兔腹主动脉球囊损伤后IL-8对VSMCs增殖的影响
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摘要
经皮冠状动脉腔内成形术(percutaneous transluminal coronary angioplasty,PTCA)是治疗冠心病安全、有效的方法,但术后3～6个月再狭窄发生率达30%～50%,严重影响其远期疗效。再狭窄的发生机制至今尚未完全阐明。目前,大多数学者认为血管平滑肌细胞向内膜下迁移并过度增殖是其关键环节之一,因此血管平滑肌细胞增殖的调节成为研究的焦点。一些研究资料显示球囊损伤后血管再狭窄与血管弹性回缩、血栓的形成和机化,血管平滑肌细胞(VSMCs)过度增殖及细胞外基质的聚集等有关。其中VSMCs的过度增殖可能是再狭窄形成的主要原因,对血管进行球囊扩张后,血管内皮和中膜平滑肌细胞受到牵拉、损伤,在修复过程中在一系列生长因子的刺激作用下,VSMCs过度增殖、并向内膜方向迁移。因而抑制VSMCs过度增殖以防治再狭窄成为广大医务工作者关注和研究的课题。
白细胞介素-8(Interleukin-8,IL-8)是趋化因子CXC亚家族的一员,主要由单核细胞产生,其主要生理活性是趋化和激活中性粒细胞并分泌大量的黏附分子,使中性粒细胞表面CD11b/CD18受体上调。IL-8可以诱导平滑肌细胞的增殖和迁移,是一个促血管生成因子,在炎症反应过程中起着重要的作用。IL-8能促使单核细胞在内皮细胞上的滚动转变成强有力的黏附。研究发现,升高的IL-8水平与冠状动脉疾病的发病有关,并且可以作为心脏事件的预测因子。
目的:本研究通过球囊扩张拉伤兔腹主动脉,建立动脉再狭窄模型,造影检查腹主动脉管腔狭窄变化情况,采用组织病理观察血管球囊扩张术后内膜和中层平滑肌的结构改变,利用免疫组化技术观察IL-8蛋白阳性表达和PCNA阳性表达细胞数,研究IL-8对血管平滑肌细胞(VSMCs)增殖的影响,为防治PCI术后再狭窄提供可靠的理论依据。
方法:选择雄性新西兰大白兔24只为实验对象,体重2.50-3.25kg,由河北医科大学实验动物中心提供。以上实验动物随机分为实验组(experiment group)、治疗组(treatment group)和假手术组(sham group),每组各8只动物。实验组和治疗组动物通过穿刺股动脉,送入球囊拉伤腹主动脉。治疗组动物通过耳缘静脉注射IL-8单克隆抗体进行干预。假手术组动物只进行股动脉穿刺和留置鞘管,不进行球囊扩张拉伤。
1.分别于实验前,实验后4小时、1天、3天,1周、2周、4周,耳缘静脉采血4ml,检测三组动物血清IL-8水平。
2.术后4周时处死动物进行病理组织学检查,应用光学显微镜和计算机病理图象分析系统分析测定以下指标:内膜中膜厚度、面积,计算血管狭窄程度[(邻近正常血管管径-狭窄段最小管径)/邻近正常血管管径]。
3.利用免疫组化染色技术观察IL-8蛋白表达情况,增殖细胞核抗原PCNA染色分析后,用光学显微镜和计算机病理图象分析系统测定每40倍视野中PCNA阳性细胞比例,计算阳性细胞数和阳性细胞百分率。
结果:
1.三组实验动物之间体重、月龄、血脂等一般情况比较,差异无统计学意义(P>0.05)。
2.术前IL-8水平比较,实验组、治疗组、假手术组三组之间无明显差异,实验组动物球囊损伤4小时后IL-8水平即开始升高,术后1d达到峰值,持续增高4周,且明显高于治疗组和假手术组。治疗组和假手术组动物IL-8水平无上述变化规律。
3.实验组动物腹主动脉明显狭窄,组织学检查内膜面积和中膜面积、血管狭窄程度等指标大于治疗组和假手术组(P<0.01),治疗组管腔有所狭窄,假手术组动物管腔无明显变化,治疗组与假手术组无显著性差异(P>0.05)。相关分析显示,IL-8水平与内膜厚度、内膜面积、中膜厚度、中膜面积等呈正相关(相关系数r分别为0.905,0.897,0.852,0.846,P均<0.01)。
4.免疫组化显示,实验组与治疗组和假手术组比较,IL-8蛋白阳性表达明显升高(P<0.05),治疗组高于假手术组,无明显差异。PCNA阳性细胞比例比较,实验组明显高于治疗组与假手术组(P<0.05),治疗组明显高于假手术组(P<0.05)。相关分析显示IL-8阳性表达细胞数与PCNA阳性细胞数呈正相关,相关系数r=0.857(P<0.01)。
结论:
1.通过介入方法进行球囊拉伤可成功建立兔腹主动再狭窄动物模型。
2.腹主动脉球囊损伤后IL-8水平高表达,血管明显狭窄,经IL-8单克隆抗体治疗后,动脉狭窄程度明显减轻。IL-8水平与动脉狭窄程度呈正相关。
3.球囊损伤引起腹主动脉局部IL-8水平高表达,并导致血管平滑肌细胞增殖。经IL-8单克隆抗体治疗后,IL-8水平下降,并抑制平滑肌细胞的增殖。
Percutaneous transluminal coronary angioplasty (PTCA) was a safe and effective method to treat coronary artery disease, but the restenosis rate after 3 to 6 months of the operation could reach to 30% to 50%, that seriously affected their long-term effects. The mechanism of restenosis had not yet been fully clarified. At present, most scholars believed that the migration to the subintimal and excessive proliferation of the vascular smooth muscle cells was essential, therefore the regulation of the proliferation of vascular smooth muscle cells became the focus of the study. Some research data showed that the restenosis after balloon injury was associated with vascular recoil, thrombus formation, excessive proliferation of VSMCs and accumulation of extracellular matrix. The excessive proliferation of VSMCs might be the main reason for the formation of restenosis. After the balloon dilation of blood vessels, vascular endothelial and medial smooth muscle cells were stretched and damaged. the VSMCs could excessive proliferated and moved to the inner membrance under the stimulation of series growth factors during the repair process. Therefore to inhibit the excessive proliferation of VSMCs to prevent and cure the restenosis was a subject concerned and researched by medical workers.
