急性缺血性脑卒中患者内皮祖细胞的动员
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摘要
背景血管内皮功能异常诱发动脉粥样硬化和血栓形成致血管闭塞是急性缺血性脑卒中(acute ischemic stroke, AIS)发生的关键环节。内皮祖细胞(endothelial progenitor cells,EPCs)为一群骨髓来源的CD34+/KDR+/CD133+细胞,存在于外周循环中,具有增殖和分化为内皮细胞的能力。作为细胞储存库,EPCs可随时替代功能丧失的内皮,有助于维持内皮完整性[1],阻止动脉粥样硬化的发生和发展。同时,作为组织缺血的反应,EPCs从骨髓动员后进入外周循环分化为成熟内皮细胞参与血管再生促使缺血事件的恢复[2,3]。基质细胞衍生因子-1(stromal cell-derived factor-1,SDF-1),属于CXC族的趋化因子家族成员,可与EPCs表面受体CXCR4结合,促进EPCs向缺血或血管损伤处归巢[4]。
目的本研究动态测定了AIS患者外周循环中EPCs数量,与脑血管病相关危险因子、梗死体积等进行相关性分析;同时检测外周循环中SDF-1的含量,以探讨AIS后EPCs的动员机制。
方法随机选取2008年11月至2009年12月重庆医科大学附属第二医院神经内科发病时间在24h内的AIS住院患者(AIS组)20例,同期选择年龄配对的健康志愿者20人作为正常对照组。抽取静脉血分离单个核细胞,以CD34+/KDR+细胞作为EPCs标记,进行流式细胞分析,分别检测AIS发病后第1,7,14,21d的EPCs数量,并采用酶联免疫吸附法检测SDF-1浓度。EPCs变化率定义为(EPC14d-EPC1d)与EPC1d比值。
结果(1)AIS组循环EPCs基线水平低于正常对照组(0.022±0.013 vs 0.051±0.020;P<0.01)。(2)基于秩次的Spearman等级相关分析显示:AIS组基线EPCs数量与收缩压、舒张压、甘油三酯、低密度脂蛋白、空腹血糖等多种脑血管危险因素呈负相关(r值分别为-0.953,-0.864,-0.545,―0.623,―0.587;P值均<0.01);与年龄、性别、高密度脂蛋白无显著相关性(P>0.05)。多元逐步回归分析显示,收缩压和低密度脂蛋白是影响EPCs水平的主要独立因素。(3)AIS组患者循环EPCs数量于发病后7d升高,14d达到高峰值,21d呈下降趋势。AIS组患者EPCs变化率与梗死体积正相关(r= 0.692;P<0.01);(4)AIS组患者发病后第7d外周循环SDF-1含量明显升高,14d达到高峰,21d呈降低趋势。14d时SDF-1含量与梗死体积正相关(r=0.774;P<0.01)。( 5 ) AIS组患者EPCs变化率与14d SDF-1含量正相关(r=0.682;P<0.01)。
结论AIS患者基线EPCs数量较正常对照组低,与脑血管危险因素存在相关性。AIS发病后外周循环EPCs水平增加,提示作为脑梗死后的应激反应,EPCs从骨髓动员后进入外周循环。AIS后EPCs的动员可能与缺血脑组织SDF-1表达增加相关。
Background
Vascular endothelial dysfunction induce atherosclerosis and thrombosis of vascular occlusion, which plays a key role in acute ischemic stroke (AIS).Endothelial progenitor cells (EPCs), a group of bone marrow-derived CD34+ / KDR+ / CD133+ cells, present in the peripheral circulation with the ability to proliferate and differentiate into endothelial cells. As a cell repository, EPCs can replace endothelial cells which lost function, therefore help to maintain endothelial integrity[1]and prevent the occurrence and development of atherosclerosis. On the other hand, as a response to tissue ischemia, EPCs can be mobilized from bone marrow into peripheral circulation and differentiate into mature endothelial which involved in angiogenesis to promote the recovery of ischemic events[2,3]. Stromal cell-derived factor -1 (SDF-1), one member of CXC chemokine family, can combine with EPCs surface receptor CXCR4 and promote EPCs to homing to ischemic or vascular injury site[4].
