CELLULAR AND MOLECULAR BASIS OF LUNG TOLERANCE OF OZONE

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Our long range goal is to understand the molecular and cellular basis of lung tolerance (resistance) to the potentially damaging effects of ozone; in particular, as a first approach, to gain more understanding of the lung's tolerance to ozone as it occurs in vivo. Toward this end we offer three specific aims: 1) To continue to study the regulation of manganese superoxide dismutase (MnSOD) gene expression in response to in vivo exposure of rats to 0.25 ppm or less of ozone. More specifically, to elucidate the basis for the recently found 10-fold disparity between the magnitude of the increase in lung concentration of MnSOD mRNA and the smaller increase in lung activity of MnSOD in response to 0.25 ppm O3. 2) To determine the mechanism(s) responsible for the elevation of lung activity of MnSOD induced by treating rats with bacterial lipopolysaccharide (endotoxin). This endotoxin-induced rise in MnSOD activity is associated with virtually complete protection against an otherwise edemogenic concentration of ozone without a detectable elevation in activity of Cu,Zn superoxide dismutase, catalase, or glutathione peroxidase. 3) To identify cells in terminal bronchioles and alveoli a) whose MnSOD gene expression is responsive to ozone under conditions used in specific aim 1, and b) that take part in the endotoxin-induced increase in MnSOD gene expression under conditions studied in specific aim 2. The endotoxin-model allows us to compare the same cell types in "nontolerant" and "tolerant" lungs and to determine if cells whose MnSOD gene expression is responsive to endotoxin are distributed throughout the lung or are strategically located in a manner that might be expected to prevent edema. To achieve this aim we will use in situ hybridization of the mRNA for MnSOD, and immunolocalization of MnSOD, in all quantitative ultrastructural analysis of the intact lung. We believe our preliminary data indicate all aspects of the work are feasible and will provide fundamental new information on a major atmospheric pollutant and in a relatively neglected area (molecular and cellular aspects of antioxidant enzyme response to ozone).