Opal S M, Palardy J E, Parejo N A, Creasey A A
Brown University School of Medicine, Providence, RI, USA.
Crit Care Med. 2001 Jan;29(1):13-7. doi: 10.1097/00003246-200101000-00003.
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.
Prospective, randomized, experimental study.
An experimental animal research laboratory.
Eighty BALB/c mice for the superantigen model, and 56 BALB/c mice for the CLP model.
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 microg iv) and a sublethal dose of E. coli 0111:B4 lipopolysaccharide (LPS; 75 microg 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.
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-gamma, and tumor necrosis factor-alpha levels were unchanged by rhTFPI treatment, but significantly reduced LPS (p = .006) and IFNgamma (p = .001) levels were found in the peritoneal fluid.
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 shock.
在小鼠超抗原诱导的休克模型和盲肠结扎穿孔（CLP）腹膜炎模型中研究重组人组织因子途径抑制剂（rhTFPI）。
前瞻性、随机、实验性研究。
实验动物研究实验室。
用于超抗原模型的80只BALB/c小鼠，以及用于CLP模型的56只BALB/c小鼠。
在超抗原诱导的休克模型中，动物在静脉注射金黄色葡萄球菌肠毒素B（SEB；10微克）和亚致死剂量的大肠杆菌0111：B4脂多糖（LPS；75微克腹腔注射）后，每12小时皮下注射rhTFPI（350毫克/千克）（n = 30）或生理盐水对照（n = 30），持续60小时。对照组分别单独接受SEB（n = 10）和单独接受LPS（n = 10）。在CLP模型中，使用21号针（n = 9）或23号针（n = 14）进行CLP，每8小时给予rhTFPI或生理盐水，持续48小时。还包括假手术对照组（n = 10）。
SEB和LPS对照组的死亡率为0%。接受SEB和LPS的生理盐水对照组的死亡率为64%（30只中的19只），而接受rhTFPI治疗的动物死亡率为20%（30只中的6只；p <.01）。rhTFPI治疗组的白细胞介素-6水平（61.8±41皮克/毫升对285±63皮克/毫升；p <.05）显著低于对照组，但肿瘤坏死因子-α或干扰素-γ水平无差异。在CLP实验中，大口径（21号）针穿刺后，rhTFPI治疗的动物与对照组相比没有生存优势。CLP后，小口径针（23号）穿刺，rhTFPI组的7天死亡率显著改善（21.4%[rhTFPI]对71.4%[对照组]，p <.01）。rhTFPI治疗对血浆LPS、白细胞介素-6、干扰素-γ和肿瘤坏死因子-α水平无影响，但在腹腔液中发现LPS（p =.006）和IFNγ（p =.001）水平显著降低。
组织因子途径抑制剂显著提高了超抗原诱导的休克模型和多微生物腹腔感染模型中的死亡率，支持其在脓毒症休克临床试验中的潜在应用。
