PROTECTION FROM OXYGEN TOXICITY BY PHARMACOLOGIC THERAPY

过去五年取得的进展使我们的努力集中在 细胞外抗氧化酶在调节肺泡灌洗液中的作用 炎症 初步数据表明，超氧化物歧化酶， 结合并保留在肺泡表面衬里层和细胞外 间隔物在治疗小鼠和亚人灵长类动物模型中均有效， 氧中毒 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 狒狒的肺氧中毒 交付将在 剂量和输送均匀性。 雾化的影响 rh Mn SOD在保护肺氧中毒中的作用将用 损伤的生理和病理标准。 该项目还将 专注于开发一种SOD模拟物， 通过给它带正电荷或附着在 对糖胺聚糖具有结合特性的肽。 的 这些SOD模拟物的功效将在以下小鼠模型中确定： 氧中毒 此外，该项目还将评估以下方面的作用： 使用rh Mn SOD加表面活性剂的组合疗法， 在治疗肺氧合方面有积极的益处 毒性 我们的目标是确定两种药物的联合治疗 现在显示有效的试剂将在治疗中产生附加的益处。 急性肺损伤的治疗。 我们现在可以测试 急性肺损伤的新疗法， 高度功效。

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.