This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.High concentrations of oxygen and increased airway pressure are administered to most preterm neonates with respiratory distress syndrome. Among the survivors, 20 percent to 30 percent develop a form of chronic lung disease called bronchopulmonary dyplasia (BPD). Tissue damage caused by the superoxide anion (O2-) and other free oxygen radicals has been implicated in the pathogenesis of BPD. We have synthesized a class of novel, small Mn(III) porphyrin mimetics of superoxide dismutase (SOD) and catalase. These compounds have been shown to be effective in blocking injury in cell culture and whole animal models of oxidative stress. Preliminary results now suggest that these SOD mimetics will be efficacious in protecting against the oxidative stress component of BPD in premature infants. We propose designing, synthesizing, and characterizing Mn(III)-porphyrins with high SOD activity that can be delivered to critical targets located in the intracellular and extracellular spaces of the lung. The efficacy of the new SOD mimetics will be tested on BPD through use of the Bronchopulmonary Resource Center in San Antonio. Our specific goals in this proposal are to 1) determine the pharmacokinetic/toxicity profiles of our existing lead SOD mimetics; 2) design and develop new SOD mimetics; 3) screen new SOD mimetics in nonprimate models of oxidative injury; 4) test SOD mimetics in baboon BPD; and, 5) determine the mode of action of SOD mimetics in the BPD model. We expect these studies to provide new insights on the role of oxidative stress in BPD and to provide a novel new therapeutic approach to reduce the impact of this devastating disease in premature infants.
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