Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis -: A quantitative MRI study
Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis -: A quantitative MRI study
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DOI：
10.1093/brain/awh068
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发表时间：
2004-03-01
期刊：
影响因子：
14.5
通讯作者：
de Vries, HE
中科院分区：
文献类型：
--
作者：
Floris, S;Blezer, ELA;de Vries, HE
增强的脑血管通透性和细胞浸润标志着多发性硬化早期病变的发生。到目前为止，这些事件的确切顺序及其在病变形成和疾病进展中的作用仍然未知。在这里，我们提供了定量的证据表明，血脑屏障渗漏是一个早期事件，并在大量的细胞浸润的急性实验性过敏性脑脊髓炎（EAE），多发性硬化症的动物相关的发展。在疾病过程中，通过定量体内MRI分别监测脑血管渗漏和单核细胞浸润。磁共振增强造影剂二乙烯三胺五乙酸钆（Gd-DTPA），反映血管渗漏，发生伴随着神经系统的迹象，并已在最高水平在这个阶段的疾病。免疫组化分析也证实了存在的血清衍生的蛋白质，如纤维蛋白原周围的脑血管在疾病的早期，而没有细胞浸润可以检测到。MRI进一步证明，Gd-DTPA渗漏明显先于单核细胞浸润，如基于超小氧化铁颗粒（USPIO）的造影剂所示，其仅在完全爆发的EAE期间最大。超微结构和免疫组化研究显示，USPIO存在于炎症病变内新浸润的巨噬细胞中。为了验证USPIO作为评估治疗策略的非侵入性工具的用途，用免疫调节剂3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂洛伐他汀治疗EAE动物，其改善临床评分。MRI显示，洛伐他汀治疗的动物脑中USPIO负荷显著减少。数据表明，脑血管渗漏和单核细胞贩运到大脑中是两个不同的过程中的发展，在多发性硬化症，这可以监测在线与MRI使用USPIO和Gd-DTPA作为造影剂的炎性病变。这些研究还表明，USPIO是一种有价值的工具，可以可视化体内单核细胞浸润，并定量评估新疗法（如洛伐他汀）的疗效。
Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive cellular infiltration in the development of acute experimental allergic encephalomyelitis (EAE), the animal correlate of multiple sclerosis. Cerebrovascular leakage and monocytes infiltrates were separately monitored by quantitative in vivo MRI during the course of the disease. Magnetic resonance enhancement of the contrast agent gadolinium diethylenetriaminepentaacetate (Gd-DTPA), reflecting vascular leakage, occurred concomitantly with the onset of neurological signs and was already at a maximal level at this stage of the disease. Immunohistochemical analysis also confirmed the presence of the serum-derived proteins such as fibrinogen around the brain vessels early in the disease, whereas no cellular infiltrates could be detected. MRI further demonstrated that Gd-DTPA leakage clearly preceded monocyte infiltration as imaged by the contrast agent based on ultra small particles of iron oxide (USPIO), which was maximal only during full-blown EAE. Ultrastructural and immunohistochemical investigation revealed that USPIOs were present in newly infiltrated macrophages within the inflammatory lesions. To validate the use of USPIOs as a non-invasive tool to evaluate therapeutic strategies, EAE animals were treated with the immunomodulator 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, lovastatin, which ameliorated clinical scores. MRI showed that the USPIO load in the brain was significantly diminished in lovastatin-treated animals. Data indicate that cerebrovascular leakage and monocytic trafficking into the brain are two distinct processes in the development of inflammatory lesions during multiple sclerosis, which can be monitored on-line with MRI using USPIOs and Gd-DTPA as contrast agents. These studies also implicate that USPIOs are a valuable tool to visualize monocyte infiltration in vivo and quantitatively assess the efficacy of new therapeutics like lovastatin.