This is a revision of application R01 HL074104-01 reviewed in February 2003. Accelerated decline in FEV1 predicts morbidity, mortality and functional limitation. Disproportionately low FEV1 is a cardinal sign of Chronic Obstructive Pulmonary Disease, a common, expensive, and serious disease. Studies relying on measured FEV1 take a long time and large numbers. If valid biomarkers were available, they could be used to efficiently screen potential therapies and identify persons at risk for the development of COPD. Our studies using cDNA microarray technology, have established associations between COPD and two chemokine receptors, CXCR-2 and CXCR-5 using cellular constituents of bronchoalveolar fluid in COPD patients. We propose to evaluate whether peripheral blood mononuclear cell expression of these and related biomarkers predict accelerated FEV1 decline in an established community-based cohort, the Health ABC study. Spirometry was performed on 2075 participants in Year 5 of the study. We propose to repeat spirometry in Years 8 and 10 of the study to test the hypotheses that: 1) peripheral blood mononuclear cell mRNA expression of CXCR-2, CXCR-5, IL-8 and IL- 6 will predict the accelerated decline in FEV1 over a five-year period in both those with airway obstruction and those without; and 2) serum levels of IL-8, IL-6, C-reactive protein will predict the accelerated decline in FEV1 over a five-year period in both those with airway obstruction and those without. COPD has increasingly been seen to be a systemic disease characterized by loss of lower extremity lean body mass, loss of strength, and poor endurance. These changes are important features of the diminished physical function seen with the disease. We suspect that some of the biomarkers associated with COPD may be as much related to changes in physical symptoms as to changes in pulmonary function. Therefore, we propose to test the additional hypothesis: 3) inflammatory biomarkers will predict the accelerated loss of lean body mass, loss of strength and loss of endurance over a 5- year period. Because this study is being done as an ancillary study to an established cohort in which many of the study measures either have or will be performed, these hypotheses can be tested in a cost-efficient manner.

R01HL074104

2004-05-07

2009-04-30