Understanding health effects of pollutant exposure must include determination of the effects of repeated exposures, and the effects on individuals with chronic respiratory disease. Preliminary data from our laboratory suggest that the airway inflammation associated with cigarette smoking may alter cellular responses to ozone exposure. Individuals with asthma may be at increased risk from repeated exposures to ozone because of underlying airway inflammation. We propose to investigate the effects of single 4-hour exposures to 0.22 ppm ozone on the airways of asthmatic subjects, and to determine the effects of four sequential daily ozone exposures on the airways of healthy and asthmatic subjects. Changes in lung function in both healthy and asthmatic subjects will be monitored using pulmonary function tests and nonspecific airway responsiveness. Possible delayed or persistent effects of repeated exposure on asthmatics will be detected using home monitoring of peak flow rates. Cellular, biochemical, and molecular effects will be studied using fiberoptic bronchoscopy with bronchoalveolar lavage, brush biopsies, and endobronchial biopsies after both single and repeated exposures to ozone. Cell populations and subpopulations in lavage will be assessed using flow cytometry and immunofluorescence techniques. Morphometry of endobronchial biopsy specimens will be used to confirm changes in inflammatory cells seen on lavage. We will examine changes in pro- inflammatory cytokines by measuring protein product in bronchoalveolar lavage fluid, and gene expression in alveolar macrophages and bronchial epithelial cells. A quantitative multiplex competitive reverse transcriptase-polymerase chain reaction method recently developed in our laboratory will be used to measure gene expression in bronchial epithelial cells since the cells obtained by brush biopsies are limited. Pollutant-induced changes in gene expression will be compared in cells from normal and asthmatic subjects. Since polymorphisms in cytokine genes may explain variability in responses among ozone-exposed volunteers, we will bank genomic DNA from blood leukocytes prospectively. This will allow us to compare subjects with the largest inflammatory response to those with the smallest inflammatory response to determine whether cytokine gene polymorphisms explain individual differences. Flow cytometry will be used to quantitate the respiratory burst in individual lavage cell populations, and to investigate mechanisms of receptor signaling that lead to release of toxic oxygen species by airway inflammatory cells in healthy and asthmatic subjects exposed to ozone. Data obtained from these studies will help to determine whether repeated exposures to ozone enhance airway inflammation and injury in healthy and asthmatic subjects.
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