预防移植静脉内膜增生和再狭窄的实验研究
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摘要
自1898年Gluck等首次将自体静脉用于动脉重建以来,自体静脉移植越来越多地被用于临床,迄今仍是修复肢体动脉缺损和冠状动脉旁路手术的主要方法,但常因内膜增生、再狭窄等原因影响远期疗效,Raja报道术后10年通畅率不足50%,因此有效预防移植静脉移植后内膜增生和再狭窄一直是大量的骨外科、血管外科、心脏外科学者研究的热点。移植静脉发生内膜增生是为了适应环境改变而发生的结构性重塑形,病理过程涉及到血栓形成,内皮细胞的免疫激活,白细胞的粘附、浸润,血管平滑肌细胞的迁移、增殖和凋亡,细胞外基质的形成和迁移,各种因子的激活和信号传导等机制,是一个受多种因素影响、多因子和多基因参与、多种机制调控的连续变化的病理过程,机制非常复杂,因此从根本上彻底阻止移植静脉再狭窄的发生至今仍是一个亟待解决的难题。
内膜增生是移植静脉发生再狭窄最根本和最主要的病理变化,因此减轻移植静脉内膜的过度增生是预防移植静脉再狭窄的关键,基于此我们设计本课题,通过实验研究探讨以下三个问题:1、局部应用5-氟尿嘧啶对移植静脉内膜增生的影响;2、单层和双层自体静脉外支架对移植静脉内膜增生的影响;3、抑制外周组织粘连对移植静脉内膜增生的影响。
第一部分局部应用5-氟尿嘧啶抑制移植静脉内膜增生的实验研究
平滑肌细胞的过度增殖、迁移是移植静脉发生内膜增生最关键的机制,因此抑制平滑肌细胞的过度增殖、迁移,诱导平滑肌细胞凋亡,合理地调控血管的重构,是预防移植静脉内膜增生和再狭窄最直接有效的途径。5-氟尿嘧啶(5-FU)是一种嘧啶类的抗代谢药物,可以通过干扰DNA合成的途径抑制细胞增殖,诱导细胞凋亡,局部应用安全性高。Cragg研究发现5-氟尿嘧啶对体外培养的平滑肌细胞增殖有明显抑制作用。基于此,我们建立家兔自体颈外静脉-颈总动脉模型,通过实验动物验证局部应用5-氟尿嘧啶是否能够抑制在体移植静脉平滑肌细胞增殖和诱导平滑肌细胞凋亡,从而调控血管的重构,预防移植静脉再狭窄的发生。
目的:探讨局部应用5-氟尿嘧啶(5-fluorouracil, 5-FU)对动脉缺损静脉移植后内膜增生的影响。
方法:选用64只5月龄雄性新西兰大白兔,体重2.8~3.0kg,随机分为A、B、C、D四组(n=16)。切取右侧颈外静脉3cm,游离左侧颈总动脉,中间切除长约1cm,建立动脉缺损模型,将切取静脉远近端倒置后用9-0无损伤缝线端端吻合于动脉缺损,吻合结束后A组、B组、C组动物分别用于50mg/ml、25mg/ml、12.5mg/ml的5-氟尿嘧啶中浸泡的脑棉(大小为12mm×30mm×1mm)完全包裹移植静脉外膜方式给药,共5次,每次1min,D组用生理盐水取代5-氟尿嘧啶同样方法处理。分别于术后1、2、4、6周切取移植静脉,行HE染色、Masson染色观察移植静脉管壁组织学变化,PCNA免疫组化染色、TUNEL标记染色观察移植静脉平滑肌细胞增殖和凋亡情况,透射电镜观察细胞超微结构变化。
结果:HE染色、Masson染色观察到:术后1、2、4、6周A组、B组移植静脉内膜增厚均明显小于C组和D组,PCNA免疫组化染色和TUNEL法标记染色观察到:术后1、2、4周A组、B组增殖细胞少于C组和D组,术后1、2周内膜、中膜凋亡细胞A组和B组明显多于C组和D组。内膜厚度、内膜增生程度、管腔狭窄程度结果分别为:1周A组12.69±1.68μm,0.73±0.05,0.025±0.003;B组17.52±2.01μm,0.86±0.06,0.027±0.004;C组21.92±1.85μm,1.06±0.09,0.036±0.006;D组26.45±3.86μm,1.18±0.08,0.041±0.005。2周A组24.61±2.91μm,0.86±0.06,0.047±0.003;B组37.28±2.78μm,1.17±0.09,0.060±0.004;C组46.52±2.25μm,1.41±0.08,0.073±0.003;D组52.07±3.29μm,1.45±0.05,0.081±0.006。4周A组61.09±6.84μm,1.38±0.08,0.106±0.007;B组63.61±8.25μm,1.40±0.07,0.107±0.010;C组80.04±7.65μm,1.64±0.07,0.129±0.011;D组84.45±9.39μm,1.68±0.10,0.138±0.014。6周A组65.27±5.25μm,1.46±0.07,0.113±0.005;B组65.82±7.12μm,1.45±0.05,0.112±0.011;C组84.45±6.39μm,1.69±0.09,0.135±0.007;D组87.27±8.96μm,1.76±0.05,0.140±0.012。均为A组、B组小于C组和D组(P<0.05)。内膜的增殖指数、凋亡指数和外膜的增殖指数、凋亡指数结果分别为:1周A组4.83±1.96,30.51±4.01,14.61±2.17,9.23±1.40;B组8.01±2.18,29.27±5.18,20.25±3.18,6.93±1.05;C组9.09±1.27,19.21±3.16,26.80±3.13,3.89±1.11;D组12.25±2.13,28.71±4.17,19.01±4.12,3.83±1.34。