The role of mucus and pulmonary surface interactions in lung defense

 描述(申请人提供)：粘液清除异常是环境和/或遗传原因引起的慢性支气管炎患者表型的重要因素。在囊性纤维化(CF)和慢性阻塞性肺疾病(COPD)患者中，由于呼吸道水合作用减少和粘蛋白分泌增加，呼吸道粘液浓度增加似乎是一个统一的主题。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，以阐明高浓度粘液导致疾病发病的机制。我们假设黏液脱水，结合中性粒细胞弹性蛋白酶(NE)引起的黏液生物物理性质的改变，导致中性粒细胞炎症，产生黏附黏液，黏附于上皮细胞，并在纤毛和咳嗽介导的清除机制的减慢/失败中产生。我们发展了一种新的粘液运输系统的描述，即“双胶”粘液层/纤毛层(PCL)假说，该假说强调粘液层中分泌粘蛋白的浓度，即它们的水化作用，以预测疗效。 粘液清除能力。基于这个模型，我们假设正常的粘液清除需要(1)充分的呼吸道表面水化和(2)粘液和细胞表面之间没有强烈的粘连相互作用。这个项目的主要目标是了解粘液和PCL层是如何保持健康的，以及它们在疾病中是如何失效的。在三个相互作用的目标中检验的假设将被用来扩大我们对肺清除系统的理解。在目标1中，我们将研究PCL在呼吸道防御中的作用，建立在我们之前发表的这一层生物物理学工作的基础上。在目标2中，我们进行研究，以了解粘液脱水和去甲肾上腺素如何改变粘液层的渗透和粘连特性。最后，在目标3中，我们将结合在目标1和2中获得的知识，了解粘液和PCL层如何相互作用来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。

 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.