Cerebral malaria: role of microparticles and platelets in alterations of the blood-brain barrier
Cerebral malaria: role of microparticles and platelets in alterations of the blood-brain barrier
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DOI：
10.1016/j.ijpara.2006.02.005
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发表时间：
2006-05-01
影响因子：
4
通讯作者：
Grau, Georges Emile
中科院分区：
文献类型：
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作者：
Combes, Valery;Coltel, Nicolas;Grau, Georges Emile
脑型疟疾（CM）的脑病变的特征在于脑微血管内的恶性疟原虫寄生的红细胞（PRBC）、白细胞和血小板的隔离，促炎细胞因子的过度释放以及血脑屏障（BBB）的破坏。我们评估了PRBC和血小板相互作用并诱导脑内皮功能改变的可能性。使用内皮损伤的体外模型，我们表明血小板可以充当PRBC和内皮细胞（EC）之间的桥梁，使PRBC与缺乏细胞粘附受体的内皮结合。此外，血小板通过诱导其单层完整性的改变和增加其凋亡而增强PRBC对脑EC的细胞毒性。这些研究结果提供了深入了解的机制，血小板可能是有害的脑内皮细胞在CM。炎性和感染性疾病的另一个方面是它们经常导致血管和血细胞的激活。这种活化导致增强的囊泡形成，即循环微粒（MP）的释放。因此，我们探讨了马拉维疟疾儿童的血浆内皮MP水平。血浆MP数量显着增加入院时，只有在严重疟疾并发昏迷的患者。使用CM的实验小鼠模型，我们使用囊泡形成能力受损的遗传缺陷小鼠评估MP的致病性影响。这种缺乏ABCA-1基因的小鼠，在感染伯氏疟原虫ANKA后，显示出对CM的完全抗性。当从感染的易感动物中纯化时，MP能够减少正常血浆凝血时间，并显着增强幼稚巨噬细胞的肿瘤坏死因子释放。总之，这些数据提供了一个新的洞察致病机制，导致神经综合征。ABCA-1基因缺失可完全保护大脑免受与MP产生受损相关的病理损害，这一发现为重度疟疾的治疗改善提供了新的潜在靶点。(c)2006年澳大利亚寄生虫学会由爱思唯尔有限公司出版。保留所有权利。
Brain lesions of cerebral malaria (CM) are characterised by a sequestration of Plasmodium falciparum-parasitised red blood cells (PRBC), leucocytes and platelets within brain microvessels, by an excessive release of pro-inflammatory cytokines as well as by disruption of the blood-brain barrier (BBB). We evaluated the possibility that PRBC and platelets interact and induce functional alterations in brain endothelium. Using an in vitro model of endothelial lesion, we showed that platelets can act as bridges between PRBC and endothelial cells (EC) allowing the binding of PRBC to endothelium devoid of cytoadherence receptors. Furthermore, platelets potentiated the cytotoxicity of PRBC for brain EC by inducing an alteration of the integrity of their monolayer and increasing their apoptosis. These findings provide insights into the mechanisms by which platelets can be deleterious to the brain endothelium during CM. Another aspect of inflammatory and infectious diseases is that they often lead to activation of vascular and blood cells. Such activation results in an enhanced vesiculation, i.e. the release of circulating microparticles (MP). We thus explored plasma levels of endothelial MP in Malawian children with malaria. Plasma MP numbers were markedly increased on admission,only in patients with severe malaria complicated with coma. Using the experimental mouse model of CM, we evaluated the pathogenic implications of MP using genetically deficient mice in which the capacity to vesiculate is impaired. Such mice, lacking the ABCA-1 gene, upon infection by Plasmodium berghei ANKA, showed complete resistance to CM. When purified from infected susceptible animals, MP were able to reduce normal plasma clotting time and to significantly enhance tumour necrosis factor release from naive macrophages. Altogether these data provide a novel insight into the pathogenic mechanisms leading to the neurological syndrome. The finding that ABCA-1 gene deletion confers complete protection against cerebral pathology, linked to an impaired MP production, provides new potential targets for therapeutic amelioration of severe malaria. (c) 2006 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.