血浆IL-8和中性粒细胞表面CD11b/CD18在急性冠脉综合征及PCI术后变化的研究
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摘要
目的与研究背景
冠状动脉粥样斑块不稳定、破裂和随即的血小板聚集和血栓形成是急性冠脉综合征的重要发病机制。已有大量证据表明炎症在不稳定斑块的发生、演变以及斑块破裂过程中起着至关重要的作用。一些与AS相关的炎症细胞产生和释放大量细胞因子，激活血管内皮细胞，改变其本身的抗粘附性和抗凝性。此外，炎症细胞因子减少基质合成，增加其降解，导致斑块破裂，进一步促进ACS的发生发展。近年来研究，血浆IL-8和中性粒细胞表面粘附分子CD11b/CD18是机体重要的炎症反应标志物，参与机体的炎症反应，在冠状动脉粥样硬化病理的发生发展中起着重要的作用。IL-8作为重要的炎症因子，上调PMN表面CD11b/CD18的表达，CD11b/CD18为粘附分子β2整合素超家族中的一员，它可促进PMN与内皮细胞粘附并浸润而发生炎症反应，激活的CD11b/CD18可直接激活凝血因子X为Xa，上调白细胞与纤维蛋白原结合可促进促凝反应，也促进了血小板与白细胞相互作用，进一步激活血小板及血栓形成，以上都导致了斑块不稳定及ACS的发生。大量研究表明PCI术后再狭窄与炎症反应的激活有关。目前关于血浆IL-8及CD11b/CD18表达与ACS的发生相关的报道较少。本研究主要目的于探讨血浆IL-8及中性粒细胞表面CD11b/CD18水平与急性冠脉综合征的关系，并比较行PTCA及支架置入术前后IL-8、CD11b/CD18变化及意义。
方法
1．病例选择 选择2002年11月至2003年9年于吉林大学第二医院心内科住院病人，根据WHO1979年制订标准分为AMI、UA及SA三组。AMI病人15例包括13例Q波心梗及2例非Q波心梗。UA诊断18例包括初发性
心绞痛、恶化劳力性心绞痛、自发性心绞痛和梗塞后心绞痛（不包括变异性心绞痛）。其中12例行PTCA及支架置入术。SA组12例，6个月内胸痛发作频率、强度及诱因无明显变化。10例正常对照组，来自于健康体检者，其年龄、性别等因素与病例组相匹配。以上组均排除外恶性肿瘤、急慢性感染、自身免疫性疾病、外伤等疾病，同时除外冠心病以外的其他心脏疾病如心衰、风湿性心脏病等。
2．血样采集 病人于入院后24小时内采肘静脉血2mL，如行PTCA及支架置入术，于术后24小时内再次采静脉血2mL，均加入含有EDTA的抗凝塑料管中，即刻送往实验室行流式细胞仪检查；同时抽取肘静脉血2mL于EDTA的抗凝塑料管中，以1500转/分离心20分钟，分离出血浆后存储在-80℃冰箱中待测。正常对照组为清晨空腹采血。
3．IL-8的测定 应用双抗体夹心ABC-ELISA法分别测定患者血浆中IL-8的含量。
4．CD11b/CD18的测定 应用全血流式细胞术检测患者中性粒细胞表面CD11b/CD18的表达。
5.统计学处理 计量资料以±s表示，对照及AMI、UA、SA、三组间比较行单因素方差分析，组间两两比较采用q检验，PCI术前后比较采用配对的t检验，P<0.05有统计学意义。
结果
1．患者的一般临床资料 本研究选择急性冠脉综合征患者33例，其中AMI患者15例，包括13例Q波心梗及2例非Q波心梗。UA患者18例，其中12例行PTCA及支架置入术。SA患者12例，对照健康组10例。各组患者在性别、年龄、吸烟史及血脂等均无显著性差异。ACS患者给予常规阿司匹林、硝酸酯类等治疗。
2．AMI组、UA组、SA组及正常对照组之间中性粒细胞表面表达CD11b/CD18及血浆IL-8水平比较，应用流式细胞仪测中性粒细胞表面CD11b/CD18表达，AMI组（8.98±0.49）和UA组（7.95±0.57）CD11b/CD18水平明显高于SA组（3.13±0.59）及对照组（2.73±0.25）（P<0.05），AMI组CD11b/CD18水平显著高于UA组（P<0.05），SA组与对照组比较无显著差异。
应用ELISA法测定血浆IL-8水平，AMI组（38.69±6.71pg/ml）和UA组（34.72±4.31 pg/ml）IL-8水平明显高于SA组（22.52±2.12 pg/ml）及对照组（19.44±1.38 pg/ml）（P<0.05）。AMI组IL-8水平显著高于UA组（P<0.05）。SA组与对照组比较无显著差异。
3．在UA组中，行PTCA及支架置入术后CD11b/CD18表达及IL-8水平与术前变化的比较，结果表明术后血浆IL-8水平（44.02±7.05pg/ml）及中性粒细胞CD11b/CD18表达水平（13.13±3.50）较术前明显升高。P<0.05，有统计学意义。
结论
急性冠脉综合征患者血浆IL-8水平及中性粒细胞表面CD11b/CD18表达明显升高。
IL-8及CD11b/CD18水平有可能成为不稳定斑块的一个预测指标。
PCI术后IL-8及CD11b/CD18水平升高，可能成为预测术后再狭窄的指标之一。
Background and Objective
Coronary plaque disruption,with consequent platelet aggregation and thrombosis,is the most important mechanism by which atherosclerosis leads to the acute coronary syndrome.There is substantial evidence implicating an inflammatory process in the occurrence,development and disruption of vulnerable plaques.Some inflammotory cell related to atherosclerosis can generate and release cytokines that have the potential to activate the endothelium,transforming its natural antiadhesive and anticoagulant properies.Furthermore,inflammatory cytokinges may reduce matix synthesis and increase its degradation,favouring plaque rupture,contributing to ACS.For some years,some studies have proved