Yared A, Albrightson-Winslow C, Griswold D, Takahashi K, Fogo A, Badr K F
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232-2372.
J Am Soc Nephrol. 1991 Jul;2(1):45-56. doi: 10.1681/ASN.V2145.
Leukotriene B4 (LTB4) is the major 5-lipoxgenase product released during early experimental glomerulonephritis. To test its functional relevance, its actions in the normal rat kidney and its influence on renal function in the heterologous phase of mild nephrotoxic serum-induced glomerular injury were examined. Intrarenal administration of leukotriene B4 resulted in mild vasorelaxant and natriuretic responses which were shared by 12(R)-hydroxyeicosatetraenoic acid but not 12(S)-leukotriene B4 or 12(S)-hydroxyeicosatetraenoic acid, suggesting activation of a common recognition site with a requirement for 12(R) stereochemistry. The polymorphonuclear cell-specific activator, N-formyl-Met-Leu-Phe, stimulated leukotriene B4 production from isolated perfused kidneys harvested from nephrotoxic serum-treated rats to a significantly greater degree than from control animals treated with nonimmune rabbit serum. The renal production of leukotriene B4 correlated directly and strongly (r = 0.79, P less than 0.01) with renal myeloperoxidase activity, suggesting interdependence of leukotriene B4 generation and polymorphonuclear cell infiltration. In vivo, intrarenal administration of leukotriene B4 to rats with mild nephrotoxic serum-induced injury was associated with an increase in polymorphonuclear cell infiltration, reduction in renal plasma flow rate, and marked exacerbation of the fall in glomerular filtration rate, the latter correlating strongly with the number of infiltrating polymorphonuclear cells/glomerulus, whereas inhibition of 5-lipoxygenase led to preservation of glomerular filtration rate and abrogation of proteinuria. Thus, although devoid of vasoconstrictor actions in the normal kidney, increased intrarenal generation of leukotriene B4 during early nephrotoxic serum-induced glomerular injury amplifies leukocyte-dependent reductions in glomerular perfusion and filtration rates, likely due to enhancement of polymorphonuclear cell recruitment/activation.
白三烯B4（LTB4）是早期实验性肾小球肾炎期间释放的主要5-脂氧合酶产物。为了测试其功能相关性，研究了其在正常大鼠肾脏中的作用及其对轻度肾毒性血清诱导的肾小球损伤异源期肾功能的影响。肾内给予白三烯B4会导致轻度血管舒张和利钠反应，12（R）-羟基二十碳四烯酸也有此反应，但12（S）-白三烯B4或12（S）-羟基二十碳四烯酸则无此反应，这表明存在一个共同识别位点的激活，且需要12（R）立体化学结构。多形核细胞特异性激活剂N-甲酰基-Met-Leu-Phe刺激肾毒性血清处理大鼠分离的灌注肾脏产生白三烯B4的程度，明显高于用非免疫兔血清处理的对照动物。白三烯B4的肾脏生成与肾髓过氧化物酶活性直接且强烈相关（r = 0.79，P < 0.01），表明白三烯B4生成与多形核细胞浸润相互依存。在体内，对轻度肾毒性血清诱导损伤的大鼠肾内给予白三烯B4与多形核细胞浸润增加、肾血浆流速降低以及肾小球滤过率下降显著加剧有关，后者与浸润的多形核细胞/肾小球数量密切相关，而抑制5-脂氧合酶则可使肾小球滤过率得以保留并消除蛋白尿。因此，尽管白三烯B4在正常肾脏中没有血管收缩作用，但在早期肾毒性血清诱导的肾小球损伤期间，肾内白三烯B4生成增加会放大白细胞依赖性的肾小球灌注和滤过率降低，这可能是由于多形核细胞募集/激活增强所致。
