Using a molecule similar to one found in an
experimental cancer drug, researchers at the Johns
Hopkins Bloomberg School of Public Health demonstrated
that activation of a key component of the
lung's antioxidant defense system, Nrf2, can prevent
emphysema in mice.
The researchers believe that activation of Nrf2 could
be a novel target for therapies to
prevent chronic obstructive pulmonary disease, which
comprises emphysema and chronic bronchitis.
COPD is a major public health problem and the
fourth-leading cause of death in the United States.
The study was published Dec. 22 in the online Early
Edition of PNAS: Proceedings of the National
Academy of Sciences.
"There are no effective therapies for COPD, and there
is an urgent need to develop novel
intervention strategies. Targeting the Nrf2 pathway
presents a novel strategy which needs to be
tested for its efficacy in intervening COPD in patients,"
said Shyam Biswal, senior author of the study
and an associate professor in the Bloomberg School's
Department of Environmental Health Sciences
and the Division
of Pulmonary and Critical Care Medicine at the Johns
Hopkins School of Medicine.
Nrf2 (nuclear factor erythroid-derived 2-related
factor 2) works as a "master gene" that turns
on numerous antioxidant and pollutant-detoxifying genes to
protect the lungs from environmental
pollutants, such as cigarette smoke. Biswal previously
identified that disruption of Nrf2 expression in
mice caused early onset and severe emphysema. More
recently, his team demonstrated for the first
time a close correlation between the Nrf2 decline and the
progression of COPD in humans.
For the current study, Biswal, along with postdoctoral
fellows Thomas Sussan, Tirumalai
Rangasamy and David J. Blake, observed mice exposed to
cigarette smoke to determine if activation of
Nrf2 could prevent emphysema. Exposed mice — fed a
diet containing CDDO-Im, which is known to
activate Nrf2 — were significantly less likely to
have oxidative stress and lung cell damage associated
with emphysema. The researchers also noted substantially
improved function in the portion of the
heart responsible for circulating oxygenated blood through
the body, a function that is typically
diminished with emphysema. CDDO-Im is closely related to
CDDO-Me, an experimental cancer drug
approved for phase II clinical trials.
"Nrf2 is an important regulator of the body's
antioxidant defense system, and activation of
Nrf2 is a promising therapeutic strategy for attenuating
COPD progression in patients," said Thomas
Sussan, lead author of the study.
According to the researchers, COPD affects more than
16 million Americans and is the only
disease among the top-10 causes of death with a rising
mortality rate in the United States. It is
predicted to be the third-largest cause of death by 2020
and has already reached worldwide epidemic
proportions.
The researchers were supported by grants from the
National Institutes of Health; National
Heart, Lung and Blood Institute; National Cancer Institute;
Flight Attendants Medical Research
Institute; Maryland Cigarette Restitution Fund; National
Foundation for Cancer Research; Reata
Pharmaceuticals; National Institute on Environmental Health
Sciences; PhRMA Foundation; and
Bernard A. and Rebecca S. Bernard Foundation.
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