Interleukin -8 (IL-8) was a member of the CXC chemokine subfamily, and mainly produced by mononuclear cells. The chief physiological activity of IL-8 was to chemokine and activate the neutrophils and secrete a large number of adhesion molecules to increase the receptors of CD11b/CD18 on the surface of neutrophil cells. IL-8 was a pro-angiogenic factor which could induce the proliferation and migration of smooth muscle cells and played an important role in the process of inflammatory response. IL-8 could promote monocyte rolling on endothelial cells into a strong adhesion. The study found that elevated levels of IL-8 was related to the pathogenesis of coronary artery disease, and could be used as the predictors of cardiac events.
Objective: In this study, animal models of restenosis were made by balloon inflation in abdominal aorta of rabbits. The extent of luminal stenosis was examined by angiography. The structural change of intima andmedium were observed by means of pathology. The expression of IL-8 protein and PCNA-positive cells were surveyed using immunohistochemistry technology. The influence of IL-8 levels on proliferation of vascular smooth muscle cells was studied systemly. Our study would provide a reliable theoretical basis for the prevention and treatment of restenosis after PCI.
Methods: Twenty-four male New Zealand white rabbits were selected. They were purchased from the Test Animal Center of Hebei Medical University, weighted from 2.5kg to 3.25 kg. They were randomly assigned to experiment group (n=8),treatment group (n=8) and sham group (n=8). Rabbits in experiment group and treatment group were injuried in abdominal aorta by balloon inflation after punctured in femoral artery. Monoclonal antibody of IL-8 was injected by venous in rabbits of treatment group. Rabbits in sham group were punctured only in femoral artery.
1.The peripheral blood was collected at the time of before the experiment and four hours、one day、three days、one week、two weeks、four weeks after the operation. The levels of IL-8 were measured by enzyme linked immunosorbent assay (ELISA) respectively.
2. Put the rabbits to death 4 weeks after the surgery and take an histopathologic examination, contented such as luminal area, intima and tunica media area, angiostenosis of blood vessel were assayed by light microscope and computer image analysis system.
3.The expression of IL-8 protein was examined by means of immunohistochemistry staining technology. After proliferating cell nuclear antigen (PCNA) stained, the ratio of masculine cells was calculated per 40 times field of vision using light microscope and computer image analysis system. Index of masculine cells was determined.
Results:
1. There was no statistical difference among the three groups of experimental animals in general data (P>0.05).
2. The preoperative levels of IL-8 was no significant difference among the three groups. The levels of IL-8 in the rabbits of experiment group began to raise in four hours and achieved to peak in one day after balloon inflation. The higher levels of this inflammatory factor would last four weeks. There was no variation above in treatment and sham group.
3. It was observed that the abdominal aorta become stenosis obviously in experiment group. The area of intima and tunica media as well as extent of stenosis in experiment group were bigger than those in treatment group and sham group. There was no statistical difference between treatment and sham group. Correlation analysis indicated that there were positive relations between IL-8 and luminal area, area of intima and tunica medias respectively(r=0.905,0.897,0.852,0.846,P<0.01).
4. It showed that the expression of IL-8 protein in experiment group was significantly higher than others (P<0.05). There was no statistical difference between treatment group and sham group. Compared with treatment group and sham group, the number and ratio of PCNA in experiment group increased significantly (P<0.05). Treatment group was higher than sham group (P<0.05). Correlation analysis showed that expression of IL-8-positive cells and PCNA-positive cells was positively correlated, the correlation coefficient r = 0.857 (P<0.01).
Conclusions:
1 The restenosis model in abdominal aorta of rabbits could be established successfully by means of intervention which injuried aorta with balloon inflation;
2 The high levels of IL-8 was caused by balloon injury in abdominal aorta. The severity of stenosis became lessen after intervention by monoclonal antibody of IL-8. Positive corelation was found between level of IL-8 and severity of arterial stenosis.
3 The higher expression of IL-8 protein was caused by balloon injury in abdominal aorta. It led to proliferation of vascular smooth muscle cells. The level of IL-8 protein decreased after intervention by monoclonal antibody of IL-8.Therefore, proliferation of vascular smooth muscle cells was inhibited.
