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.

患有黏液阻塞性肺疾病（CF、COPD和哮喘）的患者存在黏液清除率降低的问题