3）的比率 粘蛋白的氧化导致其他交联。我们假设粘液层的这种改变 会产生更“粘性”（更粘，粘附，耐泪液）粘液，很难被清除 纤毛殴打和沙发的动作。目前缺乏了解这种变化如何变化的知识 粘液改变粘液的生物物理特性以及这种变化如何导致粘液清除率降低。 为了回答这些问题，AIM 1中的研究旨在测试改变粘液浓度的效果 和MUC5AC：MUC5B生物物理特性的MUC5B比（流变，粘合剂和粘性强度，以及 摩擦）以及这种改变如何影响咳嗽和纤毛殴打的粘液清除率。一旦有 建立了疾病如何改变粘液清除，我们的目标是支持TPPG临床项目3和4 是确定如何最好地恢复粘液对象患者的粘液清除率。我们假设这一点 有两种单独但完整的方法可以从气道中清除粘附的粘液。这 最简单的是通过水合降低粘液浓度。第二是分解 通过使用还原剂减少粘蛋白分子量，粘液。重要的是，我们假设 这种方法可能是加性/协同作用。在AIM 2中，我们将通过降低来检验这些假设 粘蛋白分子量/大小的介导的变化与粘液中水合介导的变化结合 集中于粘液生物物理特性的变化，并评估这些变化对 刺激纤毛和咳嗽介导的粘液间隙。在AIM 3中，我们将评估炎症的作用 - 粘液在形成胶粘剂，不可舒适的粘液凝胶中介导的氧化，可以严重 限制航空公司的清关。我们将检验以下假设：仅保湿方法还不够，但是 水合物加还原剂的组合需要恢复粘液清除率。总体而言，研究 在项目1中，预计将通过促进我们对机制的理解来支持其他TPPG项目 疾病中粘液清除不良并确定水合的最有效疗法组合 并降低药物以最大程度地恢复CF，COPD和哮喘患者的粘液清除率。