脑型疟辅助治疗研究进展

doi:10.12140/j.issn.1000-7423.2023.03.016

中国寄生虫学与寄生虫病杂志 ›› 2023, Vol. 41 ›› Issue (3): 361-373.doi: 10.12140/j.issn.1000-7423.2023.03.016

脑型疟辅助治疗研究进展

曹伟¹(), 王一², 张熙致³, 仝国栋², 杨超², 沈燕², 赵亚²^,^*()

1 空军军医大学基础医学院2018 级临床医学（八年制），陕西西安 710032
2 空军军医大学基础医学院微生物与病原生物学教研室，陕西西安 710032
3 空军军医大学基础医学院 2019 级临床医学（五年制），陕西西安 710032

收稿日期:2022-12-08 修回日期:2023-04-18 出版日期:2023-06-30 发布日期:2023-06-25
通讯作者: *赵亚（1972-），男，博士，教授，从事疟原虫感染与免疫相关研究。E-mail: zhaoya@fmmu.edu.cn
作者简介:曹伟（1999-），男，本科生，从事疟原虫感染与免疫相关研究。E-mail：2692148901@qq.com
基金资助:
国家自然科学基金(82072298);国家自然科学基金(82002158)

Research progress in adjunctive therapy of cerebral malaria

CAO Wei¹(), WANG Yi², ZHANG Xizhi³, TONG Guodong², YANG Chao², SHEN Yan², ZHAO Ya²^,^*()

1 Grade 2018 Clinical Medicine (Eight-Year Program), Basic Medical College, Air Force Medical University, Xi’an 710032, Shaanxi, China
2 Department of Medical Microbiology and Parasitology, Basic Medical College, Air Force Medical University, Xi’an 710032, Shaanxi, China
3 Grade 2019 Clinical Medicine (Five-Year Program), Basic Medical College, Air Force Medical University, Xi’an 710032, Shaanxi, China

Received:2022-12-08 Revised:2023-04-18 Online:2023-06-30 Published:2023-06-25
Contact: *E-mail: zhaoya@fmmu.edu.cn
Supported by:
National Natural Science Foundation of China(82072298);National Natural Science Foundation of China(82002158)

摘要/Abstract

摘要：

脑型疟是恶性疟原虫感染的主要致死性并发症之一，发病机制尚不完全清楚。但目前的研究多认为，被疟原虫感染的红细胞黏附脑微血管内皮细胞引发的脑部微循环阻塞，以及由此产生的脑血管内皮细胞活化和炎细胞浸润共同导致的免疫病理损伤，协同造成血脑屏障破坏和脑水肿，是脑型疟最主要的发病机制。因此，脑血管内皮细胞活化、受损的程度是决定脑型疟进展、结局的关键因素之一。现有临床研究证明，即便给予积极有效的青蒿素类药物杀虫治疗也不能完全缓解脑型疟症状和可能继发的神经组织损伤，而联用糖皮质激素抗炎治疗副作用大。脑型疟辅助治疗研究涉及其发病机制的多个环节，但由于恶性疟原虫生活史特点和高度抗原变异等诸多因素影响，现有辅助治疗方法均未获预期疗效，亟待探索脑型疟辅助治疗新方法。本文主要以保护脑血管内皮细胞为靶点，从提升内皮细胞的自我保护功能和抑制其他炎细胞或有害因子2个方面对内皮细胞损伤的脑型疟辅助治疗研究进展进行综述。

关键词: 脑型疟, 血管内皮细胞, 辅助治疗

Abstract:

Cerebral malaria is one of the major fatal complications of Plasmodium falciparum infection, and the pathogenesis is not fully understood. However, most of the current studies believe that the main pathogenesis of cerebral malaria is the obstruction of cerebral microcirculation caused by infected red blood cells adhering to cerebrovascular endothelial cells and the resulting immunopathological damage caused by the activation of cerebrovascular endothelial cells and the infiltration of inflammatory cells, which synergistically result in the disruption of blood-brain barrier and brain edema. Therefore, the magnitude of immune activation and damage to the cerebrovascular endothelial cells is one of the key factors in determining the progression and outcome of cerebral malaria. Existing clinical studies have proved that even active and effective anti-malarial treatment with artemisinin-based drugs cannot completely alleviate the celebral malaria symptoms and the possible subsequent neurological tissue damage, while the combination with anti-inflammatory treatment of glucocorticoids may cause serious side effects. The study on combination therapies of cerebral malaria involves multiple links for relevant pathogenesis, while the existing adjunctive therapies have not achieved the expected curative effect due to various factors, such as the complex life cycle and high antigenic variation of P. falciparum. Therefore, new combination therapies are urgently needed. This paper provides a brief review of the current progress in combination therapies against cerebral malaria with the target of protecting cerebrovascular endothelial cells by enhancing the self-protection function of endothelial cells and inhibiting the damage of other inflammatory cells or harmful factors to endothelial cells.

Key words: Cerebral malaria, Vascular endothelial cell, Adjunctive therapy

中图分类号:

R531.33

曹伟, 王一, 张熙致, 仝国栋, 杨超, 沈燕, 赵亚. 脑型疟辅助治疗研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2023, 41(3): 361-373.

CAO Wei, WANG Yi, ZHANG Xizhi, TONG Guodong, YANG Chao, SHEN Yan, ZHAO Ya. Research progress in adjunctive therapy of cerebral malaria[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2023, 41(3): 361-373.

