Medana I M, Chan-Ling T, Hunt N H
Department of Pathology, University of Sydney, Australia.
Glia. 1996 Jan;16(1):51-64. doi: 10.1002/(SICI)1098-1136(199601)16:1<51::AID-GLIA6>3.0.CO;2-E.
To determine whether astrocytes play a critical role in the pathogenesis of experimental murine cerebral malaria (EMCM), we examined changes in astrocyte morphology and distribution, using retinal wholemounts, in three models: a fatal cerebral malaria (CM) model, in which mice die showing cerebral symptoms; a "resolving" model, in which mice exhibit mild cerebral symptoms, but then recover; and a non-CM model, in which cerebral symptoms are not seen. In the fatal model, retinal astrocytes lost their even distribution from day 3 post-inoculation (p.i.) with malaria parasites, progressing to gliosis (day 5 p.i.), well before the onset of cerebral symptoms on day 6-7 p.i. At the terminal stage of the disease there was a loss of astrocyte processes contacting retinal vessels, often along vessel segments containing adherent monocytes. These features occurred in a mild form in the resolving model and were absent in the non-CM models. To investigate the mechanisms underlying these astrocytic changes, we carried out two experimental manipulations. Firstly, since dexamethasone ameliorates cerebral complications in the fatal CM model, the astrocytic response was monitored after dexamethasone treatment on days 0 and 1 p.i., or days 3 and 4 p.i. Second, to determine whether increased blood-retinal barrier (BRB) permeability initiates the astrocyte changes, breakdown of the BRB was induced experimentally by intra-carotid injection of arabinose and astrocyte morphology and distribution were examined 12, 24, and 48 h later. Retinal astrocytes in both the dexamethasone- and the arabinose-treated groups showed loss of even astrocyte distribution but no loss of astrocyte ensheathment of vessels. It is concluded that: i) astrocytes are involved in the pathogenesis of EMCM, since these changes are only prominent in the fatal model and occur substantially before the onset of cerebral symptoms; ii) the initial changes in astrocyte distribution may be a consequence of the increase in BRB permeability; and iii) the immune response triggered by the malaria parasite may be responsible for the loss of astrocyte ensheathment of vessel segments.
为了确定星形胶质细胞在实验性小鼠脑型疟疾（EMCM）发病机制中是否起关键作用，我们使用视网膜整装片，在三种模型中检测了星形胶质细胞形态和分布的变化：一种是致命性脑型疟疾（CM）模型，小鼠出现脑部症状后死亡；一种是“恢复性”模型，小鼠表现出轻度脑部症状，但随后恢复；还有一种是非CM模型，未观察到脑部症状。在致命性模型中，从接种疟原虫后第3天起，视网膜星形胶质细胞就失去了均匀分布，发展为胶质增生（接种后第5天），远早于接种后第6 - 7天脑部症状的出现。在疾病终末期，常常沿着含有黏附单核细胞的血管段，星形胶质细胞与视网膜血管接触的突起会丧失。这些特征在恢复性模型中以轻度形式出现，而在非CM模型中则不存在。为了研究这些星形胶质细胞变化的潜在机制，我们进行了两项实验操作。首先，由于地塞米松可改善致命性CM模型中的脑部并发症，我们在接种后第0天和第1天或第3天和第4天给予地塞米松治疗后，监测星形胶质细胞的反应。其次，为了确定血视网膜屏障（BRB）通透性增加是否引发星形胶质细胞变化，通过颈内注射阿拉伯糖实验性诱导BRB破坏，并在12、24和48小时后检查星形胶质细胞的形态和分布。地塞米松处理组和阿拉伯糖处理组的视网膜星形胶质细胞均显示出星形胶质细胞均匀分布的丧失，但血管的星形胶质细胞包被未丧失。得出以下结论：i）星形胶质细胞参与了EMCM的发病机制，因为这些变化仅在致命性模型中显著，且在脑部症状出现之前就已大量发生；ii）星形胶质细胞分布的初始变化可能是BRB通透性增加的结果；iii）疟原虫引发的免疫反应可能是血管段星形胶质细胞包被丧失的原因。
