NOVEL INFLAMMATORY MEDIATORS IN GLOMERULONEPHRITIS

这项拟议的工作旨在：1)利用体外生化研究 为了研究血管活性物质的合成 (前列腺素、血栓烷)和前炎性 (羟基二十碳四烯酸、白三烯和烷基醚) (甘油磷脂)介体在培养大鼠肾小球细胞中的作用 响应于定义的免疫反应物和2)在体内使用 生理学检查(肾清除和微穿刺术)以评估 药物抑制细胞合成的作用研究进展 上述作用的药理拮抗作用 肾血流动力学紊乱的介体 大鼠实验性肾小球肾炎的诱导。这个 体外检测的免疫反应物有：抗体 针对肾小球上皮细胞中存在的海曼抗原， 抗大鼠胸腺细胞抗体及其与Thy-L样蛋白的反应 大鼠肾小球系膜细胞上存在的抗原，补体成分 补体C3a和C5a、膜攻击复合体C5b-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中时 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，增强的 生物合成活性和介体合成发生。鉴于 体外研究旨在鉴定肾小球细胞类型(S) 能够对这些反应进行介体合成 反应物/激动剂，生理学研究的主要目的 是证明或反驳体内的介质合成是 与肾血流动力学紊乱相关的三种模型 实验性抗体诱导的肾小球肾炎：肾毒性 血清GN或抗-GBM病、被动型Heymann肾炎和抗-GBM 胸腺细胞血清(抗THY-1抗体)诱导的肾小球病变。在……里面 这些模型很好地定义了肾小球血流动力学扰动 在注射抗体后发生。此外，肾小球 对二十烷基醚和烷基醚磷脂的合成进行了改进。 因此，拟议的体内和体外研究补充了 并预计所获得的信息将 提供生化和生理事件的证据 发生在肾小球的免疫损伤是相互关联的 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.