2周A组18.92±3.73,36.16±2.27,22.31±3.94,10.72±2.32;B组19.16±3.26,32.41±3.74 , 30.51±4.01 , 5.13±2.22; C组25.97±2.17 , 29.24±2.11 ,37.81±4.50,5.94±1.79;D组27.06±2.91,27.15±2.51,42.71±3.60,5.21±1.91。4周A组10.17±1.21,11.73±3.21,20.00±3.16,5.19±1.83;B组11.18±2.01,11.23±2.15,21.13±2.62,4.99±1.41;C组15.01±2.03,11.04±2.84,24.64±2.98,4.15±2.31;D组15.96±2.44,12.21±3.68,28.70±2.08,4.86±1.69。6周A组6.67±2.10,5.69±2.31,2.51±1.53,3.84±1.41;B组6.67±1.81,5.04±1.71,2.47±1.51,3.53±1.34;C组6.88±2.01,5.99±2.13,3.40±0.98,3.74±1.03;D组8.21±2.27,6.01±2.03,3.28±1.09,3.64±1.08。术后1、2、4周的细胞增殖指数均为A组、B组小于C组和D组(P<0.05),术后1、2周内膜、中膜细胞凋亡指数A组和B组均大于C组和D组(P<0.05)。透射电镜观察到A组、B组相对于C组和D组粗面内质网、高尔基体、核糖体等合成细胞器含量明显减少。
结论:局部应用5-FU可抑制移植静脉平滑肌细胞增殖,诱导术后早期平滑肌细胞凋亡,有效地减轻内膜增生,降低移植静脉管腔再狭窄程度。
第二部分自体静脉外支架对移植静脉内膜增生影响的实验研究
1963年,Parsonne等首先报道了于移植静脉周围应用外支架(external stent)能够减轻移植静脉的内膜增生,有效地预防移植静脉狭窄,之后许多学者通过实验研究证实应用外支架是一种很有前景的预防移植静脉狭窄的措施。外支架的作用是对抗移植静脉移植后的早期扩张,通过刺激新生外膜形成或直接对抗作用使移植静脉管腔内的血流动力学特性更加接近动脉,从而减少因血流动力学改变所引发的一系列病理改变。目前应用的外支架多为人工合成材料,植入体内可引发慢性炎症、局部感染、静脉外膜纤维化等不良反应,而且其弹性和顺应性与动脉差异很大,因此并不能充分发挥减少移植静脉血流动力学改变的作用。我们选用自体相容性好、弹性和顺应性与动脉相近的自体静脉作为移植静脉的外支架,在移植静脉外周放置单层和双层自体静脉外支架,通过动物实验观察自体静脉外支架能否对抗移植静脉的早期扩张,抑制平滑肌细胞增生,预防移植静脉再狭窄的发生。
目的:探讨自体静脉外支架对动脉缺损静脉移植后内膜增生的影响。
方法:选用36只5月龄雄性新西兰大白兔,体重2.8~3.0kg,随机分为A组、B组和C组(n=12)。切取右侧颈外静脉6cm,等分为三段,远心段均用作移植静脉,B组以中段作为自体外支架,A组以近心段套叠中段做成双层自体外支架。游离左侧颈总动脉,中间切除长约0.5cm,建立动脉缺损模型,将移植静脉远近端倒置后吻合于动脉缺损,通血后行移植静脉外径测量。分别于术后2、4周切取移植静脉,行HE染色、Masson染色观察移植静脉管壁组织学变化,PCNA免疫组化染色观察移植静脉平滑肌细胞增殖情况。
结果:通血后移植静脉直径A组1.62±0.31mm,B组2.21±0.40mm,C组2.65±0.58mm,A组 结论:双层自体静脉外支架可以有效地抑制移植静脉内膜增生,减轻移植静脉管腔再狭窄程度。
第三部分抑制外周组织粘连对移植静脉内膜增生影响的实验研究
移植静脉植入后均与外周组织间存在明显的粘连,粘连机制是移植静脉外膜滋养血管长入、从外周组织获得血运的途径。如果采取措施阻止外周粘连,阻止外膜滋养血管长入,屏蔽移植静脉从周围组织获得血运,可能导致内膜缺血,而内膜缺血促进促有丝分裂原的产生,是内膜增生的重要原因。Fogelstrand和Zhang等学者通过动物实验研究发现外周组织来源的平滑肌细胞也是导致移植静脉内膜增生的重要细胞来源,外周组织源性平滑肌细胞通过外周组织粘连迁移至移植静脉,参与内膜增生的形成,阻断外周组织的粘连可以抑制内膜增生。因此,阻止外周组织粘连对移植静脉内膜增生可以产生两种相反的作用机制,究竟哪一种机制占主导地位,抑制周围组织粘连将对内膜增生产生怎样的影响是一个需要探究的课题。透明质酸钠局部应用可以抑制粘连的发生,而且透明质酸钠为液性,局部应用后不通过改变移植静脉的生物力学机制影响内膜增生。因此,我们设计采用移植静脉周围应用透明质酸钠的方法抑制移植静脉周围组织粘连,与常规移植静脉对照,揭示其抑制外周组织粘连对移植静脉平滑肌细胞增殖、细胞因子(PDGF)的表达和分布以及对内膜增生的影响。
目的:探讨抑制外周组织粘连对移植静脉平滑肌细胞增殖、细胞因子(PDFG)的表达和分布以及对内膜增生的影响。
