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

• 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
• 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

 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（由适用提供）：粘液清除率异常是由环境和/或遗传原因引起的慢性支气管炎患者表型的重要原因。气道粘液浓度的增加，由于气道水合减少和粘蛋白分泌增加，似乎代表了囊性纤维化（CF）和COPD患者的统一主题。然而，我们对控制粘液清除涉及的基本机制的了解，需要阐明高浓度粘液产生疾病发病机理的机制。我们假设粘液脱水，与中性粒细胞弹性酶（NE）在嗜中性粒细胞感染的结果中结合使用粘液生物物理特性的改变，产生粘附的粘液，可“坚持”上皮细胞，并在纤毛和贫民窟介导的清除机构的减速/失败中产生。我们已经开发了一种对粘液传输系统的新颖描述，即“两吉尔”粘液层/周围层（PCL）假设，该假设强调了分泌的粘蛋白浓度的作用，即水合，在粘液层中预测效率 基于此模型，我们假设正常的粘液清除需要（1）气道表面足够的水合，（2）粘液与细胞表面之间没有强烈的粘合性相互作用。该项目的主要目标是了解粘液和PCL层如何保持健康以及它们如何在疾病中失败。假设在三个相互作用的目标中测试的测试将用于扩展我们对肺通量系统的理解。在AIM 1中，我们将基于我们先前发表的该层生物物理学的工作，研究PCL在气道防御中的作用。在AIM 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凝聚力。最后，在AIM 3中，我们将结合AIM 1和2中获得的知识，以了解粘液和PCL层相互作用以维持纤毛和咳嗽介导的粘液清除率，以及它们为什么在疾病中失败。