CC16: A Link between Airway Infection and Obstructive Lung Disease

项目摘要 哮喘和慢性阻塞性肺病是美国最常见的慢性肺部疾病。研究表明， 表明哮喘是慢性阻塞性肺疾病最重要的危险因素，它是通过肺功能低下的过程发展起来的。 从学龄儿童一直到成年。然而，在理解基本的 这一进程的潜在机制。俱乐部细胞分泌蛋白(CC16)已被描述为其 可能作为肺上皮细胞损伤的生物标志物，我们小组最近的研究得出结论，Low 循环CC16水平预测儿童肺功能发育受损和哮喘或COPD风险增加 在成人生活中。在我们的队列中，血清CC16水平低而抗体水平升高的成人哮喘患者 抗肺炎支原体(MP)的人患气流受限的几率显著增加8倍。 这些研究强调了对完整的免疫系统的迫切需要，以防止肺功能下降 并提供证据表明，持续的早期感染可能是理解之前被忽视的环节 哮喘进展为有固定气流限制的重症哮喘。我们开发了一个早期的小鼠模型 WT或CC16缺陷小鼠在断奶前感染MP的生活暴露和肺功能评估 在成年后发现CC16-/-小鼠有持续性的呼吸道炎症，并且显著高于1000% 与WT对照组相比，基线气道阻力可能归因于炎症和呼吸道 改建。总体假设是CC16在MP驱动的炎症中起到保护作用，即 依赖于与其新发现的受体整合素VLA-4的结合。CC16的健肺作用 炎症、重构和呼吸道高反应性。这一假设将通过追求三个方面来检验 具体目标：1)确定CC16缺乏对肺部炎症、重构和肺组织的影响 使用肺炎支原体感染小鼠模型的功能，包括早期生活和成人之间的比较 感染，2)确定CC16预防炎症、重塑和血管丢失的机制 肺功能依赖于VLA-4受体，3)决定CC16缺陷的影响 肺炎支原体感染对炎症、重塑因子和肺功能的影响 人类纵向队列。这项提议是创新的，因为我们确定了一种以前未知的 CC16受体，黏附分子VLA-4，我们使用了一种新的翻译方法来测试我们的 假设使用体外研究、动物模型和来自具有良好特征的本地和 国际同龄人。这项拟议的研究意义重大，因为这些发现将描述一种新的机制 CC16起保护性作用，并可立即适用于其他肺 病原体。由于CC16是一种信息性和预测性的生物标志物，我们的研究可能提供一种新的治疗方法 治疗低循环CC16患者的方法，以防止肺功能随时间推移而下降。

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.