Reduction in levels of matrix metalloproteinases and increased expression of tissue inhibitor of metalloproteinase-2 in response to mild hypothermia therapy in experimental stroke
Reduction in levels of matrix metalloproteinases and increased expression of tissue inhibitor of metalloproteinase-2 in response to mild hypothermia therapy in experimental stroke
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DOI：
10.3171/jns.2005.103.2.0289
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发表时间：
2005-08-01
影响因子：
4.1
通讯作者：
Yenari, MA
中科院分区：
文献类型：
--
作者：
Lee, JE;Yoon, YJ;Yenari, MA
Object.亚低温是一种强大的神经保护剂，前瞻性临床试验的结果表明，它可能会改善某些情况下的神经结果。这种保护的一个方面与预防血脑屏障（BBB）破坏有关。基质金属蛋白酶（MMPs）参与了血脑屏障的破坏，因为它们可以降解细胞外基质。在这项研究中，作者探讨了低温和MMPs之间的关系，以及亚低温治疗导致的BBB保存是否是由于MMP表达的改变。将大鼠大脑中动脉闭塞2小时;在缺血发作后立即将动物维持在常温或轻度低温（33 ℃）状态。在缺血开始后2、6和24小时收集动物的脑。在24小时进行对比增强的T-1加权磁共振成像以评估BBB破坏的程度。与先前的报道一致，在维持低温状态的大鼠脑中，T-1加权图像上检测到的BBB破坏区域较小（正常体温组8.6 +/-3%的脑;低温组0.2 +/-0.1%的脑; p < 0.01）。MMP-2和MMP-9在转录和翻译水平上的表达在缺血损伤后6小时和24小时在低温脑中减少。基质金属蛋白酶-9主要定位于单核细胞来源的细胞，但也观察到在神经元和星形胶质细胞。基质金属蛋白酶-2在一些神经元和星形胶质细胞中被发现，但在炎性细胞中没有发现。此外，低温还可增加内源性MMP抑制剂、金属蛋白酶组织抑制剂-2的水平。作者得出结论，亚低温减弱血脑屏障破坏，降低MMP表达，抑制MMP活性。
Object. Mild hypothermia is a robust neuroprotectant, and the results of prospective clinical trials have indicated that it may improve neurological outcome in certain instances. One aspect of this protection has been associated with the prevention of blood-brain barrier (BBB) disruption. Matrix metalloprotemases (MMPs) have been implicated in BBB disruption because they can degrade the extracellular matrix. In this study the authors explored the relationship between hypothermia and MMPs and whether BBB preservation resulting from mild hypothermia therapy is due to alterations in MMP expression.Methods. Rats were subjected to middle cerebral artery occlusion for 2 hours; the animals were maintained in a state of normothermia or mild hypothermia (33 degrees C) immediately after the onset of ischemia. The animals' brains were collected 2, 6, and 24 hours after ischemia began. Contrast-enhanced T-1-weighted magnetic resonance imaging was performed at 24 hours to assess the extent of BBB disruption.Consistent with prior reports, areas of BBB disruption detected on T-1-weighted images were smaller in the brains of rats maintained in a state of hypothermia (normothermia group 8.6 +/- 3% of the brain; hypothermia group 0.2 +/- 0.1% of the brain; p < 0.01). Expression of both MMP-2 and MMP-9 at the transcriptional and translational levels was reduced in hypothermic brains at 6 hours and 24 hours after ischemic injury. Matrix metalloprotemase-9 was primarily localized to cells of monocytic origin but was also observed in neurons and astrocytes. Matrix metalloprotemase-2 was found in some neurons and astrocytes but not in inflammatory cells. In addition, hypothermia increased the levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-2.Conclusions. The authors conclude that mild hypothermia attenuates BBB disruption, decreases MMP expression, and suppresses MMP activity.