Understanding the Origins of Early COPD

摘要 慢性阻塞性肺疾病病因认识上的根本性差距 慢性阻塞性肺疾病（COPD）是这种高度流行和缺乏任何疾病修饰疗法的主要原因。 致命的疾病开发和测试这种疗法将需要定义发生在细胞中的生物过程。 人肺诱导小气道异常（SAA），最早COPD病理学， 从潜在可逆的SAA转变为不可逆的肺气肿或气道重塑。我们的长期目标 是通过了解COPD的早期阶段来阻止其进展。我们的核心假设是：SAA （可通过胸部成像检测）识别易受影响的年轻吸烟者，其解剖疾病风险较高 进展SAA的结果，部分来自独特类型的自身攻击性宿主免疫反应（可检测到的）。 通过测量上皮基因特征和免疫细胞功能）和来自改变的气道表面液体 （通过分析气道粘蛋白可检测）。这些过程共同导致SAA可被一种新的高- 分辨率胸部计算机断层扫描（HRCT）度量（PRMfSAD），我们已经开发。获得的知识 在这个项目中，将使我们能够非侵入性地识别疾病进展的个体， 病理生理机制，可以治疗靶向。在这个项目中，我们将利用 SPIROMICS的基础设施，一个NHLBI资助的COPD项目，招募了一个新的年龄在35岁以下的人群， 50岁，这一群体在目前的队列中没有代表。将在临床访视时对受试者进行分析， 入组和随访三年后。在每次访视时，他们将接受临床数据收集， 支气管扩张剂肺功能测定、HRCT、诱导痰和呼出气冷凝液。100个主题将 也进行了单支气管镜检查研究。在目标1中，我们将确定HRCT- 在早期COPD中定义SAA和疾病进展。具体来说，我们将定义 基线PRMfSAD和放射学疾病进展至PRM定义的肺气肿 三年在目的2中，我们将通过分析肺源性SAA， 生物标志物。为了实现这一目标，我们将通过支气管肺泡灌洗（BAL）收集生物标本，并从 节段和远端气道。我们将基线PRMfSAD与气道中的IL-17基因特征相关联， 上皮次要分析将探索基线PRMfSAD与激活状态的相关性， BAL白细胞的功能容量以及总气道粘蛋白浓度。在目标3中， 确定痰液是否可以作为早期COPD的非侵入性生物标志物。具体而言，我们将：a） 将基线痰液总粘蛋白浓度与基线SAA相关联;以及（B）将基线痰液总粘蛋白浓度与基线SAA相关联 粘蛋白浓度及其3年内随HRCT异常进展的变化。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， 为开发疾病修饰疗法奠定了基础。

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.