Rcn2對動脈損傷后內膜增生的影響及機制研究(碩士)

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Rcn2對動脈損傷后內膜增生的影響及機制研究(碩士)(論文40000字)
摘 要
目的:動脈粥樣硬化是冠心病,缺血性中風和外周動脈疾病的主要原因。動脈粥樣硬化病變可能直接或間接造成動脈狹窄或閉塞,影響重要器官的血供,并引起相應的缺血癥狀。介入經皮血管成形術及支架置入術是治療閉塞性動脈疾病的主要方法。隨著介入器械的發展及技術的進步,介入腔內治療閉塞性動脈疾病有了長遠的進步,但術后再狹窄問題仍然沒有徹底解決。新生內膜增生是術后再狹窄的主要病理過程,新生內膜病變主要來源于由中膜向內膜異常增殖和遷移的血管平滑肌細胞。最近的一些研究指出血管再狹窄可能受到飲食因素及遺傳因素等的影響。前期研究中我們發現C3H和C57小鼠在Apoe敲除后動脈硬化易感性差異顯著。通過數量性狀基因座(QTL)的方法發現網鈣結合蛋白2(Rcn2)可能是導致這一差異的關鍵基因。本研究將首先通過動物實驗明確Rcn2在高脂飲食加劇動脈損傷后內膜增生過程中的作用,并進一步探討敲除Rcn2能夠抑制內膜增生。其次通過細胞實驗明確沉默Rcn2能夠抑制血管平滑肌細胞增殖遷移及由ox-LDL誘發的炎癥反應。最后在下肢動脈硬化閉塞癥患者血漿中檢測Rcn2表達水平,分析Rcn2能夠成為預測支架后再狹窄的生物學標志物。
研究方法:1、動物實驗中選取8-12周齡、體重20-25g的C57BL/6 Apoe-/-小鼠(C57)、C57BL/6 Apoe-/-Rcn2-/-小鼠(Rcn2),建立頸動脈結扎損傷模型。一組小鼠維持普通飲食。另一組在頸動脈損傷前1周開始喂食高脂飲食并一直維持高脂飲食至實驗結束。分別于術后1天,3天,以及1,2和4周獲得頸動脈標本。病理學檢查比較損傷段頸動脈管腔面積,內膜面積,內膜與中膜面積比值等形態學指標。免疫組化染色鑒定內膜增生病變的細胞成分。ElISA檢測動物血清促炎因子分泌水平及血脂。2、細胞實驗利用原代培養C57 Apoe-/-小鼠主動脈平滑肌細胞,選擇用不同濃度的ox-LDL(50ug/ml,100ug/ml,150ug/ml,200ug/ml)刺激血管平滑肌細胞后,檢測Rcn2在 mRNA水平和蛋白水平表達情況。利用siRNA轉染血管平滑肌細胞,劃痕試驗檢測血管平滑肌細胞的遷移能力。MTT檢測血管平滑肌細胞的增殖能力。ELISA法檢測細胞上清液中MCP-1及VCAM-1的含量。3、收集2012年1月至2014年12月共篩選了258例連續的股腘動脈CTO病變患者的臨床隨訪資料。其中180例患者納入本研究,檢測了其中62例患者留存血漿中的Rcn2表達水平,并與15例健康對照比較分析。同時還分析了患者中性粒細胞與淋巴細胞比值(NLR)與再狹窄等的相關性。
結果:1、普通飲食組C57小鼠發生了輕度高脂血癥,總膽固醇水平為308.5±60.3mg/dl,而高脂飲食組的總膽固醇水平為858.5±88.4mg/dl,為嚴重高脂血癥(p<0.001)。兩組HDL膽固醇水平都很低,甘油三酯水平相當(159.3±37.1 mg/dl和149.5±19.2mg/dl,p>0.05)。高脂飲食組在術后1周后出現內膜增生,高脂飲食組在術后2周出現內膜增生。隨著時間的增加,兩組內膜病灶均增大。術后4周時,高脂飲食組頸動脈平均內膜增生面積大約為普通飲食組的4倍(分別為112,987±11,395μm2和29,539±7,001μm2; n = 5,P< 0.001)。組織學上,高脂飲食術后1周后和普通飲食術后2周的內膜病變主要由泡沫細胞組成。在高脂飲食術后2周,內膜增生是典型的纖維斑塊,其含有被纖維帽覆蓋的許多泡沫細胞。在4周時,兩個飲食組的內膜病變發展到更晚期的階段,包含新生血管和動脈管腔明顯變窄。Rcn2在普通飲食組的內膜病變中低表達,而在高脂飲食組的內膜病變中高表達。Rcn2在高脂飲食組血漿中濃度明顯高于普通飲食組。(18.93±1.76ng/ml, 33.03±15.01ng/ml,n=5, p=0.029)。高脂飲食Rcn2小鼠發生了輕度高脂血癥,總膽固醇水平為明顯低于C57小鼠(264±56mg/dl和858.5±88.4mg/dl,n=5,p<0.001),HDL膽固醇和甘油三酯在兩組中均無差異。Rcn2敲除明顯抑制高脂飲食條件下,C57 Apoe-/-小鼠頸動脈損傷后內膜增生。主要抑制血管平滑肌細胞由中層向內膜下遷移,抑制血管壁細胞MCP-1的表達。術后4周,在Rcn2小鼠血漿中MCP-1(202.3±39.6ng/ml, 349.3±67.1ng/ml,n=5, p=0.009)及VCAM-1(110.6±20.7ng/ml, 240.3±50.1ng/ml,n=5, p=0.002)濃度明顯低于C57小鼠。2、選擇用不同濃度的ox-LDL(50ug/ml,100ug/ml,150ug/ml,200ug/ml)刺激血管平滑肌細胞4小時,Rcn2的mRNA表達和蛋白水平在150ug/ml時表達最高。用si Rcn2轉染血管平滑肌細胞后用ox-LDL 刺激24小時,MTT測試顯示,沉默Rcn2可抑制ox-LDL誘導的平滑肌細胞增殖(p<0.05)。用平板劃痕實驗檢測發現沉默Rcn2后,穿過劃痕的血管平滑肌細胞數量顯著減少(p<0.05)。ELISA檢測細胞上清液中MCP-1及VCAM-1濃度顯示沉默Rcn2可抑制ox-LDL誘導的平滑肌細胞分泌MCP-1及VCAM-1(p<0.05)。3、共180例接受支架植入的股腘動脈CTO患者(男性,141例[78.3%];女性,39例[21.7%])納入本研究。