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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077612-02
Application #
6931970
Study Section
Epidemiology of Clinical Disorders and Aging Study Section (ECDA)
Program Officer
Croxton, Thomas
Project Start
2004-08-02
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$888,821
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Xu, Jiayi; Bartz, Traci M; Chittoor, Geetha et al. (2018) Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function. Br J Nutr 120:1159-1170
Oelsner, Elizabeth C; Balte, Pallavi P; Cassano, Patricia A et al. (2018) Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study. Am J Epidemiol 187:2265-2278
Burkart, Kristin M; Sofer, Tamar; London, Stephanie J et al. (2018) A Genome-Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos. Am J Respir Crit Care Med 198:208-219
Liu, Chia-Ying; Parikh, Megha; Bluemke, David A et al. (2018) Pulmonary artery stiffness in chronic obstructive pulmonary disease (COPD) and emphysema: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study. J Magn Reson Imaging 47:262-271
Madahar, Purnema; Duprez, Daniel A; Podolanczuk, Anna J et al. (2018) Collagen biomarkers and subclinical interstitial lung disease: The Multi-Ethnic Study of Atherosclerosis. Respir Med 140:108-114
Barr, R Graham (2018) Rethinking Chronic Obstructive Pulmonary Disease. Chronic Pulmonary Insufficiency and Combined Cardiopulmonary Insufficiency. Ann Am Thorac Soc 15:S30-S34
Oelsner, Elizabeth C; Smith, Benjamin M; Hoffman, Eric A et al. (2018) Prognostic Significance of Large Airway Dimensions on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Ann Am Thorac Soc 15:718-727
Prokopenko, Dmitry; Sakornsakolpat, Phuwanat; Fier, Heide Loehlein et al. (2018) Whole-Genome Sequencing in Severe Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol 59:614-622
Demenais, Florence; Margaritte-Jeannin, Patricia; Barnes, Kathleen C et al. (2018) Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. Nat Genet 50:42-53
Smith, Benjamin M; Traboulsi, Hussein; Austin, John H M et al. (2018) Human airway branch variation and chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A 115:E974-E981

Showing the most recent 10 out of 164 publications