VASOACTIVE LIPOXYGENASE PRODUCTS IN GLOMERULAR INJURY

肾小球疾病是人类肾功能衰竭的主要原因。为 正因为如此，肾小球损伤的介质一直是 广泛研究的目标。角色的审视 血管活性多肽，儿茶酚胺，补体级联， 哈格曼因子相关系统，氧气代谢产物， 环氧合酶产物和其他损伤介质已导致 认识到肾小球滤过性损伤和 渗透选择性函数是高度复杂的最终结果 这些不同系统之间的相互作用。尽管有很多 关于每个调解人的贡献的争议 在涉及的问题上，人们对 中性粒细胞和巨噬细胞/单核细胞 起源于肾小球功能障碍的始发和持续。这 这一发现激起了人们对生物活动的兴趣 在这些细胞激活过程中释放的化合物，包括 花生四烯酸的环氧合酶和脂氧合酶(LO)产物 酸。拟议研究的目的是试图给出一个定义 花生四烯酸LO产物在介导细胞凋亡中的作用 肾小球血流灌注、滤过和 在选定的、临床相关的情况下看到的渗透选择性功能 实验性肾小球损伤模型。实验性的 方法包括：(1)通过肾小球检查 微穿刺术和葡聚糖清除技术，肾小球 外源性给予硫多肽白三烯的反应 (LTC4、D4和E4)和15-LO产物脂氧素A和B(2) 明确这些化合物在调节肾小球中的作用 肾毒性血清功能障碍与内毒素诱导 肾小球损伤，通过测量其内源性 它们的发生速率及其生理选择性拮抗 行为。(3)评估肾小球细胞的能力 在适当的情况下产生这些化合物的亚群 刺激。肾小球内存在LO活动， 离体肾小球LT受体的鉴定 我们和其他人展示LO产品的强大影响 生理和病理状态下肾小球和系膜细胞功能的研究 病理生理条件，使他们的调查 肾小球效应可能会带来回报。

Glomerular disease is a major cause of renal failure in man. For this reason, the mediators of glomerular injury have been the target of extensive research. Examination of the roles of vasoactive peptides, catecholamines, the complement cascade, Hageman factor-related systems, oxygen metabolites, cyclooxygenase products, and other mediators of injury has led to the realization that impairment of glomerular filtration and permselectivity function is the end-result of highly complex interactions among these various systems. Despite much controversy regarding the contribution of each of the mediators involved, consensus exists as to the central role of the polymorphonuclear leukocyte and cells of macrophage/monocyte origin in initiating and perpetuating glomerular dysfunction. This finding has generated interest in the biologically active compounds released during the activation of these cells, including the cyclooxygenase and lipoxygenase (LO) products of arachidonic acid. The aim of the proposed studies is to attempt a definition of roles of LO products of arachidonic acid in mediating the impairment of glomerular perfusion, filtration, and permselectivity functions seen in selected, clinically relevant models of experimental glomerular injury. The experimental approach involves: (1) Examining, through glomerular micropuncture and dextran clearance techniques, the glomerular responses to exogenously administered sulfidopeptide leukotrienes (LTC4, D4, and E4) and the 15-LO products, lipoxins A and B. (2) Defining the roles of these compounds in mediating glomerular dysfunction in nephrotoxic serum and endotoxin-induced glomerular injury, through measurement of their endogenous generation rates and selective antagonism of their physiologic actions. (3) Assessing the capacity of glomerular cell subpopulations to generate these compounds upon appropriate stimulation. The presence of LO activity within the glomerulus, the identification of LT receptors on isolated glomeruli, and the demonstration by us and others of potent effects of LO products on glomerular and mesangial cell function under physiologic and pathophysiologic conditions, render the investigation of their glomerular effects potentially rewarding.