Pulmonary oxygen injury remains a significant cause of morbidity in intensive care units often resulting in chronic pulmonary dysfunction. In neonates, oxygen exposure may alter normal postnatal lung growth and development, leading to syndromes like bronchopulmonary dysplasia. Our previous work demonstrated that increased manganese superoxide dismutase (Mn-SOD) protects against oxidant injury in vitro and in vivo. This application will test the hypothesis that resistance to pulmonary oxygen injury can be increased by adenoviral-mediated transfer of the human manganese superoxide dismutase (hMn-SOD) to respiratory epithelium. A replication deficient adenoviral vector (AvMn-SOD) will be used to transfer the hMn-SOD cDNA to respiratory epithelial cells in vitro and in vivo. In vitro studies will test the ability of AvMn-SOD to direct the synthesis of active Mn-SOD protein in murine respiratory epithelial cells, prior to beginning studies in mice. in vivo, AvMn-SOD will be used to increase Mn- SOD in the distal respiratory epithelium . The dose response and time course of viral mediated Mn-SOD expression will be characterized and its cellular localization identified. To test the hypothesis that AvMn-SOD treatment protects against pulmonary oxygen injury, and preserves postnatal lung growth, adult and neonates will be exposed to hyperoxia and lung injury evaluated biochemically, morphologically an functionally. Results from this application will provide the rational basis for somatic gene therapies designed to protect humans from the adverse consequences of medically required hyperoxia.
| Warner, B B; Stuart, L A; Papes, R A et al. (1998) Functional and pathological effects of prolonged hyperoxia in neonatal mice. Am J Physiol 275:L110-7 |
