Hasegawa N, Kandra T G, Husari A W, Veiss S, Hart W T, Hedgpeth J, Wydro R, Raffin T A
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236, USA.
Am J Respir Crit Care Med. 1996 Jun;153(6 Pt 1):1831-7. doi: 10.1164/ajrccm.153.6.8665042.
Activation of the coagulation system is postulated to play an important role in the pathogenesis of endotoxin-induced tissue injury. Thrombomodulin (TM) is an endothelial cell membrane glycoprotein receptor for thrombin. Once bound to TM, thrombin loses its procoagulant activity, which results in decreased clotting. In addition, the binding of thrombin to TM activates the endogenous anticoagulant pathway through protein C. We studied the effect of recombinant human TM (rh-TM) on endotoxin-induced multiple-system organ failure (MSOF) in Sprague-Dawley rats weighing 400 to 450 g: 2 mg/kg of rh-TM was injected (T1/2 = 4.5 h) 30 min prior to intravenous injection of 20 mg/kg of Escherichia coli endotoxin. The study presented here consisted of three separate experiments. Experiment 1: 24-h survival study. Experiment 2: multiple-system organ microthrombi study in which 125I-human fibrinogen was injected 30 min prior to an endotoxin or saline injection and tissue microthrombi formation was assessed by measuring the percentage of organ radioactivity (lung, heart, liver, and kidney) against total injected radioactivity (microthrombi index, MI) 2.25 h after an endotoxin or saline injection. Experiment 3: endotoxin-induced MSOF study in which 125I-rat albumin was injected 5 h after an endotoxin or saline injection, and endotoxin-induced organ injury was evaluated by measuring tissue wet-to-dry ratios (W/D) and tissue-to-plasma 125I-rat albumin concentration ratios (T/P) 8 h after the endotoxin or saline injection. Blood contamination in samples from Experiments 2 and 3 was corrected by using 131I-rat albumin measurements. Pretreatment with rh-TM improved the survival from 12 h through 23 h as compared with that of the endotoxin control group (p < 0.05). However, at 24 h, after essentially all injected rh-TM had been eliminated, there was no difference in survival. Significant reductions in MI, W/D, and T/P in the organs sampled were observed in the rh-TM pretreated groups (p < 0.05). In conclusion, rh-TM improved short-term but not overall survival and decreased MSOF in endotoxemic rats.
凝血系统的激活被认为在内毒素诱导的组织损伤发病机制中起重要作用。血栓调节蛋白（TM）是凝血酶的一种内皮细胞膜糖蛋白受体。一旦与TM结合，凝血酶就会失去其促凝活性，从而导致凝血减少。此外，凝血酶与TM的结合通过蛋白C激活内源性抗凝途径。我们研究了重组人TM（rh-TM）对体重400至450克的Sprague-Dawley大鼠内毒素诱导的多系统器官衰竭（MSOF）的影响：在静脉注射20毫克/千克大肠杆菌内毒素前30分钟注射2毫克/千克的rh-TM（半衰期=4.5小时）。此处呈现的研究由三个独立实验组成。实验1：24小时存活研究。实验2：多系统器官微血栓研究，在内毒素或生理盐水注射前30分钟注射125I-人纤维蛋白原，并在注射内毒素或生理盐水2.25小时后通过测量器官放射性（肺、心脏、肝脏和肾脏）占总注射放射性的百分比（微血栓指数，MI）来评估组织微血栓形成。实验3：内毒素诱导的MSOF研究，在内毒素或生理盐水注射5小时后注射125I-大鼠白蛋白，并在注射内毒素或生理盐水8小时后通过测量组织湿重与干重比（W/D）和组织与血浆125I-大鼠白蛋白浓度比（T/P）来评估内毒素诱导的器官损伤。实验2和3样本中的血液污染通过使用131I-大鼠白蛋白测量进行校正。与内毒素对照组相比，rh-TM预处理从12小时至23小时提高了存活率（p<0.05）。然而，在24小时时，基本上所有注射的rh-TM都已消除后，存活率没有差异。在rh-TM预处理组中观察到所取器官的MI、W/D和T/P显著降低（p<0.05）。总之，rh-TM改善了内毒素血症大鼠的短期但非总体存活率，并降低了MSOF。