白细胞介素-8(Interleukin-8,IL-8)是趋化因子CXC亚家族的一员,主要由单核细胞产生,其主要生理活性是趋化和激活中性粒细胞并分泌大量的黏附分子,使中性粒细胞表面CD11b/CD18受体上调。IL-8可以诱导平滑肌细胞的增殖和迁移,是一个促血管生成因子,在炎症反应过程中起着重要的作用。IL-8能促使单核细胞在内皮细胞上的滚动转变成强有力的黏附。研究发现,升高的IL-8水平与冠状动脉疾病的发病有关,并且可以作为心脏事件的预测因子。
目的:本研究通过球囊扩张拉伤兔腹主动脉,建立动脉再狭窄模型,造影检查腹主动脉管腔狭窄变化情况,采用组织病理观察血管球囊扩张术后内膜和中层平滑肌的结构改变,利用免疫组化技术观察IL-8蛋白阳性表达和PCNA阳性表达细胞数,研究IL-8对血管平滑肌细胞(VSMCs)增殖的影响,为防治PCI术后再狭窄提供可靠的理论依据。
方法:选择雄性新西兰大白兔24只为实验对象,体重2.50-3.25kg,由河北医科大学实验动物中心提供。以上实验动物随机分为实验组(experiment group)、治疗组(treatment group)和假手术组(sham group),每组各8只动物。实验组和治疗组动物通过穿刺股动脉,送入球囊拉伤腹主动脉。治疗组动物通过耳缘静脉注射IL-8单克隆抗体进行干预。假手术组动物只进行股动脉穿刺和留置鞘管,不进行球囊扩张拉伤。
1.分别于实验前,实验后4小时、1天、3天,1周、2周、4周,耳缘静脉采血4ml,检测三组动物血清IL-8水平。
2.术后4周时处死动物进行病理组织学检查,应用光学显微镜和计算机病理图象分析系统分析测定以下指标:内膜中膜厚度、面积,计算血管狭窄程度[(邻近正常血管管径-狭窄段最小管径)/邻近正常血管管径]。
3.利用免疫组化染色技术观察IL-8蛋白表达情况,增殖细胞核抗原PCNA染色分析后,用光学显微镜和计算机病理图象分析系统测定每40倍视野中PCNA阳性细胞比例,计算阳性细胞数和阳性细胞百分率。
结果:
1.三组实验动物之间体重、月龄、血脂等一般情况比较,差异无统计学意义(P>0.05)。
2.术前IL-8水平比较,实验组、治疗组、假手术组三组之间无明显差异,实验组动物球囊损伤4小时后IL-8水平即开始升高,术后1d达到峰值,持续增高4周,且明显高于治疗组和假手术组。治疗组和假手术组动物IL-8水平无上述变化规律。
3.实验组动物腹主动脉明显狭窄,组织学检查内膜面积和中膜面积、血管狭窄程度等指标大于治疗组和假手术组(P<0.01),治疗组管腔有所狭窄,假手术组动物管腔无明显变化,治疗组与假手术组无显著性差异(P>0.05)。相关分析显示,IL-8水平与内膜厚度、内膜面积、中膜厚度、中膜面积等呈正相关(相关系数r分别为0.905,0.897,0.852,0.846,P均<0.01)。
4.免疫组化显示,实验组与治疗组和假手术组比较,IL-8蛋白阳性表达明显升高(P<0.05),治疗组高于假手术组,无明显差异。PCNA阳性细胞比例比较,实验组明显高于治疗组与假手术组(P<0.05),治疗组明显高于假手术组(P<0.05)。相关分析显示IL-8阳性表达细胞数与PCNA阳性细胞数呈正相关,相关系数r=0.857(P<0.01)。
结论:
1.通过介入方法进行球囊拉伤可成功建立兔腹主动再狭窄动物模型。
2.腹主动脉球囊损伤后IL-8水平高表达,血管明显狭窄,经IL-8单克隆抗体治疗后,动脉狭窄程度明显减轻。IL-8水平与动脉狭窄程度呈正相关。
3.球囊损伤引起腹主动脉局部IL-8水平高表达,并导致血管平滑肌细胞增殖。经IL-8单克隆抗体治疗后,IL-8水平下降,并抑制平滑肌细胞的增殖。
Percutaneous transluminal coronary angioplasty (PTCA) was a safe and effective method to treat coronary artery disease, but the restenosis rate after 3 to 6 months of the operation could reach to 30% to 50%, that seriously affected their long-term effects. The mechanism of restenosis had not yet been fully clarified. At present, most scholars believed that the migration to the subintimal and excessive proliferation of the vascular smooth muscle cells was essential, therefore the regulation of the proliferation of vascular smooth muscle cells became the focus of the study. Some research data showed that the restenosis after balloon injury was associated with vascular recoil, thrombus formation, excessive proliferation of VSMCs and accumulation of extracellular matrix. The excessive proliferation of VSMCs might be the main reason for the formation of restenosis. After the balloon dilation of blood vessels, vascular endothelial and medial smooth muscle cells were stretched and damaged. the VSMCs could excessive proliferated and moved to the inner membrance under the stimulation of series growth factors during the repair process. Therefore to inhibit the excessive proliferation of VSMCs to prevent and cure the restenosis was a subject concerned and researched by medical workers.
Interleukin -8 (IL-8) was a member of the CXC chemokine subfamily, and mainly produced by mononuclear cells. The chief physiological activity of IL-8 was to chemokine and activate the neutrophils and secrete a large number of adhesion molecules to increase the receptors of CD11b/CD18 on the surface of neutrophil cells. IL-8 was a pro-angiogenic factor which could induce the proliferation and migration of smooth muscle cells and played an important role in the process of inflammatory response. IL-8 could promote monocyte rolling on endothelial cells into a strong adhesion. The study found that elevated levels of IL-8 was related to the pathogenesis of coronary artery disease, and could be used as the predictors of cardiac events.
Objective: In this study, animal models of restenosis were made by balloon inflation in abdominal aorta of rabbits. The extent of luminal stenosis was examined by angiography. The structural change of intima andmedium were observed by means of pathology. The expression of IL-8 protein and PCNA-positive cells were surveyed using immunohistochemistry technology. The influence of IL-8 levels on proliferation of vascular smooth muscle cells was studied systemly. Our study would provide a reliable theoretical basis for the prevention and treatment of restenosis after PCI.
Methods: Twenty-four male New Zealand white rabbits were selected. They were purchased from the Test Animal Center of Hebei Medical University, weighted from 2.5kg to 3.25 kg. They were randomly assigned to experiment group (n=8),treatment group (n=8) and sham group (n=8). Rabbits in experiment group and treatment group were injuried in abdominal aorta by balloon inflation after punctured in femoral artery. Monoclonal antibody of IL-8 was injected by venous in rabbits of treatment group. Rabbits in sham group were punctured only in femoral artery.