根據支架再狹窄(ISR)的發生情況和ISR發生的時間將患者分為3組:非ISR組、早期ISR組(1年內)及晚期ISR組。非ISR組和早期ISR組的基線NLR,糖尿病,高脂血癥,平均病變長度,流出道數量存在顯著差異。在早期ISR組,基線NLR顯著高于晚ISR組相應的值(P = 0.03),且兩組在處理ISR過程中球囊預擴張使用率(P <0.01),遠端栓塞發生率(P <0.01)存在差異。單變量分析顯示,基線NLR≥3.62與早期ISR相關,基線NLR <3.62和NLR≥3.62組的早期ISR率分別為16%和32.72%(P <0.01,Table 2)。 多變量logistic分析提示,基線NLR≥3.62是股腘動脈CTO患者支架置入術后早期ISR的獨立預測因子。共檢測62例患者及15例健康對照的血漿Rcn2濃度。依據患者在隨訪1年時是否出現再狹窄分為未再狹窄組和再狹窄組。采用單因素方差分析組間差異,發現三組組Rcn2濃度具有統計學差異(F=29.59,P<0.001)。Rcn2濃度與NLR明顯正相關,而且Rcn2濃度與低密度脂蛋白膽固醇及缺血程度均相關。受試者操作特征曲線分析(ROC)用Rcn2和早期ISR來定義Rcn2截止值。ROC曲線下面積為0.901,Rcn2濃度為80.43 ng/ml,敏感性和特異性分別為79.92%和83.72%(p<0.001)。
結論:1、高脂飲食明顯加劇C57小鼠頸動脈損傷后內膜增生。增生的內膜病變主要包括血管平滑肌細胞、泡沫細胞以及新生血管等。Rcn2在高脂飲食誘導的C57小鼠動脈內膜病變中高表達。Rcn2敲除能夠明顯抑制高血脂誘導動脈損傷后的內膜增生。主要抑制血管平滑肌細胞的增殖遷移及炎癥反應。2、ox-LDL能夠誘導血管平滑肌細胞Rcn2表達增加。沉默Rcn2能夠有效抑制ox-LDL誘導的血管平滑肌細胞增殖及遷移。沉默Rcn2能夠有效抑制ox-LDL誘導的血管平滑肌細胞促炎因子分泌。3、基線NLR≥3.62是股腘動脈CTO患者支架置入術后早期ISR的獨立預測因子。基線NLR與 ISR再次介入的難易程度和遠端栓塞發生有關。Rcn2在股腘動脈CTO患者中表達明顯升高。Rcn2 與NLR呈正相關,并與患者下肢缺血程度及低密度脂蛋白膽固醇水平相關。Rcn2有望成為下肢動脈硬化閉塞癥介入術后再狹窄的生物學標志物。
關鍵詞:網鈣結合蛋白2;血管平滑肌細胞;新生內膜病變;再狹窄;下肢動脈硬化閉塞癥

Abstract
Objective: atherosclerosis is the main cause of coronary heart disease, ischemic stroke and peripheral artery disease. Atherosclerotic lesions may directly or indirectly cause arterial stenosis or occlusion, affect the blood supply of important organs, and cause corresponding ischemic symptoms. Percutaneous transluminal angioplasty and stent placement are the main methods for the treatment of occlusive arterial diseases. With the development of interventional devices and the progress of technology, endovascular treatment of occlusive arterial disease has made long-term progress. However, the problem of restenosis has not yet been completely solved. Neointimal hyperplasia is the main pathological process of restenosis after operation. Neointimal lesions are mainly derived from vascular smooth muscle cells, which proliferate and migrate from the medial membrane to the intima. Recent studies have suggested that vascular restenosis may be affected by dietary factors and genetic factors. In previous studies, we found significant differences in the susceptibility to arteriosclerosis in C3H and C57 mice after Apoe knockout. Through quantitative trait loci (QTL) method, it is found that the net calcium binding protein 2 (Rcn2) may be the key gene that causes this difference. In this study, we first identified the role of Rcn2 in the process of intimal hyperplasia after high-fat