CC16: A Link between Airway Infection and Obstructive Lung Disease

CC16：气道感染与阻塞性肺病之间的联系

• 批准号: 10458607
• 负责人: Julie Gunnells Ledford
• 金额: $ 44.53万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458607
• 关键词: 5 year old; Adrenal Cortex Hormones; Adult; Affect; Age; Airway Resistance; Animal Model; Antibodies; Asthma; Attenuated; Automobile Driving; Bacteria; Binding; Binding Sites; Biological Markers; Cell Adhesion Molecules; Cells; Child; Childhood; Childhood Asthma; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Data; Development; Diagnosis; Disease; Distal; Emergency department visit; Epidemiology; Epithelial Cells; Exposure to; Foundations; Gene Expression; General Population; Genes; Growth; Human; Immune system; Impairment; Individual; Infection; Inflammation; Inflammatory; Integrin Binding; Integrin alpha4beta1; Integrins; International; Lead; Life; Ligands; Link; Longitudinal Studies; Longitudinal cohort; Lung; Mediator of activation protein; Modeling; Mus; Mycoplasma pneumoniae; Obstructive Lung Diseases; Oral; Participant; Patients; Persons; Play; Predisposition; Proteins; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Inflammation; Reporting; Research; Respiratory Tract Infections; Risk; Risk Factors; Role; Saline; Sampling; School-Age Population; Secretory Cell; Serum; Severities; Site; Testing; Time; United States; Uteroglobin; Weaning; airway epithelium; airway hyperresponsiveness; airway inflammation; airway obstruction; airway remodeling; asthmatic; cell injury; chronic infection; cohort; early life exposure; innovation; lung pathogen; mouse model; novel; novel therapeutic intervention; predictive marker; prevent; programs; pulmonary function; pulmonary function decline; receptor; recruit; response; secretory protein; systemic inflammatory response; translational approach; young adult

PROJECT ABSTRACT Asthma and COPD are the most commonly diagnosed chronic lung diseases in the United States. Studies have shown that asthma is the most important risk factor for COPD that develops through a course of low lung function from school age that tracks into adulthood. However, there is a fundamental gap in understanding the basic underlying mechanisms of this progression. Club cell secretory protein (CC16) has been described for its potential as a biological marker of lung epithelial cell injury and recent studies by our group concluded that low circulating CC16 levels predict impaired lung function growth in childhood and increased risk of asthma or COPD in adult life. In our cohort, adults with asthma with low serum CC16 levels and elevated levels of antibodies against M. pneumoniae (Mp) have a striking 8-fold increase in their odds of developing airflow limitation. These studies highlight the critical need for an intact immune system that protects against lung function decline and provide evidence that persistent early life infections may be a previously overlooked link in understanding progression of asthma into severe asthma with fixed airflow limitation. We developed a mouse model of early life exposure to Mp in which WT or CC16 deficient mice are infected pre-weaning and assessed for lung function in adulthood and found that CC16-/- mice have persistent airway inflammation and a striking >1000% over baseline airways resistance as compared to WT controls, which is likely attributed to inflammation and airway remodeling. The overall hypothesis is that CC16 plays a protective role during Mp-driven inflammation that is dependent on binding to its newly discovered receptor, the integrin VLA-4. The action of CC16 attenuates lung inflammation, remodeling and airway hyperresponsiveness. This hypothesis will be tested by pursuing three specific aims: 1) Determine the impact of CC16 deficiency on pulmonary inflammation, remodeling and lung function using M. pneumoniae infection mouse models that include comparisons between an early life and adult infections, 2) Determine if the mechanism by which CC16 protects against inflammation, remodeling and loss of lung function is dependent on the VLA-4 receptor, and 3) Determine the impact of CC16 deficits in association with Mp infection on inflammation, remodeling factors and lung function using data and samples from multiple human longitudinal cohorts. This proposal is innovative in that we have identified a previously unknown receptor for CC16, adhesion molecule VLA-4 and we employ a novel translational approach to test our hypothesis using ex vivo studies, animal models, and human samples from well-characterized local and international cohorts. The proposed research is significant in that these findings will describe a new mechanism by which CC16 functions in a protective manner and may be immediately applicable to other pulmonary pathogens. Since CC16 is an informative and predictive biomarker, our studies may provide a novel therapeutic approach for treating individuals with low circulating CC16 in order to prevent lung function decline over time.

项目摘要 哮喘和COPD是美国最常见的慢性肺部疾病。研究 表明哮喘是COPD最重要的危险因素，COPD是通过肺功能降低过程发展的， 从学龄期到成年期然而，在理解基本的 这一进程的基本机制。俱乐部细胞分泌蛋白（CC 16）已被描述为其 作为肺上皮细胞损伤的生物学标志物的潜力，我们小组最近的研究得出结论， 循环CC 16水平可预测儿童期肺功能受损、生长发育以及哮喘或COPD风险增加 在成年生活中。在我们的队列研究中，血清CC 16水平低和抗体水平升高的哮喘成人患者， 分支杆菌肺炎支原体（Mp）感染者发生气流受限的几率显著增加8倍。 这些研究强调，迫切需要一个完整的免疫系统，防止肺功能下降 并提供证据表明，持续的早期感染可能是以前忽视的一个环节， 哮喘进展为伴有固定气流受限的重度哮喘。我们开发了一种小鼠模型， 终生暴露于MP，其中WT或CC 16缺陷型小鼠在断奶前感染并评估肺功能 发现CC 16-/-小鼠具有持续的气道炎症， 与WT对照相比，基线气道阻力可能归因于炎症和气道阻力， 重塑总的假设是CC 16在MP驱动的炎症过程中起保护作用， 依赖于与其新发现的受体整合素VLA-4的结合。CC 16的作用减弱肺 炎症、重塑和气道高反应性。这一假设将通过以下三个方面来检验： 具体目的：1）确定CC 16缺乏对肺部炎症、重塑和肺功能的影响。 函数使用M。肺炎感染小鼠模型，包括早期生命和成年之间的比较 2）确定CC 16保护免受炎症、重塑和细胞丢失的机制是否与CC 16的作用有关。 肺功能依赖于VLA-4受体，3）确定CC 16缺陷的影响， 使用来自多个机构的数据和样本，研究Mp感染对炎症、重塑因子和肺功能的影响 人类纵向队列。这一建议是创新的，因为我们已经确定了一个以前未知的 CC 16受体，粘附分子VLA-4，我们采用了一种新的翻译方法来测试我们的 使用离体研究、动物模型和来自良好表征的当地和 国际同行。这项研究的意义在于，这些发现将描述一种新的机制。 CC 16以保护性方式发挥作用，可立即应用于其他肺部疾病。 病原体由于CC 16是一种信息性和预测性生物标志物，我们的研究可能提供一种新的治疗方法， 本发明涉及一种用于治疗具有低循环CC 16的个体以防止肺功能随时间下降的方法。