The role of platelet activation and particulate matter exposure in COPD morbidity

项目摘要/摘要 慢性阻塞性肺疾病(COPD)是美国第三大死亡原因， 心血管疾病是导致发病率和死亡率的重要原因。暴露在空气中 污染是慢性阻塞性肺疾病和心血管疾病的常见危险因素。美国人把大部分的时间花在 他们在室内的时间和我们的研究小组已经表明，室内颗粒物(PM)浓度高 与更严重的COPD发病率有关。有证据表明，长期以来一直与心血管疾病有关的血小板激活， 可能在PM暴露的病理生理后果中发挥作用。PM暴露已被认为 小鼠、健康受试者和心血管疾病患者的血小板活化标志物升高。高架 据报道，稳定和加重的COPD患者中也有血小板活化的标志物。 然而，无论PM暴露是否与COPD患者血小板活化增加相关，a 特别是暴露于高空气污染的高危人群，以及血小板激活是否在 COPD的发病率仍不清楚。我们假设暴露在室内PM浓度升高的是 与血小板活化增加有关，血小板活化与呼吸和心血管疾病有关 慢性阻塞性肺疾病患者的发病率。研究活化的血小板在PM反应中的潜在作用 在暴露和COPD发病率方面，我们建议增加对血小板激活标志物的重复测量 在100名患有中重度COPD的前吸烟者中，登记参加了一项研究(清洁空气)，以调查 室内空气净化器对COPD发病率的干预包括作为亚临床试验的一部分的中间心血管结果 研究(净化空气心脏)。这项提议有两个新颖的目标。首先，确定两者之间的关联 COPD患者的室内PM浓度和血小板活化，我们将增加 血小板活化的三个标志物(11-脱氢-血栓素B2、可溶性P-选择素和 在三次访问(基线、3个月和6个月)的每次访问时)，同时利用量化 作为母体研究的一部分进行的环境暴露和临床表型分析。第二，到 确定血小板活化与呼吸道并发症和中度心血管疾病的关系 COPD患者的预后，我们将检查所测量的血小板标志物的相关性 激活与呼吸结果，如肺功能、症状、6分钟步行距离和质量 生命和中等心血管结局，如内皮功能障碍、血管僵硬和肺功能升高 动脉压。我们将利用参与者在父母中的共病的广泛特征 通过测量新的肺动脉内径来扩展CV表型的研究(评估正确 心脏劳损)和冠状动脉钙(量化冠状动脉疾病)。如果我们发现血小板活化 与PM暴露或COPD发病率有关，未来抗血小板治疗的潜在研究 COPD患者的治疗目标将是合理的。

Project Summary/Abstract Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death in the US with cardiovascular (CV) disease representing a significant cause of morbidity and mortality. Exposure to air pollution represents a common risk factor for COPD and CV disease. People in the US spend the majority of their time indoors and our research group has shown that high indoor particulate matter (PM) concentrations are linked to worse COPD morbidity. Evidence suggests that platelet activation, long implicated in CV disease, may play a role in the pathophysiologic consequences of PM exposure. PM exposure has been associated with elevated markers of platelet activation in mice, healthy subjects and those with CV disease. Elevated markers of platelet activation have also been reported in patients with stable and exacerbated COPD. However, whether PM exposure is associated with increased platelet activation in patients with COPD, a population particularly at-risk for high air pollution exposures, and whether platelet activation plays a role in COPD morbidity remains unknown. We hypothesize that exposure to elevated indoor PM concentrations is associated with increased platelet activation and that platelet activation is associated with respiratory and CV morbidity among patients with COPD. To study the potential role of activated platelets in response to PM exposure and in COPD morbidity, we propose adding repeated measurement of markers of platelet activation in 100 former smokers with moderate-severe COPD enrolled in a study (CLEAN Air) to investigate the effect of an indoor air purifier intervention on COPD morbidity that includes intermediate CV outcomes as part of a sub- study (CLEAN Air Heart). This proposal has two novel aims. First, to determine the association between indoor PM concentrations and platelet activation among individuals with COPD, we will add measurement of three markers of platelet activation (11-dehydro-thromboxane B2, soluble P-selectin, and soluble CD40 ligand) at each of three visits (baseline, 3 and 6 months) while capitalizing on the quantification of environmental exposures and clinical phenotyping performed as part of the parent study. Second, to determine the association of platelet activation with respiratory morbidity and intermediate CV outcomes in patients with COPD, we will examine the association of the measured markers of platelet activation with respiratory outcomes such as lung function, symptoms, six-minute walk distance, and quality of life, and intermediate CV outcomes such as endothelial dysfunction, vascular stiffness and elevated pulmonary artery pressure. We will exploit the extensive characterization of participants' comorbidities in the parent studies while expanding CV phenotyping by newly measuring pulmonary artery diameter (to evaluate right heart strain) and coronary artery calcium (to quantify coronary artery disease). If we find that platelet activation is associated with PM exposure or COPD morbidity, future investigation of antiplatelet therapy as a potential therapeutic target in patients with COPD would be warranted.