DEVELOPMENT OF PARTIAL TOLERANCE TO THE GASTROINTESTINAL EFFECTS OF HIGH-DOSES OF RECOMBINANT TUMOR-NECROSIS-FACTOR-ALPHA IN RODENTS
DEVELOPMENT OF PARTIAL TOLERANCE TO THE GASTROINTESTINAL EFFECTS OF HIGH-DOSES OF RECOMBINANT TUMOR-NECROSIS-FACTOR-ALPHA IN RODENTS
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DOI：
10.1172/jci113245
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发表时间：
1987-12-01
影响因子：
15.9
通讯作者：
LIGGITT, D
中科院分区：
文献类型：
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作者：
PATTON, JS;PETERS, PM;LIGGITT, D
用单次静脉内注射重组人肿瘤坏死因子-α（rHuTNF-α）治疗健康大鼠和小鼠。引起了剂量依赖性胃肠炎症30 min内胃排空受阻，小肠和大肠组织水肿。在盲肠中，在剂量≥ 4小时后出现出血。250 μ g/kg。盲肠在rHuTNF-α后表现出急性炎症反应。治疗类似于在相同剂量下在肿瘤坏死中观察到的。 血管内皮肿胀，附着并穿透内皮的中性粒细胞和其他白细胞数量增加，最终发生出血。每天注射rHuTNF-α治疗大鼠。(250μ g/kg/d）治疗3周，未能产生恶病质。在24-48小时内，大鼠变得对rHuTNF-α的出血作用具有抗性，然而，细胞因子在治疗10天后仍引起胃排空的暂时性阻断。在5或10天的间隔治疗产生的结果类似于初始注射。这些结果表明，当rHuTNF-α每隔5-10天给药，而不是每天给药。
Treatment of healthy rats and mice with a single intravenous injection of recombinant human tumor necrosis factor-alpha (rHuTNF-.alpha.) caused a dose-dependent gastrointestinal inflammation. Within 30 min gastric emptying was blocked and tissue edema occurred in the small and large intestine. In the cecum hemmorhage occured after 4 h at doses .gtoreq. 250 .mu.g/kg. The cecum exhibited an acute inflammatory response following rHuTNF-.alpha. treatment similar to that seen in tumor necrosis at the same dose. The vascular endothelium became swollen, increased numbers of neutrophils and other leukocytes attached to and penetrated the endothelium, and finally hemorrhage occurred. Treatment of rats with daily injections of rHuTNF-.alpha. (250 .mu.g/kg per d) for 3 wk failed to produce cachexia. Within 24-48 h rats became resistant to the hemorrhagic effect of rHuTNF-.alpha., however, the cytokine still caused a transitory block of gastric emptying after 10 d of treatment. Treatment at 5- or 10-d intervals produced results similar to the initial injection. These results suggest that maximum hemorrhagic response will occur when rHuTNF-.alpha. is administered at intervals of 5-10 d rather than daily.