Li J X, Oliver J R, Lu C Y, Philips J B
Department of Pediatrics, University of Alabama at Birmingham 35233-7335, USA.
Am J Med Sci. 1995 Sep;310(3):103-10. doi: 10.1097/00000441-199531030-00004.
The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.
内毒素诱导的急性血流动力学紊乱和低氧血症的早期阶段由多种因素介导，包括类花生酸和肿瘤坏死因子-α（TNFα）。血栓素A2是与内毒素血症相关的早期肺动脉高压的主要介质，但在内毒素血症持续期间观察到的长期血流动力学紊乱的潜在机制尚不清楚。作者使用长期植入仪器的幼猪模型来确定几种类花生酸和TNFα在长期内毒素诱导的肺动脉高压和其他心血管紊乱中的作用。动物每小时静脉注射40微克/千克内毒素，持续30分钟，然后每小时注射20微克/千克。在所有动物中，内毒素输注期间均出现持续性肺动脉高压、心输出量降低和低氧血症。内毒素输注3小时后，以30至60分钟的间隔静脉注射1毫克/千克达美格雷（一种血栓素A2合成抑制剂）、5毫克/千克去甲二氢愈创木酸（一种5-脂氧合酶抑制剂）和20毫克/千克己酮可可碱（一种TNFα抑制剂），注射顺序随机。达美格雷和己酮可可碱降低了肺动脉压和阻力，并提高了动脉血氧张力。己酮可可碱注射后心输出量显著增加。尽管持续输注内毒素，这些血流动力学效应仍持续30至60分钟。达美格雷和己酮可可碱治疗后，血浆中血栓素B2和TNFα的浓度分别恢复到内毒素注射前的基线值。给予去甲二氢愈创木酸后未观察到有益效果。基于这些结果，血栓素A2和TNFα，而非5-脂氧合酶产物，在幼猪长期内毒素诱导的肺动脉高压和低氧血症中起积极作用。联合阻断血栓素A2和TNFα在临床上可能对治疗新生儿晚期败血症有用。
