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The newspaper of The Johns Hopkins University November 8, 2004 | Vol. 34 No. 11
Gene Found to Defend Against Environmental Pollutants

By Kenna Lowe
School of Public Health

Researchers at the Johns Hopkins Bloomberg School of Public Health and other institutions have identified a "master gene" in mice that controls the action of 50 other genes whose products protect the lungs against environmental pollutants. The researchers believe their findings will provide a better understanding of the human body's defense mechanisms and could lead to the identification of what factors make some people more susceptible to lung diseases. The article is published in the Nov. 1 issue of The Journal of Clinical Investigation.

The so-called "master gene" — called Nrf2, for nuclear factor erythroid-derived 2-related factor 2 — 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, senior author of the study and an assistant professor in the Bloomberg School'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, 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, or COPD, which affects more than 16 million Americans and is the fourth highest cause of death in the 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, first co-author of the study and a postdoctoral fellow in Biswal's lab, said 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.

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."

The study was supported by grants from the Maryland Cigarette Restitution Fund, 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 Biswal, Rangasamy and Rajesh Thimmulappa, a postdoctoral fellow, Thomas Kensler, professor of environmental health sciences, co-authored the study. Additional co-authors are Sorachai Srisuma, Chung Cho, Lijie Zhen, Masayuki Yamamoto, Irina Petrache and Rubin Tuder.


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