Pappo I, Bercovier H, Berry E, Gallilly R, Feigin E, Freund H R
Department of Surgery, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
JPEN J Parenter Enteral Nutr. 1995 Jan-Feb;19(1):80-2. doi: 10.1177/014860719501900180.
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 LD50 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.
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 LD50 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.
Lower endotoxin doses were required to achieve LD50 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.
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.
在先前的研究中，我们证明了肠道中革兰氏阴性菌过度生长，以及腹膜巨噬细胞释放肿瘤坏死因子（TNF）增加，这表明内毒素、TNF或两者可能作为肝毒素在全肠外营养（TPN）和肠道休息期间导致肝脂肪变性。本研究试图更好地确定这两种介质各自的作用。第一部分研究了与自由进食和自由进食并输注生理盐水的大鼠相比，不同剂量内毒素在TPN处理大鼠中的半数致死剂量（LD50）。在第二部分中，我们对接受TPN和肠道休息的大鼠反复给予抗TNF单克隆抗体。
在第一组实验中，87只雄性Sabra大鼠被随机分为三组：自由进食、输注生理盐水和输注TPN。在实验的第7天，所有大鼠静脉注射不同剂量（1.5、2.5、5.0、7.5和10mg/kg）的内毒素。在注射后24小时测定三组以及不同剂量脂多糖测试中的LD50。在第二组实验中，38只雄性Sabra大鼠被随机分为三组：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。
与自由进食组（7.5mg/kg）相比，两个静脉输注组（2.5至5.0mg/kg）达到LD50所需的内毒素剂量更低（p <.03）。这些发现表明静脉处理大鼠对内毒素致死作用的易感性适度增加。使用抗TNF抗体可显著降低TPN大鼠中明显升高的肝脏总脂肪和甘油三酯水平。TPN期间腹膜巨噬细胞增强的TNF产生被抗TNF抗体完全消除，这可能是TNF产生受抑制的结果。
在TPN和肠道休息期间，肠道中革兰氏阴性菌过度生长导致内毒素持续移位，从而导致巨噬细胞释放TNF增加。TNF导致肝功能障碍，在本实验模型中表现为肝脂肪变性。给予抗TNF-α单克隆抗体可显著减轻TPN诱导的肝脂肪变性。