diet aggravating arterial injury, and further explored that knockout of Rcn2 could inhibit intimal hyperplasia through animal experiments. Secondly, it is clear that Rcn2 can inhibit the proliferation and migration of vascular smooth muscle cells and the inflammatory response induced by ox-LDL through cell test. Finally, the level of Rcn2 expression was detected in the plasma of the patients with arteriosclerosis obliterans of the lower extremities, and the analysis of Rcn2 could be a biological marker for predicting the restenosis of the stent.
Methods: 1. In animal experiments, 8-12 week old, 20-25g weight C57BL/6 Apoe-/- mice (C57) and C57BL/6 Apoe-/-Rcn2-/- mice (Rcn2) were selected to establish carotid artery ligation injury model. One group of mice maintained an ordinary diet. The other group fed a high - fat diet 1 weeks before the carotid artery injury and maintained a high - fat diet until the end of the experiment. Carotid artery specimens were obtained at 1 days, 3 days after operation, and 1,2 and 4 weeks respectively. Pathological examination compared the area of the carotid artery, the area of the intima, the ratio of the intima and the area of the middle membrane. Immunohistochemical staining was used to identify the cell components of endometrial hyperplasia. The serum levels of pro-inflammatory factors and blood lipids were detected by ElISA. 2, in cell experiments, primary cultured C57 Apoe-/- mouse aortic smooth muscle cells were selected and stimulated with different concentrations of ox-LDL (50ug/ml, 100ug/ml, 150ug/ml, 200ug/ml) to stimulate vascular smooth muscle cells, and Rcn2 expression at mRNA level and protein level was detected. Vascular smooth muscle cells were transfected by siRNA, and the migration ability of vascular smooth muscle cells was detected by scratch test. MTT was used to detect the proliferation of vascular smooth muscle cells. The content of MCP-1 and VCAM-1 in cell supernatant was detected by ELISA. 3, from January 2012 to December 2014 were selected from 258 consecutive cases of femoral popliteal artery lesions in patients with clinical follow-up data CTO. 180 of the patients were included in the study, and the level of Rcn2 expression in the remaining plasma of 62 patients was detected and compared with 15 healthy controls. The correlation between the ratio of neutrophil to lymphocyte (NLR) and restenosis was also analyzed.
