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：
9305127
负责人：
BRIAN M BUTTON
金额：
$ 37.77万
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 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9305127
关键词：
Adhesions Adhesives Affect Asthma Biophysics Breathing Cause of Death Cell surface Cells Chronic Bronchitis Chronic Obstructive Airway Disease Cilia Coughing Coupled Cystic Fibrosis Data Dehydration Disease Ensure Epithelial Cells Excision Exposure to Failure Friction Gel Genetic Goals Health Hydration status Infection Infectious Agent Inflammation Inflammation Mediators Inflammatory Inflammatory Response Innate Immune System Ion Transport Knowledge Leukocyte Elastase Liquid substance Lung Lung diseases Manuscripts Measures Mediating Metabolic Clearance Rate Modeling Molecular Weight Movement Mucins Mucociliary Clearance Mucous body substance Obstructive Lung Diseases Osmotic Pressure Pathogenesis Patients Persons Phenotype Plant Roots Polymers Property Publishing Role Sampling Series Structure Surface System Techniques Testing Therapeutic Water Work absorption airway surface liquid base biophysical properties cohesion density design experimental study mucin hypersecretion neutrophil novel novel strategies public health relevance viscoelasticity

项目摘要

DESCRIPTION (provided by applicant): Abnormal mucus clearance is an important contributor to the phenotype of patients with chronic bronchitis resulting from environmental and/or genetic causes. Increases in airway mucus concentration, as the result of reduced airway hydration and increased mucin secretion, appear to represent a unifying theme in both cystic fibrosis (CF) and COPD patients. However, major advances in our knowledge of the fundamental mechanisms involved in regulating mucus clearance are required to elucidate the mechanism by which hyperconcentrated mucus produces disease pathogenesis. We hypothesize mucus dehydration, combined with alterations in mucus biophysical properties by neutrophil elastase (NE) as a result of neutrophilic inflammation, produces adherent mucus that "sticks" to epithelial cells and produces in a slowing/failure of cilia- and cough-mediated clearance mechanisms. We have developed a novel description of mucus transport system, i.e., the "two-gel" mucus layer/periciliary layer (PCL) hypothesis that emphasizes the role of the concentration of secreted mucins, i.e., their hydration, in the mucus layer to predict the efficacy of mucus clearance. Based on this model, we hypothesize that normal mucus clearance requires (1) adequate hydration of the airway surface and (2) an absence of strong adhesive interaction between mucus and cell surface. The main goal of this project is to understand how the mucus and PCL layers are maintained in health and how they fail in disease. Hypothesizes tested in three interacting Aims will be used to expand our understanding of the pulmonary clearance system. In Aim 1, we will investigate the role of the PCL in airway defense, building upon our previously published work in the biophysics of this layer. In Aim 2, we perform studies to understand how mucus dehydration and NE alter the osmotic and cohesive properties of the mucus layer. Finally, in Aim 3, we will combine the knowledge gained in Aims 1 and 2 to understand the how the mucus and PCL layers interact to maintain cilia- and cough-mediated mucus clearance, and why they fail in disease.

描述（由申请人提供）：由于环境和/或遗传原因，粘液清除异常是导致慢性支气管炎患者表型的一个重要因素。由于气道水合作用减少和粘蛋白分泌增加，气道粘液浓度增加。然而，我们需要在调节粘液清除的基本机制方面取得重大进展，以阐明其机制。我们研究了粘液脱水，加上中性粒细胞炎症导致的中性粒细胞弹性蛋白酶（NE）引起的粘液生物物理特性的改变，产生“粘”在上皮细胞上的粘液，并导致纤毛减慢/衰竭。 - 和咳嗽介导的清除机制。我们开发了一种粘液运输系统的新颖描述，即“双凝胶”粘液。粘液层/纤毛周围层（PCL）假说强调粘液层中分泌的粘蛋白浓度（即它们的水合作用）对预测功效的作用基于该模型，我们追求正常的粘液清除需要（1）气道表面充分的水合作用以及（2）粘液和细胞表面之间不存在强粘附相互作用。该项目的主要目标是了解。粘液层和 PCL 层如何保持健康以及它们如何在疾病中失效在三个相互作用的目标中测试的假设将用于扩展我们对肺部清除系统的理解在目标 1 中，我们将研究 PCL 在疾病中的作用。气道防御，以我们之前发表的该层生物物理学工作为基础，在目标 2 中，我们进行研究以了解粘液脱水和 NE 如何改变粘液层的渗透和粘性特性。最后，在目标 3 中，我们将结合起来。目标 1 和 2 中获得的知识，以了解粘液和 PCL 层如何相互作用以维持纤毛和咳嗽介导的粘液清除，以及它们在疾病中失败的原因。