Fiedler V B, Loof I, Sander E, Voehringer V, Galanos C, Fournel M A
Pharma Research Center, Bayer AG, Wuppertal, Federal Republic of Germany.
J Lab Clin Med. 1992 Oct;120(4):574-88.
In a rhesus monkey endotoxin sepsis model established by intravenous administration of 300 mg/kg D-galactosamine and 0.1 microgram/kg lipopolysaccharide from Salmonella abortus equi, hemodynamic, respiratory, metabolic and hematologic variables; levels of blood gases; monkey leukocyte elastase levels, and blood plasma concentrations of tumor necrosis factor--alpha (TNF) were monitored for 6 hours after administration, and again after 24 hours. Thirty minutes after administration of lipopolysaccharide, either 15 mg/kg anti-TNF monoclonal antibody (MoAB; n = 6) or vehicle placebo (saline solution; n = 4) were given intravenously. During this short-term experiment the organ functions were not different between the treatment groups. However, anti-TNF MoAb afforded morphologic protection from heart, lung, liver, and kidney damage after lipopolysaccharide challenge. Coagulation responses (platelet count and levels of fibrinogen, antithrombin III, and thrombin-antithrombin III complex) were smaller in anti-TNF MoAB-treated monkeys. Plasma TNF levels (WEHI cell cytotoxicity assay) reached a peak (350 pg/ml) 60 minutes after lipopolysaccharide administration in vehicle control subjects but no TNF was detected in the anti-TNF MoAB-treated monkeys. All control animals died 67 +/- 30 hours after lipopolysaccharide administration from multiorgan failure. On the contrary, all anti-TNF MoAB-treated animals survived 14 days (p > 0.005 vs placebo group mortality). Thus in short-term monkey experiments our study indicates protection against lipopolysaccharide-induced endotoxin sepsis by anti-TNF MoAB, which may have clinical relevance for the treatment of human septicemia.
通过静脉注射300mg/kg D-半乳糖胺和0.1μg/kg流产马沙门氏菌脂多糖建立恒河猴内毒素血症模型，给药后6小时及24小时后监测血流动力学、呼吸、代谢和血液学变量；血气水平；猴白细胞弹性蛋白酶水平以及肿瘤坏死因子-α（TNF）的血浆浓度。注射脂多糖30分钟后，静脉注射15mg/kg抗TNF单克隆抗体（MoAB；n = 6）或赋形剂安慰剂（盐溶液；n = 4）。在这个短期实验中，各治疗组之间的器官功能没有差异。然而，抗TNF MoAb在脂多糖攻击后为心脏、肺、肝和肾提供了形态学保护。抗TNF MoAb治疗的猴子的凝血反应（血小板计数以及纤维蛋白原、抗凝血酶III和凝血酶-抗凝血酶III复合物水平）较小。在赋形剂对照受试者中，脂多糖给药60分钟后血浆TNF水平（WEHI细胞细胞毒性测定）达到峰值（350pg/ml），但在抗TNF MoAb治疗的猴子中未检测到TNF。所有对照动物在脂多糖给药后67±30小时死于多器官功能衰竭。相反，所有抗TNF MoAb治疗的动物存活了14天（与安慰剂组死亡率相比，p>0.005）。因此，在短期猴子实验中，我们的研究表明抗TNF MoAb可预防脂多糖诱导的内毒素血症，这可能对人类败血症的治疗具有临床意义。
