We have shown that plasma concentrations of glutathione disulfide are increased in premature infants independent of respiratory system disease, suggesting that these infants are experiencing a significant oxidant stress even when exposed to low concentrations of supplemental oxygen. This oxidant stress correlates with a predisposition to develop """"""""Oxygen radical mediated"""""""" chronic diseases, of which BPD is a prominent example. Animal models of oxygen radical mediated lung injury have largely centered around hyperoxia-exposure as the means of generating lung injury. We propose to generate adenoviral vectors which express a variety of antioxidant genes for administration to premature baboons which develop BPD in a classic model. 1-3 Initial studies will be performed using an adenovirus which bears the beta-galactosidase marker gene to determine the efficacy of adenoviruses as vectors for the delivery of transgenes to the lungs of ventilated prematures. Subsequent studies will examine the simultaneous delivery of adenoviral vectors and surfactant preparations to determine whether surfactant administration interferes with adenoviral transduction of pulmonary tissue. Successful transgene delivery in this setting would facilitate the treatment of RDS and BPD by permitting a dual approach to the prevention of lung injury. Initial studies of antioxidant gene delivery will be performed using a vector which contains the MnSOD gene. This will be delivered to premature baboons at 140 days gestation; they will be compared with untreated baboons using a clinical scale for severity of acute and chronic disease and by histologic comparison of lung tissue for the stigmata of BPD. Finally, a series of adenoviral vectors containing other antioxidant genes will be prepared; these will include glutathione reductase, glutathione peroxidase, gamma-glutamyl cysteine synthetase and nitric oxide synthase. These vectors will be used singly or in combination to discover the most effective treatment protocol for the prevention of oxygen toxicity in ventilated prematures.
|O'Donovan, D J; Katkin, J P; Tamura, T et al. (1999) Gene transfer of mitochondrially targeted glutathione reductase protects H441 cells from t-butyl hydroperoxide-induced oxidant stresses. Am J Respir Cell Mol Biol 20:256-63|