肿瘤坏死因子α诱发脑水肿的机制

The mechanism of brain edema induced by tumor necrosis factor-alpha

目的:研究肿瘤坏死因子(αTumor necrosis fctor-alpha,TNF-α)对水通道蛋白4(Aquaporin4,AQP4)和血脑屏障(Blood-brain barrier,BBB)通透性的影响,探讨TNF-α诱发脑水肿的机制。方法:90只成年SD大鼠,其中45只用于脑含水量和脑组织AQP4 mRNA表达的测定,将其随机分为空白对照组(A组,n=5)、生理盐水组(NS组,n=20)、TNF-α组(TNF-α组,n=20),NS组和TNF-α组按注射后处死的时间再分为1h组、6h组、24h组、72h组,每组各为5只;其余45只用于BBB通透性的观察,分组方法同前。采用干湿重法计算脑含水量,采用RT-PCR法观察脑组织AQP4 mRNA表达的变化,采用伊文思兰法监测BBB通透性。结果:大鼠脑内注射TNF-α后脑含水量和脑组织AQP4 mRNA表达在1h均未见明显变化(P>0.05),均于6h达到高峰,之后逐渐降低,72h脑含水量降到正常水平,但AQP4 mRNA表达仍高于正常(P<0.05);脑组织EB含量1h开始升高,6h迅速达到高峰,之后逐渐降低,72h仍高于正常(P<0.05);BBB通透性与AQP4 mRNA表达呈显著正相关(R=0.839,P<0.01),与脑水肿变化趋势一致。结论:TNF-α通过上调APQ4表达,增加BBB通透性,参与脑水肿形成和发展。

Objective：To investigate aquaporin4（AQP4） expression and blood-brain barrier（BBB） permeability after intracerebral injection of tumor necrosis fctor-alpha（TNF-α ） so as to explore the mechanism of brain edema induced by TNF-α in the rats. Methods：Forty-five adult SD rats,which were used to detected brain water contents and AQP4 expression were divided randomly into groups：control group（Group A with 5 rats）,normal sodium group（NS Group with 20 rats）,tumor necrosis fctor-alpha group（TNF-α Group with 20 rats）. The NS groups and the TNF-α groups were studied after the microinjection at an interval of 1h,6h,24h and 72h,respectively （n=5 for each group）. Other Forty-five adult SD rats were used detected BBB permeability. The grouping approach was the same as the former.The brain edema models were established by microinjection of TNF-α into the cortex. We detected brain water contents by dry-wet weight method,AQP4 mRNA expression by RT-PCR and BBB permeability by EB method. Results ：Brain water contents reached peak at 6 hours and gradually recovered normal level at 72h after intracerebral injection of TNF-α. AQP4 mRNA expression wasn＇t obvious at lh（P〉0.05）,peaked at 6h and it was higher than normal at 72h（P〈0.05）. The level of EB contents rose at lh,peaked at 6h,then descended gradually. There was a significantly positive correlation between AQP4 mRNA expression and BBB permeability（R=0.839,P〈0.01）. Conclusions： TNF-α may have a function in the development and deterioration of the brain edema via up-regulating AQP4 expression and increasing BBB permeability.