Results: 1. In the general diet group, C57 mice developed mild hyperlipidemia, the total cholesterol level was 308.5 + 60.3mg/dl, while the total cholesterol level in the high-fat diet group was 858.5 + 88.4mg/dl, which was severe hyperlipidemia (p<0.001). The levels of HDL cholesterol in the two groups were very low, and the levels of triglycerides were equal (159.3 + 37.1 mg/dl and 149.5 + 19.2mg/dl, p>0.05). The hyperlipidemia group appeared intimal hyperplasia 1 weeks after the operation, and the high fat diet group appeared intimal hyperplasia at the 2 week after the operation. With the increase of time, the two groups of endometrium lesions were all increased. At the 4 week after operation, the average intimal hyperplasia area of the carotid artery in the high-fat diet group was about 4 times higher than that in the ordinary diet group (112987, 11395, M2 and 29539 + 7001 m2, respectively); n = 5, P< 0.001). Histologically, 1 weeks after the high fat diet and 2 weeks after the common diet, the endometrium was mainly composed of foam cells. At 2 weeks after the high fat diet, endometrial hyperplasia is a typical fibrous plaque, which contains many foam cells covered by a fibrous cap. At 4 weeks, the endarterosis of the two diet groups developed to a more advanced stage, including the narrowing of the neovascularization and the arterial lumen. The expression of Rcn2 is low in the endocardial lesions of the common diet group, and is highly expressed in the endintimal lesions of the high fat diet group. The plasma concentration of Rcn2 in the high fat diet group was significantly higher than that in the normal diet group. (18.93 + 1.76ng/ml, 33.03 + 15.01ng/ml, n=5, p=0.029). The high-fat diet Rcn2 mice had mild hyperlipidemia, the total cholesterol level was significantly lower than that of C57 mice (264 + 56mg/dl and 858.5 + 88.4mg/dl, n=5, p<0.001), HDL cholesterol and triglyceride were not different in the two groups. Rcn2 knockout obviously inhibited the intimal hyperplasia of the carotid artery in C57 Apoe-/- mice under the high fat diet. It mainly inhibits the migration of vascular smooth muscle cells from the middle layer to the intima, and inhibits the expression of MCP-1 in the vascular wall cells. At 4 weeks after operation, the concentrations of MCP-1 (202.3 + 39.6ng/ml, 349.3 + 67.1ng/ml, n=5, p=0.009) and VCAM-1 (110.6 + 20.7ng/ml, 240.3 + 50.1ng/ml, n=5, p=0.002) in plasma of Rcn2 mice were significantly lower than those of the mice. 2, we choose different concentrations of ox-LDL (50ug/ml, 100ug/ml, 150ug/ml, 200ug/ml) to stimulate vascular smooth muscle cells for 4 hours, the mRNA expression and protein level of Rcn2 are highest at 150ug/ml. After transfection of Si Rcn2 into vascular smooth muscle cells, ox-LDL was stimulated for 24 hours. MTT test showed that Rcn2 could inhibit ox-LDL induced smooth muscle cell proliferation (p<0.05). The number of vascular smooth muscle cells passing through scratches was significantly reduced (p<0.05) after Rcn2 was detected by a flat scratch test. The concentration of MCP-1 and VCAM-1 in the supernatant of ELISA showed that silent Rcn2 inhibited the secretion of MCP-1 and VCAM-1 (p<0.05) by ox-LDL induced smooth muscle cells. The pressure of 3, a total of 180 patients who underwent stent implantation of the femoral popliteal artery in patients with CTO (male 141 cases, female 39 cases, [78.3%]; [21.7%]) were included in this study. According to the occurrence of ISR and the time of ISR, the patients were divided into 3 groups: non ISR group, early ISR group (1 years) and late ISR group. There were significant differences in baseline NLR, diabetes, hyperlipidemia, mean lesion length, and the number of outflow channels in the non ISR group and the early ISR group. In the early ISR group, baseline NLR was significantly higher than that in the late ISR group (P = 0.03), and there was a difference in the rate of balloon dilation (P <0.01) and the incidence of distal embolization (P <0.01) between the two groups during the treatment of ISR. Univariate analysis showed that baseline NLR is more than 3.62 and the early ISR, NLR <3.62 and NLR = 3.62 of baseline group of early ISR rates were 16% and 32.72% (P <0.01, Table 2). Multivariate logistic analysis showed that the baseline NLR = 3.62 is a independent predictor of early ISR popliteal artery stent implantation in patients with CTO. The plasma concentrations of Rcn2 were measured in 62 patients and 15 healthy controls. Restenosis was divided into no restenosis group and restenosis group based on the 1 years of follow-up. It was found that the concentration of Rcn2 in the three groups was statistically different (F=29.59, P<0.001) by single factor analysis of variance. The concentration of Rcn2 was positively correlated with NLR, and the concentration of Rcn2 was associated with low density lipoprotein cholesterol and the degree of ischemia. The operator's operation characteristic curve analysis (ROC) uses Rcn2 and early ISR to define the Rcn2 cut-off value. The area under the ROC curve was 0.901, the concentration of Rcn2 was 80.43 ng/ml, and the sensitivity and specificity were 79.92% and 83.72% respectively (p<0.001).
