Understanding the Origins of Early COPD

摘要 对慢性阻塞性肺疾病病因认识上的根本差距 慢性阻塞性肺病(COPD)是这种高度流行和缺乏任何疾病修改疗法的主要责任 致命的疾病。开发和测试这种疗法将需要定义发生在 导致小气道异常(SAA)的人类肺，这是COPD最早的病理，并导致 从潜在的可逆性SAA过渡到不可逆性肺气肿或气道重塑。我们的长期目标 是通过了解COPD的早期阶段来阻止其进展。我们的中心假设是：SAA (可通过胸部成像检测)识别出易患解剖疾病风险较高的年轻吸烟者 进步。SAA的部分原因是特殊类型的自身攻击性宿主免疫反应(可检测到 通过测量上皮基因特征和免疫细胞功能)和改变的呼吸道表面液体 (可通过分析呼吸道粘液检测到)。这些过程共同导致了SAA可由一种新的高密度的 我们开发的分辨率胸部计算机断层扫描(HRCT)指标(PRMfSAD)。所获得的知识 这个项目将允许我们以非侵入性的方式识别疾病进展的个体，同时还定义 可靶向治疗的病理生理机制(S)。在本项目中，我们将利用 SPIROMICS的基础设施，NHLBI资助的COPD计划，以招募35岁的新队列个人- 50年，这是一个在当前队列中没有代表的群体。受试者将在临床就诊时进行分析， 并经过三年的跟踪调查。在每次就诊时，他们将接受临床数据收集，并在 支气管扩张剂肺活量、HRCT、诱导痰、呼出冷凝液。一百名受试者将 还要接受一次支气管镜检查。在目标1中，我们将确定HRCT与 明确了SAA和早期COPD的疾病进展。具体地说，我们将定义 基线PRMfSAD和放射学疾病进展为PRM定义的肺气肿的进展 三年了。在目标2中，我们将通过对肺来源的分析来探索SAA在早期COPD中的生物学基础。 生物标志物。为了实现这一点，我们将通过支气管肺泡灌洗(BAL)收集生物检疫菌，并从 节段性和远端气管。我们将基线PRMfSAD与呼吸道中的IL-17基因特征相关联 上皮组织。二次分析将探索基线PRMfSAD与激活状态和 BAL白细胞的功能能力，以及总的呼吸道粘蛋白浓度。在《目标3》中，我们将 确定痰是否可以作为早期COPD的非侵入性生物标志物。具体来说，我们将：a) 相关基线痰总粘蛋白浓度与基线SAA；和，(B)相关基线痰总 粘蛋白浓度及其随HRCT异常进展的3年变化。这种方法 使我们能够将HRCT和病理异常联系起来，以确定潜在的靶向机制，从而为 开发疾病修正疗法的基金会。

ABSTRACT The fundamental gap existing in understanding the origins of Chronic Obstructive Pulmonary Disease (COPD) is centrally responsible for the lack of any disease-modifying therapies for this highly prevalent and lethal disease. Developing and testing such therapies will require defining the biologic process occurring in the human lung that induce small airway abnormality (SAA), the earliest COPD pathology, and which cause transition from potentially reversible SAA to irreversible emphysema or airway remodeling. Our long term goal is to arrest COPD progression by understanding its earliest stages. Our Central Hypotheses are: SAA (detectable by chest imaging) identifies susceptible younger smokers at heightened risk of anatomic disease progression. SAA results, in part, from distinctive types of auto-aggressive host immune reactions (detectable by measuring epithelial gene signatures and immune cell function) and from altered airway surface liquid (detectable by analyzing airway mucin). These processes collectively lead to SAA detectable by a novel high- resolution chest computed tomography (HRCT) metric (PRMfSAD) we have developed. The knowledge gained in this project will allow us to identify individuals with disease progression noninvasively, while also defining pathophysiological mechanism(s) that can be therapeutically targeted. In this project we will leverage the infrastructure of SPIROMICS, an NHLBI funded COPD program, to recruit a new cohort of individuals aged 35- 50 years, a group which are not represented in the current cohort. Subjects will be analyzed at clinical visits at enrollment and after three years of follow-up. At each visit, they will undergo clinical data collection, post- bronchodilator spirometry, HRCT, induced sputum, and exhaled breath condensate. One hundred subjects will also undergo a single research bronchoscopy. In Aim 1, we will determine the relationship between HRCT- defined SAA and disease progression in early COPD. Specifically we will define the relationship between baseline PRMfSAD and development of radiographic disease progression to PRM defined emphysema over three years. In Aim 2 we will explore the biological basis of SAA in early COPD by analysis of lung-derived biomarkers. To achieve this we will collect biospecimens by bronchoalveolar lavage (BAL), and from segmental & distal airways. We will correlate baseline PRMfSAD with an IL-17 gene signatures in airway epithelium. Secondary analyses will explore correlations of baseline PRMfSAD with the activation states and functional capacity of BAL leukocytes, as well as with total airway mucin concentration. In Aim 3 we will determine whether sputum can serve as a non-invasive biomarker of early COPD. Specifically we will: a) correlate baseline sputum total mucin concentration with baseline SAA; and, (b) correlate baseline sputum total mucin concentration and its change over 3 years with progression of HRCT abnormalities. This approach enables us to link HRCT and pathologic abnormality to define potentially targetable mechanisms laying the foundation for developing disease-modifying therapies.