PROTECTION FROM OXYGEN TOXICITY BY PHARMACOLOGIC THERAPY

过去五年的进展使我们将努力集中在 细胞外抗氧化酶在肺泡调节中的作用 发炎。初步数据表明，超氧化物歧化酶 结合并保持在肺泡表面衬里层和细胞外 SPACE在治疗小鼠和非人灵长类动物模型方面都有效 氧气中毒。我们现在建议确定最佳雾化剂量 重组人(Rh)锰超氧化物歧化酶(Mn-SOD)治疗 一只狒狒的肺氧中毒。将在以下时间优化交付 在剂量和给药均匀度方面。雾化空气的影响 Rh-Mn-SOD对肺氧毒性的保护作用 损伤的生理和病理标准。该项目还将 专注于开发一种可靶向结合的超氧化物歧化酶模拟物 通过给它带正电荷或附着在 具有与糖蛋白结合的特性的多肽。这个 这些超氧化物歧化酶模拟物的有效性将在小鼠模型中确定。 氧气中毒。此外，该项目还将评估 使用重组人锰超氧化物歧化酶和表面活性物质的联合治疗 在治疗肺氧合方面有积极的益处 毒性。目标将是确定两种药物的联合治疗是否 现在被证明有效的药物将在 急性肺损伤的治疗。我们现在可以测试独特的 治疗急性肺损伤的新形式，显示出显著的希望 药效高。

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.