Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis
Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis
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DOI：
10.1128/iai.68.2.615-620.2000
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发表时间：
2000-02-01
影响因子：
3.1
通讯作者：
Täuber, MG
中科院分区：
文献类型：
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作者：
Leib, SL;Leppert, D;Täuber, MG
本研究旨在探讨基质金属蛋白酶（MMP）在细菌性脑膜炎大鼠模型炎症反应和神经元损伤发生中的作用。与β -肌动蛋白管家基因相比，编码特异性MMPs （MMP-3、MMP-7、MMP-8和MMP-9）和炎症细胞因子肿瘤坏死因子α (tnf - α)的mRNA在感染后20小时在皮质匀浆中显著（P < 0.04）上调。同时，与未感染细菌性脑膜炎的动物相比，感染细菌性脑膜炎的大鼠脑脊液（CSF）中MMP-9和tnf - α的浓度显著升高（P = 0.002），并呈密切相关（r = 0.76; P < 0.001）。在感染时开始使用羟肟酸型MMP抑制剂（GM6001，每12小时腹腔注射65 mg/kg）显著降低脑脊液中MMP-9 （P < 0.02）和tnf - α (P < 0.02)水平。感染后25.5 +/- 5.7 h的组织病理学显示神经元损伤（中位数[范围]为3.5% [0 ~ 17.5%]），GM6001显著降低神经元损伤至0% (0 ~ 10.8%)（P < 0.01）。这是第一个证明MMPs有助于细菌性脑膜炎中神经元损伤的发展，并且抑制MMPs可能是预防该疾病导致的脑损伤的有效方法的报告。
The present study was performed to evaluate the role of matrix metalloproteinases (MMP) in the pathogenesis of the inflammatory reaction and the development of neuronal injury in a rat model of bacterial meningitis. mRNA encoding specific MMPs (MMP-3, MMP-7, MMP-8, and MMP-9) and the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) were significantly (P < 0.04) upregulated, compared to the beta-actin housekeeping gene, in cortical homogenates at 20 h after infection. In parallel, concentrations of MMP-9 and TNF-alpha in cerebrospinal fluid (CSF) were significantly increased in rats with bacterial meningitis compared to uninfected animals (P = 0.002) and showed a close correlation (r = 0.76; P < 0.001). Treatment with a hydroxamic acid-type MMP inhibitor (GM6001; 65 mg/kg intraperitoneally every 12 h) beginning at the time of infection significantly lowered the MMP-9 (P < 0.02) and TNF-alpha (P < 0.02) levels in CSF. Histopathology at 25.5 +/- 5.7 h after infection showed neuronal injury (median [range], 3.5% [0 to 17.5%] of the cortex), which was significantly (P < 0.01) reduced to 0% (0 to 10.8%) by GM6001. This is the first report to demonstrate that MMPs contribute to the development of neuronal injury in bacterial meningitis and that inhibition of MMPs may be an effective approach to prevent brain damage as a consequence of the disease.