Structural Determinants of Disease Progression in COPD

项目概要/摘要 慢性阻塞性肺病（COPD）是一种肺部炎症性疾病， 它影响美国2400万成年人，是第三大死亡原因。最近 研究挑战了COPD是一致进展的范式，但不同的机制， 疾病进展的轨迹还不清楚。治疗进展的一个主要障碍是， 改变疾病进展的是我们无法精确地对具有可变疾病轨迹的个体进行表型; 缺乏可靠的替代生物标志物来预测个体受试者的临床进展。此外，现有 药物治疗对呼吸系统疾病的发病率有一定的影响，并且不能影响FEV 1的下降率。 这些药物靶向气道紧张度和炎症，没有直接靶向涉及气道结构变化的药物。 气道或肺泡重塑（肺气肿），导致FEV 1变化。因此，理解上的一个主要差距是 确定决定疾病的结构性气道/肺泡重塑的相互依赖途径 这将为COPD提供更精确的诊断和治疗策略。 COPD的起源被认为是在直径小于2 mm的小的传导气道中，但是这些传导气道被认为是小的。 数据大多是跨部门的。此外，COPD的特征在于气道重塑和肺泡上皮细胞增生。 这两个过程都可能导致疾病的发生和发展。我们的初步研究结果 表明疾病进展的发生是由于肺部结构变化的复杂相互作用， 肺实质和气道中，包括正常肺实质的机械拉伸，肺气肿的分布， 和气道重塑疾病进展并不完全反映在FEV 1的变化和结构的进展。 疾病是疾病轨迹的重要决定因素。基于这些发现，我们假设， 气道和肺泡室中的解剖和机械因素有助于疾病进展， 慢性阻塞性肺病 为了验证这些假设，我们将分析来自两个大型的特征良好的队列（遗传学）的数据。 COPD流行病学、COPD基因、COPD研究中的亚群和中间结果指标， SPIROMICS），5年随访，具体目标如下。本申请的目标1将是确定 机械影响的肺是否导致肺气肿的发生和发展。在目标2中，我们将确定 肺气肿的空间分布是否影响疾病进展。在目标3中，我们将确定 气道重塑的纵向变化与肺功能下降有关。 这些结果将确定疾病进展的机制，建立新的成像生物标志物，并帮助 创建精确的模型，这将允许开发更有针对性的治疗方法，以减缓疾病的进展。

Project Summary/ Abstract Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lungs that results in airflow limitation; it affects 24 million adults in the United States, and is the third leading cause of death. Recent studies challenge the paradigm that COPD is uniformly progressive, but the mechanisms that underlie distinct trajectories of disease progression are not well understood. A major hurdle in the advancement of therapies that alter the progression of disease is our inability to precisely phenotype individuals with variable disease trajectories; reliable surrogate biomarkers to predict clinical progression in individual subjects are lacking. Furthermore, existing pharmacotherapies have a modest impact on respiratory morbidity and fail to impact the rate of FEV1 decline. These medications target airway tone and inflammation, and none directly target structural changes involving the airways or alveolar remodeling (emphysema) that underlie FEV1 change. Thus, a major gap in understanding is the identification of inter-dependent pathways of structural airway/alveolar remodeling that determine disease progression which would inform more precise diagnostic and therapeutic strategies for COPD. The origins of COPD are believed to be in the small conducting airways less than 2 mm in diameter but these data are mostly cross-sectional. In addition, COPD is characterized by both airway remodeling and alveolar destruction; it is likely that both processes contribute to disease initiation and progression. Our preliminary findings suggest that disease progression occurs due to a complex interplay of structural changes in the lungs, both in the parenchyma and in the airways, including mechanical stretch of normal parenchyma, distribution of emphysema, and airway remodeling. Disease progression is not reflected entirely by FEV1 changes and progression of structural disease is an important determinant of disease trajectory. Based on these findings, we hypothesize that structural anatomic and mechanical factors in both the airway and alveolar compartments contribute to disease progression in COPD. To test these hypotheses, we will analyze data from two large well-characterized cohorts (Genetic Epidemiology of COPD, COPDGene, and Subpopulations and Intermediate Outcome Measures in COPD Study, SPIROMICS) with 5-year follow-up with the following specific aims. Aim 1 of this application will be to determine whether mechanically affected lung leads to initiation and progression of emphysema. In Aim 2, we will determine whether the spatial distribution of emphysema influences disease progression. In Aim 3, we will determine whether longitudinal changes in airway remodeling are associated with lung function decline. The results will identify mechanisms of disease progression, establish novel imaging biomarkers, and help create precise models that will allow development of more targeted therapies to attenuate disease progression.