肝性脑病的血脑屏障功能障碍:病理生理学、诊断评估和治疗观点。

IF 3.5 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Loic Le Guennec, Sarah Mouri, Dominique Thabut, Nicolas Weiss
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引用次数: 0

摘要

肝性脑病(HE)被定义为一系列神经和神经心理障碍,并发肝功能不全和/或门系统性分流,并与高死亡率、生活质量受损和交通事故高风险相关。除了高氨血症,全身性炎症现在被认为是HE的关键诱发因素。过去三十年积累的证据表明,血脑屏障(BBB)——调节脑和血液之间的分子、免疫和血流动力学交换的多细胞界面——的功能障碍也起着主要的致病作用。在实验和临床HE中,细胞因子和氨驱动的紧密连接蛋白(claudin-5, occludin, ZO-1/-2)的丢失,星形细胞水通道蛋白-4的错定位,周细胞结构损伤和淋巴血流受损共同增加血管通透性,促进细胞毒性和血管源性水肿。小胶质细胞的同时激活和内皮粘附分子的上调促进了白细胞的募集,而依赖于NF-κ b的atp结合盒和溶质载体转运体的重编程改变了大脑对外源性药物、胆汁酸和氨基酸的处理。更好地了解这些相互关联的机制为bbb定向干预开辟了道路,例如血管生成素-1类似物,鞘氨醇-1-磷酸受体调节剂或cladin -5肽模拟物,可以补充经典的降氨疗法。本文综述了血脑屏障功能障碍对HE发病机制的影响,并总结了针对该屏障的新兴治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Blood-brain barrier dysfunction in hepatic encephalopathy: pathophysiology, diagnostic assessment and therapeutic perspectives.

Hepatic encephalopathy (HE) is defined as the spectrum of neurological and neuro-psychological disturbances that complicate liver insufficiency and/or portosystemic shunt and is associated with excess mortality, impaired quality of life and a higher risk of traffic accidents. In addition to hyperammonaemia, systemic inflammation is now recognised as a pivotal precipitant of HE. Accumulating evidence over the past three decades indicates that dysfunction of the blood-brain barrier (BBB)-the multicellular interface that regulates molecular, immune and haemodynamic exchanges between brain and blood-also plays a central pathogenic role. In experimental and clinical HE, cytokine- and ammonia-driven loss of tight-junction proteins (claudin-5, occludin, ZO-1/-2), astrocytic aquaporin-4 mislocalisation, pericyte structural injury and impaired glymphatic flow converge to increase vascular permeability and promote cytotoxic and vasogenic oedema. Concurrent activation of microglia and up-regulation of endothelial adhesion molecules facilitate leukocyte recruitment, whereas NF-κB-dependent re-programming of ATP-binding cassette and solute-carrier transporters alters cerebral handling of xenobiotics, bile acids and amino acids. A better understanding of these interconnected mechanisms opens the way to BBB-directed interventions such as Angiopoietin-1 analogues, sphingosine-1-phosphate-receptor modulators or claudin-5 peptidomimetics that could complement classic ammonia-lowering therapies. This review critically examines how BBB dysfunction contributes to the pathogenesis of HE and summarizes emerging therapeutic approaches targeting the barrier.

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来源期刊
Metabolic brain disease
Metabolic brain disease 医学-内分泌学与代谢
CiteScore
5.90
自引率
5.60%
发文量
248
审稿时长
6-12 weeks
期刊介绍: Metabolic Brain Disease serves as a forum for the publication of outstanding basic and clinical papers on all metabolic brain disease, including both human and animal studies. The journal publishes papers on the fundamental pathogenesis of these disorders and on related experimental and clinical techniques and methodologies. Metabolic Brain Disease is directed to physicians, neuroscientists, internists, psychiatrists, neurologists, pathologists, and others involved in the research and treatment of a broad range of metabolic brain disorders.
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