1.The peripheral blood was collected at the time of before the experiment and four hours、one day、three days、one week、two weeks、four weeks after the operation. The levels of IL-8 were measured by enzyme linked immunosorbent assay (ELISA) respectively.
2. Put the rabbits to death 4 weeks after the surgery and take an histopathologic examination, contented such as luminal area, intima and tunica media area, angiostenosis of blood vessel were assayed by light microscope and computer image analysis system.
3.The expression of IL-8 protein was examined by means of immunohistochemistry staining technology. After proliferating cell nuclear antigen (PCNA) stained, the ratio of masculine cells was calculated per 40 times field of vision using light microscope and computer image analysis system. Index of masculine cells was determined.
Results:
1. There was no statistical difference among the three groups of experimental animals in general data (P>0.05).
2. The preoperative levels of IL-8 was no significant difference among the three groups. The levels of IL-8 in the rabbits of experiment group began to raise in four hours and achieved to peak in one day after balloon inflation. The higher levels of this inflammatory factor would last four weeks. There was no variation above in treatment and sham group.
3. It was observed that the abdominal aorta become stenosis obviously in experiment group. The area of intima and tunica media as well as extent of stenosis in experiment group were bigger than those in treatment group and sham group. There was no statistical difference between treatment and sham group. Correlation analysis indicated that there were positive relations between IL-8 and luminal area, area of intima and tunica medias respectively(r=0.905,0.897,0.852,0.846,P<0.01).
4. It showed that the expression of IL-8 protein in experiment group was significantly higher than others (P<0.05). There was no statistical difference between treatment group and sham group. Compared with treatment group and sham group, the number and ratio of PCNA in experiment group increased significantly (P<0.05). Treatment group was higher than sham group (P<0.05). Correlation analysis showed that expression of IL-8-positive cells and PCNA-positive cells was positively correlated, the correlation coefficient r = 0.857 (P<0.01).
Conclusions:
1 The restenosis model in abdominal aorta of rabbits could be established successfully by means of intervention which injuried aorta with balloon inflation;
2 The high levels of IL-8 was caused by balloon injury in abdominal aorta. The severity of stenosis became lessen after intervention by monoclonal antibody of IL-8. Positive corelation was found between level of IL-8 and severity of arterial stenosis.
3 The higher expression of IL-8 protein was caused by balloon injury in abdominal aorta. It led to proliferation of vascular smooth muscle cells. The level of IL-8 protein decreased after intervention by monoclonal antibody of IL-8.Therefore, proliferation of vascular smooth muscle cells was inhibited.
引文
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15姚玉宇,冷静,彭韬,等.兔动脉内膜损伤后血管狭窄模型的建立及动态观察的研究.江苏医药.1999,25(12): 910-911
16高炜,霍勇,朱国英,等.再狭窄的细胞和分子生物学(一).中国介入心脏病学杂志.1997,5(2):84-91
17王伟,周丽娟,杨万松,等.血管去内皮损伤后平滑肌细胞凋亡的实验观察.实用心脑肺血管病杂志. 2000,8(1): 7-9
18刘威.经皮冠状动脉腔内成形术后再狭窄及其发生机理.广州医学院报. 2000,28(4): 93-98
19刘凡光.血管成形术后平滑肌细胞增值的机制.国外医学心血管分册. 1997,24(6): 10-12
20 Wilcox TN. Thronbin and other potential mechanisms underlying restenosis. Circulation,1991,84(1): 423
21 Gerszten RE, Garcia-Zepeda EA, Lim YC,et al. MCP-1 and IL-8 triggerfirm adhesion of monocytes to vascular endothelium under flow conditions.Nature, 1999,398: 718-723
22 Westlin WF,Gimbrone MA. Neutrophil-mediated damage of human vascular endothelium. Am J Pathol 1993,142: 117-128
23 Rot A. Endothelial cell binding of NAP-1/IL-8: Role in neutrophil emigration. Immunol Today 1992, 13: 291-294
24 ChenS, ReesA.Atherosclerosis and lipoproteins: vascular cell senescence and atherosclerosis. Current opinion in lidology.2007,18(5): 600-602
25 Paulsson J,Dadfar E,Held C,et al. Activation of peripheral and in vivo transmigated neutrophils inpatients with stable coronary artery disease.Atherosclerosis,2007,192(2): 328-334
26 Aukrust P,Yndestad A,Smith C,et al. Chemokines in cardiovascular risk prediction.Thromb Haemost,2007,97(5): 748-754
27 Yu H, Sliedregt K,Overkleef H, et al. Therapeutic Potential of a SyntheticPeptide Inhibitor of Nuclear Factor of Activated T Cells as AntirestenoticAgent. Arteriocler Thromb Vasc Biol.2006,10: 1161-1175
28 Rus HG, Vlaicu R, Niculesch F, et al. Interleukin-6 and inteleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis,1996,127: 263-271
29 Shin WS,Szuba A,Rockson SG, et al. The role of chemokines human cardiovascular pathology: enhanced biological insights Atherosclerosis,2002,160: 91-102
