Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis
Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis
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DOI：
10.1016/s0165-0173(01)00101-1
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发表时间：
2001-10-01
影响因子：
--
通讯作者：
Leib, SL
中科院分区：
文献类型：
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作者：
Leppert, D;Lindberg, RLP;Leib, SL
基质金属蛋白酶（MMP）是靶向细胞外基质（ECM）化合物以及许多其他蛋白质的Zn 2+依赖性内肽酶家族。它们的蛋白水解活性在生理和病理条件下作为组织重塑的效应机制，并作为炎症的调节剂。在神经炎性疾病的背景下，MMP涉及诸如以下过程：（a）血脑屏障（BB B）和血神经屏障开放，（B）血液来源的免疫细胞对神经组织的侵入，（c）细胞因子和细胞因子受体的脱落，和（d）外周和中枢神经系统疾病中的直接细胞损伤。本文综述了MMPs在多发性硬化症（MS）和细菌性脑膜炎（BM）中的作用，这两种神经炎性疾病目前的治疗方法不足以预防大多数患者的严重残疾。酶活性的抑制可以防止MMP介导的神经元损伤由于过度活跃或偏离免疫反应在这两种疾病。MMP释放的下调可能是IFN-β和类固醇在MS中的有益作用的分子基础。相反，合成MMP抑制剂提供了关闭已经活化的MMP的酶活性的可能性。在MS和BM的动物模型中，它们有效地减轻了临床疾病症状，并防止了由于过度的金属蛋白酶活性引起的脑损伤。然而，这组新化合物在人类疾病中的治疗用途所需的靶谱尚未充分确定，并且可能根据疾病的类型和阶段而不同。目前可用的MMP抑制剂在MMP家族中显示出很少的靶特异性，并且可能由于干扰MMP的生理功能而导致副作用。来自人MS和BM的结果表明，只有有限数量的对每种疾病特异的MMP被上调。具有选择性靶点的MMP抑制剂为MS和BM的更有效治疗提供了可能性，并可能在不久的将来进入临床试验。(C)2001 Elsevier Science BY保留所有权利。
Matrix metalloproteinases (MMPs) are a family of Zn2+-dependent endopeptidases targeting extracellular matrix (ECM) compounds as well as a number of other proteins. Their proteolytic activity acts as an effector mechanism of tissue remodeling in physiologic and pathologic conditions, and as modulator of inflammation. In the context of neuro-inflammatory diseases, MMPs have been implicated in processes such as (a) blood-brain barrier (BBB) and blood-nerve barrier opening, (b) invasion of neural tissue by blood-derived immune cells, (c) shedding of cytokines and cytokine receptors, and (d) direct cellular damage in diseases of the peripheral and central nervous system. This review focuses on the role of MMPs in multiple sclerosis (MS) and bacterial meningitis (BM), two neuro-inflammatory diseases where current therapeutic approaches are insufficient to prevent severe disability in the majority of patients. Inhibition of enzymatic activity may prevent MMP-mediated neuronal damage due to an overactive or deviated immune response in both diseases. Downregulation of MMP release may be the molecular basis for the beneficial effect of IFN-beta and steroids in MS. Instead, synthetic MMP inhibitors offer the possibility to shut off enzymatic activity of already activated MMPs. In animal models of MS and BM, they efficiently attenuated clinical disease symptoms and prevented brain damage due to excessive metalloproteinase activity. However, the required target profile for the therapeutic use of this novel group of compounds in human disease is not yet sufficiently defined and may be different depending on the type and stage of disease. Currently available MMP inhibitors show little target-specificity within the MMP family and may lead to side-effects due to interference with physiological functions of MMPs. Results from human MS and BM indicate that only a restricted number of MMPs specific for each disease is up-regulated. MMP inhibitors with selective target profiles offer the possibility of a more efficient therapy of MS and BM and may enter clinical trials in the near future. (C) 2001 Elsevier Science BY All rights reserved.