Conclusion: 1. High fat diet obviously aggravate the intimal hyperplasia of C57 mice after carotid artery injury. Hyperplastic endometrial lesions mainly include vascular smooth muscle cells, foam cells and neovascularization. Rcn2 is highly expressed in the intima lesions of C57 mice induced by high fat diet. Rcn2 knockout can obviously inhibit the hyperplasia of intima after hyperlipidemia induced arterial injury. It mainly inhibits the proliferation, migration and inflammation of vascular smooth muscle cells. 2, ox-LDL can induce the increase of Rcn2 expression in vascular smooth muscle cells. Rcn2 silencing can effectively inhibit the proliferation and migration of vascular smooth muscle cells induced by ox-LDL. Rcn2 silencing can effectively inhibit the secretion of proinflammatory cytokines in vascular smooth muscle cells induced by ox-LDL. 3, baseline NLR more than 3.62 independent predictors of early ISR femoral popliteal artery stent implantation in patients with CTO. The degree of difficulty in the re intervention of baseline NLR and ISR is associated with the occurrence of distal embolism. The expression of Rcn2 in femoral popliteal artery in patients with CTO increased significantly. Rcn2 has a positive correlation with NLR and is related to the degree of lower limb ischemia and low density lipoprotein cholesterol levels in the patients. Rcn2 is expected to be a biological marker for restenosis after interventional therapy for arteriosclerosis obliterans of the lower extremities.
Keywords: Rcn2; Vascular smooth muscle cells; Neointimal lesion; Restenosis. Arteriosclerosis obliterans
英文縮略語
英文縮寫    英文全稱    中文全稱
AS    Arteriosclerosis    動脈粥樣硬化
PTA    Percutaneous transluminal angioplasty    血管成形術
DCB    Drug-coated balloon    藥物涂層球囊
DES    Drug-eluting stent    藥物洗脫支架
ISR    In-stent restenosis    支架再狹窄
VSMC    Vascular smooth muscle cells    血管平滑肌細胞
Apoe    Apolipoprotein E    載脂蛋白E
QTL    Quantitative trait locus    數量性狀基因座
Rcn2    Reticulocalbin-2    網鈣結合蛋白-2
Ox-LDL    Oxidized low density lipoprotein    氧化低密度脂蛋白
LDL    Low density lipoprotein    低密度脂蛋白
VCAM-1    Vascular cell adhesion molecule -1    血管細胞粘附因子-1
MCP-1    Monocyte chemoattractant protein-1    單核細胞趨化蛋白-1
DMEM    dulbecco’s modified eagle’s medium    達爾伯克氏改良伊格爾氏培養基
FBS    Fetal bovine serum    胎牛血清
BSA    bovine serum albumin    牛血清白蛋白
PBS    phosphate buffer solution    磷酸鹽緩沖液
α-SMA    α-Smooth muscle actin    α-平滑肌肌動蛋白
vWF    von Willebrand Factor    血管性血友病因子
MMP    matrix metalloprotein    基質金屬蛋白酶
FITC    fluorescein isothiocyanate    異硫氰酸熒光素
IL    interleukin    白細胞介素
LPS    Lipopolysaccharide    脂多糖
PAGE    polyacryrlamide gel electropho- resis    聚丙烯酰胺凝膠電泳
