Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure.
Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure.
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DOI：
10.1002/hep.23203
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发表时间：
2009-12
期刊：
影响因子：
13.5
通讯作者：
Nguyen, Justin H.
中科院分区：
文献类型：
--
作者：
Chen, Feng;Ohashi, Norifumi;Li, Wensheng;Eckman, Christopher;Nguyen, Justin H.
急性肝功能衰竭(ALF)的脑水肿仍然是致命的。血管生成机制在脑水肿中的作用尚未被探讨。我们先前已经证明基质金属蛋白酶-9(MMP9)在脑水肿的发病机制中起作用。在这里，我们表明，在体外和ALF小鼠的大脑中，基质金属蛋白酶-9介导紧密连接蛋白的破坏。利用PCDNA3.1(+)/Myc-His A表达载体，将基质金属蛋白酶-9基因导入小鼠脑内皮细胞。用基质金属蛋白酶组织抑制因子(TIMP-1)基因或GM6001抑制基质金属蛋白酶-9的表达。用偶氮甲烷诱导小鼠ALF。脑内皮细胞内源性过表达的基质金属蛋白酶-9导致紧密连接蛋白occludin和claudin-5的显著降解。紧密连接蛋白的改变与FITC-葡聚糖分子的通透性增加有关。TIMP-1和GM6001可逆转紧密连接蛋白的降解和通透性的增加。当将基质金属蛋白酶-9外源性加入脑内皮细胞时，也发现了类似的结果。我们还发现，GM6001逆转了ALF小鼠脑内紧密连接蛋白的降解。紧密连接蛋白在ALF小鼠的大脑中明显受到干扰。这些数据证实了基质金属蛋白酶-9在ALF脑水肿的血管生成机制中的重要作用。
Brain edema in acute liver failure (ALF) remains lethal. The role of vasogenic mechanisms of brain edema has not been explored. We previously demonstrated that matrix metalloproteinase-9 (MMP-9) contributes to the pathogenesis of brain edema. Here, we show that MMP-9 mediates disruptions in tight junction proteins in vitro and in brains of mice with ALF. We transfected murine brain endothelial cells with MMP-9 cDNA using pc DNA3.1 (+)/Myc-His A expression vector. Tissue inhibitor of matrix metalloproteinases (TIMP-1) cDNA transfection or GM6001 was used to inhibit MMP-9. ALF was induced in mice with azoxymethane. Endogenous overexpression of MMP-9 in brain endothelial cells resulted in significant degradation of tight junction proteins occludin and claudin-5. The alterations in tight junction proteins correlated with increased permeability to FITC-dextran molecules. The degradation of tight junction proteins and the increased permeability were reversed by TIMP-1 and GM6001. Similar results were found when MMP-9 was exogenously added to brain EC. We also found that tight junction proteins degradation was reversed with GM6001 in brains of mice with ALF. Tight junction proteins are significantly perturbed in brains of mice with ALF. These data corroborate the important role of MMP-9 in the vasogenic mechanism of brain edema in ALF.
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影响因子：
3.3
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