Project at a Glance

Title: Effect of GSTM1 genotype on ozone-induced allergic airway inflammation

Principal Investigator / Author(s): Balmes, John

Contractor: University of California, San Francisco

Contract Number: 03-315

Research Program Area: Health & Exposure

Topic Areas: Health Effects of Air Pollution


Epidemiological data suggest that persons with asthma may have greater morbidity as measured by health care utilization after O3 exposure than normal, healthy persons. Animal toxicological data provide evidence that O3 exposure can affect immune function, including enhancement of allergic inflammatory responses in the lungs. Previous controlled human exposure studies have confirmed that O3 exposure can enhance both the early and late bronchoconstrictor responses to inhaled antigen in allergic asthmatic subjects. The effects of O3 exposure on lower airway and late-phase inflammatory responses have not been adequately studied. Recently, data from both controlled human exposure and epidemiological studies have suggested that a common genetic polymorphism in an antioxidant enzyme, glutathione S-transferase 1 (GSTM1), is an important determinant of susceptibility to the respiratory effects of inhaled O3. We designed an experiment to determine whether persons with allergic asthma have increased susceptibility to O3 as a consequence of enhanced airway inflammatory responses to local endobronchial allergen challenge. This experiment was also designed to determine whether the effects of inhaled O3 on the specific airway inflammatory responses to allergen were enhanced in asthmatic individuals with the GSTM1 null genotype. The experiment used a repeated-measures design, each subject completing both O3 and filtered air (FA) exposures within the experiment, with the order of the exposures counter-balanced. Subjects were screened prior to beginning the experimental protocol so that 50% had the GSTM1 null genotype. Ten asthmatic subjects with specific sensitization to the house dust mite, Dermatophagoides pteronyssinus (DP), were exposed separately to 0.16 ppm O3 and FA control for 4 hr with intermittent exercise. At 20 hr post-exposure, subjects underwent a challenge bronchoscopy during which DP allergen was instilled in a sub-segmental bronchus of the right middle lobe and saline was instilled in a sub-segmental bronchus of the right upper lobe. Six hours later, a second sampling bronchoscopy was performed to collect samples of airway lining fluid from each challenged bronchus for analyses of cellular and biochemical markers of non-specific and specific allergic inflammatory responses. Subjects underwent lung function testing pre- and immediately post-exposure, 18 hr post-exposure prior to and then hourly after the challenge bronchoscopy until the sampling bronchoscopy. Exposure to O3 induced an expected decrease in lung function. The decrease in lung function 6 hours after O3-allergen was greater than that after FA-allergen. While the neutrophilic inflammatory response was non-significantly greater after O3-allergen compared to that after FA-allergen, the levels of multiple cytokines (GM-CSF, IL-1β, IL-4, IL-5, IL-8, IL-10, IL-13, and TNFα) were lower after O3-allergen than after FA-allergen. These results suggest that while prior exposure to O3 may enhance the bronchoconstrictor response to allergen, it has somewhat conflicting effects on the airway inflammatory response to allergen. Neutrophil chemotaxis to the airways may be increased, but at least some cytokine responses may be decreased. While there were no significant differences in lung function to O3 based on GSTM1 genotype, the inflammatory response to allergen was consistently lower in the GSTM1-null subjects. Because of the small sample size, caution should be applied in interpretation of these results.

For questions regarding this research project, including available data and progress status, contact: Research Division staff at (916) 445-0753

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