Redl H, Schlag G, Bahrami S, Kargl R, Hartter W, Woloszczuk W, Davies J
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.
J Lab Clin Med. 1994 Dec;124(6):796-801.
Big-endothelin (big-ET) is one of the endothelium-derived vasoactive substances that plays an important role in regulating the vascular tone. Because the role of this agent in bacteremia remains unknown, we investigated whether bacteremia induces the release of big-ET in a subhuman primate model and whether tumor necrosis factor (TNF) is an important mediator of big-ET release. To study this, we infused 8 male baboons (17 to 19 kg body weight) intravenously for 2 hours with Escherichia coli (5 x 10(8) CFU/kg) and observed them for 72 hours. Plasma was obtained at various intervals and assayed for big-ET by using immunoassay. Four bacteremic animals given vehicle only showed a peak big-ET plasma concentration of 15.1 +/- 4.6 fmol/ml at 10 hours, as compared with a baseline concentration of 0.9 +/- 0.5 fmol/ml. Administration of anti-TNF monoclonal antibodies (CB6, 15 mg/kg) 2 hours before E. coli infusion in additional animals prevented the rise in plasma TNF levels (5.7 +/- 2.5 ng/ml versus nondetectable) and significantly (p < 0.01) attenuated the release of big-ET. Hemodynamic measurements revealed the typical pattern of sepsis, with generally more stable circulatory conditions in the anti-TNF-treated animals. Moreover, the mortality rate decreased from 100% to 0% with anti-TNF treatment. These studies, therefore, lead us to conclude that TNF, directly or indirectly through another mediator, plays an important role in the endothelin production/release during bacteremia and that neutralization of circulating TNF appears to be beneficial for improving the survival after bacteremia.
大内皮素（big-ET）是内皮源性血管活性物质之一，在调节血管张力方面发挥着重要作用。由于该物质在菌血症中的作用尚不清楚，我们研究了在非人灵长类动物模型中菌血症是否会诱导大内皮素的释放，以及肿瘤坏死因子（TNF）是否是大内皮素释放的重要介质。为了研究这一点，我们给8只雄性狒狒（体重17至19千克）静脉输注大肠杆菌（5×10⁸CFU/千克），持续2小时，并观察72小时。在不同时间间隔采集血浆，采用免疫分析法检测大内皮素。仅给予赋形剂的4只菌血症动物在10小时时血浆大内皮素浓度峰值为15.1±4.6 fmol/ml，而基线浓度为0.9±0.5 fmol/ml。在另外的动物中，在输注大肠杆菌前2小时给予抗TNF单克隆抗体（CB6，15毫克/千克）可防止血浆TNF水平升高（5.7±2.5纳克/毫升对检测不到），并显著（p<0.01）减弱大内皮素的释放。血流动力学测量显示出典型的脓毒症模式，抗TNF治疗的动物循环状况总体上更稳定。此外，抗TNF治疗使死亡率从100%降至0%。因此，这些研究使我们得出结论，TNF直接或通过另一种介质间接在菌血症期间内皮素的产生/释放中起重要作用，中和循环中的TNF似乎有利于提高菌血症后的生存率。
