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

项目总结/文摘

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.