RELATIONSHIPS BETWEEN PROSTANOIDS AND CELLULR INJURY

该实验室以前的研究表明， 内毒素或补体激活血浆对动物体内结果的影响 在具有显著血液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。 的目的 拟议的研究是描述革兰氏阴性杆菌与 细菌内毒素、补体系统和花生四烯酸产物 酸级联。 目前的研究将在三个不同的地方进行 代表三个生理组织层次的模型。 离体肝切片~（14）C花生四烯酸代谢的研究 和粒细胞制剂将表征体外应答， 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幅度将是 表征了 进一步的研究将在体外进行， 离体灌注兔肝模型，以表征 激活补体对细胞前列腺素类产生的影响。 此外，本发明还提供了一种方法， 将进行研究以确定补体的机制， 花生四烯酸级联的激活。 其中包括研究 使用钙流入抑制剂、磷脂酶抑制剂和自由基 拾荒者 还将在兔模型中进行体内研究， 建立与内毒素诱导的生理事件相关的序列 细胞损伤、补体激活和前列腺素类产生。 研究 将包括用眼镜蛇毒因子激活补体系统 同时测量内源性前列腺素类产生; 底物刺激内源性前列腺素类产生 补充并同时评估CH 50补体滴度， 和内毒素给药到补体充足和耗尽的动物 前列腺素定量 这些体外和体内结果 研究将描述以前未被认识到的 内源性补体激活、前列腺素类产生和随后的 病理生理学 这些数据不仅有助于了解 内毒素休克的病理生理学，但也应该有价值， 了解和管理其他与补体相关的疾病状态， 血液透析肺损伤，Festival综合征，系统性狼疮 红斑和肾小球肾炎。

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.