Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the United States, and COPD prevalence and mortality are increasing, particularly among women and minorities. Despite the magnitude of the problem, therapeutic options are limited. Although smoking is the principal cause of COPD, only 10 percent of heavy smokers develop severe COPD. Recent research on the pathogenesis of COPD includes hypotheses relating oxidative stress, chronic inflammation and endothelial activation to alveolar destruction and subsequent loss of lung function. Evidence linking systemic inflammation and endothelial dysfunction to the pathogenesis of COPD in human populations has the potential to suggest novel molecular pathways and targets for therapies for COPD. The biological model that underlies the proposed epidemiological study is that alterations in endothelial function are associated with the pathogenesis of subclinical COPD and emphysema, in part through the effects of systemic inflammation on the vascular endothelium. The Multi-Ethnic Study of Atherosclerosis (MESA) cohort provides a unique opportunity to evaluate this model in a well-characterized, multiethnic population. MESA has existing measures of baseline flow-mediated endothelial-dependent dilation of the brachial artery during reactive hyperemia and CT scans repeated over follow-up. The proposed study would add a measure of spirometry and cotinine for a 50 percent stratified, random sample (n=3,250) of the MESA cohort and would re-analyze CT scans for lung density, a measure of emphysema.
The specific aims are to test the hypotheses that: 1) flow-mediated endothelialdependent dilation of the brachial artery is associated with lower lung function, lower lung density on CT scan, and greater longitudinal decline in lung density; 2) elevated levels of inflammatory biomarkers known to influence or interact with endothelial function (slCAM-1 and E-selectin) are associated with lower lung function, lower lung density on CT scan, and greater longitudinal decline in lung density; 3) variants in genes that encode for these biomarkers and related pathways (slCAM-1, E-selectin and eNOS genes) modify these associations and that of smoking and lung function. Use of the MESA cohort would yield relatively cost effective results about the role of endothelial dysfunction in COPD and emphysema. This novel hypothesis, if confirmed, has the potential to lead directly to the testing of currently available therapies for endothelial dysfunction in COPD. ? ?
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