30 Boekholdt SM, Peters RJ , Hack CE,et al. IL-8 plasma concentrations andthe risk of future coronary artery disease in apparently healthy men andwomen: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol. 2004,24(8): 1503-1538
31 Aukrust P, Yndestad A, Smith C,et al. Chemokines in cardiovascular risk prediction.Thromb Haemost 2007,97(5): 748-754
32 Herder C,Baumert J,Thorand B,et al.Chemokines and incident coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. Arterioscler Thromb Vasc Biol. 2006,26(9): 2147-2152
33 Bravo R,Frank R,Blunder PA,et al. Cyclin/PCNA is the auxiliary protein of DNA polymerases.Nature,1987,326: 515-517
34 Roos G,Jing Y,Landberg G,et al.Determination of epitope of an inhibitory antibody to PCNA.Exp Cell Res,1996,226: 208
35 Miniati DN,Hoyt EG,Feeley BT,et al. Ex vivo antisense oligonucleotides to proliferating cell nuclear antigen and Cdc2 kinase inhibit graft cononary artery disease.circulaion, 2000,102(19 Suppl 3): 237-242
1 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation, 2002,105 :1135–1143
2 Prescott SM, McIntyre TM, Zimmerman GA, et al. Molecular events in acute inflammation. Arterioscler Thromb Vasc Biol,2002,22: 727–733
3 Fleeting RM. The Fleming Unified Theory of Vascular Disease: a link between atherosclerosis inflammation, and bacterially aggravated atherosclerosis. Angiology. 2000,51(1):87-89
4 Sheikine Y ,Hansson GK. Chemokines and atherosclerosis. Ann Med, 2004,36(2) :98-118
5 Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell, 2001, 104: 503-516
6 Mach F. The role of chemokines in atherosclerosis. Curr Atheroscler Rep, 2001, 3: 243-251
7 Bursill CA, Channon KM, Greaves DR. The role of chemokines in atherosclerosis: recent evidence from experimental models and population genetics. Curr Opin Lipidol ,2004, 15(2) :145-149
8 Gerard C ,Rollins BJ.Chemokines and disease. Nat Immunol ,2001, 2: 108-115
9 Mackay CR.Chemokines: immunology, s high impact factors. Nat Immunol, 2001, 2: 95-101
10 Houshmand P, Zlotnik A. Therapeutic applications in the chemokine superfamily. Curr Opin Chem Biol, 2003, 7 : 457-460
11 Grainger DJ, Reckless J. Broad-spectrum chemokine inhibitors (BSCIs) and their anti-inflammatory effects in vivo. Biochem Pharmacol. 2003 Apr 1: 65(7): 1027-1034
12 Sheikine Y, Hansson GK. Chemokines and atherosclerosis. Ann Med, 2004, 36(2): 98-118
13 Fernando-Bazan J, Bacon KB, Hadiman G, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature, 1997, 385: 640-644
14 Kennedy J, Kelner G, Kleyensteuber S, et al. Molecular cloning and functional characterization of human lymphotactin. J Immunol, 1995, 155: 203-209
15 Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity, 2000, 12(2): 121-127
16 Thelen M. Dancing to the tune of chemokines. Nat Immunol, 2001, 2: 129-134
17 Kim CH. Chemokine-chemokine receptor network in immune cell trafficking. Curr Drug Targets Immune Endocr Metabol Disord. 2004 Dec;4(4): 343-361
18 Christopherson K, Hromas R. Chemokine regulation of normal and pathologic immune responses. Stem Cells, 2001, 19(5): 388-396
19 Murphy PM, Baggiolini M, Charo IF. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev, 2000, 52(1): 145-176
20 Baggiolini M. Chemokines and leucocyte traffic. Nature, 1998, 392:
565-568
21 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med, 1999, 340:115-126
22 Paoletti R, Gotto AM Jr, Hajjar DP. Inflammation in atherosclerosis and implications for therapy. Circulation, 2004, 109(23 Suppl 1): III20-26
23 Shishehbor MH, Bhatt DL. Inflammation and atherosclerosis. Curr Atheroscler Rep, 2004, 6(2): 131-139
24 Linton MF, Fazio S. Macrophages, inflammation, and atherosclerosis. Int J Obes Relat Metab Disord, 2003, 27(Suppl 3): S35-40
25 eape TJ, Rayner K, Manning CD. Expression and cellular localization of the CC chemokines PARC and ELC in human atherosclerotic plaques. Am J Pathol, 1999, 154(2): 365-374
26 Sheikine Y, Hansson GK. Chemokines and atherosclerosis. Ann Med, 2004, 36(2): 98-118
27 Greaves DR et al. Linked chromosome 16q13 chemokines,macrophage-derived chemokine, fractralkine and thymus-and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Aterioscler Thromb Vasc Biol, 2001,21: 923-929
28 Ikeda U, Matsui K, Murakami Y, et al. Monocyte chemoattractant protein-1 and coronary artery diease. Clin Cardiol, 2002, 25: 143-147
29 Gu L, Tseng SC, Rollins BJ. Monocyte chemoattractant protein-1. Chem Immunol, 1999, 72: 7-29
30 MehrabianM, Sparkes RS, Mohandas T, et al. Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11. 2- q21. 1 [J]. Genomics, 1991, 9 (1): 200-203
31 Deo R, Khera A, McGuire DK. Association among plasma levels of monocyte chemoattractant protein-1, traditional cardiovascular risk factors, and subclinical atherosclerosis. J Am Coll Cardiol, 2004, 44(9): 1812-1818
32 Kusano KF, Nakamura K, Kusano H. Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis. Circ J, 2004, 68(7): 671-676
33庞林华.生理科学进展, 1994,25(1): 54-59
34 Wozni KA et al. Immunology, 1993,79: 608-615
