LETHAL HYPOGLYCEMIA AND HYPOTHERMIA INDUCED BY ADMINISTRATION OF LOW-DOSES OF TUMOR-NECROSIS-FACTOR TO ADRENALECTOMIZED RATS
LETHAL HYPOGLYCEMIA AND HYPOTHERMIA INDUCED BY ADMINISTRATION OF LOW-DOSES OF TUMOR-NECROSIS-FACTOR TO ADRENALECTOMIZED RATS
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DOI：
10.1016/0026-0495(90)90042-b
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发表时间：
1990-03-01
影响因子：
9.8
通讯作者：
SHILONI, E
中科院分区：
文献类型：
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作者：
CHAJEKSHAUL, T;BARASH, V;SHILONI, E
肾上腺切除（Adex）大鼠对静脉（IV）注射重组人肿瘤坏死因子（rHuTNF）的敏感性增加，表现为死亡率显著增加。死亡的大鼠表现出严重的低血糖和体温过低。在假手术大鼠（30 μ g/100 g体重）中给予致死剂量的2.5或10 μ g/100 g体重（3%或12%）rHuTNF在其注射后4小时内分别导致50%或100%的死亡率。预先给予地塞米松或间歇性葡萄糖输注保护动物免受rHuTNF的致死作用。吲哚美辛没有改变rHuRNF治疗的Adex大鼠的死亡率，但在假手术大鼠中阻止了死亡率。死亡的大鼠体温明显下降，但只有Adex大鼠在低剂量TNF后发生低血糖。地塞米松预处理可预防Adex和假手术大鼠的低温，而吲哚美辛仅对假手术大鼠有效，不能预防Adex大鼠的低温或低血糖。在存活的rHuTNF处理的Adex大鼠中，体温迅速升高，血糖降低至30 mg/dL，血清胰岛素浓度降低至6 μ U/mL，肝糖原含量降低98%，并且观察到肝磷酸烯醇丙酮酸羧激酶（PEPCK）和肝微粒体葡萄糖-6-磷酸酶活性的显著降低。反复给rHuTNF处理的Adex大鼠静脉注射葡萄糖导致血糖和胰岛素浓度增加，肝糖原含量增加。向假手术大鼠注射2.5至10 μ g/100 g体重的rHuTNF引起体温显著但较慢的升高。它还分别诱导肝糖原含量减少50%和85%，而仅在注射10 μ g/100 g体重rHuTNF后观察到肝PEPCK和微粒体葡萄糖-6-磷酸酶活性的减少。即使在注射40 μ g/100 g体重后，血清葡萄糖和胰岛素水平保持不变，但在施用90 μ g/100 g体重rHuTNF后发生严重的低血糖。在Adex和假手术大鼠中，rHuTNF注射增加血清三酰甘油和减少脂肪组织脂蛋白脂酶。结论：肾上腺切除使大鼠对rHuTNF的致死作用敏感。死亡率增加与rHuTNF给药和糖皮质激素缺乏对葡萄糖稳态的联合作用导致的严重低血糖相关，并且可以通过地塞米松或葡萄糖治疗逆转。
An increased sensitivity of adrenalectomized (Adex) rats to intravenous (IV) injection of recombinant human tumor necrosis factor (rHuTNF) was manifested by a marked increase in the rate of mortality. The rats that died exhibited severe hypoglycemia and hypothermia. Administration of 2.5 or 10 .mu.g/100 g body weight (3% or 12%) of the lethal dose in sham-operated rats (30 .mu.g/100 g body weight) rHuTNF caused a mortality rate of 50% or 100%, respectively, within 4 hours of its injection. Pre-administration of dexamethasone or intermittent glucose infusion protected the animals from the lethal effect of rHuTNF. Indomethacin did not change the mortality rate in rHuRNF-treated Adex rats, but prevented it in sham-operated rats. The rats that died exhibited a marked decrease in body temperature, but only Adex rats developed hypoglycemia after low doses of TNF. Pretreatment with dexamethasone prevented the hypothermia in both Adex and sham-operated rats, wile indomethacin was effective only in sham-operated rats and did not prevent the hypothemia or the hypoglycemia in Adex rats. In the surviving rHuTNF-treated Adex rats, a rapid increase in body temperature occurred, blood glucose decreased to 30 mg/dL, serum insulin concentration decreased to 6 .mu.U/mL, liver glycogen content was reduced by 98%, and a significant reduction in liver phosphoenolpyruvate carboxykinase (PEPCK) and liver microsomal glucose-6-phosphatase activities was observed. Repeated administration of glucose IV to rHuTNF-treated Adex rats caused an increase in blood glucose and insulin concentrations, and some repletion in liver glycogen content. Injection of rHuTNF, 2.5 to 10 .mu.g/100 g body weight, to sham-operated rats caused a significant but slower increase in body temperature. It also induced a 50% and 85% reduction in liver glycogen content, respectively, while reduction in liver PEPCK and microsomal glucose-6-phosphatase activities was observed only after injection of 10 .mu.g/100 g body weight rHuTNF. Serum glucose and insulin levels remained unchanged even after injection of 40 .mu.g/100 g body weight, but severe hypoglycemia developed following administration of 90 .mu.g/100 g body weight rHuTNF. In both Adex and sham-operated rats, rHuTNF injection increased serum triacylglycerol and decreased adipose tissue lipoprotein lipase. It is concluded that adrenalectomy sensitizes rats to the lethal effect of rHuTNF. The increased mortality was associated with severe hypoglycemia resulting from the combined effect of rHuTNF administration and the lack of glucocorticoids on glucose homeostasis, and may be reversed by treatment with either dexamethasone or glucose.