Lianos E A, Andres G A, Dunn M J
J Clin Invest. 1983 Oct;72(4):1439-48. doi: 10.1172/JCI111100.
Glomerular arachidonate cyclooxygenation by isolated rat glomeruli was assessed in vitro in antiglomerular basement membrane (anti-GBM) antibody-induced glomerulonephritis by radioimmunoassay for prostaglandins (PG) and thromboxane. After a single intravenous injection of rabbit anti-rat GBM serum, we observed enhancement of glomerular thromboxane B2 (TxB2) synthesis as early as 2 to 3 h with smaller increments in PGF2 alpha, PGE2 and 6-keto-PGF1 alpha synthetic rates. On day 2 of the disease, the glomerular synthesis of TxB2 and, to a lesser extent, PGF2 alpha and PGE2 remained enhanced, whereas on days 8, 11, and 14, TxB2 was the only prostanoid synthesized at increased rates. Glomerular TxB2 synthesis correlated with the presacrifice 24-h protein excretion. 60 min after intravenous infusion of anti-GMB serum, glomerular filtration rate (GFR) decreased (0.66 +/- 0.04 to 0.44 +/- 0.03 ml/min per 100 g, P less than 0.05), without a significant change in renal plasma flow (RPF): 1.97 +/- 0.23 to 1.80 +/- 0.23 ml/min per 100 g) and without a change in glomerular PG synthetic rates. At 2 h, GFR and RPF reached a nadir (0.25 +/- 0.04 and 1.3 +/- 0.1 ml/min per 100 g, respectively) coinciding with a fivefold increment in glomerular TxB2. By 3 h GFR and RPF partially recovered to 0.43 +/- 0.07 and 1.77 +/- 0.20 ml/min per 100 g, respectively, P less than 0.05, despite further increments in TxB2 synthesis. This recovery of GFR and RPF coincided with increments in vasodilatory PG, (PGE2 and PGI2). The thromboxane synthetase inhibitor OKY-1581 markedly inhibited platelet and glomerular TxB2 synthesis and preserved GFR at 1, 2, and 3 h. Another thromboxane synthetase inhibitor, UK-38485, also completely inhibited platelet and glomerular TxB2 synthesis and prevented decrements of GFR at 2 and 3 h. A cyclooxygenase inhibitor, ibuprofen, inhibited platelet TxB2 and PGE2 synthesis and significantly reduced glomerular PGE2 but not TxB2 synthesis. In the ibuprofen-treated rats, the partial recoveries of GFR and RPF at 3 h were attenuated. The in vitro glomerular TxB2 synthesis correlated inversely with the presacrifice GFR and filtration fraction. These observations indicate that in anti-GBM nephritis there is enhanced synthesis of TxA2 and PG in the glomerulus that mediate changes in renal hemodynamics.
通过前列腺素（PG）和血栓素的放射免疫测定法，在体外评估了抗肾小球基底膜（anti-GBM）抗体诱导的肾小球肾炎中分离的大鼠肾小球的花生四烯酸环氧化作用。单次静脉注射兔抗大鼠GBM血清后，我们最早在2至3小时观察到肾小球血栓素B2（TxB2）合成增强，而PGF2α、PGE2和6-酮-PGF1α合成率的增加较小。在疾病的第2天，TxB2以及程度较轻的PGF2α和PGE2的肾小球合成仍然增强，而在第8、11和14天，TxB2是唯一合成速率增加的前列腺素。肾小球TxB2合成与处死前24小时的蛋白尿排泄相关。静脉输注抗GBM血清60分钟后，肾小球滤过率（GFR）下降（从每100克0.66±0.04降至0.44±0.03毫升/分钟，P<0.05），肾血浆流量（RPF）无显著变化（从每100克1.97±0.23降至1.80±0.23毫升/分钟），肾小球PG合成率也无变化。在2小时时，GFR和RPF达到最低点（分别为每100克0.25±0.04和1.3±0.1毫升/分钟），同时肾小球TxB2增加了五倍。到3小时时，GFR和RPF部分恢复到每100克分别为0.43±0.07和1.77±0.20毫升/分钟，P<0.05，尽管TxB2合成进一步增加。GFR和RPF的这种恢复与血管舒张性PG（PGE2和PGI2）的增加同时发生。血栓素合成酶抑制剂OKY-1581显著抑制血小板和肾小球TxB2合成，并在1、2和3小时时维持GFR。另一种血栓素合成酶抑制剂UK-38485也完全抑制血小板和肾小球TxB2合成，并防止2和3小时时GFR下降。环氧化酶抑制剂布洛芬抑制血小板TxB2和PGE2合成，并显著降低肾小球PGE2但不降低TxB2合成。在布洛芬治疗的大鼠中，3小时时GFR和RPF的部分恢复减弱。体外肾小球TxB2合成与处死前GFR和滤过分数呈负相关。这些观察结果表明，在抗GBM肾炎中，肾小球中TxA2和PG的合成增强，介导了肾血流动力学的变化。
