NOVEL INFLAMMATORY MEDIATORS IN GLOMERULONEPHRITIS

拟议的工作旨在：1）采用体外生物化学研究 为了研究血管活性物质的合成， （前列腺素，血栓烷）和促炎性 （羟基二十碳四烯酸、白三烯和烷基醚 甘油磷脂）介质的培养大鼠肾小球细胞 响应于确定免疫反应物和2）体内应用 生理学研究（肾清除率和显微穿刺），以评价 药物抑制合成的作用，或 药理学拮抗作用的上述 介质对肾血流动力学扰动发生以下 诱导大鼠实验性肾小球肾炎。 的 体外测试的免疫反应物是：抗体 针对肾小球上皮细胞中存在的Heymann抗原， 抗大鼠胸腺细胞抗体，与Thy-1样 存在于大鼠系膜细胞上的抗原，补体成分， C3 a和C5 a，膜攻击复合物C5 b-9和血小板 衍生阳离子蛋白、血小板因子-4和血小板衍生 生长因子当这些反应物沉积在肾小球时 在肾小球免疫损伤的演变过程中，它们可以诱导 血流动力学紊乱或介导肾小球细胞损伤。 此外，当它们在体外与肾小球细胞结合时， 发生生物合成活性和介体合成。 而 体外研究旨在鉴定肾小球细胞类型 能够响应这些介质合成 反应物/激动剂，生理学研究的关键目的 是为了证明或反驳体内介质合成是 与三种模型中的肾血流动力学扰动相关， 实验性抗体诱导的肾小球肾炎（GN）：肾毒性 血清GN或抗GBM疾病、被动Heymann肾炎和抗- 胸腺细胞血清（抗Thy 1抗体）诱导的肾小球病。 在 这些模型很好地定义了肾小球血流动力学扰动 发生在抗体给药后。 此外，肾小球 类二十烷酸和烷基醚磷脂的合成得到增强。 因此，拟议的体内和体外研究补充了 彼此，预计所积累的信息将 提供了生化和生理事件 肾小球免疫损伤的发生是相互关联的， 为具体干预提供基础。

The proposed work aims to: 1) employ in vitro biochemical studies in order to investigate the synthesis of vasoactive (prostaglandins, thromboxanes) and proinflammatory (hydroxyeicosatetraenoic acids, leukotrienes, and alkyl ether glycerophospholipids) mediators by cultured rat glomerular cells in response to defined immunologic reactants and 2) employ in vivo physiologic studies (renal clearance and micropuncture) to evaluate the effects of pharmacologic inhibition of the synthesis or pharmacologic antagonism of the action of the aforementioned mediators on renal hemodynamic perturbations occurring following induction of experimental glomerulonephritis in the rat. The immunologic reactants to be tested in vitro are: antibodies against the Heymann antigen present in glomerular epithelial cells, antibody against rat thymocytes and reactive with Thy-l-like antigens present on rat mesangial cells, the complement components C3a and C5a, the membrane attack complex C5b-9 and the platelet derived cationic proteins, platelet factor-4 and platelet derived growth factor. When these reactants are deposited in glomeruli during the evolution of glomerular immune injury, they can induce hemodynamic perturbations or mediate glomerular cell injury. Moreover, when they bind to glomerular cells in vitro, an enhanced biosynthetic activity and mediator synthesis occurs. Whereas the in vitro studies aim to identify the glomerular cell type(s) capable of mediator synthesis in response to these reactants/agonists, the key purpose of the physiological studies is to prove or disprove that mediator synthesis in vivo is associated with renal hemodynamic perturbations in three models of experimental antibody induced glomerulonephritis (GN): nephrotoxic serum GN or anti-GBM disease, passive Heymann nephritis and anti- thymocyte serum (anti-thy 1 antibody) induced glomerulopathy. In these models well defined glomerular hemodynamic perturbations occur following antibody administration. Moreover, the glomerular synthesis of eicosanoids and alkyl ether phospholipids is enhanced. The proposed in vivo and in vitro studies, therefore, complement each other and it is anticipated that the information accrued will provide evidence that biochemical and physiological events occurring in glomerular immune injury are interrelated and will provide the groundwork for specific intervention.