The Role of Airway Mucus in Infection and Inflammation

气道粘液在感染和炎症中的作用

• 批准号: 10413048
• 负责人: Susan Elizabeth Birket
• 金额: $ 44.54万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413048
• 关键词: Acute; Age; Age-Months; Agonist; Airway Disease; Airway Fibrosis; Animal Model; Appearance; Bacteria; Bacterial Infections; Biological Models; Bronchiectasis; Characteristics; Chronic; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Research; Complementary DNA; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Disease; Environment; Event; Exhibits; Exposure to; FDA approved; Genomics; Genotype; Gland; Goals; Human; Hydration status; Hyperviscosity; Impairment; In Situ; Incidence; Infection; Inflammation; Inflammatory; Institution; Interleukin-1 beta; Interruption; Intervention; Laboratories; Lead; Link; Long-Term Effects; Lung diseases; Lung infections; Modeling; Mucins; Mucociliary Clearance; Mucous body substance; Neutrophilic Infiltrate; Obstruction; Optical Coherence Tomography; Pathology; Patients; Phenotype; Population; Predisposition; Property; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pulmonary Cystic Fibrosis; Rattus; Resolution; Role; Secondary to; Staphylococcus aureus; Staphylococcus aureus infection; Testing; Toll-like receptors; VX-770; Variant; Virus Diseases; Viscosity; acute infection; age related; airway inflammation; chronic infection; cystic fibrosis airway; cystic fibrosis mucus; cystic fibrosis patients; cytokine; imaging modality; improved; in vitro Model; inflammatory marker; innovation; insight; lung development; muco-obstructive airway diseases; mucus clearance; neutrophil; novel; novel therapeutics; overexpression; pathogen; patient population; premature; pulmonary function; rat genome; small molecule; targeted treatment; therapeutic development; therapeutic target; therapy resistant; tool

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.

项目总结/摘要 异常的粘液纤毛清除（MCC）是囊性纤维化（CF）肺病的关键组成部分， 假设导致该患者人群中慢性肺部感染的高发病率;反过来 慢性感染的存在被认为会使MCC缺陷恶化，产生粘液阻塞的循环， 感染和难以中断或逆转的炎症。然而，机制和相互作用 造成这种现象的原因还不清楚。开发了新的动物模型，如CF大鼠， 在我们的机构，在确定导致慢性感染的关键因素方面是有用的。 CF气道中的病原体铜绿假单胞菌。该动物模型发展了MCC缺陷 逐步地，提供了一个模型，研究患者的早期疾病以及晚期疾病。在这 CF的模型，粘液必须在暴露于铜绿假单胞菌以转换感染之前异常 慢性表型在粘液异常发展之前暴露的CF大鼠能够清除 感染携带人源化G551 D-CFTR基因组插入物的新大鼠模型对FDA批准的 CFTR调节剂治疗CF疾病的根本缺陷。使用创新的微光学 相干断层扫描（µOCT）是一种高分辨率反射成像模式，可以同时 非侵入性评估气道水化，纤毛跳动和粘液运输和粘度原位，我们可以 分析CF大鼠模型在感染前和感染后（有或无CFTR）的粘液缺陷方面 调制器。使用这些工具，本提案将寻求调查导致患者 CF将急性感染转变为慢性感染，具有以下独立但互补的目标： 1.确定Muc 5 b是否是促进慢性铜绿假单胞菌的粘液的特定组分 感染 2.确定炎症是否是必要的和足够的，以加速粘液缺陷，诱发 慢性铜绿假单胞菌感染。 3.确定新的高效CFTR调节剂是否通过正常化来促进铜绿假单胞菌的清除 气道中的异常粘液。 该提案将确定导致CF肺病感染和进展的早期事件 以及这与该患者人群中铜绿假单胞菌从间歇性转为慢性的关系， 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， 我们对CF呼吸病理学的了解，并帮助确定适用于 干预