Medana Isabelle M, Turner Gareth D H
Malaria Research Group, Nuffield Department of Clinical Laboratory Sciences, Oxford University, Oxford, UK.
Int J Parasitol. 2006 May 1;36(5):555-68. doi: 10.1016/j.ijpara.2006.02.004. Epub 2006 Mar 10.
Malaria represents a continuing and major global health challenge and our understanding of how the Plasmodium parasite causes severe disease and death remains poor. One serious complication of the infection is cerebral malaria, a clinically complex syndrome of coma and potentially reversible encephalopathy, associated with a high mortality rate and increasingly recognised long-term sequelae in survivors. Research into the pathophysiology of cerebral malaria, using a combination of clinical and pathological studies, animal models and in vitro cell culture work, has focussed attention on the blood-brain barrier (BBB). This represents the key interface between the brain parenchyma and the parasite, which develops within an infected red cell but remains inside the vascular space. Studies of BBB function in cerebral malaria have provided some evidence for parasite-induced changes secondary to sequestration of parasitised red blood cells and host leukocytes within the cerebral microvasculature, such as redistribution of endothelial cell intercellular junction proteins and intracellular signaling. However, the evidence for a generalised increase in BBB permeability, leading to cerebral oedema, is conflicting. As well as direct cell adhesion-dependent effects, local adhesion-independent effects may activate and damage cerebral endothelial cells and perivascular cells, such as decreased blood flow, hypoxia or the effects of parasite toxins such as pigment. Finally, a number of systemic mechanisms could influence the BBB during malaria, such as the metabolic and inflammatory complications of severe disease acting 'at a distance'. This review will summarise evidence for these mechanisms from human studies of cerebral malaria and discuss the possible role for BBB dysfunction in this complex and challenging disease.
疟疾仍然是全球持续面临的重大健康挑战，而我们对于疟原虫如何导致严重疾病和死亡的了解仍然有限。感染的一种严重并发症是脑型疟疾，这是一种临床上复杂的昏迷综合征，伴有潜在可逆性脑病，死亡率高，且幸存者中越来越多地出现长期后遗症。利用临床和病理研究、动物模型以及体外细胞培养工作相结合的方法，对脑型疟疾病理生理学的研究已将重点放在血脑屏障（BBB）上。血脑屏障是脑实质与疟原虫之间的关键界面，疟原虫在受感染的红细胞内发育，但仍留在血管腔内。对脑型疟疾中血脑屏障功能的研究为寄生虫诱导的变化提供了一些证据，这些变化继发于脑微血管内被寄生的红细胞和宿主白细胞的滞留，例如内皮细胞间连接蛋白的重新分布和细胞内信号传导。然而，关于血脑屏障通透性普遍增加导致脑水肿的证据存在矛盾。除了直接的细胞黏附依赖性作用外，局部的非黏附依赖性作用可能会激活并损伤脑内皮细胞和血管周细胞，如血流减少、缺氧或疟色素等寄生虫毒素的作用。最后，一些全身机制可能会在疟疾期间影响血脑屏障，例如严重疾病的代谢和炎症并发症在“远处”发挥作用。本综述将总结来自脑型疟疾人体研究的这些机制的证据，并讨论血脑屏障功能障碍在这种复杂且具有挑战性的疾病中可能发挥的作用。
