Downregulation of matrix metalloproteinase-9 and attenuation of edema via inhibition of ERK mitogen activated protein kinase in traumatic brain injury
Downregulation of matrix metalloproteinase-9 and attenuation of edema via inhibition of ERK mitogen activated protein kinase in traumatic brain injury
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DOI：
10.1089/089771502320914642
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发表时间：
2002-11-01
影响因子：
4.2
通讯作者：
Lo, EH
中科院分区：
文献类型：
--
作者：
Mori, T;Wang, XY;Lo, EH
新数据表明基质金属蛋白酶 9 (MMP-9) 在脑损伤的病理生理学中发挥着关键作用。然而，体内涉及的调节机制仍不清楚。在这项研究中，我们重点关注有丝分裂原激活蛋白激酶 (MAPK) 通路，该通路可能在创伤性脑损伤后触发 MMP-9。我们的目的是证明抑制细胞外信号调节激酶 (ERK) 可以降低 MMP-9 水平，减少血脑屏障损伤，并减轻小鼠大脑受控皮质冲击引起的创伤后水肿。蛋白质印迹显示磷酸-ERK 在创伤后迅速上调。 U0126 可抑制 ERK 上游激酶 MEK，有效阻止 ERK 激活。创伤后，明胶酶谱显示 MMP-9 增加。 U0126 显着降低创伤诱导的 MMP-9 水平。相应地，U0126 改善了紧密连接蛋白 ZO-1（MMP-9 底物）的降解，并显着减轻组织水肿。创伤后 7 天，与生理盐水处理的对照组相比，U0126 显着减少了创伤性病变体积。这些数据表明，ERK MAPK 通路在创伤后触发 MMP-9 的上调，并进一步表明，针对调节有害 MMP-9 活性的上游信号机制可能会揭示创伤性脑损伤的新治疗机会。
Emerging data suggest that matrix metalloproteinase-9 (MMP-9) plays a critical role in the pathophysiology of brain injury. However, the regulatory mechanisms involved in vivo remain unclear. In this study, we focus on a mitogen activated protein kinase (MAPK) pathway that may trigger MMP-9 after traumatic brain injury. We aim to show that inhibition of the extracellular signal regulated kinase (ERK) would attenuate MMP-9 levels, reduce blood-brain barrier damage, and attenuate edema after trauma induced by controlled cortical impact in mouse brain. Western blots showed that phospho-ERK was rapidly upregulated after trauma. Treatment with U0126, which inhibits MEK, the kinase upstream of ERK, effectively prevented the activation of ERK. After trauma, gelatin zymography showed an increase in MMP-9. U0126 significantly reduced trauma-induced MMP-9 levels. Correspondingly, U0126 ameliorated the degradation of the tight junction protein ZO-1, which is an MMP-9 substrate, and significantly attenuated tissue edema. At 7 days after trauma, traumatic lesion volumes were significantly reduced by U0126 compared with saline-treated controls. These data indicate that the ERK MAPK pathway triggers the upregulation in MMP-9 after trauma, and further suggest that targeting the upstream signaling mechanisms that regulate deleterious MMP-9 activity may reveal new therapeutic opportunities for traumatic brain injury.