The so-called "master gene"--nuclear factor erythroid-derived 2-related factor 2 (Nrf2)--is activated in response to environmental pollutants such as cigarette smoke, and then turns on numerous antioxidant and pollutant-detoxifying genes to protect the lungs from developing emphysema.
Shyam Biswal, PhD, senior author of the study and an assistant professor in the Bloomberg School of Public Health's Department of Environmental Health Sciences, said, "The important thing to remember is that the degree of lung damage depends on the ability to defend against environmental factors. We now know that Nrf2 is the key player in protection even in the case of chronic exposure to pollutants."
In 2002, Dr. Biswal and colleagues were the first to show that activation of Nrf2 in response to an anticancer agent--Sulforaphane--can turn on antioxidant genes, but little was known about Nrf2-regulated genes and their role in lung inflammatory diseases caused by chronic exposure to environmental agents. By exposing mice to cigarette smoke, the researchers were able to learn which gene controlled this natural defense mechanism.
The researchers found that disruption of the Nrf2 gene caused earlier onset and more severe emphysema in a strain of mice that is resistant to cigarette smoke-related emphysema.Through gene chip analysis, the researchers were able to identify 50 Nrf2-dependent antioxidant and cytoprotective pulmonary genes that work together to protect the lungs from cigarette-smoke-induced emphysema. A gene chip allows researchers to monitor the complex interactions of thousands of genes on a whole genome rather than one at time.
Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease (COPD), which affects more than 16 million Americans and is the fourth highest cause of death in United States. COPD, the only disease among the top 10 causes of death with a rising incidence rate in the United States, is predicted to reach worldwide epidemic proportions.
Tirumalai Rangasamy, PhD, first coauthor of the study and a postdoctoral fellow in Dr. Biswal's lab, explained that whereas cigarette smokers make up 85 percent of COPD patients, other environmental risk factors can include air pollution and chronic occupational exposure to various dusts.
Dr. Biswal said, "With this new gene and environmental interaction discovery, in the future we may be able to identify people who are genetically predisposed to developing lung diseases--not just COPD--that are caused by environmental factors. The responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco-smoke-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation."
"Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice" is published in the November 1, 2004, issue of The Journal of Clinical Investigation.
The study was supported by grants from the Maryland Cigarette Restitution Fund, the Young Scientist Clinical Award from the Flight Attendant Medical Research Institute, National Institutes of Health National Cancer Institute and National Institute of Environmental Health Science to the Johns Hopkins Center in Urban Environmental Health.
Along with Dr. Biswal and postdoctoral fellows from his lab, Dr. Rangasamy and Rajesh K. Thimmulappa, professor Thomas Kensler, with the Bloomberg School of Public Health's Department of Environmental Health Sciences, coauthored the study. Additional co-authors include Sorachai S. Srisuma, Chung Y. Cho, Lijie Zhen, Masayuki Yamamoto, Irina Petrache and Rubin M. Tuder.
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