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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