颅内动脉粥样硬化性狭窄性疾病血管新生及与炎症因子关系机制

发布时间：2017-12-26 23:24

本文关键词：颅内动脉粥样硬化性狭窄性疾病血管新生及与炎症因子关系机制　出处：《北京协和医学院》2017年博士论文　论文类型：学位论文

【摘要】：目的:颅内大动脉粥样硬化性狭窄是缺血性脑卒中的重要病因,患者有较高的缺血性脑卒中发病与复发风险。血管新生,作为侧支循环途径之一,对狭窄血管流域的血流灌注起重要的代偿作用。炎症因子在急性缺血性脑卒中患者中与神经损伤以及修复均密切相关,并可通过与多种血管新生因子相互作用调节血管新生过程,颅内动脉粥样硬化性患者的慢性缺氧状态可诱导炎症因子的表达,虽然有体外试验与动物模型的证据,但对其在临床样本中的实际效应尚不可知。本研究通过分子影像学成像方法评估颅内大动脉粥样硬化性狭窄患者颅内血管新生现象,探讨炎性因子在颅内动脉狭窄患者血管新生发生机制中可能的作用。方法:纳入17例有脑血管事件史的颅内大动脉粥样硬化性狭窄或闭塞的患者,采用全自动生化分析仪检测血清中的超敏C反应蛋白,酶联免疫吸附试验检测αvβ3整合素与脂蛋白磷脂酶A2的水平,定量蛋白芯片白介素IL-1α、IL-1β、IL-4、IL-6、IL-8、IL-10、IL-17 与细胞黏附分子 VCAM-1、ICAM-1 以及 TNF-α、IFN-γ、TGF-β、IGF-1的血清浓度进行测定,并与健康对照组进行比较。其中10例患者行头68Ga-PRGD2PET/MR检查,通过视觉分析判定高摄取灶,勾画感兴趣区并分别测定高摄取灶侧与对侧的标准摄取值峰值与平均值,以及相应位置动脉自旋标记图像所得的脑血流量,计算双侧比值,并对患者的侧支循环情况进行系统性评估。以末次脑缺血事件后时间6个月为临界值,将病例组分为症状亚组与非症状亚组进行亚组分析,并对临床、影像学表现与侧支循环状态及血清炎症因子水平的相关性进行统计分析。结果:10名行PET/MR检查的患者中有6名患者存在PRGD2高摄取,标准摄取值峰值为0.46±0.05,平均值为0.32±0.13,LCR介于3.75与68.00之间,与对侧有显著性差异(p0.0001)。影像学标记物中,FLAIR血管高信号与动脉通过伪影在症状性亚组患者中显著高于非症状亚组(p=0.031),且两者之间存在良好的一致性(kappa=0.683)。病例组 IL-6(p=0.009)、IGF-1(p=0.003)、VCAM-1(p=0.017)水平显著高于对照组,且在症状亚组分析中无显著性差异。IL-6作为脑卒中复发相关的血清学标记物,临界值为6.6pg/ml。结论:颅内动脉粥样硬化性患者病程的急慢性期均存在血管新生现象,与末次脑缺血事件后时间无显著相关性。炎症因子IL-6、IGF-1、VCAM-1在有脑血管事件史的重度颅内动脉粥样硬化性狭窄或闭塞患者血清中水平明显高于健康人群,其中IL-6可能与脑卒中复发风险相关。
[Abstract]:Objective: intracranial large atherosclerotic stenosis is an important cause of ischemic stroke, and patients have higher risk of ischemic stroke and recurrence. Angiogenesis, as one of the collateral circulation pathways, plays an important compensatory role in the blood flow perfusion in the narrow vascular basin. Inflammatory cytokines are closely related in acute ischemic stroke patients with nerve injury and repair, and can regulate the process of angiogenesis with various angiogenic factors interaction, expression of chronic hypoxia induced intracranial atherosclerotic patients with inflammatory factors, although the test in vitro and animal model of evidence, but the actual effect on in clinical samples is unknown. In this study, we evaluated the intracranial angiogenesis in patients with intracranial atherosclerotic stenosis by molecular imaging, and explored the possible role of inflammatory factors in angiogenesis in patients with intracranial artery stenosis. Methods: in 17 patients with cerebrovascular events in the history of intracranial atherosclerotic stenosis or occlusion in patients with high sensitivity C reactive protein in serum by automatic biochemical analyzer and enzyme-linked immunosorbent assay for detection of alpha v beta 3 integrin and lipoprotein associated phospholipase A2 level quantitative protein chip alpha, interleukin IL-1 IL-1, IL-4, IL-6, beta IL-8, IL-10, IL-17, ICAM-1 and cell adhesion molecule VCAM-1 and TNF- alpha, TGF- beta, IFN- gamma, IGF-1 serum concentrations were measured, and compared with controls. Among which 10 cases were checked by 68Ga-PRGD2PET/MR, determined by visual analysis of high uptake lesions, regions of interest were measured and high uptake foci ipsilateral and contralateral to the standard uptake value peak and average values, and the corresponding position of arterial spin labeling image the cerebral blood flow, the calculation of bilateral ratio, and systematic evaluation of the collateral circulation patients. Taking the time of 6 months after the last cerebral ischemia as the critical value, the case group was divided into symptom subgroup and non symptom subgroup. Results: of the 10 patients who underwent PET/MR examination, 6 patients had PRGD2 high ingestion, the standard uptake peak value was 0.46 + 0.05, the mean value was 0.32 + 0.13, LCR was between 3.75 and 68, and there was a significant difference from the contralateral side (P0.0001). In the imaging markers, FLAIR vascular hyperintensity and arterial artifact were significantly higher in the symptomatic subgroup than those in the non symptomatic subgroup (p=0.031), and there was a good agreement between them (kappa=0.683). The levels of IL-6 (p=0.009), IGF-1 (p=0.003) and VCAM-1 (p=0.017) in the case group were significantly higher than those in the control group, and there was no significant difference in the subgroup analysis of the symptoms. IL-6 is a serological marker associated with stroke recurrence, with a critical value of 6.6pg/ml. Conclusion: there are angiogenic phenomena in the acute and chronic period of the course of intracranial atherosclerotic patients, and there is no significant correlation with the time after the last cerebral ischemia. Inflammatory factors IL-6, IGF-1 and VCAM-1 levels in serum of patients with severe intracranial atherosclerotic stenosis or occlusion with cerebrovascular events were significantly higher than those in healthy subjects. IL-6 may be associated with recurrence risk of stroke.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R743.3

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