RELATIONSHIPS BETWEEN PROSTANOIDS AND CELLULR INJURY

该实验室以前的研究表明，给药后 内毒素或补体激活的血浆对动物的活体结果 在具有显著血流动力学的前列腺素生物合成的激活中 对微血管完整性的后果和影响。该计划的目标是 拟议的研究是为了刻画革兰氏阴性与 细菌内毒素、花生四烯酸的补体系统及其产物 酸级联。目前的研究将在三个不同的方面进行 代表生理组织的三个层次的模型。 14C花生四烯酸在离体肝切片中的代谢研究 粒细胞制剂将表征细胞的体外反应 花生四烯酸级联到内毒素和补体治疗。图案和 环氧合酶和脂氧合酶途径的大小将是 特色化的。进一步的研究将在体外进行， 离体兔肝脏灌流模型的实验研究 激活补体对细胞类前列腺素的产生。此外, 将进行研究以确定补体的机制 花生四烯酸级联反应的激活。这些将包括研究 使用钙内流抑制剂、磷脂酶抑制剂和自由基 搜索者。活体研究也将在兔模型中进行，以 建立与内毒素相关的生理事件序列 细胞损伤、补体激活和前列腺素类物质的产生。研究 将包括用眼镜蛇毒素激活补体系统 同时测量内源性前列腺素的产生； 底物对内源性前列腺素合成的刺激作用 补充同时评估CH50补体滴度， 和内毒素注射来补充充盈和耗尽的动物 前列腺素定量。来自体外和体内的这些结果 研究将表征以前未被认识到的关系 内源性补体激活、前列腺素类物质的产生及随后 病理生理学。这些数据不仅有助于理解 内毒素休克的病理生理学，但也应在 了解和管理其他补体相关疾病状态，如 血液透析致肺损伤、Felty综合征、系统性红斑狼疮 红斑性肾炎和肾小球肾炎。

Previous studies from this laboratory suggest that the administration of either endotoxin or complement activated plasma to animals in vivo results in activation of prostaglandin biosynthesis with significant hemodynamic consequences and effects on microvascular integrity. The objective of the proposed research is to characterize the relationship between gram negative bacterial endotoxin, the complement system and products of the arachidonic acid cascade. The present studies will be undertaken in three different models representing three levels of physiologic organization. Investigations of 14C arachidonic acid metabolism in isolated liver slice and granulocyte preparations wil characterize the in vitro response of the arachidonic cascade to endotoxin and complement treatment. The pattern and magnitude of both cyclo-oxygenase and lipoxygenase pathways will be characterized. Further studies will be carried out in vitro in an isolated, perfused rabbit liver model to characterize the direct effect of activated complement on cellular prostanoid production. In addition, studies will be undertaken to determine the mechanism of complement activation of the arachidonic acid cascade. These will include studies using calcium influx inhibitors, phospholipase inhibitors and free radical scavangers. In vivo studies will also be carried out in a rabbit model to establish the sequence of physiologic events related to endotoxin induced cellular injury, complement activation, and prostanoid production. Studies will include activation of the complement system with cobra venom factor with concurrent measurement of endogeneous prostanoid production; stimulation of endogenous prostanoid production by substrate supplementation with concurrent assessment of the CH50 complement titer, and endotoxin administration to complement replete and depleted animals with prostanoid quantitation. Results from these in vitro and in vivo studies will characterize the previously unrecognized relationship between endogenous complement activation, prostanoid production and subsequent pathophysiology. This data will be of value in not only understanding the pathophysiology of endotoxic shock, but should also be of value in understanding and managing other complement related disease states such as hemodialysis induced lung injury, Felty's Syndrome, systemic lupus erythematosus and glomerulonephritis.