PROTECTION FROM OXYGEN TOXICITY BY PHARMACOLOGIC THERAPY

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Progress during the past five years has led to focusing our efforts on the role of extracellular antioxidant enzymes in regulating alveolar inflammation. Preliminary data suggests that superoxide dismutases which bind to and remain in the alveolar surface lining layer and extracellular spaces are effective in treating both murine and subhuman primate models of oxygen toxicity. We now propose to determine an optimum aerosolized dose of recombinant human (rh) manganese superoxide dismutase (Mn SOD) to treat pulmonary oxygen toxicity in a baboon. The delivery will be optimized in terms of both dose and uniformity of delivery. The effects of aerosolized rh Mn SOD in protecting pulmonary oxygen toxicity will be determined using both physiologic and pathologic criteria of injury. This project will also focus on the development of an SOD mimetic which can be targeted to bind to extraocular surfaces either by giving it a positive charge or attaching peptides which have binding properties for glycasominoglycains. The efficacy of these SOD mimetics will be determined in murine models of oxygen toxicity. In addition, the project will evaluate the role of combination therapy using rh Mn SOD plus surfactants which have also been shown to have positive benefit in the treatment of pulmonary oxygen toxicity. The goal will be to determine whether combination therapy of two agents now shown to be effective will produce an additive benefit in the treatment of acute lung injury. We are now in the position to test unique new forms of therapy for acute lung injury which show marked promise for a high degree of efficacy.