Biennial Report of the Director

Research in Diseases, Disorders, and Health Conditions
Chronic Diseases and Organ Systems
Chronic Obstructive Pulmonary Disease (COPD)

COPD is a serious but largely preventable lung disease that makes breathing difficult. It has two forms, emphysema and chronic obstructive bronchitis, that tend to coexist in most people. Emphysema and chronic obstructive bronchitis damage the lungs in different ways, but both make breathing difficult. COPD is the third most common cause of death in the U.S. More than 12 million Americans are currently diagnosed with COPD, and researchers estimate that 12 million more have it but do not know that they do. Doctors diagnose COPD using a simple breathing test called spirometry that measures how well the lungs are working. Symptoms of COPD include chronic shortness of breath, a cough with mucus production, and wheezing. Smoking is the leading cause of COPD in the U.S., but genetic and environmental factors such as air pollution also play a role.

Significant and ongoing research investments by the NIEHS are directed at uncovering the relationships between exposure to agents such as ozone, particulate matter, endotoxins, excessive heat, and other environmental triggers and cardiopulmonary disease. One such discovery may lead to more effective treatment of COPD; a researcher studying toxic red tides has isolated a substance from the algae called brevenal that acts as an antitoxin and has been shown in animal studies to prevent, reduce, and reverse bronchoconstriction at very low doses.117

Large, multi-center clinical trials are evaluating the efficacy of several treatments/therapies that are available for immediate use. The Long-term Oxygen Treatment Trial is testing the ability of supplemental oxygen treatment to prevent deaths and hospitalizations in patients with COPD and less-than-severe hypoxemia (oxygen deficiency). A trial conducted by NHLBI’s COPD Clinical Research Network is testing whether simvastatin, a drug approved for cardiovascular diseases, can be used to reduce the frequency of COPD exacerbations. Another trial is comparing the long-term immune response of COPD patients to two different pneumococcal vaccinations.

Because COPD involves a wide range of abnormalities, different patients with COPD may require specific treatments. Studies are underway to define subgroups of patients for whom different therapeutic approaches should be used. The COPD Gene study is evaluating 10,000 current and former smokers, with and without COPD, to better categorize the various abnormalities seen on x-ray CT lung images and to identify genetic traits that are associated with specific manifestations of the disease. The Lung Genomic Research Consortium is performing state of the art, high-throughput molecular analyses of lung tissues removed from patients with COPD to find molecular “fingerprints” that indicate different subtypes of the disease. The SubPopulations and InteRmediate Outcome Measures in COPD Study will define subpopulations of COPD patients by extensive molecular and clinical phenotyping and will also identify intermediate outcome measures that can be used to improve the efficiency of future clinical trials.

COPD patients often suffer from multiple afflictions. For example, lung cancer is 4–5 times more frequent in COPD patients than in smokers without COPD. To investigate the cellular and molecular mechanisms that contribute to both COPD and lung cancer, NHLBI and NCI have recently awarded seven grants to promote research on the connections between these diseases of the lung, which together cause over a quarter of a million deaths in the U.S. each year.

A number of recent studies are pointing towards better medical approaches for treating COPD. An antibiotic was found to decrease the frequency of exacerbations and improve quality of life. A broccoli sprout derivative was found to potentially augment the anti-inflammatory effects of steroids in COPD. Researchers are testing new approaches to protect against cigarette-smoke induced damage to the lung. For example, using an animal model of emphysema, a recent study showed a prominent role for the enzyme superoxide dismutase in protecting mice from cigarette smoke-induced damage, suggesting that therapeutic interventions that augment SOD3 may be helpful.118 In another animal model, investigators identified a protein that mediates the rate of cell degradation in mice exposed to cigarette smoke leading to epithelial cell death and alveolar space enlargement. This observation suggests another therapeutic target in emphysema.119

COPD is believed to have a strong genetic component. A genome-wide association study for COPD identified a potential gene related to susceptibility.120In another genome-wide association study, investigators identified several potential genes that may confer susceptibility in an area of the genome that has previously been associated with cigarette smoking behavior. In similar studies, regions of the genome were identified that could provide insight into the molecular mechanisms regulating pulmonary function.121

While the effect size of these genetic variants is small in comparison with the estimated effect of cigarette smoke exposure, the discovery of additional genetic risk variants for COPD is an important step toward the development of new preventative and therapeutic approaches for this disease. This work underscores the importance of gene environment interactions in determining individual susceptibility to COPD and findings in this area may have practical implications for disease prevention.122

As COPD accounts for more than 300 million patients worldwide, NHLBI is participating in discussions with the World Health Organization (WHO) and other international groups regarding strategies for dealing with COPD at the global level. COPD surveillance data are being collected in developing countries through the NHLBI Centers of Excellence in Global Health. In addition to smoking, globally indoor air pollution also contributes to the risk for COPD. An NIH-wide workshop on indoor air pollution and cook stoves was held in 2011 that identified research strategies that could have important implications for preventing COPD globally.

117Nguyen-Huu TD, et al. Toxicon. 2010;56(5):792–6. PMID: 19682481.
118Yao H, et al. Proc Natl Acad Sci U S A. 2010;107(35):15571–6. PMID: 20713693.
119Chen ZH, et al. Proc Natl Acad Sci U S A. 2010;107(44):18880–5. PMID: 20956295.
120Cho MH, et al. Nat Genet. 2010;42(3):200–2. PMID: 20173748.
121Soler Artigas M, et al. Nat Genet. 2011;43(11):1082–90. PMID: 21946350.
122Sørheim IC, et al. Chest. 2010;138(5):1125–32. PMID: 20595457.