NOVEL INFLAMMATORY MEDIATORS IN GLOMERULONEPHRITIS

拟议的研究有以下目标：1)建立 具有代表性的大鼠肾小球免疫损伤实验模型 各种形式的人类免疫介导的肾小球疾病。 2)分离的免疫损伤肾小球的特征 三类新奇炎性物质的生物合成机制 介体：a)花生四烯酸环氧合产物(前列腺素和 血栓烷；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)相互关系 肾小球生物合成花生四烯酸代谢物(二十烷类化合物)和 PAF-乙醚与肾血流动力学和肾小球内的微扰 实验性肾小球肾炎对蛋白质的通透性。 这些目标与肾小球损伤的机制直接相关。 肾小球肾炎，因为他们的目标是探索 是由肾小球内免疫反应物的相互作用触发的 并负责释放促炎介质。这个 要研究的介质是有效的血管活性化合物(前列腺素和 血栓烷)，诱导趋化作用(单羟基脂肪酸和 白三烯)和增加血管通透性(白三烯， PAF-ACETER)。它们在合成过程中的合成特征的鉴定 因此，肾小球肾炎的演变可以允许特定的 为了有益地改变它们的效果而进行的药理操作。 实验方法将采用：1)免疫病理学方法 为了建立三种重要的实验性肾小球肾炎模型： 抗肾小球基底膜病、膜性肾小球肾炎和 血清病肾小球肾炎。2)生化方法(色谱学 分析和放射免疫分析)用于表征和定量 肾小球前列腺素、血栓烷、单羟基二十碳四烯酸 酸、白三烯和PAF-乙醚。3)生理学方法(整体 肾清除和尿蛋白分析)以确定插管的特征 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通透性。据预计， 从拟议研究中获得的信息将提供新的见解 探讨肾小球肾炎的病理生理和病理生化。

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.