Darling G, Fraker D L, Jensen J C, Gorschboth C M, Norton J A
Surgical Metabolism Section, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Cancer Res. 1990 Jul 1;50(13):4008-13.
Treatment of rats with either intermittent bolus i.v. injections or continuous i.v. infusions of the same sublethal daily dose of tumor necrosis factor (TNF) results in decreased food intake and decreased nitrogen balance compared to saline-treated control rats. After 4 days of treatment, rats treated with intermittent bolus doses of TNF develop tolerance to the nutritional effects and consume normal amounts of food and have nitrogen balance similar to those of saline treated rats. Rats receiving the continuous infusion of TNF do not. Rats treated with both routes of TNF lose more weight than pair fed rats who eat the same mean amount as the continuous TNF treated group. In addition, 56% of rats receiving continuous infusion TNF die during the 8-day experimental period while rats receiving either intermittent bolus TNF or similar food intake (pair fed) do not. Body composition studies of rats that completed the 8 days of treatment indicate that rats receiving either continuous infusion or intermittent bolus TNF have increased percentages of body water and reduced percentages of body solid compared to saline treated control rats. Rats pair fed to the food intake of continuous TNF treated rats also had increased percentages of body water and reduced percentages of body solid, but changes were significantly less than those observed in continuous TNF infused rats. Continuous TNF infusion reduced total body nitrogen and potassium while pair feeding did not reduce potassium and reduced nitrogen to a lesser degree. Pair feeding and continuous TNF infusion reduced total body fat to a similar extent. Twice a day administration of TNF resulted in lesser changes in carcass water, solid, nitrogen, lipid, and potassium than continuous infusion of the same dose of TNF. The results indicate that continuous infusion of TNF can produce anorexia, weight loss, edema, loss of body protein, lipid and cell mass, and lethality which is markedly ameliorated with bolus doses of TNF. The findings are consistent with the hypothesis that slow continuous secretion of sublethal amounts of TNF may mediate cancer cachexia.
与生理盐水处理的对照大鼠相比，用相同亚致死日剂量的肿瘤坏死因子（TNF）进行间歇性静脉推注或持续性静脉输注来处理大鼠，会导致食物摄入量减少和氮平衡降低。处理4天后，用间歇性静脉推注剂量的TNF处理的大鼠对营养作用产生耐受性，食物摄入量正常，氮平衡与生理盐水处理的大鼠相似。接受TNF持续输注的大鼠则没有。两种TNF给药途径处理的大鼠比按相同平均摄入量进食的配对喂养大鼠体重减轻更多。此外，在8天的实验期内，接受TNF持续输注的大鼠中有56%死亡，而接受间歇性静脉推注TNF或相似食物摄入量（配对喂养）的大鼠则没有死亡。对完成8天处理的大鼠进行身体成分研究表明，与生理盐水处理的对照大鼠相比，接受持续输注或间歇性静脉推注TNF的大鼠体内水分百分比增加，身体固体百分比降低。与持续接受TNF处理的大鼠食物摄入量相同的配对喂养大鼠体内水分百分比也增加，身体固体百分比降低，但变化明显小于持续输注TNF的大鼠。持续输注TNF会降低全身氮和钾含量，而配对喂养不会降低钾含量，且对氮的降低程度较小。配对喂养和持续输注TNF对全身脂肪的降低程度相似。每天两次给予TNF导致的胴体水分、固体、氮、脂质和钾的变化小于相同剂量TNF持续输注导致的变化。结果表明，持续输注TNF可导致厌食、体重减轻、水肿、身体蛋白质、脂质和细胞量的损失以及致死性，而静脉推注TNF可明显改善这些情况。这些发现与以下假设一致：亚致死量TNF的缓慢持续分泌可能介导癌症恶病质。
