Efficacy of a recombinant endotoxin neutralizing protein in rabbits with Escherichia coli sepsis.

Circulatory shock Pub Date : 1994-02-01
R Saladino, C Garcia, C Thompson, B Hammer, J Parsonnet, T Novitsky, G Siber, G Fleisher
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Abstract

Gram-negative bacterial sepsis is associated with endotoxemia and a high mortality rate. In previous studies, we demonstrated the therapeutic benefit of an anti-lipopolysaccharide factor isolated from amebocytes of Limulus polyphemus, and of a recombinant version of this protein, termed endotoxin neutralizing protein (ENP), in rabbits challenged with purified lipopolysaccharides. To assess the benefit of ENP in treating a live bacterial infection, we established a rabbit model of Escherichia coli (E. coli) peritonitis and bacteremia with high mortality despite gentamicin treatment. Twenty-four pairs of New Zealand white rabbits were challenged intraperitoneally (IP) with E. coli O18ac K1 in 5% porcine mucin (mean bacteria per dose = 2.5 x 10(8)). The animals were treated with intravenous (i.v.) gentamicin (2.5 mg/kg), and with either ENP (5 mg/kg) or saline i.v. at 1 hr after E. coli challenge. All rabbits were bacteremic 1 hr after challenge (geometric mean 4.1 +/- 1.2 x 10(4) cfu/mL). Peak geometric mean serum endotoxin (2.62 v 10.54 EU/mL, P = .013) and tumor necrosis factor (TNF) (2540 v 6438 TNF units/mL, P = .046) concentrations were lower in ENP-treated animals as compared to control animals. Seven of 24 animals treated with ENP survived 24 hr compared with 4 of 24 controls (Kaplan-Meier analysis, P = .19). However, in the subgroup of 13 paired animals in whom bacteremia was eliminated by gentamicin treatment, 5 of 13 ENP-treated animals survived 24 hr, compared with 1 of 13 controls (Kaplan-Meier analysis, P = .032).(ABSTRACT TRUNCATED AT 250 WORDS)

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重组内毒素中和蛋白对家兔大肠杆菌败血症的治疗效果。
革兰氏阴性细菌性败血症与内毒素血症和高死亡率有关。在之前的研究中,我们证明了从多足鲎变形细胞中分离的抗脂多糖因子,以及该蛋白的重组版本,称为内毒素中和蛋白(ENP),在纯化脂多糖刺激的兔子中具有治疗作用。为了评估ENP治疗活细菌感染的益处,我们建立了一种大肠杆菌腹膜炎和菌血症的兔子模型,尽管庆大霉素治疗,但死亡率很高。24对新西兰大白兔腹腔注射含5%猪黏液的大肠杆菌O18ac K1(每剂量平均细菌数= 2.5 × 10(8))。小鼠在大肠杆菌攻毒后1小时静脉注射庆大霉素(2.5 mg/kg)和ENP (5 mg/kg)或生理盐水。所有家兔在攻毒后1小时呈菌血症(几何平均值4.1 +/- 1.2 × 10(4) cfu/mL)。enp处理动物的峰值几何平均血清内毒素(2.62 v 10.54 EU/mL, P = 0.013)和肿瘤坏死因子(TNF) (2540 v 6438 TNF单位/mL, P = 0.046)浓度低于对照动物。24只接受ENP治疗的动物中有7只存活了24小时,而24只对照组中有4只存活了24小时(Kaplan-Meier分析,P = .19)。然而,在庆大霉素治疗消除菌血症的13只配对动物亚组中,13只接受enp治疗的动物中有5只存活了24小时,而13只对照组中有1只存活了24小时(Kaplan-Meier分析,P = 0.032)。(摘要删节250字)
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