Gene at Root of Urban Air Pollution's Lung Effects
ORLANDO, Fla. – Duke University Medical Center
pulmonologists have linked a gene to the lung irritation
commonly suffered following chronic exposure to ozone, a major
component of urban air pollution. Should the new finding in
mice be corroborated in human studies, drugs that block the
function of the gene might serve as useful treatments for
patients with asthma, the researchers said.
The new study adds to earlier work highlighting the
importance of genetic factors in determining the lung's
response to environmental toxins by pinpointing a key player in
the process, said Duke pulmonologist John Hollingsworth II,
M.D., lead author of the study.
"The lung is constantly exposed to a broad spectrum of
environmental toxins, which can impact the severity of asthma,"
said Hollingsworth. "While the body's response to environmental
exposures can facilitate the clearance of pathogens, it can
also lead to injury and compromised lung function. By
understanding the molecular mechanisms that initiate
inflammation and injury, we may advance on new treatments to
prevent the damage."
Hollingsworth presented the research at the 100th
International Conference of the American Thoracic Society on May
25, 2004. The study will also appear in a forthcoming issue of
the American Journal
of Respiratory and Critical Care Medicine. The work was
supported by the Department of Veterans' Affairs, the National
Institute of Environmental Health Sciences, the National Heart
Lung and Blood Institute and GlaxoSmithKline.
Ozone is an unstable molecule comprising three oxygen atoms.
Natural ozone in the upper atmosphere plays an important role
in filtering out ultraviolet rays from the sun. In the lower
atmosphere, however, man-made ozone pollution results from a
chemical reaction with nitrous oxide compounds released in
automobile exhaust and industrial emissions, particularly under
warm, sunny conditions. Such ozone is toxic in small
concentrations and can exacerbate asthma and other respiratory
The researchers exposed mice with and without a functional
copy of the gene TLR4 to four environmental challenges. They
were aerosolized lipopolysaccharide, a component of bacterial
cell membranes ubiquitous in the environment, particulate
matter, and high and low doses of ozone.
TLR4 encodes a component of the innate immune system, the
body's first line of defense against foreign invaders. Earlier
work linked the gene to the lung's response to bacterial
infection and inhaled lipopolysaccharides, Hollingsworth said,
a result which the current study confirmed. Research led by
Steve Kleeberger, Ph.D., of the National Institute of
Environmental Health Sciences, had further suggested a role for
the gene in airway injury induced by ozone, he added.
The new study expands TLR4's role in directing the lung's
response to environmental exposures by highlighting its
potential importance in exacerbation of asthma following ozone
inhalation. The researchers found that ozone levels comparable
to those experienced during consecutive red alert days --
during which the U.S. Environmental Protection Agency
recommends people limit outdoor activity -- also led to the
hyper-responsiveness or twitching of the lungs characteristic
of asthma only in animals with a working copy of the innate
Mice lacking a functional copy of TLR4 continued to suffer
lung injury in response to particulate matter and acute ozone
exposure. However, they were protected from many of the airway
effects of prolonged exposure to lower doses of ozone. The
result suggests that the ramifications of toxin inhalation in
the lung vary depending upon the nature of the toxin and
exposure conditions, Hollingsworth said.
"Ozone exposure is important in the big picture,
particularly in urban settings," he said. "Drugs that target
the components critical to the lung's response to such
exposures might serve as effective treatments for patients with
The Duke team will next conduct studies of humans to confirm
the gene's importance to the effects of inhaled air pollution.
The human and mouse genes are known to play similar functional
roles in innate immunity.
Collaborators on the study include Donald Cook, Ph.D., David
Brass, Ph.D., Julia Walker, Ph.D., W. Michael Foster, Ph.D.,
and David A. Schwartz, M.D., all of Duke. Daniel Morgan, Ph.D.,
of the National Institute of Environmental Health Sciences also
contributed to the research.