Matrix Metalloproteinase-9 Expression is Enhanced by Ischemia and Tissue Plasminogen Activator and Induces Hemorrhage, Disability and Mortality in Experimental Stroke.
Matrix Metalloproteinase-9 Expression is Enhanced by Ischemia and Tissue Plasminogen Activator and Induces Hemorrhage, Disability and Mortality in Experimental Stroke.
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缺血和组织纤溶酶原激活剂增强基质金属蛋白酶-9的表达并诱导实验性脑卒中出血、残疾和死亡
DOI：
10.1016/j.neuroscience.2021.01.003
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发表时间：
2021-04-15
期刊：
影响因子：
3.3
通讯作者：
Reed GL
中科院分区：
文献类型：
--
作者：
Saleem S;Wang D;Zhao T;Sullivan RD;Reed GL
基质金属蛋白酶-9 （MMP-9）降解胶原蛋白和其他细胞基质蛋白。急性缺血性脑卒中后，MMP-9水平升高与出血、再灌注不足和脑卒中严重程度相关。然而，明确的数据表明MMP-9本身会导致缺血性脑卒中的不良结果是有限的。在实验性缺血性卒中再灌注模型中，我们检测了缺血和重组组织纤溶酶原激活剂（r-tPA）治疗是否影响MMP-9的表达，并使用特异性抑制剂来检测MMP-9是否影响脑损伤和恢复。脑卒中后，MMP-9在脑缺血半球与非缺血半球的表达显著增加（p<0.001）。MMP-9在缺血半脑的表达，而非缺血半脑的表达，在r-tPA处理下进一步升高（p<0.001）。为了确定MMP-9的表达是否与r-tPA治疗后的卒中结局有关，我们测试了三种不同的抗体MMP-9抑制剂。与r-tPA和生理盐水治疗相比，r-tPA和MMP-9抗体抑制剂治疗显著减少脑出血11.3至38.6倍（p<0.01），脑肿胀2.8至4.3倍（p<0.001），脑梗死2.5至3.9倍（p<0.0001）。同样，与r-tPA和生理盐水治疗相比，r-tPA和MMP-9抗体抑制剂治疗显著改善了神经行为结果（p<0.001），减轻了体重（p<0.001），延长了生存期（p<0.01）。综上所述，长时间缺血和r-tPA都选择性地增强了缺血半球MMP-9的表达。当与r-tPA联合使用时，特异性MMP-9抑制剂可显著减少脑出血、肿胀、梗死、残疾和死亡，这表明阻断MMP-9的有害作用可能改善缺血性卒中后的预后。
Matrix metalloproteinase-9 (MMP-9) degrades collagen and other cellular matrix proteins. After acute ischemic stroke, increased MMP-9 levels are correlated with hemorrhage, lack of reperfusion and stroke severity. Nevertheless, definitive data that MMP-9 itself causes poor outcomes in ischemic stroke are limited. In a model of experimental ischemic stroke with reperfusion, we examined whether ischemia and recombinant tissue plasminogen activator (r-tPA) therapy affected MMP-9 expression, and we used specific inhibitors to test if MMP-9 affects brain injury and recovery. After stroke, MMP-9 expression increased significantly in the ischemic vs. non-ischemic hemisphere of the brain (p<0.001). MMP-9 expression in the ischemic, but not the non-ischemic hemisphere, was further increased by r-tPA treatment (p<0.001). To determine whether MMP-9 expression contributed to stroke outcomes after r-tPA treatment, we tested three different antibody MMP-9 inhibitors. When compared to treatment with r-tPA and saline, treatment with r-tPA and MMP-9 antibody inhibitors significantly reduced brain hemorrhage by 11.3 to 38.6-fold (p<0.01), brain swelling by 2.8 to 4.3-fold (p<0.001) and brain infarction by 2.5 to 3.9-fold (p<0.0001). Similarly, when compared to treatment with r-tPA and saline, treatment with r-tPA and an MMP-9 antibody inhibitor significantly improved neurobehavioral outcomes (p<0.001), decreased weight loss (p<0.001) and prolonged survival (p<0.01). In summary, both prolonged ischemia and r-tPA selectively enhanced MMP-9 expression in the ischemic hemisphere. When administered with r-tPA, specific MMP-9 inhibitors markedly reduced brain hemorrhage, swelling, infarction, disability and death, which suggests that blocking the deleterious effects of MMP-9 may improve outcomes after ischemic stroke.
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影响因子：
8
作者：
Chen XW;Yu TJ;Zhang J;Li Y;Chen HL;Yang GF;Yu W;Liu YZ;Liu XX;Duan CF;Tang HL;Qiu M;Wang CL;Zheng H;Yue J;Guo AM;Yang J
通讯作者：
Yang J
影响因子：
8.3
作者：
Gumbinger, Christoph;Gruschka, Philipp;Ringleb, Peter
通讯作者：
Ringleb, Peter
影响因子：
6.9
作者：
Fagan, Susan C.;Lapchak, Paul A.;Liebeskind, David S.;Ishrat, Tauheed;Ergul, Adviye
通讯作者：
Ergul, Adviye
影响因子：
2.9
作者：
Golab, Piotr;Boguszewska-Czubara, Anna;Kurzepa, Jacek
通讯作者：
Kurzepa, Jacek
无症状脑出血可能会使接受血栓切除术的急性缺血性中风患者的临床结果恶化
DOI：
10.1016/j.jstrokecerebrovasdis.2019.02.006
发表时间：
2019-06-01
影响因子：
2.5
作者：
Jiang, Fang;Zhao, Wenbo;Ji, Xunming
通讯作者：
Ji, Xunming