Institute of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Neurocrit Care. 2023 Aug;39(1):218-228. doi: 10.1007/s12028-023-01770-w. Epub 2023 Jun 22.
Aneurismal subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke that, despite improvement through therapeutic interventions, remains a devastating cerebrovascular disorder that has a high mortality rate and causes long-term disability. Cerebral inflammation after SAH is promoted through microglial accumulation and phagocytosis. Furthermore, proinflammatory cytokine release and neuronal cell death play key roles in the development of brain injury. The termination of these inflammation processes and restoration of tissue homeostasis are of utmost importance regarding the possible chronicity of cerebral inflammation and the improvement of the clinical outcome for affected patients post SAH. Thus, we evaluated the inflammatory resolution phase post SAH and considered indications for potential tertiary brain damage in cases of incomplete resolution.
Subarachnoid hemorrhage was induced through endovascular filament perforation in mice. Animals were killed 1, 7 and 14 days and 1, 2 and 3 months after SAH. Brain cryosections were immunolabeled for ionized calcium-binding adaptor molecule-1 to detect microglia/macrophages. Neuronal nuclei and terminal deoxyuridine triphosphate-nick end labeling staining was used to visualize secondary cell death of neurons. The gene expression of various proinflammatory mediators in brain samples was analyzed by quantitative polymerase chain reaction.
We observed restored tissue homeostasis due to decreased microglial/macrophage accumulation and neuronal cell death 1 month after insult. However, the messenger RNA expression levels of interleukin 6 and tumor necrosis factor α were still elevated at 1 and 2 months post SAH, respectively. The gene expression of interleukin 1β reached its maximum on day 1, whereas at later time points, no significant differences between the groups were detected.
By the herein presented molecular and histological data we provide an important indication for an incomplete resolution of inflammation within the brain parenchyma after SAH. Inflammatory resolution and the return to tissue homeostasis represent an important contribution to the disease's pathology influencing the impact on brain damage and outcome after SAH. Therefore, we consider a novel complementary or even superior therapeutic approach that should be carefully rethought in the management of cerebral inflammation after SAH. An acceleration of the resolution phase at the cellular and molecular levels could be a potential aim in this context.
动脉瘤性蛛网膜下腔出血（SAH）是一种出血性中风，尽管通过治疗干预有所改善，但仍然是一种破坏性的脑血管疾病，死亡率高，导致长期残疾。SAH 后大脑炎症通过小胶质细胞聚集和吞噬作用来促进。此外，促炎细胞因子的释放和神经元细胞死亡在脑损伤的发展中起着关键作用。考虑到大脑炎症的可能慢性化以及 SAH 后受影响患者的临床结果的改善，这些炎症过程的终止和组织内稳态的恢复至关重要。因此，我们评估了 SAH 后的炎症消退阶段，并考虑了在不完全消退的情况下潜在的三级脑损伤的指征。
通过血管内丝穿孔在小鼠中诱导蛛网膜下腔出血。动物在 SAH 后 1、7 和 14 天以及 1、2 和 3 个月时被处死。脑冷冻切片用离子钙结合接头蛋白-1 免疫标记以检测小胶质细胞/巨噬细胞。神经元核和末端脱氧核苷酸三磷酸 - 尼克末端标记染色用于可视化神经元的继发性细胞死亡。通过定量聚合酶链反应分析脑样本中各种促炎介质的基因表达。
我们观察到，在损伤后 1 个月，由于小胶质细胞/巨噬细胞积聚和神经元细胞死亡减少，组织内稳态得到恢复。然而，在 SAH 后 1 和 2 个月，白细胞介素 6 和肿瘤坏死因子-α 的信使 RNA 表达水平仍然升高。白细胞介素 1β 的基因表达在第 1 天达到最大值，而在稍后的时间点，各组之间没有发现显著差异。
根据本文提供的分子和组织学数据，我们为 SAH 后脑实质中炎症不完全消退提供了一个重要的指征。炎症消退和组织内稳态的恢复是疾病病理学的一个重要贡献，影响 SAH 后对脑损伤和结果的影响。因此，我们认为一种新的补充甚至优越的治疗方法应该在 SAH 后大脑炎症的管理中被重新认真考虑。在细胞和分子水平上加速消退阶段可能是这方面的一个潜在目标。
