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

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

粘液阻塞性肺病（CF、COPD 和哮喘）患者的粘液清除能力降低由于呼吸道中粘稠、粘附的粘液积聚，以了解其发病机制。对于这些疾病，有必要了解介导有效粘液清除的机制健康状况以及该系统的改变如何导致每种疾病的粘液清除失败。总体假设是，疾病中粘液清除能力的降低是多种变化的结果根据我们的初步数据，气道粘液的成分和物理性质发生了变化。粘液特性的产生是由于：1) 与疾病相关的粘液浓度增加，2) MUC5AC（主要哮喘粘蛋白）与 MUC5B（主要 CF/COPD 粘蛋白）的比率，和/或 3) 我们发现粘液层发生了这种变化，从而导致了额外的交联。会产生更“粘”（更粘稠、更粘附、更抗撕裂）的粘液，更难被清除目前尚不清楚纤毛跳动和咳嗽的作用如何发生变化。粘液会改变粘液的生物物理特性，以及这些变化如何导致粘液清除率降低。为了回答这些问题，目标 1 中的研究旨在测试改变粘液浓度的效果 MUC5AC:MUC5B 比例对粘液生物物理特性（流变性、粘附力和内聚强度，以及摩擦）以及这种改变如何影响咳嗽和纤毛跳动后的粘液清除率。已经确定疾病如何改变粘液清除，这是我们的目标，以支持 tPPG 临床项目 3 和 4 目的是确定如何最好地恢复粘液阻塞患者的粘液清除能力。有两种独立但互补的方法可以清除呼吸道中粘附的粘液。最简单的方法是通过水合作用来降低粘液浓度，第二种方法是破坏粘液的结构。重要的是，我们发现了这一点。这些方法可能是相加/协同的。在目标 2 中，我们将通过关联约简来检验这些假设。药剂介导的粘蛋白分子量/大小变化与水合介导的粘液变化相结合重点关注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清除在目标 3 中，我们将评估炎症的作用。介导粘液氧化形成渗透性、不可膨胀的粘液凝胶，这会严重影响我们将检验这样的假设：仅靠水合方法是不够的，但需要采用一种方法。总的来说，需要结合水合剂和还原剂来恢复粘液清除率。项目 1 预计将通过增进我们对机制的理解来支持其他 tPPG 项目疾病中粘液清除缺陷的研究并确定最有效的水合治疗组合以及还原剂，以最大程度地恢复 CF、COPD 和哮喘患者的粘液清除能力。