Involvement of the p38 MAPK signaling pathway in overexpression of matrix metalloproteinase-9 during the course of brain edema in 1,2-dichloroethane-intoxicated mice
Involvement of the p38 MAPK signaling pathway in overexpression of matrix metalloproteinase-9 during the course of brain edema in 1,2-dichloroethane-intoxicated mice
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DOI：
10.1016/j.neuro.2018.07.022
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发表时间：
2018-12-01
期刊：
影响因子：
3.4
通讯作者：
Jin, Yaping
中科院分区：
文献类型：
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作者：
Jin, Xiaoxia;Liao, Yingjun;Jin, Yaping
1，2-二氯乙烷（1，2-dichloroethane，1，2-DCE）是一种工业溶剂，近年来大量资料表明，1，2-DCE亚急性中毒可引起脑病，主要病理改变为脑水肿。然而，其潜在机制尚不清楚。在本研究中，我们假设p38 MAPK（p38）信号通路在1，2-DCE中毒小鼠中可以被激活，这反过来又刺激转录因子，如核因子-κ B（NF-κ B）和激活蛋白-1（AP-1），然后增强促炎因子的表达，包括基质金属蛋白酶-9（MMP-9），最终导致血脑屏障（BBB）破坏和脑水肿形成。结果表明，中毒小鼠脑含水量和血脑屏障通透性明显增加。同时，中毒小鼠脑内磷酸化p38（p-p38）和抑制性KBa（p-IKB）的水平以及MMP-9、c-jun、c-fos和p65的表达水平也显著增加。相反，这些小鼠中ZO-1、occludin和claudin-5的蛋白水平显著降低，但它们的JAM-1蛋白水平显著升高。我们的研究结果表明，p-p38水平在中毒小鼠的大脑中被抑制预处理与p38抑制剂。抑制p-p38表达后，脑组织含水量、NF-κ B和AP-1的DNA结合活性以及MMP-9、c-jun、c-fos、p65、p-I κ B和JAM-1的表达水平降低，而ZO-1、occludin和claudin-5的蛋白水平显著升高。综上所述，我们的研究结果表明，p38信号通路可能被激活，并参与了1，2-DCE中毒小鼠脑水肿的过程。
Accumulated data have revealed that subacute poisoning of 1,2-dichloroethane (1,2-DCE), an industrial solvent used in some countries can cause encephalopathy, in which brain edema is the main pathological change. However, the underlying mechanisms are unclear. In the present study, we hypothesized that the p38 MAPK (p38) signaling pathway could be activated in 1,2-DCE-intoxicated mice, which in turn stimulates transcription factors, such as nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), and then enhances the expression of proinflammatory factors, including matrix metalloproteinase-9 (MMP-9), finally leading to blood-brain barrier (BBB) disruption and brain edema formation. Our results revealed that brain water content and BBB permeability increased significantly in the intoxicated mice. Meanwhile, the levels of phosphorylated p38 (p-p38) and inhibitory KBa (p-IKB), as well as the expression levels of MMP-9, c-jun, c-fos, and p65, also increased markedly in the brains of intoxicated mice. Conversely, the protein levels of ZO-1, occludin and claudin-5 in these mice decreased markedly, but their JAM-1 protein levels increased dramatically. Our results revealed that p-p38 levels in the brains of intoxicated mice were suppressed by pretreatment with a p38 inhibitor. In response to suppressed p-p38 levels, the brain water contents and DNA binding activities of NF-kappa B and AP-1, as well as the expression levels of MMP-9, c-jun, c-fos, p65, p-I kappa B and JAM-1, decreased, whereas the protein levels of ZO-1, occludin and claudin-5 increased markedly. Taken together, our findings indicated that the p38 signaling pathway might be activated and involved in the course of brain edema in 1,2-DCE-intoxicated mice.