ENDOTOXIN INDUCED LUNG INJURY

在内毒素诱导的弥漫性肺损伤动物模型中，我们 建议调查的假设，发病机制， 损伤包括肺的氧化损伤， 诱导的蛋白酶/抗蛋白酶失衡和 环核苷酸代谢 此外，我们建议， 类花生酸和血小板活化因子（PAF）作为部分释放 内毒素血症介导的炎症反应 肺功能的改变和炎症因子的相互作用 细胞与肺 为了验证这些假设，我们建议 测量血液中脂质过氧化产物的研究 肺组织中的抗氧化酶和肺淋巴液 内毒素和确定外源性抗氧化剂的作用， 内源性抗氧化剂对内毒素反应的诱导。 我们将测量一组蛋白酶和抗蛋白酶， 支气管肺泡灌洗液（BAL）、血液和肺淋巴液， 确定消耗（氯胺-T）或增强的影响 （α-1-抗胰蛋白酶）的抗蛋白酶活性对反应 内毒素血症 我们将测量 内毒素对类花生酸释放和血小板活化的影响 肺中的因子，并确定抑制 这种释放对内毒素的反应。 我们将收集 淋巴细胞和肺泡巨噬细胞， 用于体外测量趋化因子、类花生酸的内毒素 生产PAF。 我们将定义贩运 中性粒细胞、淋巴细胞（包括亚群）和巨噬细胞， 反应期间的血液、肺淋巴液、BAL液和肺组织 并确定干预措施的影响， 炎症细胞运输反应的病理生理学。 我们将确定抑制肺部呼吸的机制 前列腺素E2对内毒素血症的反应。 最后我们将 确定是否有周期性的药物操作 核苷酸代谢将阻止或逆转 内毒素血症引起的肺血管通透性增高。 这些 研究，结合本提案中的其他研究，将允许 内毒素肺损伤发病机制的定义 并展示合理的治疗和预防方法 可能对人类有用。

In an animal model of endotoxin induced diffuse lung injury, we propose to investigate the hypotheses that the pathogenesis of the injury involves oxidant injury to the lungs, an endotoxin induced proteinase/antiproteinase imbalance and alterations in cyclic nucleotide metabolism. Further, we propose that eicosanoids and platelet activating factor (PAF) released as part of the inflammatory response to endotoxemia mediate alterations in lung function and interactions of inflammatory cells with the lungs. To test these hypotheses, we propose studies which will measure lipid peroxidation products in blood and lung lymph and antioxidant enzymes in lung tissue after endotoxin and determine effects of exogenous antioxidants and induction of endogenous antioxidants on the endotoxin response. We will measure a panel of proteinases and antiproteinases in bronchoalveolar lavage (BAL) fluid, blood and lung lymph and determine effects of depletion (chloramine-T) or enhancement (alpha-1-antitrypsin) of antiproteinase activity on the responses of the lungs to endotoxemia. We will measure effects of endotoxin on release of eicosanoids and platelet activating factor in the lungs and determine effects of drugs which inhibit such release on the endotoxin reaction. We will collect lymphocytes and alveolar macrophages from sheep given endotoxin for in vitro measurements of chemotaxin, eicosanoid and PAF production. We will define the trafficking of neutrophils, lymphocytes (including subsets) and macrophages in blood, lung lymph, BAL fluid and lung tissue during the response to endotoxin and determine effects of interventions which alter the pathophysiology of the response on inflammatory cell traffic. We will determine the mechanism of suppression of the lungs' response to endotoxemia by prostaglandin E2. Finally, we will determine whether pharmacologic manipulation of cyclic nucleotide metabolism will prevent or reverse the increase in lung vascular permeability caused by endotoxemia. These studies, combined with others in this proposal, will permit a definition of the pathogenesis of endotoxin induced lung injury and demonstrate rational approaches for therapy and prevention which may be useful in humans.