The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis
The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis
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DOI：
10.1097/00003246-200101000-00003
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发表时间：
2001-01-01
影响因子：
8.8
通讯作者：
Creasey, AA
中科院分区：
文献类型：
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作者：
Opal, SM;Palardy, JE;Creasey, AA
目的：研究重组人组织因子途径抑制物(RhTFPI)在超抗原诱导的小鼠休克模型和盲肠结扎穿孔(CLP)腹膜炎模型中的作用。设计：前瞻性、随机、实验研究。地点：实验动物实验室。研究对象：80只BALB/c小鼠作为超抗原模型，56只BALB/c小鼠作为CLP模型。干预：在超抗原诱导的休克模型中，每12小时皮下注射重组人组织因子途径抑制物350 mg/kg(n=30)或生理盐水对照组(n=30)。10杯静脉注射)和亚致死剂量的大肠杆菌0111：B4脂多糖(脂多糖；75杯ip)。对照组：SEB组(n=10)和LPS组(n=10)。在CLP模型中，用21号针(n=9)或23号针(n=14)每隔8小时给药一次，持续48小时。另设假手术对照组(n=10)。测量和主要结果：SEB组和脂多糖对照组死亡率为0。生理盐水对照组动物死亡率为%(19/30)，而重组人肿瘤坏死因子治疗组动物死亡率为20%(6/30；p<；0.01)。在CLP实验中，大口径(21口径)针刺后，rhTFPI治疗组大鼠的IL-6水平(61.8+/-41pg/mLvs.285+/-63pg/mLp<；0.05)显著低于对照组，但肿瘤坏死因子-α和干扰素-γ水平无明显差异。小口径穿刺组在CLP术后7天死亡率显著提高(23针：21.4%，对照组：71.4%，p<；0.01)。重组人肿瘤坏死因子抑制物治疗后血浆内毒素、白介素6、干扰素和肿瘤坏死因子-α水平无明显变化，但腹腔液中内毒素(p=0.006)和干扰素-γ(p=.001)水平显著降低。结论：组织因子途径抑制物显著提高超抗原性休克和多菌腹内感染模型的死亡率，支持其在脓毒症治疗的临床试验中的潜在应用。
Objectives: To study recombinant human tissue factor pathway inhibitor (rhTFPI) in a superantigen-induced shock model and in a cecal ligation and puncture (CLP) model of peritonitis in mice.Design: Prospective, randomized, experimental study.Setting: An experimental animal research laboratory.Subjects: Eighty BALB/c mice for the superantigen model, and 56 BALB/c mice for the CLP model.Interventions: In the superantigen-induced shock model, animals received rhTFPI (350 mg/kg) subcutaneously every 12 hrs (n = 30) or saline control (n = 30) for 60 hrs after staphylococcal enterotoxin B (SEB; 10 mug iv) and a sublethal dose of E. coli 0111:B4 lipopolysaccharide (LPS; 75 mug ip). Control groups received SEB alone (n = 10) and LPS alone (n = 10). In the CLP model, rhTFPI or saline was given every 8 hrs for 48 hrs by using a 21-gauge needle (n = 9) or 23-gauge needle (n = 14) for CLP. A sham surgery control group (n = 10) was also included.Measurements and Main Results: There was 0% mortality in the SEB and LPS control groups. The mortality rate was 64% in the saline control group that received both SEB and LPS (19 of 30), whereas the rhTFPI-treated animals had a mortality rate of 20% (6 of 30; p < .01). The rhTFPI-treated group had significantly lower interleukin-6 levels (61.8 +/- 41 pg/mL vs. 285 +/- 63 pg/mL; p < .05) than the control group but no differences in tumor necrosis factor-alpha or interferon-gamma levels.In the CLP experiment, rhTFPI-treated animals did not have any survival advantage over the control group after the large-bore (21-gauge) needle puncture. The rhTFPI group had significantly improved 7-day mortality rate after CLP with the small-bore needle (23-gauge; 21.4% [rhTFPI] vs. 71.4% [control], p < .01). Plasma LPS, interleukin-6, interferon-, and tumor necrosis factor-alpha levels were unchanged by rhTFPI treatment, but significantly reduced LPS (p = .006) and IFN gamma (p = .001) levels were found in the peritoneal fluid.Conclusions:Tissue factor pathway inhibitor significantly improves the mortality rate in models of superantigen-induced shock and polymicrobial intra-abdominal infection, supporting its potential use in clinical trials for septic shack.