BACKGROUND Pathophysiology of aneurysmal subarachnoid hemorrhage (aSAH) is highly complex. Bleeding from ruptured aneurysm causes increase in intracranial pressure that disrupts blood-brain barrier leading to infiltration of peripheral immune cells. Interactions between the infiltrated leukocytes and the resident brain cells in the injured tissue mainly determine the delayed tissue damage. Recruitment of leukocytes in the injured brain is mainly mediated by the chemokines. Chemokine C-C motif ligand 5 (CCL5) is a potent pro-inflammatory chemokine shown to be upregulated in preclinical SAH studies. However, detailed clinical investigations exploring the association of cerebrospinal fluid (CSF) and systemic CCL5 and post-aSAH complications and clinical outcome are still lacking. This study investigated CSF and systemic CCL5 after aSAH and its association with clinical outcome and post-aSAH complications. METHODS CSF and serum from control and aSAH patients were obtained after centrifugation of the CSF and peripheral blood, and were preserved at -80 °C until quantification by an enzyme-linked immunoassay. Patient pertinent data, post-aSAH complications and clinical outcome (modified Rankin scale [mRS] and Glasgow outcome scale [GOS]) were retrieved from patient records. RESULTS A significant increase in CSF and serum CCL5 levels was observed on post-aSAH day 1 and day 7 compared to control patients. Dichotomization of patients to poor (mRS 3-6 or GOS 1-3) and good (mRS 0-2 or GOS 4-5) clinical outcomes showed significantly higher serum CCL5 levels in patients with good clinical outcome at discharge, but lower CSF CCL5 levels. Interestingly, significantly lower serum CCL5 levels were observed on post-aSAH day 7 in patients who have additional intracerebral bleeding or the patients who developed chronic hydrocephalus or pneumonia. Whereas, CSF CCL5 levels significantly increased on post-aSAH day 1 in patients developing chronic hydrocephalus, delayed ischemic neurological deficits and intraventricular hemorrhage. CSF CCL5 levels on post-aSAH day 1 were correlated with poor clinical outcome, however, serum CCL5 levels on post-aSAH day 7 were correlated with good clinical outcome. CONCLUSION Systemic and CSF CCL5 levels were elevated after aSAH and levels of serum CCL5 on day 7 were associated independently with clinical outcome (GOS and mRS) at discharge. Therapeutic approaches targeting CCL5 might be beneficial in aSAH.

中文翻译：

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脑脊液和全身趋化因子 CCL5 水平升高是动脉瘤性蛛网膜下腔出血 (aSAH) 后临床结果的预测生物标志物

背景动脉瘤性蛛网膜下腔出血（aSAH）的病理生理学非常复杂。动脉瘤破裂出血导致颅内压升高，破坏血脑屏障，导致外周免疫细胞浸润。浸润的白细胞与损伤组织中的常驻脑细胞之间的相互作用主要决定了延迟的组织损伤。受伤大脑中白细胞的募集主要由趋化因子介导。趋化因子 CC 基序配体 5 (CCL5) 是一种有效的促炎趋化因子，在临床前 SAH 研究中显示上调。然而，仍然缺乏探索脑脊液 (CSF) 与全身 CCL5 以及 aSAH 后并发症和临床结果之间关系的详细临床研究。本研究调查了 aSAH 后脑脊液和全身 CCL5 及其与临床结果和 aSAH 后并发症的关系。方法 将CSF和外周血离心后获得对照和aSAH患者的CSF和血清，并保存在-80°C直至通过酶联免疫测定进行定量。从患者记录中检索患者相关数据、aSAH 后并发症和临床结果（改良 Rankin 量表 [mRS] 和格拉斯哥结果量表 [GOS]）。结果 与对照患者相比，在 aSAH 后第 1 天和第 7 天观察到 CSF 和血清 CCL5 水平显着增加。将患者分为差（mRS 3-6 或 GOS 1-3）和良好（mRS 0-2 或 GOS 4-5）临床结果显示出院时临床结果良好的患者血清 CCL5 水平显着升高，但降低 CSF CCL5 水平。有趣的是，在 aSAH 术后第 7 天，在有额外脑内出血的患者或发生慢性脑积水或肺炎的患者中观察到显着降低的血清 CCL5 水平。然而，在发生慢性脑积水、迟发性缺血性神经功能缺损和脑室内出血的患者中，CSF CCL5 水平在 aSAH 后第 1 天显着增加。aSAH 术后第 1 天的 CSF CCL5 水平与较差的临床结果相关，然而，aSAH 术后第 7 天的血清 CCL5 水平与良好的临床结果相关。结论 aSAH 后全身和脑脊液 CCL5 水平升高，第 7 天血清 CCL5 水平与出院时的临床结果（GOS 和 mRS）独立相关。针对 CCL5 的治疗方法可能对 aSAH 有益。在 aSAH 术后第 7 天，在有额外脑内出血的患者或发生慢性脑积水或肺炎的患者中观察到血清 CCL5 水平显着降低。然而，在发生慢性脑积水、迟发性缺血性神经功能缺损和脑室内出血的患者中，CSF CCL5 水平在 aSAH 后第 1 天显着增加。aSAH 术后第 1 天的 CSF CCL5 水平与较差的临床结果相关，然而，aSAH 术后第 7 天的血清 CCL5 水平与良好的临床结果相关。结论 aSAH 后全身和脑脊液 CCL5 水平升高，第 7 天血清 CCL5 水平与出院时的临床结果（GOS 和 mRS）独立相关。针对 CCL5 的治疗方法可能对 aSAH 有益。在 aSAH 术后第 7 天，在有额外脑内出血的患者或发生慢性脑积水或肺炎的患者中观察到血清 CCL5 水平显着降低。然而，在发生慢性脑积水、迟发性缺血性神经功能缺损和脑室内出血的患者中，CSF CCL5 水平在 aSAH 后第 1 天显着增加。aSAH 术后第 1 天的 CSF CCL5 水平与较差的临床结果相关，然而，aSAH 术后第 7 天的血清 CCL5 水平与良好的临床结果相关。结论 aSAH 后全身和脑脊液 CCL5 水平升高，第 7 天血清 CCL5 水平与出院时的临床结果（GOS 和 mRS）独立相关。针对 CCL5 的治疗方法可能对 aSAH 有益。