GENETIC REGULATION OF 03-INDUCED INFLAMMATION

Duke University, Durham NC

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Abstract

Laboratory studies have demonstrated that short-term single exposure of adult humans to ambient levels of O3 leads to inflammation of the airway. Lung inflammation is observable 3-18 hr after exposure, and is not correlated to the functional changes that arise during exposures or slowly dissipate during recovery, 1-2 hr post-exposure. The inflammation is characterized by an influx of polymorphonuclear leukocytes and increases in total protein, albumin, pro-inflammatory cytokines, and granulocyte-macrophage colony-stimulating factor in bronchoalveolar lavage fluid. Significant inter-individual variation in the inflammatory response is found among otherwise homogeneous subjects suggesting that intrinsic host factors contribute to the magnitude of beta3-induced lung injury. Further, although ambient exposure to beta3 is frequently intermittent, whether the severity of inflammation increases upon re-exposure remains controversial. Thus, basic questions remain: 1) is the inter-individual nature of the inflammatory response to O3 explained by host factors, i.e., genetic background, and 2) do inflammatory airway responses in sensitive subjects adapt upon re-exposure to O3? Understanding the mechanisms intrinsic to O3-induced airway inflammation is essential for predicting host susceptibility and risk of lung and epithelial injury from exposure to O3. Our HYPOTHESIS is that specific gene polymorphisms/mutations contribute to differential susceptibility to O3-induced lung injury in healthy subjects and are host factors that regulate risk of exposure to O3. We will use a multi-disciplinary approach that applies physiologic and genetic techniques to a controlled human exposure system. Specific aims will determine: 1) the range in susceptibility of humans to develop airway inflammation and hyperpermeability after a single exposure to O3, and 2) if subjects differentially susceptible to ozone maintain their sensitivity during intermittent exposure to O3, and 3) the association of selected genetic markers with O3-induced lung injury and airway inflammatory responses. These investigations will help to establish genetic background as a host factor in the susceptibility of humans to O3 exposure and utility of genetic factors as biomarkers of lung injury induced by inhalable oxidants and environmental pollutants.