Tumour necrosis factor-α affects blood-brain barrier permeability and tight junction-associated occludin in acute liver failure
Tumour necrosis factor-α affects blood-brain barrier permeability and tight junction-associated occludin in acute liver failure
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DOI：
10.1111/j.1478-3231.2010.02211.x
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发表时间：
2010-09-01
影响因子：
6.7
通讯作者：
Liu, Pei
中科院分区：
文献类型：
--
作者：
Lv, Sa;Song, Hong-Li;Liu, Pei
Backgroundcerebral edema leading to cerebral herniation is a major cause of death during acute liver failure（ALF），but the underlying mechanism was not clearly.AimsWe investigated the role of tumor necrosis factor（TNF）-alpha in changing the permeability of blood-brain barrier（BBB）during ALF.MethodsALF animal models were generated by administering d-galactosamine（GalN）and lipopolysaccharide，or GalN and TNF-alpha.通过首先给予抗TNF-α-IgG或抗TNF-α-R1阻断ALF诱导。我们研究了BBB通透性与伊文思蓝染色，和结构与电子microscopics.ResultsBBB通透性增加ALF小鼠和相关血清TNF-α水平升高。没有检测到血管内皮细胞（EC）凋亡，但从人类和小鼠ALF组织的细胞的电子显微镜显示紧密连接（TJ）中断和EC收缩，以及囊泡和空泡增加。此外，TJ相关蛋白occludin的表达在ALF小鼠和患者中均显著降低，尽管occludin mRNA的表达没有变化。TNF-α-IgG抗体或TNF-α-R1抗体的预防性治疗可防止ALF小鼠血脑屏障通透性、脑组织超微结构和occludin表达的改变。结论TNF-α在ALF脑水肿的发生中起重要作用，其机制可能与血管生成和细胞毒作用有关。BBB通透性增加可能是由于TJ的破坏和TJ相关蛋白occludin的丢失。
BackgroundCerebral oedema leading to cerebral herniation is a major cause of death during acute liver failure (ALF), but the underlying mechanism is not clear.AimsWe investigated the role of tumour necrosis factor (TNF)-alpha in changing the permeability of the blood-brain barrier (BBB) during ALF.MethodsALF animal models were generated by administering d-galactosamine (GalN) and lipopolysaccharide, or GalN and TNF-alpha. ALF induction was blocked by first administering anti-TNF-alpha-IgG or anti-TNF-alpha-R1. We investigated the BBB permeability with Evans blue staining, and the structure with electron microscopy.ResultsBBB permeability increased in ALF mice and correlated with elevated serum TNF-alpha levels. No vascular endothelial cell (EC) apoptosis was detected, but electron microscopy of cells from human and mouse ALF tissues revealed tight junction (TJ) disruptions and EC shrinkage, as well as increased vesicles and vacuoles. In addition, the expression of the TJ-associated protein occludin was significantly decreased in both ALF mice and patients, although the expression of occludin mRNA did not change. Changes in BBB permeability, brain tissue ultrastructure and occludin expression in ALF-induced mice could be prevented by prophylaxis treatment with either antibody to TNF-alpha-IgG or antibody to TNF-alpha-R1.ConclusionsOur results suggest that TNF-alpha plays a critical role in the development of brain oedema in ALF, and that both vasogenic and cytotoxic mechanisms may be involved. Increased BBB permeability may be because of the disruption of TJs, and loss of the TJ-associated protein occludin.