Shimizu Kampei, Kushamae Mika, Mizutani Tohru, Aoki Tomohiro
Department of Molecular Pharmacology, Research Institute, National Cerebral and Cardiovascular Center.
Department of Neurosurgery, Kyoto University Graduate School of Medicine.
Neurol Med Chir (Tokyo). 2019 Apr 15;59(4):126-132. doi: 10.2176/nmc.st.2018-0326. Epub 2019 Mar 14.
Subarachnoid hemorrhage (SAH) is mainly attributable to the rupture of intracranial aneurysms (IAs). Although the outcome of SAH is considerably poor in spite of the recent intensive medical care, mechanisms regulating the progression of IAs or triggering rupture remain to be clarified, making the development of effective preemptive medicine to prevent SAH difficult. However, a series of recent studies have been expanding our understanding of the pathogenesis of IAs. These studies have suggested the crucial role of macrophage-mediated chronic inflammation in the pathogenesis of IAs. In histopathological analyses of IA lesions in humans and induced in animal models, the number of macrophages infiltrating in lesions is positively correlated with enlargement or rupture of IAs. In animal models, a genetic deletion or an inhibition of monocyte chemotactic protein-1, a major chemoattractant for macrophages, or a pharmacological depletion of macrophages consistently suppresses the development and progression of IAs. Furthermore, a macrophage-specific deletion of Ptger2 (gene for prostaglandin E receptor subtype 2) or a macrophage-specific expression of a mutated form of IκBα which inhibits nuclear translocation of nuclear factor κB significantly suppress the development of IAs, supporting the role of macrophages and the inflammatory signaling functioning there in the pathogenesis of IAs. The development of drug therapies suppressing macrophage-mediated inflammatory responses in situ can thus be a potential strategy in the pre-emptive medicine targeting SAH. In this manuscript, we summarize the experimental evidences about the pathogenesis of IAs focused on inflammatory responses and propose the definition of IAs as a macrophage-mediated inflammatory disease.
蛛网膜下腔出血（SAH）主要归因于颅内动脉瘤（IA）的破裂。尽管近年来强化医疗护理使SAH的预后仍相当差，但调节IA进展或引发破裂的机制仍有待阐明，这使得开发有效的预防SAH的先发药物变得困难。然而，最近一系列研究不断拓展我们对IA发病机制的认识。这些研究表明巨噬细胞介导的慢性炎症在IA发病机制中起关键作用。在对人类IA病变及动物模型诱导产生的IA病变进行组织病理学分析时，病变中浸润的巨噬细胞数量与IA的增大或破裂呈正相关。在动物模型中，基因缺失或抑制单核细胞趋化蛋白-1（巨噬细胞的主要趋化因子），或药物性清除巨噬细胞均能持续抑制IA的发生和发展。此外，巨噬细胞特异性缺失Ptger2（前列腺素E受体2亚型基因）或巨噬细胞特异性表达抑制核因子κB核转位的IκBα突变体均能显著抑制IA的发生，这支持了巨噬细胞及其中的炎症信号在IA发病机制中的作用。因此，开发原位抑制巨噬细胞介导的炎症反应的药物疗法可能是预防SAH的先发药物的潜在策略。在本手稿中，我们总结了关于IA发病机制中炎症反应的实验证据，并提出将IA定义为巨噬细胞介导的炎症性疾病。
