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

描述(由研究人员提供)：慢性阻塞性肺疾病(COPD)目前是美国第四大死因。吸烟是慢性阻塞性肺疾病的主要原因，但只有少数吸烟者会出现症状。COPD的治疗选择有限；部分原因是对COPD发病机制的了解有限。肺血管改变通常发生在COPD的晚期，继发于严重的低氧血症。然而，最近的BASE研究表明，在早期COPD中，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。这些观察结果重新提出了COPD的血管假说，即肺血管的改变会导致肺功能的丧失。在EMCAP研究和多种族动脉粥样硬化(MESA)肺研究这两项队列研究中，我们发现吸烟者早期COPD患者的内皮功能受损，心输出量减少，但左心功能得到保护。这些发现提示COPD早期存在内皮功能障碍和肺血管改变。这项拟议的研究是对嵌套在两个队列中的吸烟者的横断面研究，这两个队列一起提供了一个明确的样本框架，有4617名参与者，之前有肺活量测量和CT测量。325例COPD患者(轻度COPD 100例，中度COPD 75例，重度COPD 50例，正常对照100例)将通过MR和全肺CT扫描、肺活量测定、流式细胞术和基因表达谱检测来验证下列假设：1)COPD早期肺血管和右心室功能和结构改变；2)COPD早期内皮微粒、循环内皮细胞和内皮祖细胞异常；3)COPD早期血浆血管内皮生长因子水平和外周血单核细胞(PBMC)凋亡和氮氧化物代谢途径基因表达改变。这一应用的创新方面包括新的成像模式、内皮健康的流式细胞术分析，以及用于测试潜在范式转换假说的PBMCs的mRNA表达。COPD血管假说的确认将证明现有的(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。与公共卫生相关的慢性阻塞性肺疾病(COPD)目前是美国第四大死因。COPD将在10-15年内取代中风成为第三大死亡原因。COPD的治疗选择很少；部分原因是对COPD发病机制的了解有限。这项研究旨在验证一种新的假说，即内皮功能障碍和肺动脉高压在COPD发病机制的早期。如果得到证实，这一假设将导致对目前可用的(例如，他汀类药物)和针对COPD患者内皮的新疗法(例如，干细胞)进行测试。

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.