RELATIONSHIPS BETWEEN PROSTANOIDS AND CELLULAR INJURY

我们的目标是描述脂质介质在 细胞损伤和死亡的过程。 我们已经证明 花生四烯酸（AA）参与循环休克，缺氧， 烧伤和补体介导的（C ′）肺损伤。 我们有 还观察到补体介导的类花生酸刺激 在培养的细胞中形成。 此外，短期C' 治疗可以增加长期类花生酸的形成， 对适当刺激的反应。 其目的是表征 C'直接刺激AA代谢的机制， 分离的内皮细胞，B）表征C' 与内皮细胞的相互作用， 增加类二十烷酸的释放，和c）在一个 内毒素血症模型，以确定是否补体- 介导的类二十烷酸产生的增加是生理性的， 意义 具体的研究包括评估模式， AA代谢物形成的幅度和时间过程， 培养的牛和人内皮细胞响应于C '， 研究钙在补体介导的 活化过程，膜的表征 磷脂来源的AA利用，和表征 磷脂酶A和C在刺激过程中的作用。 进一步的研究将包括确定刺激 长期补体介导增强的特异性 类二十烷酸形成的时间过程， C'后类花生酸的产生模式是否 预处理与正常细胞不同， 膜磷脂AA含量的变化， 伴随C'预处理。 与职能有关的研究 这一现象的重要性将涉及进行的实验 在离体灌注的肝脏、心脏和血管环中 确定由以下原因引起的功能变化的准备 C'充满或耗尽的动物中的内毒素血症。 上述研究将描述生化机制 通过该方法，C'活化可导致类花生酸的产生增强， 并将阐明这种现象的生理效应 在一个全球性的伤害时期。 获得的数据将是 在理解治疗方法的价值， 临床病症的管理，其特征在于C' 活化包括败血症、血液透析诱导的肺损伤， 烧伤、肾小球肾炎和各种自身免疫性疾病。

Our goal is to characterize the role of lipid mediators in the processes of cellular injury and death. We have demonstrated arachidonic acid (AA) involvement in circulatory shock, hypoxia, burn injury, and complement-mediated (C') lung injury. We have also observed complement-mediated stimulation of eicosanoid formation in cultured cells. Furthermore, short-term C' treatment can augment long-term eicosanoid formation in response to appropriate stimuli. The aims are to characterized the mechanisms by which C' directly stimulates AA metabolism in isolated endothelial cells, b) characterize the nature of the C' interaction with endothelial cells which results in the long-term augmentation of eicosanoid release, and c) carry out studies in a model of endotoxemia to determine whether complement- mediated augmentation of eicosanoid production is of physiologic significance. Specific studies include assessment of the pattern, magnitude, and time course of AA metabolite formation by cultured bovine and human endothelial cells in response to C', investigation of the role of calcium in the complement-mediated activation process, characterization of the membrane phospholipid sources of the AA utilized, and characterization of the role of phospholipases A and C in the stimulation process. Additional studies will include determinations of the stimulus specificity of the long-term complement-mediated augmentation of eicosanoid formation, the time course of this sensitization, whether the pattern of eicosanoid production after C' pretreatment differs from that in normal cells, and the long-term changes in membrane phospholipid AA content which may accompany C' pretreatment. Studies related to the functional importance of this phenomenon will involve experiments carried out in the isolated perfused liver, heart, and vascular ring preparations to determine functional changes which result from endotoxemia in animals which are either C' replete or depleted. The above studies will characterize the biochemical mechanisms by which C' activation can lead to enhanced eicosanoid production and will elucidate the physiologic effect of this phenomenon during a period of global injury. The data obtained will be of value in the understanding therapeutic approaches to the management of clinical disorders which are characterized by C' activation including septicemia, hemodialysis-induced lung injury, burn injury, glomerulonephritis, and various autoimmune diseases.