that plasma IL-8,the expression of CD11b/CD18 on neutrophile are the important makers of inflammation,participate in the process of inflammation,also playing an important role in the pathogenesis of coronary atherosclerosis .As an important inflammatory cytoking,IL-8 induce the aggregation of inflammatory cells around the plaque,regulate the surface expression on neutrophil of CD11b/CD18.As one of the adhesion β2 integrins family,CD11b/CD18 can reduce adherence and inflitration of PMN and endothelial cells,actimate factor X to Xa,upregulation the bind of leukocytes and fibrinogen resulting in the procoagulant activity of these cells.Also reduces the interaction of leukocytys and platelet,further activate platelet and thrombosis.These process induce the plaque instability and the take place of ACS.Some studies have shown that inflammatory mechamism play an important role in the process of restenosis
after percutaneous coronary interventions,with cell adhesion molecule,including Mac-1(CD11b/CD18),as key mediators.But untill now,there are few reports about the relation among the function of plasma IL-8,the expression of CD11b/CD18 on neutrophile and ACS.In this study ,in order to investigate the relationship among plasma IL-8,the expression of β2- integrin Mac-1(CD11b/CD18) on neutrophile and ACS,contrast to the levels of plasma IL-8,the expression of CD11b/CD18 in the pre- and post-procedual of percutaneous coronary intervantion.
Methods
1．Case select:According to the criteria of CHD diagnosis by WHO in 1979,45 in-patients is selected,divided into AMI,UA,and SA group.There are 15 cases in AMI,18 cases in UA(one of 12 case underwent PTCA and stent implantation),12 cases in SA,and 10 healthy adults as control.Exclusion criteria for all grous were:non-cardiac disease that includes malignant disease,infection,collagen diseases,cardiac disease other than coronary artery disease,except for ,minor mithal regurgition,wentricular failure.
2.Blood sampling protocol: Within 24 hours after patients were admission,2mL peripheral venous blood was drown into plastic anticoagulant tubes containing EDTA,immediately transferred to the laboratory.The patients underwent PTCA and stent implantation ,perpheral blood sample were taken after coronary angioplasty within 24 hours.At the same time,another 2mL venous blood were taken and centrifugating(1500g for 20 min).The plasma supernatant was store at -80℃ until analysis.
3.Measure of IL-8:Concentration of IL-8 in plasma was measured using ABC-ELISA.
4.Measure of CD11b/CD18:The expression of CD11b/CD18 on neutrophile was measured by flow cytometry.
5.Statistical analysis:Numerical variable datas expressed by X±s.The datas compared between groups used analysis of variance and q-test.The comparede pre- and post-PCI used t-test.P<0.05 that meant significant difference.