35 Rollins BJ. Chemokines. Blood, 1997, 90 (3): 909-927
36 Koch AE, Kunkel SL, Pearce WH, et al. Enchanced production of the chemotactic cytokines interleukine-8 and monocyte chemoattractant protein-1 in human abdominal aortic aneurysms. Am J Pathol. 1993, 142: 1423-1430
37 Simonini A, Mauro M, David WM, et al. IL-8 is an angiogenic factor in human coronary atherectomy tissue.Circulation,2000,10: 1519-1526
38 Rus HG, Vlaicu R, Niculesch F, et al. Interleukine-6 and interleukine-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis, 1996, 127: 263-271
39 Gerszten RE, Gerszten RE, Lim YC, et al. IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature, 1999, 398(6729): 718
40 Boisvert WA, Curtiss LK, Terkeltaub RA. Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunol Res, 2000, 21(2-3): 129-137
41 Goda S, Imai T, Yoshie O, et al. CX3C-chemokine, Fractalkine-enhanced adhesion of THP-1 cells to endothelial cells through integrin-dependent and independent mechanisms. J Immunol, 2000,164: 4313-4320
42 Bazan JF, Bacon KB,Hardiman GJ. A new class of membrane bound chemokine with a CX3C motif. Nature, 1997, 385(6617): 640-644
43 Nomiyama H, Imai T, Kusuda J, et al. Human chemokines fractalkine (SCYD1), MDC(SCYA22) and TARC(SCYA17) are clustered on chromosome 16q13. Cytogenet Cell Genet, 1998, 81(1): 10-11
44 Wong BW, Wong D, McManus BM. Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease. Cardiovasc Pathol. 2002,11: 332-338
45 Combadiere C, Potteaux S, Gao JL, et al. Decreased atherosclerotic lesion formation in CX3CR1 / apolipoprotein E double knockout mice. Circulation, 2003,107: 1009-1016
46 Lesnik P, Haskell CA, Charo JF. Decreased atherosclerosis in CX3CR1-/- mice Reveals a role for fractalkine in athcrogenesis [J]. J Clin Invest. 2003, 111: 333-340
47 Faure S, Meyer L, Costagliola D, et al. Rapid progression to AIDS in HIV+individuals with a structural variant of the chemokine receptor CX3CR1. Science, 2000,287(5461): 2274-2277
48 Moatti D, Faure S, Fumeron F, et al. polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood, 2001, 97(7): 1925-1928
49 Apostolakis S, Baritaki S, Kochiadakis GE, et al. Effects of polymorphisms in chemokine ligands and receptors on susceptibility to coronary artery disease. Thromb Res. 2007,119(1): 63-71
50 Niessner A, Marculescu R, Kvakan H, et al. Fractalkine receptor polymorphisms V2491 and T280M as genetic risk factors for restenosis.Thromb Haemost. 2005 Dec, 94(6): 1251-1256
51 McDermott DH, Halcox JP, Schenke WH, Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res, 2001, 89(5): 401-407
52 Greaves DR, Hakkinen T, Lucas AD, et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus- and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol, 2001, 21(6): 923-929
53 Umehara H, Bloom ET, Okazaki T. Fractalkine in vascular biology: from basic research to clinical disease. Arterioscler Thromb Vasc Biol, 2004, 24(1): 34-40
54 Bursill CA, Channon KM, Greaves DR. The role of chemokines in atherosclerosis: recent evidence from experimental models and population genetics. Curr Opin Lipidol, 2004, 15(2): 145-149
55 Libb P, Ridker PM, Maseri A. Inflammation and atherosclerosis[J]. Circulation, 2002, 105: 1135-1143
2 Alfonso F,Perez-Vizcayno MJ,Hernandez R,et al. Sirolimus-eluting stentsversus bare-metal stents inpatients with in-stent restenosis:results of apooled analysis of two randomized studies. Catheter Cardiovasc Intev,2008,72(4):468-469
3覃跃龙,舒茂琴,江明宏. ORC1基因RNA干扰对大鼠血管平滑肌细胞增殖的影响[J].第三军医大学学报, 2006, 28 ( 11) : 1161 -1163
4 Schwartz, RS. Pathophysiology of restenosis: interaction of thrombosis, hyperplasia, and/or remodeling. Am J Cardiol. 1998, 81(7A): 14E-17E
5中华人民共和国科学技术部.关于善待实验动物的指导性意见.2006-09-30
6 Caixeta AM,Brito FS Jr,Costa MA,et al. Enhanced inflammatory responseto coronary stenting marks the development of clinically relevant restenosis. Catheter Cardiovasc Intev,2007,69(4):500-507
7 Li JJ,Qin XW,Yang XC,et al. Randomized comparison of early inflammtoryresponse a fter sirolimus-eluting stent vs bare metal stent in native coronarylesions.Clin Chim Acta,2008,396(1-2):38-42
8 Bult H. Restenosis: a challenge for pharmacology. rends Pharmacol Sci. 2000,21(7): 274-279
9栾荣华,贾国良,李伟,等. c2myc基因mRNA核酶对血管平滑肌细胞增殖的抑制作用[J] .第四军医大学学报, 2003,24(6): 517 - 521
10 Schwartz RS , Henry TD. Pathophysiology of coronary artery restenosis [J] . Rev Cardiovasc Med , 2002, 3 (Suppl 5) : S4 - S9
11边杰芳,张柏根,钱虎声,等.反义寡核苷酸抑制血管平滑肌细胞增殖[J] .第四军医大学学报, 2000,21 (12) : 1492 - 1494
12 Freeman E J. The Ang II2induced growth of vascular s mooth muscle cellsinvolves a phos pholipase D2 mediated signaling mechanism [J]. Arch Biochem Biophys, 2000, 374 (2) : 363 - 370
13方宁远,盖保康,张世华,等.球囊血管成形术对兔血管平滑肌细胞增殖周期的影响.上海第二医科大学学报.1994, 14 4: 330-333
14 Robert S, Schuart Z, Darid R. et al. the restenosis paradigm revisited: an alternative proposal for cellular mechanisms.J Am Coll Cardiol.1992,20(5):1284-1293
15姚玉宇,冷静,彭韬,等.兔动脉内膜损伤后血管狭窄模型的建立及动态观察的研究.江苏医药.1999,25(12): 910-911
