Basic and clinical research on Tumor Necrosis Factor (TNF)

探讨了TNF细胞毒作用和坏死作用的机制。TNF敏感细胞系和TNF抗性细胞系均不能从培养上清中吸附TNF活性。酶消化TNF敏感细胞不能降低TNF的细胞毒活性。TNF诱导肿瘤细胞内源性溶酶体活性增强。加入TNF后，敏感肿瘤细胞在一定时间后显示呼吸降低，随后呼吸再次增加。超氧化物歧化酶、叠氮化钠和氟化钠可明显增强TNF的细胞毒作用。TNF可增加靶细胞内<O（_2^-）>及其它氧自由基的产生。这些结果表明髓过氧化物酶系统和糖酵解，即线粒体功能和能量代谢的重要性。TNF在体外获得的细胞毒性浓度比在体内坏死反应中在血液中达到的浓度高10至100倍。这种差异的原因之一被认为是TNF引起涉及内皮细胞的变化。组织学上，TNF给药诱导的肿瘤坏死机制可能是由于与微血管损伤相关的循环障碍引起的出血性梗死，表现为充血和肿瘤组织血管通道中的多个纤维蛋白血栓。除肿瘤组织外，其他器官无病理变化。然而，TNF引起肉芽组织坏死。在体外实验中，TNF对血管内皮细胞具有明显的生理影响，如形态改变、生长抑制或细胞毒性。

The mechanism of cytotoxic action and necrotizing action of TNF was examined. TNF activity could not be adsorbed by both TNF sensitive cell lines and TNF resistant cell lines from supernatant of the culture medium. Enzyme digestion of TNF sensitive cells failed to decrease the cytotoxic activity of TNF. TNF induced enhancement of the endogenous lysosome activity of tumor cells. Following addition of TNF, susceptible tumor cells revealed a decreased respiration after a certain period, and the respiration subsequently increased again. Superoxidase dismutase, sodium azide and sodium fluoride markedly increased the cytotoxicity of TNF. TNF increased the generation of <O(_2^-)> and other oxygen radicals in target tumor cells. These results suggest the importance of the myeloperoxidase system and glycolysis, that is, mitochondrial function and energy metabolism. The concentration of TNF acquiring in vitro cytotoxicity was 10 to 100 times higher than that reached in the blood for the in vivo necrotizing reaction. One of the reasons for this discrepancy is considered to be that TNF gives rise to changes involving endothelial cells. Histopathologically, the mechanism of tumor necrosis induced by TNF administration may be a hemorrhagic infarct due to circulatory disturbance associated with a microvascular injury manifested by hyperemia and multiple fibrin thrombi in vascular channels of tumor tissue. There were no pathologic changes in organs other than tumor tissue. However, TNF causes necrosis of granulation tissues. In vitro experiment, TNF exerts distinct physiological influences, such as morphological alteration, growth inhibition or cytotoxicity on the vascular endothelial cells.