Objectives
To test the hypothesis that EPCs mobilization occurs after acute ischemic stroke, we evaluated the number of EPCs in the process of acute stroke.,meanwhile we determined SDF-1 contnet of in peripherial blood to investigate the mechanism of EPCs Mobilization after AIS.
Methods
This study included consecutively admitted patients with AIS between November 2008 and December 2009 at Second Affiliated Hospital of Chongqing Medical University, Department of Neurology. The level of circulating EPCs (surface markers:CD34/KDR) were examined using flow cytometry at days 1, 7, 14 and 21 after acute stroke. Meanwhile, SDF-1 content was determinated by enzyme-linked immunosorbent assay. EPCs change rate was defined as (EPC14d-EPC1d) and EPC1d ratio. Results
(1) Baseline level of circulating EPCs was significantly lower in patients with AIS than the control group (0.022±0.013 vs 0.051±0.020; P<0.01). (2) Based on the Spearman rank correlation analysis,results showed blood pressure, triglyceride, LDL, fasting plasma glucose were negatively correlated (r =-0.953,-0.864, -0.545, -0.623, -0.587; P<0.01)with EPCs counts. Multiple stepwise regression analysis showed systolic blood pressure and LDL as independent predictors of EPCs levels.(3) The mumber of circulating EPCs gradually increased at day 7 after AIS, reached peak level at day 14,and decreased at day 21. EPCs change rate was positively correlated with infarct volume (r = 0.692; P<0.01).(4) The content of SDF-1 significantly increased at day 7 after AIS, reached peak level at day 14,and decreased at day 21. SDF-1 content at day 14 was positively correlated with infarct volume (r = 0.774; P<0.01). (5) EPCs change rate in patients with AIS was positively correlated with SDF-1 content at day 14(r = 0.682; P<0.01).
Conclusions
The Baseline level of circulating EPCs was lower in patients with AIS than control group. SBP and LDL are independent factors of reduced EPCs numbers.An increment of circulating EPCs may result from the mobilization of EPCs in response to stroke stress.The mechanism of EPCs mobilization maybe associated with an increased expression of SDF-1.
目的本研究动态测定了AIS患者外周循环中EPCs数量,与脑血管病相关危险因子、梗死体积等进行相关性分析;同时检测外周循环中SDF-1的含量,以探讨AIS后EPCs的动员机制。
方法随机选取2008年11月至2009年12月重庆医科大学附属第二医院神经内科发病时间在24h内的AIS住院患者(AIS组)20例,同期选择年龄配对的健康志愿者20人作为正常对照组。抽取静脉血分离单个核细胞,以CD34+/KDR+细胞作为EPCs标记,进行流式细胞分析,分别检测AIS发病后第1,7,14,21d的EPCs数量,并采用酶联免疫吸附法检测SDF-1浓度。EPCs变化率定义为(EPC14d-EPC1d)与EPC1d比值。
结果(1)AIS组循环EPCs基线水平低于正常对照组(0.022±0.013 vs 0.051±0.020;P<0.01)。(2)基于秩次的Spearman等级相关分析显示:AIS组基线EPCs数量与收缩压、舒张压、甘油三酯、低密度脂蛋白、空腹血糖等多种脑血管危险因素呈负相关(r值分别为-0.953,-0.864,-0.545,―0.623,―0.587;P值均<0.01);与年龄、性别、高密度脂蛋白无显著相关性(P>0.05)。多元逐步回归分析显示,收缩压和低密度脂蛋白是影响EPCs水平的主要独立因素。(3)AIS组患者循环EPCs数量于发病后7d升高,14d达到高峰值,21d呈下降趋势。AIS组患者EPCs变化率与梗死体积正相关(r= 0.692;P<0.01);(4)AIS组患者发病后第7d外周循环SDF-1含量明显升高,14d达到高峰,21d呈降低趋势。14d时SDF-1含量与梗死体积正相关(r=0.774;P<0.01)。( 5 ) AIS组患者EPCs变化率与14d SDF-1含量正相关(r=0.682;P<0.01)。
结论AIS患者基线EPCs数量较正常对照组低,与脑血管危险因素存在相关性。AIS发病后外周循环EPCs水平增加,提示作为脑梗死后的应激反应,EPCs从骨髓动员后进入外周循环。AIS后EPCs的动员可能与缺血脑组织SDF-1表达增加相关。
Background
Vascular endothelial dysfunction induce atherosclerosis and thrombosis of vascular occlusion, which plays a key role in acute ischemic stroke (AIS).Endothelial progenitor cells (EPCs), a group of bone marrow-derived CD34+ / KDR+ / CD133+ cells, present in the peripheral circulation with the ability to proliferate and differentiate into endothelial cells. As a cell repository, EPCs can replace endothelial cells which lost function, therefore help to maintain endothelial integrity[1]and prevent the occurrence and development of atherosclerosis. On the other hand, as a response to tissue ischemia, EPCs can be mobilized from bone marrow into peripheral circulation and differentiate into mature endothelial which involved in angiogenesis to promote the recovery of ischemic events[2,3]. Stromal cell-derived factor -1 (SDF-1), one member of CXC chemokine family, can combine with EPCs surface receptor CXCR4 and promote EPCs to homing to ischemic or vascular injury site[4].
