Elevated concentrations of oxygen and increased airway pressure are administered to preterm neonates with respiratory distress syndrome. Among the survivors, 20% to 30% develop a form of chronic lung disease called bronchopulmonary dysplasia (BPD) and which is now characterized by poor alveolarization and vascularization. Tissue injury 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 a variety of animal models of oxidative stress. Recent work has shown that AEOL 10113 by IV infusion decreases inflammation and fibrosis in the 140-day gestation plus 10 days 100% neonatal baboon model of BPD. AEOL 10113 also enhances alveolarization in the 125-day gestation model of BPD receiving PRN O2 for 14 days. Based on this preliminary work we hypothesize that: 1) An effective antioxidant mimetic with optimum dose to the lung will reduce or prevent impairment of alveolarization in premature infants, 2) Creating a more reducing environment in the lung during the first few weeks following premature delivery will have a long term benefit on lung development - permanently improving lung structure and function, and 3) BPD is a complex, multifactoral disease in which multiple therapeutic approaches are likely to be required to optimize therapy and result in normal lung structure and function. We thus propose 1) optimizing lung delivery by use of an aerosol to give highest therapeutic benefit with the lower risk of toxicity, 2) defining the dose-response relationship for AEOL 10113 in the 125-day gestation, 21-day follow-up model, 3) evaluating two new antioxidant mimetics in the 125-day gestation model, 4) extending the 125-day gestation model to a 6-month follow-up to show long term therapeutic benefit, and 5) evaluate the potential advantages of combination therapy. We believe that it should be possible to use this therapeutic strategy of a low molecular catalytic antioxidant in a human clinical trial, but it is critical to use the baboon model to optimize conditions and minimize possible toxicities.

U01HL063397

1999-08-01

2007-08-31