Pulmonary Vascular Changes in Early Chronic Obstructive Pulmonary Disease (COPD)

描述（由研究者提供）：慢性阻塞性肺疾病（COPD）目前是美国第四大死亡原因。吸烟是慢性阻塞性肺病的主要原因，但只有少数吸烟者会出现症状性慢性阻塞性肺病。慢性阻塞性肺病的治疗选择有限；部分原因是由于对COPD发病机制的了解有限。肺血管改变通常发生在COPD晚期，继发于严重低氧血症。然而，最近的实验室研究表明，内皮细胞功能障碍和血管内皮生长因子（VEGF）介导的细胞凋亡在早期COPD中存在。这些观察结果恢复了COPD的血管假说，该假说认为肺血管的改变导致肺功能的丧失。在EMCAP研究和多民族动脉粥样硬化（MESA）肺研究两项队列研究中，我们发现吸烟者早期COPD患者内皮功能受损、心输出量减少且左室功能保留。这些发现表明，内皮功能障碍和肺血管改变发生在早期COPD。拟议的研究是对吸烟者的横断面研究，嵌套在两个队列中，这两个队列共同提供了一个明确的抽样框架，共有4,617名参与者进行了先前的肺活量测定和CT测量。共有325名参与者（100例轻度、75例中度、50例重度COPD和100例健康对照）将通过MR和全肺CT成像、肺活量测定、流式细胞术和基因表达谱进行特征分析，以检验以下假设：1)肺血管和右心室的功能和结构改变发生在COPD早期；2)内皮微粒、循环内皮细胞、内皮祖细胞在COPD早期出现异常；3) COPD早期血浆VEGF水平及外周血单核细胞（PBMCs）凋亡和氮氧化物代谢通路基因表达发生改变。该应用的创新方面包括新的成像方式、内皮健康的流式细胞术分析和pbmc中的mRNA表达，以测试潜在的范式转换假设。证实COPD的血管假说将证明测试现有的（如他汀类药物）和新的（如干细胞）针对COPD内皮功能障碍的治疗方法是合理的。慢性阻塞性肺疾病（COPD）目前是美国第四大死亡原因。慢性阻塞性肺病将在10-15年内超过中风，成为第三大死亡原因。COPD的治疗选择很少；部分原因是由于对COPD发病机制的了解有限。本研究旨在验证在COPD发病早期内皮功能障碍和肺动脉高压的新假设。如果得到证实，这一假设将导致目前可用的（例如，他汀类药物）和新的（例如，干细胞）针对COPD的内皮治疗的测试。

DESCRIPTION (provided by investigator): Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the United States. Smoking is the principal cause of COPD but only a minority of smokers develops symptomatic COPD. Therapeutic options for COPD are limited; in part due to a limited understand of COPD pathogenesis. Pulmonary vascular changes are generally though to occur late in COPD, secondary to severe hypoxemia. Recent bench research, however, has shown endothelial cell dysfunction and vascular endothelial growth factor (VEGF)-mediated apoptosis in early COPD. These observations have revived the vascular hypothesis of COPD, which posits that alterations in the pulmonary vasculature lead to loss of lung function. We found impaired endothelial function and reduced cardiac output with preserved LV function in early COPD among smokers in two cohort studies, the EMCAP Study and the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. These findings suggest that endothelial dysfunction and pulmonary vascular changes occur in early COPD. The proposed study is a cross-sectional study of smokers nested among the two cohorts, which together provide a well-defined sampling frame of 4,617 participants with prior spirometry and CT measures. A total of 325 participants (100 cases with mild, 75 cases with moderate, and 50 cases with severe COPD, and 100 healthy controls) will be characterized with MR and full-lung CT imaging, spirometry, flow cytometry, and gene expression profiling to test the following hypotheses: 1) Functional and structural changes in the pulmonary vasculature and right ventricle occur early in COPD; 2) Endothelial microparticles, circulating endothelial cells, and endothelial progenitor cells are abnormal early in COPD; 3) Plasma VEGF levels and gene expression of apoptotic and nitrogen oxide metabolism pathways in peripheral blood mononucleated cells (PBMCs) are altered early in COPD. Innovative aspects of this application include novel imaging modalities, flow cytometry assays of endothelial health, and mRNA expression in PBMCs to test a potentially paradigm-shifting hypothesis. Confirmation of the vascular hypothesis of COPD would justify testing existing (e.g., statins) and novel (e.g., stem cell) therapies targeted to endothelial dysfunction in COPD. PUBLIC HEALTH RELEVANCE Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the United States. COPD will overtake stroke as the third leading cause of death in 10-15 years. Therapeutic options for COPD are few; in part due to a limited understand of COPD pathogenesis. This study is designed to test a novel hypothesis of endothelial dysfunction and pulmonary hypertension early in the pathogenesis of COPD. If confirmed, this hypothesis would lead to the testing of currently available (e.g., statins) and novel (e.g., stem cell) therapies targeted to the endothelium in COPD.