THE EFFECTS OF RECOMBINANT HUMAN THROMBOMODULIN ON ENDOTOXIN-INDUCED MULTIPLE-SYSTEM ORGAN FAILURE IN RATS

Activation of the coagulation system is postulated to play an importan t role in the pathogenesis of endotoxin-induced tissue injury. Thrombo modulin (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 thro mbin to TM activates the endogenous anticoagulant pathway through prot ein C. We studied the effect of recombinant human TM (rh-TM) on endoto xin-induced multiple-system organ failure (MSOF) in Sprague-Dawley rat s 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 experi ments. Experiment 1: 24-h survival study. Experiment 2: multiple-syste m organ microthrombi study in which I-125-human fibrinogen was injecte d 30 min prior to an endotoxin or saline injection and tissue microthr ombi formation was assessed by measuring the percentage of organ radio activity (lung, heart, liver, and kidney) against total injected radio activity (microthrombi index; MI) 2.25 h after an endotoxin or saline injection. Experiment 3: endotoxin-induced MSOF study in which I-125-r at albumin was injected 5 h after an endotoxin or saline injection, an d endotoxin-induced organ injury was evaluated by measuring tissue wet -to-dry ratios (W/D) and tissue-to-plasma I-125-rat albumin concentrat ion ratios (T/P) 8 h after the endotoxin or saline injection. Blood co ntamination in samples from Experiments 2 and 3 was corrected by using I-131-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 inj ected 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.