A role for the plasminogen activator system in inflammation and neurodegeneration in the central nervous system during experimental allergic encephalomyelitis
A role for the plasminogen activator system in inflammation and neurodegeneration in the central nervous system during experimental allergic encephalomyelitis
复制标题
DOI：
10.1016/s0002-9440(10)62996-3
复制
发表时间：
2005-08-01
影响因子：
6
通讯作者：
Gveric, D
中科院分区：
文献类型：
--
作者：
East, E;Baker, D;Gveric, D
炎症性脱髓鞘的早期迹象包括纤维蛋白（原）进入中枢神经系统（CNS）（通常被血脑屏障排除），以及纤溶酶原激活剂系统成分的上调。利用缺乏组织型纤溶酶原激活剂（tPA（-/-））和尿激酶纤溶酶原激活剂受体（uPAR（-/-））的小鼠，我们研究了PA系统对实验性过敏性脑脊髓炎（多发性硬化症动物模型）临床和病理特征的影响。 uPAR(-/-)小鼠患有早期且更严重的急性疾病，其特征是与野生型对照相比恢复不完全，并且中枢神经系统纤溶酶原激活物抑制剂-1水平显着升高。这与纤维蛋白积累相关，纤维蛋白与实验性过敏性脑脊髓炎组织中增厚的轴突上的非磷酸化神经丝共定位。相比之下，uPAR(-/-)小鼠患有延迟的、不太急性的疾病，这反映在炎症细胞的延迟浸润上。由于炎症持续增加、尿激酶型纤溶酶原激活剂（uPA）水平增加以及脱髓鞘程度加重，这些动物患上了慢性疾病。因此，纤溶酶原激活剂系统可以通过 tPA 和 uPAR 对纤维蛋白溶解和细胞的各自作用来调节 CNS 中的炎症和退行性事件。粘附/迁移，对其进行操作可能对多发性硬化症具有治疗意义。
Early signs of inflammatory demyelination include entry of fibrin(ogen) into the central nervous system (CNS), which is normally excluded by the blood-brain barrier, and up-regulation of components of the plasminogen activator system. Using mice deficient in tissue-type plasminogen activator (tPA(-/-)) and urokinase plasminogen activator receptor (uPAR(-/-)), we investigated the involvement of the PA system on the clinical and pathological features of experimental allergic encephalomyelitis, an animal model of multiple sclerosis. uPAR(-/-) mice suffered an early and a more severe acute disease characterized by incomplete recovery when compared to wild-type controls, with significantly higher CNS levels of plasminogen activator inhibitor-1. This correlated with fibrin accumulation, which co-localized with nonphosphorylated neurofilament on thickened axons in experimental allergic encephalomyelitis tissue. in contrast, uPAR(-/-) mice had a delayed, less acute disease reflected in delayed infiltration of inflammatory cells. These animals developed chronic disease as a result of steadily increased inflammation, increased levels of urokinase-type plasminogen activator (uPA), and greater degree of demyelination. Thus, the plasminogen activator system can modulate both inflammatory and degenerative events in the CNS through the respective effects of tPA and uPAR on fibrinolysis and cell. adhesion/migration, manipulation of which may have therapeutic implications for multiple sclerosis.