方法:选用24只5月龄雄性新西兰大白兔,体重2.8~3.0kg,随机分为A组、B组(n=12)。切取右侧颈外静脉3cm,游离左侧颈总动脉,中间切除长约1cm,建立动脉缺损模型,将切取静脉远近端倒置后用9-0无损伤缝线端端吻合于动脉缺损,吻合结束后A组动物用透明质酸钠凝胶0.2ml涂布于移植静脉外膜及两个吻合口。分别于术后1、2、4周行移植静脉切取前肉眼观察,切取移植静脉后行HE染色、Masson染色观察移植静脉管壁组织学变化,PCNA免疫组化染色、PDGF免疫组织化学染色观察移植静脉平滑肌细胞增殖和PDFG的表达、分布情况。
结果:术后1、2、4周肉眼观察B组移植静脉周围均有明显粘连,A组术后1、2周无粘连,术后4周有轻度粘连。HE染色、Masson染色、PCNA免疫组化染色和PDGF免疫组化染色观察到:术后2、4周A组移植静脉内膜厚度小于B组,术后1、2、4周A组增殖细胞均少于B组,术后1周A组外膜无PDGF阳性细胞,B组外膜内见阳性的炎性细胞;术后2、4周A组内膜、中膜和外膜PDGF阳性细胞均少于B组。内膜厚度、内膜增生程度、管腔狭窄程度结果分别为:1周A组25.51±3.93μm,1.18±0.07,0.041±0.005;B组26.18±4.16μm,1.19±0.09,0.042±0.006。2周A组44.27±2.53μm,1.22±0.06,0.062±0.003;B组50.99±3.76μm,1.40±0.03,0.078±0.004。4周A组69.85±6.76μm,1.49±0.07,0.114±0.009;B组84.43±6.41μm,1.69±0.09,0.137±0.007。术后2、4周A组的内膜厚度、内膜增生程度、管腔狭窄程度均小于B组(P<0.05)。内膜、中膜的增殖指数结果分别为:1周A组7.43±2.21,21.53±3.24;B组11.41±2.01,28.63±4.48。2周A组20.01±3.21,35.81±3.41;B组26.78±4.14,42.63±4.15。4周A组11.41±2.01,22.09±2.65;B组15.52±2.37,28.64±3.90。术后2、4周A组的内膜和中膜增殖指数均小于B组(P<0.05)。内膜、中膜外膜的PDGF表达率结果分别为:1周A组7.67±1.61,19.59±3.66,2.46±1.53;B组7.60±2.42,20.58±4.39,10.25±2.31。2周A组11.37±2.55,19.81±3.09,12.90±3.26;B组19.45±3.48,30.63±5.16,30.47±5.84。4周A组6.15±1.94,11.09±2.83,10.19±2.44;B组10.51±2.03,18.64±3.21,26.51±3.84。术后1周A组外膜PDGF表达率低于B组(P<0.05),术后2、4周A组的内膜、中膜和外膜PDGF表达率均小于B组(P<0.05)。
结论:局部应用透明质酸钠可以有效地抑制移植静脉外周粘连的形成,并在一定程度上减轻内膜增生;抑制外周组织粘连并不加重移植静脉内膜增生和管腔狭窄。
Autogenous vein graft has been more and more common in clinical practice since autogenous vein was first used for artery reconstruction by Gluck in 1898. Heretofore autogenous vein graft continues to be the primary method for the reconstruction of the artery defect and coronary artery bypass graft. However, the long-term therapeutic efficacy is always limited by the intimal hyperplasia and stenosis of vein graft. Raja reported that patency rate of vein graft was no more than 50% 10 years after surgery. So it is always a focus of study for the researcher of orthopaedics, vascular surgery and cardiac surgery to prevent intimal hyperplasia and stenosis of vein graft. Intimal hyperplasia is the result of remodeling for vein graft to adapt itself to a charged environment, the pathologic process comprised thrombogenesis, activating of endothelial cell, leukocyte adhesion, Leukocytic infiltrate,smooth