CM    chylomicra    乳糜顆粒
VLD L    very low     極低密度脂蛋白
HDL    High density lipoprotein    HDL
TNF-β    Tumor Necrosis Factor-β    腫瘤壞死因子-β
PDGF-BB    Platelet-Derived Growth Factor BB    血小板源性生長因子
ASO    Atherosclerotic occlusive disease    下肢動脈閉塞硬化癥
NLR    Neutrophil to lymphocyte ratio    中性粒細胞與淋巴細胞比值
CTO    Chronic Total Occlusion    慢性完全閉塞
ABI    ankle brachial index    踝肱指數
FPG    Fasting plasma glucose    空腹血糖
TC    Total cholesterol    總膽固醇
TG    Triglyceride    甘油三酯
LDL-C    Low density lipoprotein    低密度脂蛋白-膽固醇
HDL-C    High density lipoprotein
    高密度脂蛋白-膽固醇
CRP    C-reactive protein    C反應蛋白
ECM     extracellular matrix     細胞外基質
VEGF    Vascular endothelial growth factor    血管內皮生長因子
TGF    Transfer growth factor    轉移生長因子
PDGF    platelet derived growth factor    血小板衍生因子
EPCs    Endothelial progenitor cells    內皮祖細胞
SMPCs    Vascular smooth muscle progenitor cells    血管平滑肌祖細胞
G-CSF    Granulocyte colony stimulating factor    粒細胞集落刺激因子
ET-1     endothelin-1    內皮素 -1


目錄
目 錄    13
第一部分:Rcn2對動脈損傷后內膜增生的影響    13
1 前言……………………………………………… …… … …………1    13
2 材料與方法……………………………………………… …… ……4    13
3 結果………………………………………………… …… ……21    14
4 討論………………………………… …… …… …… …… ……… 32    14
5 結論……………………………………………………… …… …… 33    14
第二部分Rcn2對血管平滑肌細胞增殖、遷移功能的影響    14
1 前言…………………………………………………………………45    14
2 材料與方法……………………………………… …… …… ……48    14
3 結果………………………………………………… …… ……21    14
4 討論………………………………… …… …… …… …… ……… 32    14
5 結論……………………………………………………… …… …… 33    15
第三部分Rcn2與股腘動脈慢性完全閉塞支架再狹窄的相關性研究    15
1 前言…………………………………………………………………45    15
2 材料與方法……………………………………… …… …… ……48    15
3 結果………………………………………………… …… ……21    15
4 討論………………………………… …… …… …… …… ……… 32    15
5 結論……………………………………………………… …… …… 33    15
6 孔細胞培養板購自Corning 公司;    19
2.1.2研究對象    21
2.2.3小鼠頸動脈結扎損傷模型的建立    22
2.2.4小鼠頸總動脈取材    22
2.2.5 HE染色    22
2.2.6病理形態學分析    23
2.2.7 免疫組化染色    23
2.2.8 ElISA檢測血清促炎因子濃度及血脂    24
2.2.9統計學分析    25
3 結果    26
3.1高脂飲食加劇C57 Apoe-/-小鼠血脂升高    26
3.2高血脂促進C57 Apoe-/-小鼠頸動脈損傷后內膜增生    26
3.3 Rcn2在高脂飲食條件下增生內膜中表達增高    32
3.4 Rcn2在高脂飲食條件下血漿中的濃度升高    32
3.5 Rcn2敲除抑制高脂飲食誘發的高血脂    32
3.6 Rcn2敲除抑制C57 Apoe-/-小鼠頸動脈損傷后內膜增生    33
3.7 Rcn2敲除抑制血清MCP-1、VCAM-1水平升高    34
4 討論    34
5 結論    59
第三部分:Rcn2與股腘動脈慢性完全閉塞支架再狹窄的相關性研究    60
1 前言    60
2 材料和方法    62
3 結果    66
4 討論    74
5 結論    77
本研究創新性的自我評價    81
參考文獻    82
綜 述    89
1.炎癥反應與下肢動脈介入術后再狹窄關系    89
2.下肢動脈介入術后再狹窄的細胞機制    90
2.1內皮細胞在再狹窄中的作用    90
2.2血管平滑肌細胞在再狹窄中的作用    92
2.3單核 /巨噬細胞在再狹窄形成中的作用    92
2.4骨髓干細胞在血管修復及再狹窄過程中的作用    93
2.5血管局部炎癥與干細胞動員    95
3.炎癥因子與下肢動脈介入術后再狹窄的相關性研究    95
4.干預炎癥在治療再狹窄中的作用    97
4.1抗血小板藥物    97
4.2皮質類固醇    97
4.3他汀類藥物    98
4.4藥物涂層球囊及藥物洗脫支架    98
參考文獻    99
致謝    106

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