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 conditions.
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 immunity gene.
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 asthma."
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.