肿瘤坏死因子-α介导的内皮细胞 p65 核因子-κB 亚基苏氨酸 435 磷酸化诱导癫痫持续状态后大鼠梨状皮层血管源性水肿和中性粒细胞浸润。

Tumor necrosis factor-α-mediated threonine 435 phosphorylation of p65 nuclear factor-κB subunit in endothelial cells induces vasogenic edema and neutrophil infiltration in the rat piriform cortex following status epilepticus.

机构信息

Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon, Kangwon-Do, South Korea.

出版信息

J Neuroinflammation. 2012 Jan 12;9:6. doi: 10.1186/1742-2094-9-6.

BACKGROUND

Status epilepticus (SE) induces severe vasogenic edema in the piriform cortex (PC) accompanied by neuronal and astroglial damages. To elucidate the mechanism of SE-induced vasogenic edema, we investigated the roles of tumor necrosis factor (TNF)-α in blood-brain barrier (BBB) disruption during vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced SE.

METHODS

SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, and soluble TNF p55 receptor (sTNFp55R) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunits.

RESULTS

Following SE, most activated microglia showed strong TNF-α immunoreactivity. In addition, TNF p75 receptor expression was detected in endothelial cells as well as astrocytes. In addition, only p65-Thr435 phosphorylation was increased in endothelial cells accompanied by SMI-71 expression (an endothelial barrier antigen). Neutralization of TNF-α by soluble TNF p55 receptor (sTNFp55R) infusion attenuated SE-induced vasogenic edema and neuronal damages via inhibition of p65-Thr435 phosphorylation in endothelial cells. Furthermore, sTNFp55R infusion reduced SE-induced neutrophil infiltration in the PC.

CONCLUSION

These findings suggest that impairments of endothelial cell functions via TNF-α-mediated p65-Thr 485 NF-κB phosphorylation may be involved in SE-induced vasogenic edema. Subsequently, vasogenic edema results in extensive neutrophil infiltration and neuronal-astroglial loss.

背景

癫痫持续状态（SE）可导致梨状皮层（PC）产生严重的血管源性水肿，伴有神经元和星形胶质细胞损伤。为了阐明 SE 诱导的血管源性水肿的机制，我们研究了肿瘤坏死因子（TNF）-α 在 SE 期间血脑屏障（BBB）破坏以及在匹罗卡品诱导的 SE 大鼠癫痫模型中与 BBB 破坏相关的事件中的作用。

方法

通过匹罗卡品向大鼠脑室内输注生理盐水和可溶性 TNF p55 受体（sTNFp55R），在 SE 诱导前诱导 SE。此后，我们进行了 Fluoro-Jade B 染色和 TNF-α 和 NF-κB 亚基的免疫组织化学研究。

结果

SE 后，大多数活化的小胶质细胞表现出强烈的 TNF-α 免疫反应性。此外，TNF p75 受体表达也在内皮细胞和星形胶质细胞中检测到。此外，只有内皮细胞中 p65-Thr435 磷酸化增加，同时伴有内皮屏障抗原 SMI-71 的表达。可溶性 TNF p55 受体（sTNFp55R）输注中和 TNF-α 可通过抑制内皮细胞中 p65-Thr435 磷酸化来减轻 SE 诱导的血管源性水肿和神经元损伤。此外，sTNFp55R 输注可减少 SE 诱导的 PC 中性粒细胞浸润。