The role of mucus and pulmonary surface interactions in lung defense

 描述（由申请方提供）：粘液清除异常是环境和/或遗传原因导致慢性支气管炎患者表型的重要因素。由于气道水化减少和粘蛋白分泌增加，气道粘液浓度增加似乎代表囊性纤维化（CF）和COPD患者的统一主题。然而，在我们的知识的基本机制参与调节粘液清除的重大进展，需要阐明的机制，高浓度的粘液产生疾病的发病机制。我们假设粘液脱水，结合嗜中性粒细胞弹性蛋白酶（NE）作为嗜中性粒细胞炎症的结果，在粘液生物物理特性的改变，产生粘附的粘液，“粘”到上皮细胞，并产生在纤毛和咳嗽介导的清除机制的减缓/失败。我们已经开发了一种新的粘液运输系统的描述，即，“双凝胶”粘液层/纤毛周层（PCL）假说强调分泌粘蛋白浓度的作用，即，他们的水化作用，在粘液层，以预测疗效 粘液清除率。基于该模型，我们假设正常的粘液清除需要（1）气道表面充分水合和（2）粘液和细胞表面之间缺乏强粘附相互作用。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。在三个相互作用的目的中检验的假设将用于扩展我们对肺清除系统的理解。在目标1中，我们将研究PCL在气道防御中的作用，建立在我们以前发表的这一层的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NE如何改变粘液层的渗透和凝聚特性。最后，在目标3中，我们将联合收割机结合目标1和目标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。

 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.