Inhibition of matrix metalloproteinases and tumour necrosis factor α converting enzyme as adjuvant therapy in pneumococcal meningitis
Inhibition of matrix metalloproteinases and tumour necrosis factor α converting enzyme as adjuvant therapy in pneumococcal meningitis
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DOI：
10.1093/brain/124.9.1734
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发表时间：
2001-09-01
期刊：
影响因子：
14.5
通讯作者：
Leppert, D
中科院分区：
文献类型：
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作者：
Leib, SL;Clements, JM;Leppert, D
基质金属蛋白酶 (MMP) 和肿瘤坏死因子 α (TNF-α) 转换酶 (TACE) 协同促进细菌性脑膜炎的病理生理学。 TACE 通过蛋白水解释放多种细胞表面蛋白，包括促炎细胞因子 TNF-α 及其受体。 TNF-α 反过来刺激细胞产生活性 MMP，通过细胞外基质成分的降解促进白细胞外渗和脑水肿。在目前对幼鼠肺炎球菌脑膜炎的时间过程研究中，CSF 细胞和脑组织中的 MMP-8 和 -9 转录上调 100 至 1000 倍。脑脊液中 TNF-α 和 MMP-9 的浓度在感染后 12 小时达到峰值，并且密切相关。 BB-1101（15 mg/kg 皮下注射，每日两次）（一种基于异羟肟酸的 MMP 和 TACE 抑制剂）治疗可下调 CSF TNF-α 浓度，并降低癫痫发作和死亡率。当感染时作为预处理以及感染后 18 小时开始给药时，BB-1101 与抗生素联合治疗可减轻皮质神经元坏死和海马细胞凋亡。从功能上讲，BB-1101 的神经保护作用保留了疾病治愈 3 周后评估的大鼠的学习表现。因此，MMP 和 TACE 的联合抑制为预防细菌性脑膜炎的脑损伤和神经后遗症提供了一种新的治疗策略。
Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alpha) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-alpha and its receptors. TNF-alpha in turn stimulates cells to produce active MMPs, which facilitate leucocyte extravasation and brain oedema by degradation of extracellular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcriptionally upregulated, both in CSF cells and in brain tissue. Concentrations of TNF-alpha and MMP-9 in CSF peaked 12 h after infection and were closely correlated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF concentration of TNF-alpha and decreased the incidences of seizures and mortality. Therapy with BB-1101, together with antibiotics, attenuated neuronal necrosis in the cortex and apoptosis in the hippocampus when given as a pretreatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 preserved learning performance of rats assessed 3 weeks after the disease had been cured. Thus, combined inhibition of MMP and TACE offers a novel therapeutic strategy to prevent brain injury and neurological sequelae in bacterial meningitis.