NOVEL INFLAMMATORY MEDIATORS IN GLOMERULONEPHRITIS

本研究的主要目的是：1）建立 大鼠肾小球免疫损伤实验模型，代表性 各种形式的人类免疫介导的肾小球病。 2)免疫损伤肾小球的特征 三类“新型”炎症因子的生物合成机制 介质：a）花生四烯酸环氧化产物（花生四烯酸和 血栓烷类; B）花生四烯酸脂氧合产物 （单羟基-二十碳四烯酸和白三烯）和c） 血小板活化因子（PAF-acether）。 3)相关性 花生四烯酸代谢物（类花生酸）的肾小球生物合成， PAF-醋酸酯与肾血流动力学和肾小球的扰动 实验性肾小球肾炎中蛋白质的渗透性。 这些目的与肾小球损伤的机制直接相关 因为他们的目的是探索生物化学事件， 是由肾小球内免疫反应物的相互作用引发的 并负责释放促炎介质。 的 要研究的介质是有效的血管活性化合物（三尖杉酯碱和 血栓烷），诱导趋化性（单羟基化脂肪酸和 白三烯）和增加血管通透性（白三烯， PAF-乙酸酯）。 确定其在生物多样性期间的合成概况 因此，肾小球肾炎的演变可能允许特定的 药理学操作，以有益地改变其效果。 实验方法将采用：1）免疫病理学方法， 建立三种关键的实验性肾小球肾炎模型： 抗肾小球基底膜疾病、膜性肾小球肾炎和 血清病肾小球肾炎。 2)生物化学方法（色谱法 分析和放射免疫测定）进行表征和定量 肾小球的类胡萝卜素、血栓素、单羟基二十碳四烯酸 酸类、白三烯和PAF-乙酸。 3)生理学方法（全 肾清除率和尿蛋白分析）以表征扰动 肾血流动力学（肾小球滤过率和肾血浆流量） 以及肾小球对蛋白质的渗透性。 预计该 从拟议的研究中获得的信息将提供新的见解 肾小球肾炎的病理生理学和病理生物化学。

The proposed research has the following objectives: 1) Establishment of experimental models of glomerular immune injury in the rat, representative of the various forms of human immunologically mediated glomerulopathies. 2) Characterization in isolated immunologically injured glomeruli of the biosynthetic mechanisms of three classes of "novel" inflammatory mediators: a) arachidonate cyclo-oxygenation products (prostaglandins and thromboxanes; b) arachidonate lipoxygenation products (monohydroxy-eicosatetraenoic acids and leukotrienes) and c) platelet-activating factor (PAF-acether). 3) Correlation between glomerular biosynthesis of arachidonate metabolites (eicosanoids) and PAF-acether and pertubations in renal hemdynamics and in glomerular permeability to protein in experimental glomerulonephritis. These objective are directly related to the mechanism of glomerular injury in glomerulonephritis since they aim at exploring biochemical events which are triggered by the interaction of immune reactants within the glomerulus and are responsible for the release of pro-inflammatory mediators. The mediators to be studied are potent vasoactive compounds (prostaglandins and thromboxanes), induce chemotaxis (monohydroxylated fatty acids and leukotrienes) and increase vascular permeability (leukotrienes, PAF-acether). Identification of their synthetic profiles during the evolution of glomerulonephritis could, therefore, allow specific pharmacologic manipulations in order to beneficially modify their effects. The experimental approach will employ: 1) Immunopathologic methods in order to establish three key models of experimental glomerulonephritis: antiglomerular basement membrane disease, membranous glomerulonephritis and serum sickness glomerulonephritis. 2) Biochemical methods (chromatograhic analyses and radioimmunoassay) for the characterization and quantification of glomerular prostaglandins, thromboxanes, monohydroxy-eicosatetraenoic acids, leukotrienes and PAF-acether. 3) Physiological methods (whole kidney clearance and urine protein analyses) to characterize pertubations in renal hemodynamics (glomerular filtration rate and renal plasma flow) and in glomerular permeability to protein. It is anticipated that the information accrued from the proposed studies will provide new insights into the pathophysiology and pathobiochemistry of glomerulonephritis.