Over 150 million people live in communities where the concentrations of 03 approach or exceed the National Ambient Air Quality Standard (NAAQS) of 0.12 parts per million (ppm), and the number continues to increase. Acute and sub-acute ozone (03) exposures elicit airways inflammation and, as inflammation may be linked to the pathogenesis of a host of airway diseases, great interest has focused on the identification of susceptibility or risk factors that may pre-dispose individuals to this process. In particular, it is imperative to understand those factors that determine whether acute inflammation leads to reversible or irreversible lung injury. Compelling evidence for the explicit role of genetic susceptibility to environmental agents in humans now exists. For the purpose of identification of genetically susceptible individuals who may be at risk to adverse effects of these agents, a need for predictive animal models of genetic predisposition is recognized. We have developed a murine genetic model in which two separate loci, Inf and Inf-2, control susceptibility to acute (2 ppm/3 hr) and sub-acute (0.30 ppm/72 hr) 03- induced inflammation, respectively. Two easily distinguishable phenotypes, SUSCEPTIBLE and RESISTANT, have been identified based on airway inflammation and increased lung permeability. Moreover, the model implies that different genetic mechanisms determine susceptibility to the inflammatory effects of the two exposures. We propose to test the hypothesis that regional airway susceptibility to the inflammatory and histologic effects of chronic intermittent 03 exposures, similar to ambient urban environments, is controlled by Inf or Inf-2. Specifically, the project will determine 1) the range of biological responsiveness in regional susceptibility of airways to chronic intermittent exposures to 0.25 and 0.12 ppm 03 in inbred strains of mice, 2) the mode of inheritance of susceptibility to the effects of chronic 03 exposures on murine airways, 3) the chromosomal map assignment(s) for the locus (loci) that determine susceptibility to airway effects of chronic 03 exposures, and 4) whether differential expression of epithelial repair processes or anti-oxidant defense may contribute to susceptibility to chronic 03 exposure, and identify biomarkers of exposure in the mouse model that will be tested in human subjects exposed repeatedly to 03. One future objective of these studies is to provide a means to more easily identify individuals who are at risk to oxidant exposures. We believe that the proposed studies have potentially important implications for public health.
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