DeLa Cadena R A, Majluf-Cruz A, Stadnicki A, Tropea M, Reda D, Agosti J M, Colman R W, Suffredini A F
Department of Pathology and Laboratory Medicine, and the Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19104, USA.
Thromb Haemost. 1998 Jul;80(1):114-8.
The effects of inhibition of tumor necrosis factor (TNF) on cell and protease activation were evaluated in 18 normal volunteers given endotoxin (4 ng/kg, i.v.) after an infusion of low (10 mg/m2 i.v., n = 6) or high dose (60 mg/m2 i.v., n = 6) recombinant human dimeric TNF receptor protein (TNFR:Fc) or its vehicle (placebo n = 6). Activation of the coagulation system occurred by 2 h in the TNFR:Fc vehicle-placebo group manifested by decreased prekallikrein functional levels and increased levels of prothrombin F1+2 fragments (p < 0.0001). High or low dose TNFR:Fc delayed the fall in prekallikrein functional levels by 1 h and 4 h, respectively (p < 0.0002), but did not inhibit the increase in circulating levels of prothrombin F1+2 fragments. In contrast, endothelium activation, characterized by increased levels of tissue plasminogen activator, plasminogen activator inhibitor-1, and von Willebrand Factor antigen was blunted by both low and high dose TNFR:Fc (p < 0.001). While the endotoxin-associated decrease in platelet number was not altered, platelet-derived beta-thromboglobulin peak levels were blunted and delayed by TNFR:Fc (p < 0.02). Increased levels of neutrophil elastase were attenuated by low and high dose TNFR:Fc (p < 0.001). These results suggest that although TNF is functionally linked to the activation of endothelium, neutrophils, coagulation, and fibrinolysis, alternative pathways are present in vivo that result in activation of the kallikrein-kinin system after endotoxin-induced TNF release. These alternative pathways may limit some of the anti-inflammatory effects of TNFR:Fc.
在18名正常志愿者静脉注射内毒素（4 ng/kg）后，评估了抑制肿瘤坏死因子（TNF）对细胞和蛋白酶激活的影响。这些志愿者在输注低剂量（10 mg/m²静脉注射，n = 6）或高剂量（60 mg/m²静脉注射，n = 6）重组人二聚体TNF受体蛋白（TNFR:Fc）或其溶媒（安慰剂，n = 6）后接受内毒素注射。在TNFR:Fc溶媒-安慰剂组中，2小时内出现凝血系统激活，表现为前激肽释放酶功能水平降低和凝血酶原F1+2片段水平升高（p < 0.0001）。高剂量或低剂量TNFR:Fc分别将前激肽释放酶功能水平的下降延迟1小时和4小时（p < 0.0002），但未抑制循环中凝血酶原F1+2片段水平的升高。相比之下，低剂量和高剂量TNFR:Fc均使以内皮组织纤溶酶原激活物、纤溶酶原激活物抑制剂-1和血管性血友病因子抗原水平升高为特征的内皮激活受到抑制（p < 0.001）。虽然内毒素相关的血小板数量减少未改变，但TNFR:Fc使血小板衍生的β-血小板球蛋白峰值水平受到抑制并延迟出现（p < 0.02）。低剂量和高剂量TNFR:Fc均使中性粒细胞弹性蛋白酶水平升高受到抑制（p < 0.001）。这些结果表明，尽管TNF在功能上与内皮、中性粒细胞、凝血和纤溶的激活相关，但体内存在其他途径，在内毒素诱导TNF释放后导致激肽释放酶-激肽系统激活。这些替代途径可能会限制TNFR:Fc的一些抗炎作用。