muscle cells migration, proliferation and apoptosis, extracellular matrix formation and migration, activating cytokine and signal transducting, it is a complex and continuously changing pathogenesis influenced by multiple factor and interfered by multiple cytokine and gene. Accordingly, it has been being a pressing difficult problem to prevent the occurrence of stenosis of vein graft.
It is the critical way of preventing stenosis to inhibit the intimal hyperplasia of vein graft because intimal hyperplasia is the primary and leading pathological change of stenosis of vein graft. For this reason, we designed a project to answer 3 questions: First, to assess the effect of 5-Fluorouracil(5-FU) applied topically on intimal hyperplasia of the vein grafts; Second, to assess the effect of the autologous single-layer and double-layer venous external stents on intimal hyperplasia; Third, to assess the effect of preventing peripheral adhesion of vein graft on intimal hyperplasia.
Part 1 Inhibitory effects of topical application of 5-fluorouracil on intimal hyperplasia of the vein grafts in rabbits
The excessive proliferation and migration of vascular smooth muscle cell are the critical pathogenesis of intimal hyperplasia, so it is a immediate way of preventing intimal hyperplasia and stenosis to inhibit excessive proliferation and migration of vascular smooth muscle cell and to induce apoptosis and to regulate the remodeling of vein graft. 5-Fluorouracil(5-FU) is a antimetabolite belonging to miazines, it can inhibit cell proliferation and induce cell apoptosis, and it is very safe applied locally. Cragg reported that 5-Fluorouracil can effectively inhibit proliferation of vascular smooth muscle cell cultured in vitro. So, external jugular vein grafts was interposed into the carotid artery of rabbits and applied 5-Fluorouracil to test the effect of 5-Fluorouracil in inhibiting proliferation of vascular smooth muscle cell and inducing apoptosis of vascular smooth muscle cell in vivo and regulating the remodeling and preventing stenosis of vein graft.
Objective To assess the effect of 5-Fluorouracil(5-FU) applied topically on intimal hyperplasia of the vein grafts in rabbits.
