Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Bronchopulmonary dysplasia (BPD) is a common, diabling and sometimes fatal chronic lung disease which frequently can accompany premature birth and treatment of associated respiratory distress with artificial ventilation and high inmspired concentrations of oxygen. The biochemical basis of this disorder is not well understood. The mitochondrial citric acid cycle enzyme aaconitase appears to be the most oxygen-sensitive mammalian lung enzyme involved in energy metabolism. Regulation of aconitase activity and potential results of its inactivation have not been evaluated in humans or primates. The proposed experiments will clarify whether inactivation of aconitase occurs during the evolution of BPD in the primate model. The hypothesis that inactivation of aconitase in the premature baboon lung will be profound, related directly to inhaled oxygen tension and inversely to gestational age will be tested by measuring aconitase activity in lungs of preterm baboons of different gestational ages ventilated with different oxygen tensions. Reactivation of aconitase requires a reduced thiol such as glutathione (GSH) as well as ferrous iron. Circulating GSH and its prescursor cyst(e)ine are low in human prematures, although their lung levels are unknown. To assess their potential roles, some of the postulated determinants of aconitase activity: GSH and its precursor sulfur amino acids and mitochondrial MnSOD (superoxide dismutase) activity, as well as other antioxidant protein profiles, will be characterized in the lung during hyperoxic exposure. Oxidized, as well as reduced, forms of GSH will be measured since GSH/GSSG ratio, like aconitase, is a useful indicator of oxidant stress. The additional antioxidant proteins to be assessed include total and CuZnSOD, glutathione peroxidase and reductase glucose-6-phosphate dehydrogenase (G6PD), catalase, and thioredoxin and thioredoxin reductase, whose activity measurements have not been described in this model. mRNA's for proteins which may be especially pertinent to preservation of aconitase or other critical enzymes in energy metabolism, including those for both SOD's, G6PD, and thioredoxin also will be quantified. In addition, it is not clear that lung or liver GSH or cysteine and its precursors are maintained during ongoing hyperoxic stress in prematures. Current guidelines for cysteine supplementation of infant parenteral nutrition fluids are not based on lung GSH levels, and there is no recommendation for additional cysteine to be administered to premature infants during ventilation with high oxygen concentrations. Nor is the potential benefit or harm of such supplementation known. However, such information can be obtained in the primate model, and a randomized trial comparing the effects of early supplementation with GSH or cysteine, in the presence of adequate protein and calorie intake, to that of routine management on lung GSH, GSH/GSSG, aconitase, antioxidant profiles, clinical indiccators of disease severity, and histopahtologic severity score will be cinducted. These studies will provide both important new basic findings, as well as practical therapeutic information regading potential nutritional interventions to palliate or prevent BPD.
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