The Role of Airway Mucus in Infection and Inflammation

项目摘要/摘要 粘液纤毛清除异常(MCC)是囊性纤维化(CF)肺部疾病的重要组成部分，也是 被认为是导致该患者群体中慢性肺部感染高发病率的原因；反过来 慢性感染的存在被认为会恶化MCC缺陷，造成粘液阻塞的循环， 感染，以及难以中断或逆转的炎症。然而，其机制和相互作用 对这一现象负有责任的人还没有很好地理解。开发了新的动物模型，如CF大鼠 在我们机构，在识别导致慢性感染的关键因素方面一直很有用 致病菌铜绿假单胞菌在CF呼吸道。该动物模型发展为MCC缺陷 循序渐进地提供了一个研究早期疾病和晚期疾病患者的模型。在这 模型铜绿假单胞菌感染前粘液必须异常才能转化感染 一种慢性表型。Cf在粘液异常发展之前暴露的大鼠能够清除 感染。一种携带人源化G551D-CFTR基因组插入片段的新大鼠模型对FDA批准的反应 治疗CF病根本缺陷的CFTR型调节剂。使用创新的微光学 相干层析成像(µOCT)，一种高分辨率反射成像方式，可以同时和 无创性地评估呼吸道水化、纤毛搏动和粘液传输以及原位粘度，我们可以 有或无CFTR的CF大鼠模型感染前后粘液缺陷的分析 调制器。利用这些工具，这项提案将寻求调查导致患者患有 Cf将急性感染转变为慢性感染，有以下独立但相辅相成的目标： 1.确定MUC5B是否是粘液中促进慢性铜绿假单胞菌的特定成分 感染。 2.确定炎症是否是加速粘液缺陷的必要和充分的条件，从而诱发 呼吸道感染导致慢性铜绿假单胞菌感染。 3.确定新的高效CFTR调节剂是否通过归一化促进铜绿假单胞菌的清除 呼吸道内有异常粘液。 这项建议将确定导致CF肺部疾病感染和进展的早期事件 以及这与铜绿假单胞菌在患者群体中从间歇性转化为慢性的关系， 使用高度相关的动物模型。这些研究将提供新的基本观察结果，将有助于 我们对慢性支气管炎呼吸道病理的了解，并有助于确定适合于 干预。

Project Summary / Abstract Abnormal mucociliary clearance (MCC) is a critical component of cystic fibrosis (CF) lung disease, and is postulated to contribute to the high incidence of chronic pulmonary infections in this patient population; in turn the presence of chronic infection is thought to worsen the MCC defect, creating a cycle of mucus obstruction, infection, and inflammation that is difficult to interrupt or reverse. However, the mechanisms and interactions responsible for this phenomenon are not well understood. New animal models, such as the CF rat, developed at our institution, have been useful in identification of key factors that lead to chronic infection with the pathogen Pseudomonas aeruginosa in the CF airway. This animal model develops the MCC defect progressively, providing a model with which to study patients with early disease as well as late disease. In this model of CF, mucus must be abnormal before exposure to Pseudomonas aeruginosa to convert the infection to a chronic phenotype. CF rats exposed before the mucus abnormality develops are able to clear the infection. A new rat model harboring a humanized G551D-CFTR genomic insert respond to FDA-approved CFTR modulators that treat the fundamental defect of CF disease. Using the innovative Micro-Optical Coherence Tomography (µOCT), a high-resolution reflectance imaging modality that can simultaneously and non-invasively evaluate airway hydration, ciliary beating and mucus transport and viscosity in situ, we can analyze aspects of the mucus defect in both the CF rat model before and after infection, with or without CFTR modulators. Using these tools, this proposal will seek to investigate the mechanisms that cause patients with CF to transition acute infections into chronic ones, with the following independent but complimentary aims: 1. Determine if Muc5b is the specific component of mucus that promotes chronic Pseudomonas aeruginosa infection. 2. Determine if inflammation is necessary and sufficient to accelerate the mucus defect, predisposing the airway to chronic P. aeruginosa infection. 3. Determine if new highly effective CFTR modulators promote clearance of P. aeruginosa by normalizing abnormal mucus in the airway. This proposal will determine the early events that lead to infection and progression in CF pulmonary disease and how this relates to the conversion of P. aeruginosa from intermittent to chronic in this patient population, using a highly relevant animal model. The studies will provide new fundamental observations that will inform our understanding of the CF respiratory pathology and help identify robust therapeutic targets suitable for intervention.