Methods Sixty-four male New Zealand white rabbits, aged 5 months and weighing 2.8 to 3.0kg, were randomly divided into 4 groups: Group A, B, C and D (n=16 rabbits per group). Artery defect model was established by cutting about 1 cm artery from the middle part of the dissociated left common carotid artery. A section about 3 cm was cut from the right external jugular vein, and the harvested vein was inverted and end-to-end anastomosed to the artery defect with 9-0 non-traumatic suture. After anastomosis, the extima of the grafted veins in group A, B, and C was completely wrapped with cotton sheet (12mm×30mm×1mm in size) immersed by 5-FU at a concentration of 50.0, 25.0, and 12.5 mg/mL, respectively, and each vein was treated 5 times (1 minute at a time). In group D, the extima of the graft veins was treated with normal sal ine instead of 5-FU. The grafted veins were obtained 1, 2, 4, and 6 weeks after operation, HE staining and Masson staining were preformed for histological changes of grafted vein wall, proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and terminal deoxymudeotityl transferase mediated dUTP nick end labeling (TUNEL) staining were conducted for proliferation and apoptosis of smooth muscle cell of the grafted vein, and transmission electron microscope observation was performed for cellular ultrastructure.
Result The HE staining, Masson staining showed that the thickness of intima in group A and B was obviously less than that in group C and D at 1, 2, 4, and 6 weeks after operation. PCNA immunohistochemistry staining and TUNEL labeling staining showed that the proliferation cells in group A and B were less than that in group C and D at 1, 2, and 4 weeks after operation and the apoptotic cells in group A and B were more than that in group C and D at 1 and 2 weeks after operation. The thickness of the intima, the degree of intima hyperplasia, the degree of vessel lumen stenosis of four groups at different time points were as follows: at 1 week after operation, group A [(12.69±1.68)μm, 0.73±0.05, 0.025±0.003], group B [(17.52±2.01)μm, 0.86±0.06, 0.027±0.004], group C [(21.92±1.85)μm, 1.06±0.09, 0.036±0.006] and group D [(26.45±3.86)μm, 1.18±0.08, 0.041±0.005]; at 2 weeks after operation, group A [(24.61±2.91)μm, 0.86±0.06, 0.047±0.003], group B [(37.28±2.78)μm, 1.17±0.09, 0.060±0.004], group C [(46.52±2.25)μm, 1.44±0.08, 0.073±0.003], and group D [(52.07±3.29)μm, 1.45±0.05, 0.081±0.006]; at 4 weeks after operation, group A [(61.09±6.84)μm, 1.38±0.08, 0.106±0.007], group B [(63.61±8.25)μm, 1.40±0.07, 0.107±0.010], group C [(80.04±7.65)μm, 1.64±0.07, 0.129±0.011], and group D [(84.45±9.39)μm, 1.68±0.10, 0.138±0.014]; at 6 weeks after operation, group A [(65.27±5.25)μm, 1.46±0.07, 0.113±0.005], group B [(65.82±7.12)μm, 1.45±0.05, 0.112±0.011], group C [(84.45±6.39)μm, 1.69±0.09, 0.135±0.007], and group D [(87.27±8.96)μm, 1.76±0.05, 0.140±0.012]. Group A and B were inferior to group C and D in terms of the above three parameters 1, 2, 4 and 6weeks after operation (P<0.05). Cell proliferation index and cell apoptosis index of intima and that of media were as follows: at 1 week after operation, group A (4.83±1.96, 30.51±4.01, 14.61±2.17, 9.23±1.40), group B (8.01±2.18, 29.27±5.18, 20.25±3.18, 6.93±1.05), group C (9.09±1.27, 19.21±3.16, 26.80±3.13, 3.89±1.11) and group D (12.25±2.13, 28.71±4.17, 19.01±4.12, 3.83±1.34); at 2 weeks after operation, group A (18.92±3.73, 36.16±2.27, 22.31±3.94, 10.72±2.32), group B (19.16±3.26, 32.41±3.74, 30.51±4.01, 5.13±2.22), group C (25.97±2.17, 29.24±2.11, 37.81±4.50, 5.94±1.79), and group D (27.06±2.91, 27.15±2.51, 42.71±3.60, 5.21±1.91); at 4 weeks after operation, group A (10.17±1.21, 11.73±3.21, 20.00±3.16, 5.19±1.83), group B (11.18±2.01, 11.23±2.15, 21.13±2.62, 4.99±1.41), group C (15.01±2.03, 11.04±2.84, 24.64±2.98, 4.15±2.31), and group D (15.96±2.44, 12.21±3.68, 28.70±2.08, 4.86±1.69); at 6 weeks after operation, group A (6.67±2.10, 5.69±2.31, 2.51±1.53, 3.84±1.41), group B (6.67±1.81, 5.04±1.71, 2.47±1.51, 3.53±1.34), group C (6.88±2.01, 5.99±2.13, 3.40±0.98, 3.74±1.03), and group D (8.21±2.27, 6.01±2.03, 3.28±1.09, 3.64±1.08). Group A and B were inferior to group C and D in terms of cell proliferation index of intima and media 1, 2 and 4 weeks after operation (P<0.05). Group A and B were superior to group C and D in terms of cell apoptosis index of intima and media 1 and 2 weeks after operation (P<0.05). Transmission electron microscope observation showed that the synthetic cell organelles such as rough endoplasmic reticulum, golgi apparatus, and ribosome in group A and B were obviously less than those in group C and D.