16高炜,霍勇,朱国英,等.再狭窄的细胞和分子生物学(一).中国介入心脏病学杂志.1997,5(2):84-91
17王伟,周丽娟,杨万松,等.血管去内皮损伤后平滑肌细胞凋亡的实验观察.实用心脑肺血管病杂志. 2000,8(1): 7-9
18刘威.经皮冠状动脉腔内成形术后再狭窄及其发生机理.广州医学院报. 2000,28(4): 93-98
19刘凡光.血管成形术后平滑肌细胞增值的机制.国外医学心血管分册. 1997,24(6): 10-12
20 Wilcox TN. Thronbin and other potential mechanisms underlying restenosis. Circulation,1991,84(1): 423
21 Gerszten RE, Garcia-Zepeda EA, Lim YC,et al. MCP-1 and IL-8 triggerfirm adhesion of monocytes to vascular endothelium under flow conditions.Nature, 1999,398: 718-723
22 Westlin WF,Gimbrone MA. Neutrophil-mediated damage of human vascular endothelium. Am J Pathol 1993,142: 117-128
23 Rot A. Endothelial cell binding of NAP-1/IL-8: Role in neutrophil emigration. Immunol Today 1992, 13: 291-294
24 ChenS, ReesA.Atherosclerosis and lipoproteins: vascular cell senescence and atherosclerosis. Current opinion in lidology.2007,18(5): 600-602
25 Paulsson J,Dadfar E,Held C,et al. Activation of peripheral and in vivo transmigated neutrophils inpatients with stable coronary artery disease.Atherosclerosis,2007,192(2): 328-334
26 Aukrust P,Yndestad A,Smith C,et al. Chemokines in cardiovascular risk prediction.Thromb Haemost,2007,97(5): 748-754
27 Yu H, Sliedregt K,Overkleef H, et al. Therapeutic Potential of a SyntheticPeptide Inhibitor of Nuclear Factor of Activated T Cells as AntirestenoticAgent. Arteriocler Thromb Vasc Biol.2006,10: 1161-1175
28 Rus HG, Vlaicu R, Niculesch F, et al. Interleukin-6 and inteleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis,1996,127: 263-271
29 Shin WS,Szuba A,Rockson SG, et al. The role of chemokines human cardiovascular pathology: enhanced biological insights Atherosclerosis,2002,160: 91-102
30 Boekholdt SM, Peters RJ , Hack CE,et al. IL-8 plasma concentrations andthe risk of future coronary artery disease in apparently healthy men andwomen: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol. 2004,24(8): 1503-1538
31 Aukrust P, Yndestad A, Smith C,et al. Chemokines in cardiovascular risk prediction.Thromb Haemost 2007,97(5): 748-754
32 Herder C,Baumert J,Thorand B,et al.Chemokines and incident coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. Arterioscler Thromb Vasc Biol. 2006,26(9): 2147-2152
33 Bravo R,Frank R,Blunder PA,et al. Cyclin/PCNA is the auxiliary protein of DNA polymerases.Nature,1987,326: 515-517
34 Roos G,Jing Y,Landberg G,et al.Determination of epitope of an inhibitory antibody to PCNA.Exp Cell Res,1996,226: 208
35 Miniati DN,Hoyt EG,Feeley BT,et al. Ex vivo antisense oligonucleotides to proliferating cell nuclear antigen and Cdc2 kinase inhibit graft cononary artery disease.circulaion, 2000,102(19 Suppl 3): 237-242
1 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation, 2002,105 :1135–1143
2 Prescott SM, McIntyre TM, Zimmerman GA, et al. Molecular events in acute inflammation. Arterioscler Thromb Vasc Biol,2002,22: 727–733
3 Fleeting RM. The Fleming Unified Theory of Vascular Disease: a link between atherosclerosis inflammation, and bacterially aggravated atherosclerosis. Angiology. 2000,51(1):87-89
4 Sheikine Y ,Hansson GK. Chemokines and atherosclerosis. Ann Med, 2004,36(2) :98-118
5 Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell, 2001, 104: 503-516
6 Mach F. The role of chemokines in atherosclerosis. Curr Atheroscler Rep, 2001, 3: 243-251
7 Bursill CA, Channon KM, Greaves DR. The role of chemokines in atherosclerosis: recent evidence from experimental models and population genetics. Curr Opin Lipidol ,2004, 15(2) :145-149
8 Gerard C ,Rollins BJ.Chemokines and disease. Nat Immunol ,2001, 2: 108-115
9 Mackay CR.Chemokines: immunology, s high impact factors. Nat Immunol, 2001, 2: 95-101
10 Houshmand P, Zlotnik A. Therapeutic applications in the chemokine superfamily. Curr Opin Chem Biol, 2003, 7 : 457-460
11 Grainger DJ, Reckless J. Broad-spectrum chemokine inhibitors (BSCIs) and their anti-inflammatory effects in vivo. Biochem Pharmacol. 2003 Apr 1: 65(7): 1027-1034
12 Sheikine Y, Hansson GK. Chemokines and atherosclerosis. Ann Med, 2004, 36(2): 98-118
13 Fernando-Bazan J, Bacon KB, Hadiman G, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature, 1997, 385: 640-644
14 Kennedy J, Kelner G, Kleyensteuber S, et al. Molecular cloning and functional characterization of human lymphotactin. J Immunol, 1995, 155: 203-209
15 Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity, 2000, 12(2): 121-127
16 Thelen M. Dancing to the tune of chemokines. Nat Immunol, 2001, 2: 129-134
17 Kim CH. Chemokine-chemokine receptor network in immune cell trafficking. Curr Drug Targets Immune Endocr Metabol Disord. 2004 Dec;4(4): 343-361
18 Christopherson K, Hromas R. Chemokine regulation of normal and pathologic immune responses. Stem Cells, 2001, 19(5): 388-396
19 Murphy PM, Baggiolini M, Charo IF. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev, 2000, 52(1): 145-176
20 Baggiolini M. Chemokines and leucocyte traffic. Nature, 1998, 392:
565-568
