Coggeshall J W, Christman B W, Lefferts P L, Serafin W E, Blair I A, Butterfield M J, Snapper J R
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
J Appl Physiol (1985). 1988 Sep;65(3):1351-9. doi: 10.1152/jappl.1988.65.3.1351.
We studied the effects of a 5-lipoxygenase inhibitor, L-651,192, on the pulmonary dysfunction caused by endotoxemia in chronically instrumented unanesthetized sheep. The efficacy and selectivity of L-651,392 were tested by measuring in vivo production of leukotriene B4 (LTB4) and cyclooxygenase products of arachidonic acid after endotoxemia before and after pretreatment with L-651,392 and ex vivo from granulocytes and whole blood stimulated with calcium ionophore from sheep before and 24 h after pretreatment with L-651,392. A novel assay for LTB4 by high-performance liquid chromatography/gas chromatography/mass spectrometry techniques was developed as a measure of 5-lipoxygenase metabolism of arachidonic acid. L-651,392 proved to be an effective in vivo 5-lipoxygenase inhibitor in sheep. L-651,392 blocked the increase in LTB4 observed in lung lymph after endotoxemia in vivo in sheep as well as inhibited by 80% the ex vivo production of LTB4 by granulocytes removed from sheep treated 24 h earlier with L-651,392. Although L-651,392 blocked the increase in cyclooxygenase products of arachidonic acid observed in lung lymph after endotoxemia in vivo in sheep, the drug probably did not function directly as a cyclooxygenase inhibitor. L-651,392 did not attenuate the ex vivo production of thromboxane B2 by whole blood from sheep treated 24 h earlier with the drug. L-651,392 attenuated the alterations in pulmonary hemodynamics, lung mechanics, oxygenation, and lung fluid and solute exchange observed after endotoxemia in sheep. We speculate that 5-lipoxygenase products are a major stimulus for cyclooxygenase metabolism of arachidonic acid after endotoxemia in sheep.
我们研究了5-脂氧合酶抑制剂L-651,192对长期植入仪器的未麻醉绵羊内毒素血症所致肺功能障碍的影响。通过测量内毒素血症前后用L-651,392预处理后体内白三烯B4（LTB4）的产生以及花生四烯酸的环氧化酶产物，以及在用L-651,392预处理前和预处理后24小时用钙离子载体刺激的绵羊粒细胞和全血中离体产生的花生四烯酸的环氧化酶产物，来测试L-651,392的疗效和选择性。开发了一种通过高效液相色谱/气相色谱/质谱技术测定LTB4的新方法，作为花生四烯酸5-脂氧合酶代谢的指标。结果证明L-651,392在绵羊体内是一种有效的5-脂氧合酶抑制剂。L-651,392可阻止绵羊体内内毒素血症后肺淋巴中LTB4的增加，同时将24小时前用L-651,392处理的绵羊的粒细胞离体产生LTB4的量抑制80%。尽管L-651,392可阻止绵羊体内内毒素血症后肺淋巴中观察到的花生四烯酸环氧化酶产物的增加，但该药物可能并非直接作为环氧化酶抑制剂发挥作用。L-651,392不能减弱24小时前用该药物处理的绵羊全血离体产生血栓素B2的量。L-651,392可减轻绵羊内毒素血症后观察到的肺血流动力学、肺力学、氧合以及肺液体和溶质交换的改变。我们推测，5-脂氧合酶产物是绵羊内毒素血症后花生四烯酸环氧化酶代谢的主要刺激因素。