Conclusion Topical application of 5-FU can inhibits proliferation of vascular smooth muscle cell and induces cell apoptosis of vascular smooth muscle cell, so that it can effectively inhibit intima hyperplasia and stenosis of the vein grafts.
Part 2 The effects of the autologous venous external stents on intimal hyperplasia of the vein grafts in rabbits
In 1963, Parsonne first reported that external stent can inhibit intimal hyperplasia and stenosis of vein graft. After that, many researcher proved that the application of external stent was a promising and effective means of preventing stenosis of vein graft. External stent can counteract the early distension of vein grafted, and it made hemodynamic index of vein graft approaching that of the host artery by the means of prevoking neoadventitia forming and its counteraction, so that the pathologic process induced by the change of hemodynamic index was inhibited. At present the material of most external stent is artificial synthetics, which was likely to evoke inflammation, local infection and adventitial fibrosis of vein graft if implanted. In addition, the mechanical properties of artificial synthetics were far from artery, so this kind of external stents cannot enough inhibit the change of hemodynamic index of vein grafted. Accordingly, the autologous venous external stents, whose mechanical properties were approaching the artery and unlikely to trigger reject reaction, were selected and tested. Single-layer and double-layer venous external stents were applied to vein graft in rabbits to test the effect of autologous venous external stents in counteracting the early distension of vein
grafted and preventing intimal hyperplasia and stenosis of vein graft. Objective To assess the effect of the single-layer and double-layer autologous venous external stents on intimal hyperplasia of the vein grafts in rabbits.
Methods Thirty-six male New Zealand white rabbits, aged 5 months and weighing 2.8 to 3.0kg, were randomly divided into 3 groups: Group A, B and C, with 12 rabbits in each group. First, a section about 6cm long of vein was cut from the right external jugular vein of each rabbit and severed to have 3 equal-length segments. Next, each distal segment prepared for anastomosis. The proximal segment invaginating middle segment in group A and only middle segment in group B were used for the external stent. Later, the left common carotid artery was separated from surrounding tissue, from it a section about 0.5 cm long was cut away. Finally, the vein graft was inverted and end-to-end anastomosed to the two ends of the artery with a 9-0 suture. After bloodstream re-established, the diameter of each vein graft was measured. At 2, 4 weeks postoperative,the graft veins were cut off and histologically examined by the means of HE staining and Masson staining. The smooth muscle cells(SMC) proliferation was studied by the immunohistochemical detection of proliferating cell nuclear antigen(PCNA).
Result After bloodstream re-established, the diameters of vein graft of group A, group B and group C were 1.62±0.31mm, 2.21±0.40mm and 2.65±0.58mm respectively. The diameter of vein graft of group A was smaller than of group B and group C, and that of group B was smaller than group C. (P<0.05). At 2 and 4 weeks after operation, HE staining, Masson staining and PCNA immunohistochemistry staining showed that the thickness of intima in group A and group B was obviously less than that in group C and the proliferation cells of intimal and media in group A and group B were less than that in group C. The thickness of the intima, the degree of intima hyperplasia, the degree of vessel lumen stenosis of 3 groups at different time points were as follows: at 2 week after operation, group A [(35.13±3.24)μm, 0.88±0.03, 0.046±0.004], group B [(44.53±3.55)μm, 1.08±0.02, 0.058±0.005] and group C [(51.62±4.72)μm, 1.21±0.04, 0.068±0.007]; at 4 weeks after operation, group A [(51.73±6.08)μm, 1.01±0.07, 0.076±0.008], group B [(69.29±6.33μm), 1.32±0.08, 0.101±0.009] and group C [(85.00±7.36)μm, 1.55±0.03, 0.134±0.003]. Group A was inferior to group B and C and Group B was inferior to group C in terms of the above three parameters 2 and 4weeks after operation (P<0.05). Cell proliferation index of intima and that of media were as follows: at 2 weeks after operation, group A (16.98±3.96, 28.39±6.02), group B (24.07±4.13, 36.41±6.93) and group C (29.90±4.68, 48.45±5.60); at 4 weeks after operation, group A (6.84±1.98, 15.65±5.12), group B (11.01±2.61, 23.31±4.30) and group C (14.96±4.14, 29.64±4.15). Group A and B were inferior to group C and Group B was inferior to group C in terms of cell proliferation index of intima and media 2 and 4 weeks after operation (P<0.05).