21 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med, 1999, 340:115-126
22 Paoletti R, Gotto AM Jr, Hajjar DP. Inflammation in atherosclerosis and implications for therapy. Circulation, 2004, 109(23 Suppl 1): III20-26
23 Shishehbor MH, Bhatt DL. Inflammation and atherosclerosis. Curr Atheroscler Rep, 2004, 6(2): 131-139
24 Linton MF, Fazio S. Macrophages, inflammation, and atherosclerosis. Int J Obes Relat Metab Disord, 2003, 27(Suppl 3): S35-40
25 eape TJ, Rayner K, Manning CD. Expression and cellular localization of the CC chemokines PARC and ELC in human atherosclerotic plaques. Am J Pathol, 1999, 154(2): 365-374
26 Sheikine Y, Hansson GK. Chemokines and atherosclerosis. Ann Med, 2004, 36(2): 98-118
27 Greaves DR et al. Linked chromosome 16q13 chemokines,macrophage-derived chemokine, fractralkine and thymus-and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Aterioscler Thromb Vasc Biol, 2001,21: 923-929
28 Ikeda U, Matsui K, Murakami Y, et al. Monocyte chemoattractant protein-1 and coronary artery diease. Clin Cardiol, 2002, 25: 143-147
29 Gu L, Tseng SC, Rollins BJ. Monocyte chemoattractant protein-1. Chem Immunol, 1999, 72: 7-29
30 MehrabianM, Sparkes RS, Mohandas T, et al. Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11. 2- q21. 1 [J]. Genomics, 1991, 9 (1): 200-203
31 Deo R, Khera A, McGuire DK. Association among plasma levels of monocyte chemoattractant protein-1, traditional cardiovascular risk factors, and subclinical atherosclerosis. J Am Coll Cardiol, 2004, 44(9): 1812-1818
32 Kusano KF, Nakamura K, Kusano H. Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis. Circ J, 2004, 68(7): 671-676
33庞林华.生理科学进展, 1994,25(1): 54-59
34 Wozni KA et al. Immunology, 1993,79: 608-615
35 Rollins BJ. Chemokines. Blood, 1997, 90 (3): 909-927
36 Koch AE, Kunkel SL, Pearce WH, et al. Enchanced production of the chemotactic cytokines interleukine-8 and monocyte chemoattractant protein-1 in human abdominal aortic aneurysms. Am J Pathol. 1993, 142: 1423-1430
37 Simonini A, Mauro M, David WM, et al. IL-8 is an angiogenic factor in human coronary atherectomy tissue.Circulation,2000,10: 1519-1526
38 Rus HG, Vlaicu R, Niculesch F, et al. Interleukine-6 and interleukine-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis, 1996, 127: 263-271
39 Gerszten RE, Gerszten RE, Lim YC, et al. IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature, 1999, 398(6729): 718
40 Boisvert WA, Curtiss LK, Terkeltaub RA. Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunol Res, 2000, 21(2-3): 129-137
41 Goda S, Imai T, Yoshie O, et al. CX3C-chemokine, Fractalkine-enhanced adhesion of THP-1 cells to endothelial cells through integrin-dependent and independent mechanisms. J Immunol, 2000,164: 4313-4320
42 Bazan JF, Bacon KB,Hardiman GJ. A new class of membrane bound chemokine with a CX3C motif. Nature, 1997, 385(6617): 640-644
43 Nomiyama H, Imai T, Kusuda J, et al. Human chemokines fractalkine (SCYD1), MDC(SCYA22) and TARC(SCYA17) are clustered on chromosome 16q13. Cytogenet Cell Genet, 1998, 81(1): 10-11
44 Wong BW, Wong D, McManus BM. Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease. Cardiovasc Pathol. 2002,11: 332-338
45 Combadiere C, Potteaux S, Gao JL, et al. Decreased atherosclerotic lesion formation in CX3CR1 / apolipoprotein E double knockout mice. Circulation, 2003,107: 1009-1016
46 Lesnik P, Haskell CA, Charo JF. Decreased atherosclerosis in CX3CR1-/- mice Reveals a role for fractalkine in athcrogenesis [J]. J Clin Invest. 2003, 111: 333-340
47 Faure S, Meyer L, Costagliola D, et al. Rapid progression to AIDS in HIV+individuals with a structural variant of the chemokine receptor CX3CR1. Science, 2000,287(5461): 2274-2277
48 Moatti D, Faure S, Fumeron F, et al. polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood, 2001, 97(7): 1925-1928
49 Apostolakis S, Baritaki S, Kochiadakis GE, et al. Effects of polymorphisms in chemokine ligands and receptors on susceptibility to coronary artery disease. Thromb Res. 2007,119(1): 63-71
50 Niessner A, Marculescu R, Kvakan H, et al. Fractalkine receptor polymorphisms V2491 and T280M as genetic risk factors for restenosis.Thromb Haemost. 2005 Dec, 94(6): 1251-1256
51 McDermott DH, Halcox JP, Schenke WH, Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res, 2001, 89(5): 401-407
52 Greaves DR, Hakkinen T, Lucas AD, et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus- and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol, 2001, 21(6): 923-929
53 Umehara H, Bloom ET, Okazaki T. Fractalkine in vascular biology: from basic research to clinical disease. Arterioscler Thromb Vasc Biol, 2004, 24(1): 34-40
54 Bursill CA, Channon KM, Greaves DR. The role of chemokines in atherosclerosis: recent evidence from experimental models and population genetics. Curr Opin Lipidol, 2004, 15(2): 145-149
55 Libb P, Ridker PM, Maseri A. Inflammation and atherosclerosis[J]. Circulation, 2002, 105: 1135-1143