Results
1.Genera clinical data:All groups were comparable with respect to age ,sex,risk facor profile,such as smoking,blood lipid
2.CD11b/CD18 on neutrophile and IL-8 in plasma:CD11b/CD18 on neutrophile was detected by cytometry,the results show that the expression of CD11b/CD18 in both AMI group（8.98±0.49）and UA group （7.95±0.57）is higher than that of SA group （3.13±0.59）and control group（2.73±0.25）（P<0.05）.Compare with UA group,the CD11b/CD18 of AMI group are higher(P<0.05),and ther
冠状动脉粥样斑块不稳定、破裂和随即的血小板聚集和血栓形成是急性冠脉综合征的重要发病机制。已有大量证据表明炎症在不稳定斑块的发生、演变以及斑块破裂过程中起着至关重要的作用。一些与AS相关的炎症细胞产生和释放大量细胞因子，激活血管内皮细胞，改变其本身的抗粘附性和抗凝性。此外，炎症细胞因子减少基质合成，增加其降解，导致斑块破裂，进一步促进ACS的发生发展。近年来研究，血浆IL-8和中性粒细胞表面粘附分子CD11b/CD18是机体重要的炎症反应标志物，参与机体的炎症反应，在冠状动脉粥样硬化病理的发生发展中起着重要的作用。IL-8作为重要的炎症因子，上调PMN表面CD11b/CD18的表达，CD11b/CD18为粘附分子β2整合素超家族中的一员，它可促进PMN与内皮细胞粘附并浸润而发生炎症反应，激活的CD11b/CD18可直接激活凝血因子X为Xa，上调白细胞与纤维蛋白原结合可促进促凝反应，也促进了血小板与白细胞相互作用，进一步激活血小板及血栓形成，以上都导致了斑块不稳定及ACS的发生。大量研究表明PCI术后再狭窄与炎症反应的激活有关。目前关于血浆IL-8及CD11b/CD18表达与ACS的发生相关的报道较少。本研究主要目的于探讨血浆IL-8及中性粒细胞表面CD11b/CD18水平与急性冠脉综合征的关系，并比较行PTCA及支架置入术前后IL-8、CD11b/CD18变化及意义。
方法
1．病例选择 选择2002年11月至2003年9年于吉林大学第二医院心内科住院病人，根据WHO1979年制订标准分为AMI、UA及SA三组。AMI病人15例包括13例Q波心梗及2例非Q波心梗。UA诊断18例包括初发性
心绞痛、恶化劳力性心绞痛、自发性心绞痛和梗塞后心绞痛（不包括变异性心绞痛）。其中12例行PTCA及支架置入术。SA组12例，6个月内胸痛发作频率、强度及诱因无明显变化。10例正常对照组，来自于健康体检者，其年龄、性别等因素与病例组相匹配。以上组均排除外恶性肿瘤、急慢性感染、自身免疫性疾病、外伤等疾病，同时除外冠心病以外的其他心脏疾病如心衰、风湿性心脏病等。
2．血样采集 病人于入院后24小时内采肘静脉血2mL，如行PTCA及支架置入术，于术后24小时内再次采静脉血2mL，均加入含有EDTA的抗凝塑料管中，即刻送往实验室行流式细胞仪检查；同时抽取肘静脉血2mL于EDTA的抗凝塑料管中，以1500转/分离心20分钟，分离出血浆后存储在-80℃冰箱中待测。正常对照组为清晨空腹采血。
3．IL-8的测定 应用双抗体夹心ABC-ELISA法分别测定患者血浆中IL-8的含量。
4．CD11b/CD18的测定 应用全血流式细胞术检测患者中性粒细胞表面CD11b/CD18的表达。
5.统计学处理 计量资料以±s表示，对照及AMI、UA、SA、三组间比较行单因素方差分析，组间两两比较采用q检验，PCI术前后比较采用配对的t检验，P<0.05有统计学意义。
结果
1．患者的一般临床资料 本研究选择急性冠脉综合征患者33例，其中AMI患者15例，包括13例Q波心梗及2例非Q波心梗。UA患者18例，其中12例行PTCA及支架置入术。SA患者12例，对照健康组10例。各组患者在性别、年龄、吸烟史及血脂等均无显著性差异。ACS患者给予常规阿司匹林、硝酸酯类等治疗。
2．AMI组、UA组、SA组及正常对照组之间中性粒细胞表面表达CD11b/CD18及血浆IL-8水平比较，应用流式细胞仪测中性粒细胞表面CD11b/CD18表达，AMI组（8.98±0.49）和UA组（7.95±0.57）CD11b/CD18水平明显高于SA组（3.13±0.59）及对照组（2.73±0.25）（P<0.05），AMI组CD11b/CD18水平显著高于UA组（P<0.05），SA组与对照组比较无显著差异。
应用ELISA法测定血浆IL-8水平，AMI组（38.69±6.71pg/ml）和UA组（34.72±4.31 pg/ml）IL-8水平明显高于SA组（22.52±2.12 pg/ml）及对照组（19.44±1.38 pg/ml）（P<0.05）。AMI组IL-8水平显著高于UA组（P<0.05）。SA组与对照组比较无显著差异。
3．在UA组中，行PTCA及支架置入术后CD11b/CD18表达及IL-8水平与术前变化的比较，结果表明术后血浆IL-8水平（44.02±7.05pg/ml）及中性粒细胞CD11b/CD18表达水平（13.13±3.50）较术前明显升高。P<0.05，有统计学意义。
结论
急性冠脉综合征患者血浆IL-8水平及中性粒细胞表面CD11b/CD18表达明显升高。
IL-8及CD11b/CD18水平有可能成为不稳定斑块的一个预测指标。
PCI术后IL-8及CD11b/CD18水平升高，可能成为预测术后再狭窄的指标之一。
Background and Objective
Coronary plaque disruption,with consequent platelet aggregation and thrombosis,is the most important mechanism by which atherosclerosis leads to the acute coronary syndrome.There is substantial evidence implicating an inflammatory process in the occurrence,development and disruption of vulnerable plaques.Some inflammotory cell related to atherosclerosis can generate and release cytokines that have the potential to activate the endothelium,transforming its natural antiadhesive and anticoagulant properies.Furthermore,inflammatory cytokinges may reduce matix synthesis and increase its degradation,favouring plaque rupture,contributing to ACS.For some years,some studies have proved that plasma IL-8,the expression of CD11b/CD18 on neutrophile are the important makers of inflammation,participate in the process of