ANTITUMOR NECROSIS FACTOR ANTIBODIES REDUCE HEPATIC STEATOSIS DURING TOTAL PARENTERAL-NUTRITION AND BOWEL REST IN THE RAT
ANTITUMOR NECROSIS FACTOR ANTIBODIES REDUCE HEPATIC STEATOSIS DURING TOTAL PARENTERAL-NUTRITION AND BOWEL REST IN THE RAT
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DOI：
10.1177/014860719501900180
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发表时间：
1995-01-01
影响因子：
3.4
通讯作者：
FREUND, HR
中科院分区：
文献类型：
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作者：
PAPPO, I;BERCOVIER, H;FREUND, HR
背景资料：在以前的研究中，我们证明了肠道中革兰氏阴性菌的过度生长和腹腔巨噬细胞释放肿瘤坏死因子（TNF）的增强，这表明内毒素，TNF或两者，可能作为肝毒素在全胃肠外营养（TPN）和肠道休息期间产生肝脂肪变性。本研究试图更好地确定这两个调解人的作用。第一部分检查了不同剂量内毒素在TPN处理大鼠中的LD（50），并与自由进食和自由进食盐水灌注大鼠进行了比较。在第二部分中，我们反复给予抗TNF单克隆抗体的大鼠进行TPN和肠道休息。研究方法：在第一组实验中，将87只雄性Sabra大鼠随机分为三组：自由喂养、输注生理盐水和输注TPN。在实验第7天，所有大鼠均接受不同剂量（1.5、2.5、5.0、7.5和10 mg/kg）的内毒素IV注射。在注射后24小时测定三组和不同剂量脂多糖的LD（50）。在第二组实验中，将38只雄性Sabra大鼠随机分为三组：输注生理盐水并随意喂食大鼠食物，输注TPN，输注TPN但也接受抗TNF单克隆抗体。结果如下：与自由喂养组（7.5 mg/kg）相比，两个IV输注组（2.5至5.0 mg/kg）中达到LD（50）所需的内毒素剂量较低（p <0.03）。这些结果表明，在IV治疗的大鼠中，内毒素致死作用的敏感性适度增加。使用抗TNF抗体可显著降低TPN大鼠中显著升高的总肝脂肪和甘油三酯水平。TPN期间腹腔巨噬细胞产生的TNF增加被抗TNF抗体完全消除，可能是抑制TNF产生的结果。结论：在TPN和肠道休息期间，来自肠道中革兰氏阴性细菌过度生长的内毒素的持续移位导致巨噬细胞释放TNF的增强。TNF导致肝功能障碍，在本实验模型中描述为肝脂肪变性。TPN诱导的肝脂肪变性通过给予抗TNF-α的单克隆抗体显著减少。
Background: In previous studies, we demonstrated the overgrowth of gram-negative bacteria in the gut and an enhanced release of tumor necrosis factor (TNF) by peritoneal macrophages, suggesting that endotoxin, TNF, or both, may act as hepatotoxins to produce hepatic steatosis during total parenteral nutrition (TPN) and bowel rest. The present study attempts to better define the role of each of these two mediators. The first part examines the LD(50) for various doses of endotoxin in TPN-treated rats compared with free-feeding and free-feeding saline-infused rats. In the second part we repeatedly administered anti-TNF monoclonal antibodies to rats subjected to TPN and bowel rest. Methods: In the first set of experiments, 87 male Sabra rats were randomized into three groups: free-feeding, infused with normal saline, and infused with TPN. On day 7 of the experiment, all rats received an IV injection of endotoxin at various doses (1.5, 2.5, 5.0, 7.5, and 10 mg/kg). The LD(50) in the three groups and at the various doses of lipopolysaccharide tested was determined at 24 hours postinjection. In the second set of experiments, 38 male Sabra rats were randomized into three groups: infused with normal saline and fed rat food ad libitum, infused with TPN, and infused with TPN but also receiving monoclonal antibodies against TNF. Results: Lower endotoxin doses were required to achieve LD(50) in the two IV-infused groups (2.5 to 5.0 mg/kg) compared with the free-feeding group (7.5 mg/kg) (p < .03). These findings suggest a moderate increase in susceptibility to the lethal effect of endotoxin in IV-treated rats. The total hepatic fat and triglyceride levels, which were markedly increased in TPN rats, were significantly reduced by using anti-TNF antibodies. Enhanced TNF production by peritoneal macrophages during TPN was completely eliminated by anti-TNF antibodies, probably the result of suppressed TNF production. Conclusions: The continuous translocation of endotoxin from gram-negative bacterial overgrowth in the gut during TPN and bowel rest results in enhanced release of TNF by macrophages. TNF causes hepatic dysfunction, portrayed in the present experimental model as hepatic steatosis. TPN-induced hepatic steatosis was significantly reduced by the administration of monoclonal antibodies against TNF-alpha.