图/表 3

图1

图2

表1

本文中提及的以脑血管内皮细胞为靶点的脑型疟辅助治疗

作用靶点	作用机制	制剂	研究对象	辅助治疗效果	参考文献
NO	增加外源性NO	NO气体	重症疟疾患者	联用青蒿琥酯，未改善血脑屏障受损情况	[43-44]
NO	增加外源性NO	NO供体二亚丙基三胺壬酸酯	实验性脑型疟小鼠	单独注射，血压明显下降	[23]
NO	增加外源性NO	NO供体S-亚硝基谷胱甘肽	实验性脑型疟小鼠	单独注射，保护了血脑屏障	[45]
NO	增加外源性NO	三硝酸甘油透皮贴片	实验性脑型疟小鼠	联用蒿甲醚提高生存率	[46]
NO	增加外源性NO的同时增强NO介导的下游通路	西地那非和NO供体二亚丙基三胺壬酸酯	实验性脑型疟小鼠	单独注射，保护了血脑屏障	[47]
NO	补充eNOS的底物	L-精氨酸	重症疟疾患者	联用青蒿琥酯，未改善血脑屏障受损情况	[49]
NO	补充eNOS的底物，抑制精氨酸酶活性，减少超氧化物	瓜氨酸、聚乙二醇化超氧化物歧化酶、聚乙二醇化过氧化氢酶	实验性脑型疟小鼠	联用奎宁，提高了生存率	[50]
NO	保护内皮细胞表面的糖萼结构以恢复eNOS的活性	抗凝血酶-3	实验性脑型疟小鼠	单独注射，保护了血脑屏障	[53]
NO	促进eNOS的活化	川芎嗪	实验性脑型疟小鼠	联用青蒿琥酯提高生存率	[111-112]
Ang/Tie-2轴	提高Ang-1水平	BowAng1	实验性脑型疟小鼠	联用青蒿琥酯提高生存率	[22]
Ang/Tie-2轴	拮抗Ang-2作用	REGN910或L1-10	实验性脑型疟小鼠	单独注射，未提高生存率	[22]
vWF	直接补充ADAMTS-13、减少vWF水平	输注全血或血液置换	实验性脑型疟小鼠、脑型疟患者	对于实验性脑型疟小鼠，联用蒿甲醚，进一步提高了生存率；对于患者，有安全有效的临床案例	[71-72]
VEGF	疾病进展早期提高VEGF对血管的保护作用	洛伐他汀和VEGF-164	实验性脑型疟小鼠	单独注射，保护了血脑屏障	[82]
VEGF	疾病进展到一定阶段降低VEGF对血管的不利作用	促红细胞生成素	实验性脑型疟小鼠	单独注射，保护了血脑屏障	[83]
HO-1	在疾病早期诱导HO-1的表达	钴原卟啉IX或脂氧素A₄	实验性脑型疟小鼠	感染前注射，保护了血脑屏障	[86]
感染红细胞的黏附	抑制内皮细胞表面的EPCR与感染红细胞结合	可溶性EPCR	体外细胞实验	减少了感染红细胞（表达的PfEMP1蛋白包含CIDRα1.1结构域）对内皮细胞的黏附	[92]
感染红细胞的黏附	阻断内皮细胞表面的CD36、ICAM-1	抗CD36抗体FA6-152和抗ICAM-1抗体15.2	体外细胞实验	抗体可阻断感染红细胞对内皮细胞的黏附，但对不同疟原虫株感染的红细胞效果不同	[94]
感染红细胞的黏附	改变内皮细胞的肌动蛋白细胞骨架	大肠杆菌细胞毒性坏死性因子1	体外细胞实验	可预防感染红细胞对内皮细胞的黏附并使已黏附的感染红细胞脱落	[95]
感染红细胞的黏附	破坏PfEMP1的DBLδ1结构域	R67A-凝血酶或水蛭素	体外细胞实验	裂解PfEMP1的DBLδ1结构域中相对保守的序列，阻断了感染红细胞对内皮细胞的黏附	[99]
感染红细胞的黏附	破坏PfEMP1 的DBL1α结构域	肝素及其衍生物	体外细胞实验	可与PfEMP1蛋白的DBL1α结构域结合，抑制了感染红细胞对内皮细胞的黏附	[100-101]
促炎细胞因子	拮抗TNF-α的作用	抗TNF-α抗体B-C7	脑型疟患儿	联用蒿甲醚或奎宁，未进一步提高生存率	[104]
促炎细胞因子	拮抗TNF-α的作用	多克隆抗TNF-α抗体Fab片段CytoTAb	重症疟疾患者	联用青蒿琥酯和甲氟喹，患者临床症状缓解更快，疟原虫清除时间延长	[105]
促炎细胞因子	拮抗IFN-γ、TNF-α等多种促炎细胞因子的作用	姜黄素、穿心莲内酯等	实验性脑型疟小鼠	联用青蒿素类药物，阻止了实验性脑型疟进展	[113]
过度活化的免疫细胞	减少Ly6C^lo单核细胞向炎症灶的浸润	经免疫修饰的微粒	实验性脑型疟小鼠	联用青蒿琥酯，进一步提高了生存率	[107]
过度活化的免疫细胞	减少T细胞向炎症灶的浸润	bpV(phen)	实验性脑型疟小鼠	感染前注射，保护了血脑屏障	[108]
过度活化的免疫细胞	抑制CD8⁺T细胞脱颗粒	6-重氮-5-氧代-正亮氨酸	实验性脑型疟小鼠	单独注射，保护了血脑屏障	[109]
过度活化的免疫细胞	适度强化CD8⁺T表面PD-1受体介导的免疫抑制信号	PDL1-IgG1Fc融合蛋白	实验性脑型疟小鼠	单独注射，保护了血脑屏障	[110]

表1

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脑型疟辅助治疗研究进展

Research progress in adjunctive therapy of cerebral malaria

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