Scientists Identify Gene Responsible for Ozone-Induced Lung Hyperpermeability Injury

For the first time, scientists at the Johns Hopkins School of Public Health have pinpointed a gene that determines whether ozone will trigger a particular lung injury, hyperpermeability, in susceptible individuals. The gene - known as toll-like receptor 4 (Tlr4) - has already been implicated in the body's innate immune response and its susceptibility to toxins produced by some strains of bacteria. The toll-like receptor family of genes serves to initiate the immune response by stimulating a cascade of events that determine the host response to the invading pathogens or, as demonstrated in this study, air pollutants such as ozone. The study was published in the May 2000 issue of the American Journal of Respiratory Cell and Molecular Biology.

Acute exposure to elevated levels of ozone typically found in many densely populated urban areas is known to harm the lungs. Ozone has been shown to induce lung function changes and inflammation, and cause hyperpermeability, a disorder that leads to lung edema. In addition, recent population and epidemiological studies have associated exposure to ozone with exacerbation of asthma.

"A person's susceptibility to ozone-induced lung injury is almost certainly multi-factorial, but it is becoming increasingly clear that genetic background is important," said lead author Steven R. Kleeberger, PhD, associate professor, Environmental Health Sciences, Johns Hopkins School of Public Health. "Tlr4 is a particularly intriguing candidate gene for susceptibility to ozone because of its crucial role in innate immunity in many species, including humans, mice, and fruit flies. Diseases controlled by the innate immune system could therefore be influenced by oxidant air pollution through a mutant form of this gene.

Asthma and asthma-like symptoms may be one of these diseases." In previous research, the researchers had identified loci on two different chromosomes - 17 and 11 - that control susceptibility to ozone-induced inflammation of the lung, another type of injury.

Different strains of inbred mice were exposed to levels of ozone typically found in polluted urban areas. Testing for lung hyperpermeability, the researchers scanned the animals' genetic code to uncover variations in immune response to ozone.

Using advanced gene mapping techniques, they found a region on chromosome 4 in affected mice that showed a statistically significant variation, and were further able to refine their analysis and pinpoint the problem to Tlr4. The scientists zeroed in on Tlr4 because of its known role in determining susceptibility to bacterial toxins and, when tested, the gene was found to be a likely candidate. As a result of these findings, the scientists believe that separate genetic mechanisms may be responsible for different responses by the immune system to ozone.

The study was supported by grants from the National Institutes of Health and the Environmental Protection Agency.