About 5–10% of strokes are subarachnoid hemorrhages, a form of stroke in which a blood vessel at the base or surface of the brain bursts [27], causing blood to flow into the subarachnoid space with concomitant clinical symptoms [28]. The most common cause of SAH (85%) is an intracranial aneurysm; other causes include cerebral arteriovenous anomalies, anomalous vascular retinopathy of the base of the brain, dural arteriovenous fistulae, entrapment aneurysms, vasculitis, thrombosis in the intracranial venous system, intratumoral tumors, blood disorders, coagulopathies, and complications from anticoagulants, among others[29–31]. For some of the patients, the cause is uncertain. Subarachnoid hemorrhage (SAH) caused by ruptured aneurysm is mainly located at the bifurcation of the cerebral basal arteries, particularly near the Willis circle[32, 33]. Even if the patient survives, they may still have lasting neurological impairments, which can have a significant negative impact on their quality of life. To this day, the mechanisms leading to aneurysm rupture remain highly complex. The main contributing factors include aneurysm size larger than 7 millimeters, presence of inflammation, genetic syndromes, and hypertension[3, 34]. Studies have shown that there are five types of gut microbes that are closely related to SAH[35]. However, in this study, only two gut microbiome-related pathways were summarized through meta-analysis and were associated with subarachnoid hemorrhage (Fig. 2). Among them, the gut bacterial pathway abundance pyridoxal-5-phosphate biosynthesis I may be considered a risk factor for SAH (OR > 1). When the level of pyridoxal-5-phosphate biosynthesis I increases, it will promote the development of SAH. The MR Egger analysis showed that there was no significant level of pleiotropy in pyridoxal 5-phosphate biosynthatis I (Fig. 2). That indicates the credibility of the results. The gut bacterial pathway ambiguity glucose biosynthesis I may serve as a protective factor for SAH. The results of the meta-analysis indicate that OR = 0.68, indicating that the higher the glucose biosynthesis I, the lower the risk of SAH. The results of MR Egger also indicate that there is currently no significant level of pleiotropy.
大约 5-10%的中风是蛛网膜下腔出血,这是一种脑卒中,是指脑底部或表面的血管破裂[27],导致血液流入蛛网膜下腔,并伴随临床症状[28]。SAH 最常见的病因(85%)是颅内动脉瘤,其他病因包括脑动静脉畸形、脑底部异常血管视网膜病变、硬脑膜动静脉瘘、夹层动脉瘤、脉管炎、颅内静脉系统血栓形成、瘤内肿瘤、血液病、凝血病和抗凝剂并发症等[29-31]。部分患者的病因尚不明确。动脉瘤破裂导致的蛛网膜下腔出血(SAH)主要位于大脑基底动脉分叉处,尤其是威利斯圈附近[32, 33]。即使患者存活下来,他们仍可能存在持久的神经功能损伤,这对他们的生活质量会产生严重的负面影响。时至今日,导致动脉瘤破裂的机制仍然非常复杂。主要诱因包括动脉瘤大小超过 7 毫米、存在炎症、遗传综合征和高血压[3, 34]。研究表明,有五种肠道微生物与 SAH 密切相关[35]。然而,在本研究中,通过荟萃分析总结出的与蛛网膜下腔出血相关的肠道微生物通路只有两条(图 2)。其中,肠道细菌途径丰度吡哆醛-5-磷酸生物合成 I 可被视为 SAH 的风险因素(OR > 1)。当吡哆醛-5-磷酸生物合成 I 水平升高时,将促进 SAH 的发生。MR Egger 分析表明,5-磷酸吡哆醛生物合成 I 不存在显著的多态性(图 2)。这表明结果是可信的。肠道细菌途径模糊葡萄糖生物合成 I 可能是 SAH 的保护因素。荟萃分析结果表明,OR = 0.68,表明葡萄糖生物合成 I 越高,SAH 风险越低。MR Egger 的结果还表明,目前不存在显著的多效应水平。
Inflammation is primarily associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease[36]. In the pathogenesis of SAH, inflammation plays a crucial role, with studies showing that there is neuronal damage caused by both cellular and molecular inflammation in the subarachnoid space[37]. Congenital immune responses may promote a series of inward-outward inflammatory reactions in the subarachnoid space. Experts have proposed that postoperative inflammation in patients with hemorrhagic aneurysms can increase the probability of adverse clinical events, especially due to elevated levels of inflammatory factors such as IL-6 and TNF-α[37, 38]. Furthermore, in brain injury and the inflammatory mechanisms associated with brain injury, high levels of IL-6 and TNF-α in the cortex are associated with post-SAH red blood cell lysis[39].