Objectives
To test the hypothesis that EPCs mobilization occurs after acute ischemic stroke, we evaluated the number of EPCs in the process of acute stroke.,meanwhile we determined SDF-1 contnet of in peripherial blood to investigate the mechanism of EPCs Mobilization after AIS.
Methods
This study included consecutively admitted patients with AIS between November 2008 and December 2009 at Second Affiliated Hospital of Chongqing Medical University, Department of Neurology. The level of circulating EPCs (surface markers:CD34/KDR) were examined using flow cytometry at days 1, 7, 14 and 21 after acute stroke. Meanwhile, SDF-1 content was determinated by enzyme-linked immunosorbent assay. EPCs change rate was defined as (EPC14d-EPC1d) and EPC1d ratio. Results
(1) Baseline level of circulating EPCs was significantly lower in patients with AIS than the control group (0.022±0.013 vs 0.051±0.020; P<0.01). (2) Based on the Spearman rank correlation analysis,results showed blood pressure, triglyceride, LDL, fasting plasma glucose were negatively correlated (r =-0.953,-0.864, -0.545, -0.623, -0.587; P<0.01)with EPCs counts. Multiple stepwise regression analysis showed systolic blood pressure and LDL as independent predictors of EPCs levels.(3) The mumber of circulating EPCs gradually increased at day 7 after AIS, reached peak level at day 14,and decreased at day 21. EPCs change rate was positively correlated with infarct volume (r = 0.692; P<0.01).(4) The content of SDF-1 significantly increased at day 7 after AIS, reached peak level at day 14,and decreased at day 21. SDF-1 content at day 14 was positively correlated with infarct volume (r = 0.774; P<0.01). (5) EPCs change rate in patients with AIS was positively correlated with SDF-1 content at day 14(r = 0.682; P<0.01).
Conclusions
The Baseline level of circulating EPCs was lower in patients with AIS than control group. SBP and LDL are independent factors of reduced EPCs numbers.An increment of circulating EPCs may result from the mobilization of EPCs in response to stroke stress.The mechanism of EPCs mobilization maybe associated with an increased expression of SDF-1.
引文
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[2] Werner N,Kosiol S,Schiegl T,et al. Circulating endothelial progenitor cells and cardiovascular outcomes.N Engl [J]. Med.2005;353:999-1007.
[3] Schmidt-Lucke C,Rossig L,Fichtlscherer S,et al.Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events:proof of concept for the clinical importance of endogenous vascular repair[J].Cir culation.2005;111:2981-2987.
[4] Moore MA,Hattori K,Heissig B.et a1.Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector-mediated elevation of serum levels of SDF-1,VEGF,and angiopoietin-l [J]. Ann N Y Acad Sci,2001,938(1) 36-45.
[5] Asahara T, Murohara T, Sullivan A. Isolation of putative endothelial progenitor cells for angiogenesis[J].Science. 1997;275:964 -967.
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