Public Health Challenge

Chronic Obstructive Pulmonary Disease (COPD) is an irreversible disease caused by environmental stress factors such as cigarette smoking, air pollution and respiratory infection. COPD is the 4th leading cause of mortality in the US (16M in US, 210 M people worldwide) and expected to be 3rd by 2020. Between 15-20% of smokers develop COPD. Only one gene is known to cause COPD (?1-antitrypsin) and contributes to less than 5% of COPD. COPD is a disease state that is characterized by air flow limitation that is not fully reversible. Airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. There are two components of COPD: Chronic bronchitis: Disease characterized by the presence of symptoms of chronic cough and sputum production on most days for a minimum of 3 months a year, for at least 2 successive years and Emphysema: Disease characterized by permanent abnormal enlargement of respiratory airspaces, accompanied by the destruction of their walls, with or without obvious fibrosis. COPD is an additional risk for development of lung cancer with individuals 4-5 times as likely to be diagnosed with the two diseases compared to COPD alone. (Punturieri, 2009) Increasingly, the two diseases are seen as benefiting from common and integrated research strategies.

Research Findings

COPD patients have loss of Nrf2 activity and increased oxidative stress. Decline in NRF2-regulated antioxidants in COPD is due to loss of the positive regulator, DJ-1. Cigarette smoke (CS) inhibits bacterial clearance in lungs of Nrf2-/- mice. CS also enhances the impairment of bacterial killing in Nrf2-/- mice. Macrophages & neutrophils are defective in bacterial killing following CS exposure. Nrf2 disruption causes allergic asthma. Increased sensitivity of Nrf2-deficient mice to LPS induces lung injury and shock. Nrf2 activator protects against development of emphysema. High Nrf2 function resulting from loss of KEAP1 function confers therapeutic resistance and tumorigenicity. COPD takes 30 years to develop. It is unlikely that a drug is going to save the life of a COPD patient. All COPD drugs are targeted towards decreasing bacterial and viral exacerbation. However, it may be possible to prevent cancer in those with early COPD.

Possible Directions

Investigators at Johns Hopkins have found that Sulforaphane, a compound found in broccoli, restores the Nrf2 function. Therefore, clinical trials are underway to study Sulforaphane and its effects on the function of NrF2 in healthy people and those at high risk of developing cancer. Also, more studies of gene- environment interaction as it relates to COPD and lung cancer can be done to discover when the Nrf2 pathway is implicated in the development of cancer and when drugs like sulforaphane will be effective.

Future Research Opportunities

Biswal and colleagues are developing potent small molecules which will target the Nrf2 pathway to intervene COPD. Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research. Punturieri A, Szabo E, Croxton TL, Shapiro SD, Dubinett SM. J Natl Cancer Inst. 2009 Apr 15;101(8):554-9. Epub 2009 Apr 7.