炎症主要与阿尔茨海默病和帕金森病等各种神经退行性疾病有关[36]。在 SAH 的发病机制中,炎症起着至关重要的作用,研究表明,蛛网膜下腔的细胞和分子炎症都会造成神经元损伤[37]。先天性免疫反应可能会促进蛛网膜下腔一系列由内而外的炎症反应。有专家提出,出血性动脉瘤患者术后炎症会增加不良临床事件的发生概率,尤其是由于 IL-6 和 TNF-α 等炎症因子水平的升高[37, 38]。此外,在脑损伤和与脑损伤相关的炎症机制中,大脑皮层中高水平的 IL-6 和 TNF-α 与脑出血后红细胞溶解有关[39]。
The rupture of aneurysms causes SAH, which promotes the increase in neutrophils and inflammatory cytokines IL-6 in the brain. At the same time, an increase in IL-6 is also associated with local and periphery inflammation[40, 41]. Infiltration of inflammatory immune cells provides a potential target for treatment of SAH patients[40]. It is widely believed that IL-6 is a contributor to brain damage, potentially leading to adverse clinical outcomes with poor prognosis[42]. In the context of neuroinflammation, IL-6 is significantly associated with EBI following aneurysmal SAH. In addition, soluble gp130 (sgp130) is an IL-6 antagonist that can inhibit the production of IL-6. Conversely, IL-6 is an agonist receptor for the IL-6R. When SAH occurs, gp130 can limit the elevation of IL-6. However, when gp130 levels decline, it may contribute to cerebrovascular spasm and corresponding neuroinflammation damage[43]. Some studies have shown that recently marketed IL-6 signaling inhibitors are full-length gp130. Other studies have confirmed that proteins related to the innate immune system will be activated by the IL-6 signal and tissue-specific sgp130[44]. Some immune cells and corresponding chemokines associated with sgp130 can inhibit neuroinflammation[45, 46]. There is evidence to suggest that the main sgp130 isoform specifically binds to the IL-6/IL-6R complex, thereby inhibiting its proinflammatory function[47]. In addition, there is a related mechanism where the thioredoxin-interacting protein (TXNIP) interacts with the NLRP3 inflammasome containing the pyrin domain of the NOD-like receptor family, promoting the generation of interleukin IL-1β. The NLRP3 inflammasome belongs to the innate immune system. The NLRP3 inflammasome is essentially a complex involved in the mechanism of innate immune response, but under conditions of runaway activation, the NLRP3 inflammasome will abnormally activate the immune system and inflammation, typical examples being abnormal metabolism of mitochondria and accumulation of ROS[48]. Some studies have shown that the NLRP3 inflammasome may promote the generation of IL-1β and IL-18, which will exacerbate the post-SAH inflammation response and promote the progression of EBI[49, 50]. By inhibiting the NLRP3-related inflammatory response, it is possible to inhibit neuronal inflammation and promote recovery of neurological function[51]. Intracellular activation of NLRP3 leads to accumulation of ROS, which activates inflammasome[52]. Some strong antioxidants, such as melatonin, can inhibit EBI and inflammation after SAH[53], thereby improving the prognosis of SAH[51]. Melatonin also suppresses the levels of inflammatory cytokines such as IL-1β, IL-6 and TNF-α. These inflammatory signaling molecules promote progression of brain diseases after SAH[54]. There are multiple immune and inflammatory processes that occur in different segments after SAH, which may be related to the production of inflammatory cytokines and immunoregulatory molecules. In our study, we discovered a new inflammase-related molecule, the Urokinase type plasminogen activator. MR and meta-analysis confirmed that the Urokinase type plasminogen activator will affect SAH, and increasing the Urokinase type plasminogen activator will promote the progression of SAH, indicating that this will be a new therapeutic target.
