REGULATION AND FUNCTION OF EC-SOD

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Extracellular superoxide dismutase (EC-SOD) is the most abundant extracellular antioxidant enzyme in the lung. However its biological role in both the neonatal and adult lung, during health and disease, is poorly understood. In the lung, EC-SOD has been primarily localized to alveolar type II epithelial cells as well as to pulmonary vascular smooth muscle. Thus, EC-SOD has positioned itself to likely play an important role in both pulmonary vascular biology as well as in alveolar epithelial homeostasis. We have previously shown that the mouse lung has the highest tissue expression of EC-SOD. Further enhancing EC-SOD levels using transgenic mice overexpressing human EC-SOD in type II alveolar epithelial cells resulted in attenuation of lung injury in models of oxidative stress. The long-term goal of this project is to understand the basic biochemistry and molecular pathobiology and regulation of EC-SOD in the lung. Towards this goal, we have proposed the following specific aims: (1) Identify, map, and functionally characterize the murine EC-SOD promoter and transcriptional regulatory elements. (2) Characterize the distribution and differential gene expression pattern of various EC-SOD mRNA isoforms under normal and oxidative stress conditions. (3) Critically evaluate EC-SOD expression during lung development. (4) Test the hypothesis that reduced EC-SOD expression in premature lungs predisposes to the development of hyperoxic-induced bronchopulmonary dysplasia and that overexpression protects against its development. We expect that data derived from these studies will further our understanding of basic mechanisms involved in regulating EC-SOD expression in the lung and underlie the basis for rational development of future studies utilizing transgenic mice technology, targeted against pulmonary and cardiovascular diseases.