Conclusion The autologous venous two-layer external stents inhibit intimal hyperplasia and relieve the stenosis of the vein gratfs effectively. Part 3 The effects of inhibit perivascular adhesion on intimal hyperplasia of the vein grafts in rabbits
There was apparent adhesion between vein grafted and surrounding tissue. Perivascular adhesion was the way which vasa vasorum enter through to and hyperplasia if to prevent perivascular adhesion and vasa vasorum going in. However, Fogelstrand and Zhang et al reported that vascular smooth muscle cell derived from surrounding tissue played a very important role in intimal hyperplasia, which was proved by animal experiment. Vascular smooth muscle cell derived from surrounding tissue migrated to vein grafted through perivascular adhesion, so it can inhibit intimal hyperplasia to prevent perivascular adhesion. Accordingly, opposite actions on intimal hyperplasia were caused by preventing adhesion. It should be studied which action was dominant and what the effect of preventing adhesion on intimal hyperplasia was. Local application of sodium hyaluronate can prevent adhesion, but also it didn’t inflenced intimal hyperplasia of vein graft by biomechanical mechanism because it was liquid. For these reasons, sodium hyaluronate was applied locally to adventitia of vein graft in rabbits to test the effect of sodium hyaluronate on cell proliferation, expression and distribution of PDGF and intimal hyperplasia of vein graft.
Objective To assess the effect of sodium hyaluronate applied topically on cell proliferation, expression and distribution of PDGF and intimal hyperplasia of vein graft in rabbits.
Methods twenty-four male New Zealand white rabbits, aged 5 months and weighing 2.8 to 3.0kg, were randomly divided into 3 groups: Group A and B (n=12 rabbits per group). Artery defect model was established by cutting about 1 cm artery from the middle part of the dissociated left common carotid artery. A section about 3 cm was cut from the right external jugular vein, and the harvested vein was inverted and end-to-end anastomosed to the artery defect with 9-0 non-traumatic suture. After anastomosis, the adventitia and two anastomosis of the grafted veins in group A was applied 0.2ml sodium hyaluronate locally to. The grafted veins were obtained 1, 2 and 4 weeks after operation, HE staining and Masson staining were preformed for histological changes of grafted vein wall, proliferating cell nuclear antigen (PCNA) and platelet-derived growth factor (PDGF) immunohistochemistry staining were conducted for proliferation and expression and distribution of PDGF of the grafted vein.
Result The macroscopic observation showed that there was not apparent adhesion in group B at 1 and 2 weeks and was slight adhesion at 4 weeks after operation in group A and there was apparent adhesion in group B. HE staining, Masson staining showed that the thickness of intima in group A was obviously less than that in group B at 2 and 4 weeks after operation. PCNA and PDGF immunohistochemistry staining showed that the proliferation cells in group A was less than that in group B at 1, 2, and 4 weeks after operation and the positive cells of PDGF immunohistochemistry staining of intimal, media and adventitia in group A was less than that in group B at 1, 2 and 4 weeks after operation. The thickness of the intima, the degree of intima hyperplasia, the degree of vessel lumen stenosis of 2 groups at different time points were as follows: at 1 week after operation, group A [(25.51±3.93)μm, 1.18±0.07, 0.041±0.005] and group B [(26.18±4.16)μm, 1.19±0.09, 0.042±0.006]; at 2 weeks after operation, group A [(44.27±2.53)μm, 1.22±0.06, 0.062±0.003] and group B [(50.99±3.76)μm, 1.40±0.03, 0.078±0.004]; at 4 weeks after operation, group A [(69.85±6.76)μm, 1.49±0.07, 0.114±0.009] and group B [(84.43±6.41)μm, 1.69±0.09, 0.137±0.007]. Group A was inferior to group B in terms of the above three parameters 2 and 4weeks after operation (P<0.05). Cell proliferation index and cell apoptosis index of intima and that of media were as follows: at 1 week after operation, group A (7.43±2.21, 21.53±3.24) and group B (11.41±2.01, 28.63±4.48); at 2 weeks after operation, group A (20.01±3.21, 35.81±3.41) and group B (26.78±4.14, 42.63±4.15); at 4 weeks after operation, group A (11.41±2.01, 22.09±2.65) and group B (15.52±2.37, 28.64±3.90). Group A was inferior to group B in terms of cell proliferation index of intima and media 2 and 4 weeks after operation (P<0.05). The percentage of PDGF-positive cells of intima, media and adventitia was as follows: at 1 week after operation, group A (7.67±1.61, 19.59±3.66, 2.46±1.53) and group B (7.60±2.42, 20.58±4.39, 10.25±2.31); at 2 weeks after operation, group A (11.37±2.55, 19.81±3.09, 12.90±3.26) and group B (19.45±3.48, 30.63±5.16, 30.47±5.84); at 4 weeks after operation, group A (6.15±1.94, 11.09±2.83, 10.19±2.44) and group B (10.51±2.03, 18.64±3.21, 26.51±3.84). Group A was inferior to group B in terms of the percentage of PDGF-positive cells of intima, media and adventitia 2 and 4 weeks after operation (P<0.05) and Group A was inferior to group B that of adventitia 1 week after operation (P<0.05).