动脉瘤破裂导致 SAH,会促进脑内中性粒细胞和炎症细胞因子 IL-6 的增加。同时,IL-6 的增加还与局部和外周炎症有关[40, 41]。炎性免疫细胞的浸润为 SAH 患者的治疗提供了潜在靶点[40]。人们普遍认为,IL-6 是造成脑损伤的一个因素,有可能导致预后不良的不良临床结果[42]。在神经炎症的背景下,IL-6 与动脉瘤性 SAH 后的 EBI 显著相关。此外,可溶性 gp130(sgp130)是一种 IL-6 拮抗剂,可抑制 IL-6 的产生。相反,IL-6 是 IL-6R 的激动受体。当发生 SAH 时,gp130 可限制 IL-6 的升高。然而,当 gp130 水平下降时,可能会导致脑血管痉挛和相应的神经炎症损伤[43]。一些研究表明,最近上市的 IL-6 信号抑制剂是全长的 gp130。其他研究证实,与先天性免疫系统相关的蛋白质会被 IL-6 信号和组织特异性 sgp130 激活[44]。与 sgp130 相关的一些免疫细胞和相应的趋化因子可抑制神经炎症[45, 46]。有证据表明,主要的 sgp130 异构体能特异性地与 IL-6/IL-6R 复合物结合,从而抑制其促炎功能[47]。此外,还有一种相关机制,即硫氧还蛋白相互作用蛋白(TXNIP)与含有 NOD 样受体家族吡林结构域的 NLRP3 炎症小体相互作用,促进白细胞介素 IL-1β 的生成。NLRP3 炎症体属于先天性免疫系统。NLRP3 炎性体本质上是参与先天免疫反应机制的复合物,但在失控激活的情况下,NLRP3 炎性体会异常激活免疫系统和炎症,典型的例子是线粒体代谢异常和 ROS 的积累[48]。一些研究表明,NLRP3 炎症小体可促进 IL-1β 和 IL-18 的生成,从而加剧 SAH 后的炎症反应并促进 EBI 的进展[49, 50]。通过抑制 NLRP3 相关炎症反应,可以抑制神经元炎症,促进神经功能的恢复[51]。细胞内 NLRP3 的激活会导致 ROS 的积累,从而激活炎性体[52]。一些强抗氧化剂,如褪黑素,可以抑制 SAH 后的 EBI 和炎症[53],从而改善 SAH 的预后[51]。褪黑素还能抑制 IL-1β、IL-6 和 TNF-α 等炎症细胞因子的水平。 这些炎症信号分子会促进 SAH 后脑部疾病的进展[54]。SAH 后不同节段出现多种免疫和炎症过程,这可能与炎症细胞因子和免疫调节分子的产生有关。在我们的研究中,我们发现了一种新的炎症相关分子--尿激酶型纤溶酶原激活剂。磁共振和荟萃分析证实,尿激酶型纤溶酶原激活剂会影响 SAH,而增加尿激酶型纤溶酶原激活剂会促进 SAH 的进展,这表明这将是一个新的治疗靶点。
More and more studies have confirmed the role of inflammation in subarachnoid hemorrhage (SAH). However, due to its complex activation mechanism and vast immune system, the exact pathway of inflammation in SAH still needs further verification. Research suggests that the high incidence of bacterial pneumonia in asymptomatic aneurysmal SAH patients may be attributed to impaired immune response and decreased T cell count. Clinical studies have shown that some cases of secondary SAH may be mediated by immune-related diseases, especially immune hyperactivity disorders such as autoimmune hemolytic anemia, Crohn's disease, and hyperthyroidism[55]. Some clinical studies have also shown that SAH patients after surgical treatment may experience short-term immune dysfunction. Inhibition of certain immune cells, such as CD4+, CD8 + T cells, natural killer cells (NKs), and regulatory T cells (Tregs), will lead to worse prognosis in patients[56]. One clinical study has shown that injection of low-dose interleukin-2 (IL-2) in SAH patients can significantly inhibit the differentiation of Treg cells, thereby suppressing post-SAH neuroinflammation. Some pathological studies have indicated that reducing pro-inflammatory factors and neutrophils in the blood can promote neurological function recovery[57]. Research has shown that regulatory T cells have two main functions: inhibiting the proliferation of normal T cells and releasing cytokines[58]. Immunosuppressive regulatory T cells can inhibit pro-inflammatory factors (tumor necrosis factor-alpha and interferon-gamma) and promote the generation of anti-inflammatory factors (interleukin-10) to suppress inflammatory responses[59–61]. In this study, meta-analysis of MR results revealed that CD80 on CD62L + plasmacytoid Dendritic Cell, CD80 on plasmacytoid Dendritic Cell, CD123 on CD62L + plasmacytoid Dendritic Cell and SSC-A on plasmacytoid Dendritic Cell was positively correlated with SAH. This suggests that these four types of inflammatory cells may exacerbate the symptoms of SAH (OR > 1, Fig. 4 and Fig. 5). No significant statistical differences were found in the meta-analysis of immune cells.
越来越多的研究证实了炎症在蛛网膜下腔出血(SAH)中的作用。然而,由于其复杂的激活机制和庞大的免疫系统,炎症在 SAH 中的确切途径仍有待进一步验证。研究表明,无症状动脉瘤性 SAH 患者细菌性肺炎的高发病率可能与免疫反应受损和 T 细胞数量减少有关。临床研究表明,一些继发性 SAH 病例可能是由免疫相关疾病介导的,尤其是免疫亢进性疾病,如自身免疫性溶血性贫血、克罗恩病和甲状腺功能亢进等[55]。一些临床研究也表明,手术治疗后的 SAH 患者可能会出现短期免疫功能紊乱。某些免疫细胞,如 CD4+、CD8 + T 细胞、自然杀伤细胞(NKs)和调节性 T 细胞(Tregs)受到抑制,会导致患者预后恶化[56]。一项临床研究表明,SAH 患者注射低剂量白细胞介素-2(IL-2)可明显抑制 Treg 细胞的分化,从而抑制 SAH 后的神经炎症。一些病理研究表明,减少血液中的促炎因子和中性粒细胞可促进神经功能的恢复[57]。研究表明,调节性 T 细胞有两个主要功能:抑制正常 T 细胞的增殖和释放细胞因子[58]。免疫抑制调节性 T 细胞可抑制促炎因子(肿瘤坏死因子-α 和干扰素-γ),促进抗炎因子(白细胞介素-10)的生成,从而抑制炎症反应[59-61]。本研究对 MR 结果的荟萃分析显示,CD62L + 浆细胞树突状细胞上的 CD80、浆细胞树突状细胞上的 CD80、CD62L + 浆细胞树突状细胞上的 CD123 和浆细胞树突状细胞上的 SSC-A 与 SAH 呈正相关。这表明这四种炎症细胞可能会加重 SAH 的症状(OR > 1,图 4 和图 5)。免疫细胞的荟萃分析未发现明显的统计学差异。