Suffredini A F, Reda D, Banks S M, Tropea M, Agosti J M, Miller R
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 1995 Nov 15;155(10):5038-45.
Effects of dimeric TNF receptor (p80) Fc (TNFR:Fc) on acute phase responses were evaluated in 18 volunteers given endotoxin (4 ng/kg i.v.). Subjects were randomized to receive either placebo (n = 6), low dose TNFR:Fc (10 mg/m2 i.v., n = 6), or high dose TNFR:Fc (60 mg/m2 i.v., n = 6). TNFR:Fc blocked plasma TNF bioactivity (p = 0.001) and increased, in a dose-ordered fashion, TNF immunoactivity (p < 0.001). TNFR:Fc decreased secondary cytokine levels including IL-1 beta (p = 0.007), IL-8 (p < 0.001), IL-1 receptor antagonist (p < 0.001), granulocyte-CSF (p = 0.03), and growth regulated peptide-alpha (p = 0.001) but not macrophage inflammatory protein-1 alpha or IL-10. Low dose, but not high dose, TNFR:Fc blunted or delayed the release of epinephrine and cortisol (p < or = 0.026). Despite the absence of plasma TNF bioactivity, high dose TNFR:Fc was less immunosuppressive than low dose TNFR:Fc as measured by cytokine and stress hormone responses. Endotoxin-related symptoms were not altered by TNFR:Fc and the febrile response was delayed but not diminished (p = 0.004). Increases in cardiac index (72 +/- 19%) and heart rate (60 +/- 10%) and decreases in systemic vascular resistance index (47 +/- 7%) were unaltered by TNFR:Fc. These data suggest that the inflammatory response to endotoxin can escape from high levels of circulating TNF-blocking activity and redundant pathways, independent of circulating TNF, can sustain inflammation and clinical responses caused by acute endotoxemia.
在18名静脉注射内毒素（4 ng/kg）的志愿者中评估了二聚体肿瘤坏死因子受体（p80）Fc（TNFR:Fc）对急性期反应的影响。受试者被随机分为接受安慰剂（n = 6）、低剂量TNFR:Fc（10 mg/m²静脉注射，n = 6）或高剂量TNFR:Fc（60 mg/m²静脉注射，n = 6）。TNFR:Fc阻断了血浆TNF生物活性（p = 0.001），并以剂量依赖的方式增加了TNF免疫活性（p < 0.001）。TNFR:Fc降低了包括IL-1β（p = 0.007）、IL-8（p < 0.001）、IL-1受体拮抗剂（p < 0.001）、粒细胞集落刺激因子（p = 0.03）和生长调节肽-α（p = 0.001）在内的次级细胞因子水平，但对巨噬细胞炎性蛋白-1α或IL-10没有影响。低剂量而非高剂量的TNFR:Fc减弱或延迟了肾上腺素和皮质醇的释放（p ≤ 0.026）。尽管血浆中不存在TNF生物活性，但通过细胞因子和应激激素反应测量，高剂量TNFR:Fc的免疫抑制作用低于低剂量TNFR:Fc。TNFR:Fc未改变内毒素相关症状，发热反应延迟但未减轻（p = 0.004）。TNFR:Fc未改变心脏指数增加（72 ± 19%）、心率增加（60 ± 10%）以及全身血管阻力指数降低（47 ± 7%）。这些数据表明，对内毒素的炎症反应可以逃脱高水平的循环TNF阻断活性，并且独立于循环TNF的冗余途径可以维持急性内毒素血症引起的炎症和临床反应。
