Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia.
Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia.
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DOI：
10.4049/jimmunol.148.9.2724
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发表时间：
1992-05
影响因子：
4.4
通讯作者：
Mark K. Eskandari;G. Bolgos;Christopher J. Miller;D. Nguyen;L. Deforge;D. Remick
中科院分区：
文献类型：
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作者：
Mark K. Eskandari;G. Bolgos;Christopher J. Miller;D. Nguyen;L. Deforge;D. Remick
细胞因子已被深入研究，以描述其在感染性休克中观察到的病理生理学改变中的作用。我们通过用特异性抗体抑制TNF的活性，研究了TNF在两种充分表征的感染性休克模型的致死率中的作用。在第一种模型中，通过盲肠结扎和穿孔（CLP）诱导脓毒症，并且在第二种模型中，通过腹膜内或静脉内注射LPS诱导脓毒症。CLP后，血浆内毒素在4小时内可检测到，并在8小时达到峰值（136 +/- 109 ng/ml）。TNF生物活性在12 h达到峰值（528 +/- 267 pg/ml），显著高于假手术对照小鼠（64 +/- 31 pg/ml）。在腹腔注射LPS后，与CLP相比，TNF更快地达到峰值（90分钟），并且处于显著更高的水平（107，900 +/-25，000 pg/ml）。在脓毒性休克中研究的另一种细胞因子IL-6在CLP后12小时达到峰值，为1011 +/- 431 pg/ml，在致死性LPS后90分钟达到峰值，为16，300 +/-3，700 pg/ml。用抗TNF抗体处理小鼠，该抗体先前已显示抑制体内TNF活性。抗体治疗的CLP小鼠显着降低TNF的生物活性，但没有减少死亡率或肺嗜中性粒细胞浸润。在静脉注射LPS模型中，抗TNF抗体治疗伴随LPS注射将血浆TNF活性从80，000 +/-20，000 pg/ml降低至不可检测的水平。然而，在静脉注射或腹腔注射LPS之前立即进行抗TNF治疗并不能降低死亡率。另外，当在致死性静脉内LPS之前4小时施用抗体时，致死性没有降低。这些数据表明，在两种不同的感染性休克模型中，阻断TNF生物活性不能防止致死性。
Cytokines have been studied intensively to delineate their role in the altered pathophysiology observed in septic shock. We studied the role of TNF in the lethality of two well characterized models of septic shock by inhibiting TNF's activity with a specific antibody. In the first model, sepsis was induced by cecal ligation and puncture (CLP), and in the second model sepsis was induced by either an i.p. or i.v. injection of LPS. After CLP, plasma endotoxin was detectable within 4 h and reached a peak at 8 h (136 +/- 109 ng/ml). TNF bioactivity peaked at 12 h (528 +/- 267 pg/ml) at a significantly higher level than sham-operated control mice (64 +/- 31 pg/ml). After i.p. LPS, TNF peaked much more quickly (90 min) compared with CLP and at a significantly higher level (107,900 +/- 25,000 pg/ml). Another cytokine studied in septic shock, IL-6, peaked at 12 h after CLP at 1011 +/- 431 pg/ml, and at 90 min after lethal LPS at 16,300 +/- 3,700 pg/ml. Mice were treated with an anti-TNF antibody that has been shown previously to inhibit in vivo TNF activity. Antibody treatment of mice subjected to CLP significantly reduced TNF bioactivity but did not reduce mortality or pulmonary neutrophilic infiltration. In the i.v. LPS model, anti-TNF antibody treatment concomitant with LPS injection reduced plasma TNF activity from 80,000 +/- 20,000 pg/ml to undetectable levels. However, anti-TNF treatment immediately before either i.v. or i.p. LPS did not reduce mortality. Additionally, when the antibody was administered 4 h before the lethal i.v. LPS, there was no reduction in lethality. These data show that in two separate models of septic shock blockade of TNF biologic activity will not prevent lethality.