inflammation,also playing an important role in the pathogenesis of coronary atherosclerosis .As an important inflammatory cytoking,IL-8 induce the aggregation of inflammatory cells around the plaque,regulate the surface expression on neutrophil of CD11b/CD18.As one of the adhesion β2 integrins family,CD11b/CD18 can reduce adherence and inflitration of PMN and endothelial cells,actimate factor X to Xa,upregulation the bind of leukocytes and fibrinogen resulting in the procoagulant activity of these cells.Also reduces the interaction of leukocytys and platelet,further activate platelet and thrombosis.These process induce the plaque instability and the take place of ACS.Some studies have shown that inflammatory mechamism play an important role in the process of restenosis
after percutaneous coronary interventions,with cell adhesion molecule,including Mac-1(CD11b/CD18),as key mediators.But untill now,there are few reports about the relation among the function of plasma IL-8,the expression of CD11b/CD18 on neutrophile and ACS.In this study ,in order to investigate the relationship among plasma IL-8,the expression of β2- integrin Mac-1(CD11b/CD18) on neutrophile and ACS,contrast to the levels of plasma IL-8,the expression of CD11b/CD18 in the pre- and post-procedual of percutaneous coronary intervantion.
Methods
1．Case select:According to the criteria of CHD diagnosis by WHO in 1979,45 in-patients is selected,divided into AMI,UA,and SA group.There are 15 cases in AMI,18 cases in UA(one of 12 case underwent PTCA and stent implantation),12 cases in SA,and 10 healthy adults as control.Exclusion criteria for all grous were:non-cardiac disease that includes malignant disease,infection,collagen diseases,cardiac disease other than coronary artery disease,except for ,minor mithal regurgition,wentricular failure.
2.Blood sampling protocol: Within 24 hours after patients were admission,2mL peripheral venous blood was drown into plastic anticoagulant tubes containing EDTA,immediately transferred to the laboratory.The patients underwent PTCA and stent implantation ,perpheral blood sample were taken after coronary angioplasty within 24 hours.At the same time,another 2mL venous blood were taken and centrifugating(1500g for 20 min).The plasma supernatant was store at -80℃ until analysis.
3.Measure of IL-8:Concentration of IL-8 in plasma was measured using ABC-ELISA.
4.Measure of CD11b/CD18:The expression of CD11b/CD18 on neutrophile was measured by flow cytometry.
5.Statistical analysis:Numerical variable datas expressed by X±s.The datas compared between groups used analysis of variance and q-test.The comparede pre- and post-PCI used t-test.P<0.05 that meant significant difference.
Results
1.Genera clinical data:All groups were comparable with respect to age ,sex,risk facor profile,such as smoking,blood lipid
2.CD11b/CD18 on neutrophile and IL-8 in plasma:CD11b/CD18 on neutrophile was detected by cytometry,the results show that the expression of CD11b/CD18 in both AMI group（8.98±0.49）and UA group （7.95±0.57）is higher than that of SA group （3.13±0.59）and control group（2.73±0.25）（P<0.05）.Compare with UA group,the CD11b/CD18 of AMI group are higher(P<0.05),and ther
引文
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Mazzone A,De Servi S,Riceruti G.Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease.Circulation 1993;88:358-363