Umehara F, Okada Y, Fujimoto N, Abe M, Izumo S, Osame M
The Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan.
J Neuropathol Exp Neurol. 1998 Sep;57(9):839-49. doi: 10.1097/00005072-199809000-00005.
Matrix metalloproteinases (MMPs) have been reported to be involved in inflammatory disorders of the central nervous system (CNS). However, little is known about the role of MMPs in the pathogenesis of HTLV-I-associated myelopathy (HAM)/Tropical spastic paraparesis (TSP). To address this issue, we examined the tissue expression and localization of MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) in the spinal cord lesions of HAM/TSP using immunohistochemistry. In addition, the blood and cerebrospinal fluid (CSF) levels of MMPs and TIMPs of the patients with HAM/TSP were determined using sandwich enzyme immunoassays (SIA) and gelatin zymography. Immunohistochemical studies revealed that collagen IV and decorin immunoreactivity on the basement membrane of CNS parenchymal vessels was partially disrupted where inflammatory mononuclear cells infiltrated in active-chronic lesions of HAM/TSP. In these lesions, MMP-2 (gelatinase A) was immunostained mainly on the surface of foamy macrophages and lymphocytes, whereas MMP-9 (gelatinase B) expression was positive in the intravascular and perivascular mononuclear cells but not on foamy macrophages. In contrast, inactive chronic lesions of the spinal cords of the HAM/TSP contained fewer MMP-2-positive or MMP-9-positive mononuclear cells than active-chronic lesions. Many parenchymal vessels had thickened vascular walls which showed increased immunoreactivity to decorin. SIA revealed that production levels of MMP-2 and MMP-9 in both blood and CSF were higher in the patients with HAM/TSP than those in non-inflammatory other neurological disease controls (ONDs). Using zymography, proMMP-9 was detected more frequently in the CSF of patients with HAM/TSP than those in ONDs. Taken together, our data indicate that MMP-2 and MMP-9 may play an important role in the blood-brain barrier breakdown and tissue remodeling in the CNS of HAM/TSP.
据报道，基质金属蛋白酶（MMPs）参与中枢神经系统（CNS）的炎性疾病。然而，关于MMPs在人类嗜T细胞病毒I型相关脊髓病（HAM）/热带痉挛性截瘫（TSP）发病机制中的作用知之甚少。为解决这一问题，我们采用免疫组织化学方法检测了HAM/TSP脊髓病变中MMPs及其抑制剂金属蛋白酶组织抑制剂（TIMPs）的组织表达和定位。此外，使用夹心酶免疫测定法（SIA）和明胶酶谱法测定了HAM/TSP患者血液和脑脊液（CSF）中MMPs和TIMPs的水平。免疫组织化学研究显示，在HAM/TSP活动期-慢性期病变中，炎性单核细胞浸润处，CNS实质血管基底膜上的IV型胶原和核心蛋白聚糖免疫反应性部分被破坏。在这些病变中，MMP-2（明胶酶A）主要在泡沫巨噬细胞和淋巴细胞表面免疫染色，而MMP-9（明胶酶B）在血管内和血管周围单核细胞中表达阳性，但在泡沫巨噬细胞中不表达。相比之下，HAM/TSP脊髓的非活动期慢性病变中，MMP-2阳性或MMP-9阳性单核细胞比活动期-慢性期病变少。许多实质血管的血管壁增厚，对核心蛋白聚糖的免疫反应性增加。SIA显示，HAM/TSP患者血液和CSF中MMP-2和MMP-9的产生水平高于非炎性其他神经系统疾病对照（ONDs）。使用酶谱法，在HAM/TSP患者的CSF中比在ONDs患者中更频繁地检测到前MMP-9。综上所述，我们的数据表明，MMP-2和MMP-9可能在HAM/TSP的CNS血脑屏障破坏和组织重塑中起重要作用。