Conclusion Topical application of sodium hyaluronate prevents perivascular adhesion and inhibits intima hyperplasia. It doesn’t promote intima hyperplasia and stenosis of the vein graft to prevent perivascular adhesion.
内膜增生是移植静脉发生再狭窄最根本和最主要的病理变化,因此减轻移植静脉内膜的过度增生是预防移植静脉再狭窄的关键,基于此我们设计本课题,通过实验研究探讨以下三个问题:1、局部应用5-氟尿嘧啶对移植静脉内膜增生的影响;2、单层和双层自体静脉外支架对移植静脉内膜增生的影响;3、抑制外周组织粘连对移植静脉内膜增生的影响。
第一部分局部应用5-氟尿嘧啶抑制移植静脉内膜增生的实验研究
平滑肌细胞的过度增殖、迁移是移植静脉发生内膜增生最关键的机制,因此抑制平滑肌细胞的过度增殖、迁移,诱导平滑肌细胞凋亡,合理地调控血管的重构,是预防移植静脉内膜增生和再狭窄最直接有效的途径。5-氟尿嘧啶(5-FU)是一种嘧啶类的抗代谢药物,可以通过干扰DNA合成的途径抑制细胞增殖,诱导细胞凋亡,局部应用安全性高。Cragg研究发现5-氟尿嘧啶对体外培养的平滑肌细胞增殖有明显抑制作用。基于此,我们建立家兔自体颈外静脉-颈总动脉模型,通过实验动物验证局部应用5-氟尿嘧啶是否能够抑制在体移植静脉平滑肌细胞增殖和诱导平滑肌细胞凋亡,从而调控血管的重构,预防移植静脉再狭窄的发生。
目的:探讨局部应用5-氟尿嘧啶(5-fluorouracil, 5-FU)对动脉缺损静脉移植后内膜增生的影响。
方法:选用64只5月龄雄性新西兰大白兔,体重2.8~3.0kg,随机分为A、B、C、D四组(n=16)。切取右侧颈外静脉3cm,游离左侧颈总动脉,中间切除长约1cm,建立动脉缺损模型,将切取静脉远近端倒置后用9-0无损伤缝线端端吻合于动脉缺损,吻合结束后A组、B组、C组动物分别用于50mg/ml、25mg/ml、12.5mg/ml的5-氟尿嘧啶中浸泡的脑棉(大小为12mm×30mm×1mm)完全包裹移植静脉外膜方式给药,共5次,每次1min,D组用生理盐水取代5-氟尿嘧啶同样方法处理。分别于术后1、2、4、6周切取移植静脉,行HE染色、Masson染色观察移植静脉管壁组织学变化,PCNA免疫组化染色、TUNEL标记染色观察移植静脉平滑肌细胞增殖和凋亡情况,透射电镜观察细胞超微结构变化。
结果:HE染色、Masson染色观察到:术后1、2、4、6周A组、B组移植静脉内膜增厚均明显小于C组和D组,PCNA免疫组化染色和TUNEL法标记染色观察到:术后1、2、4周A组、B组增殖细胞少于C组和D组,术后1、2周内膜、中膜凋亡细胞A组和B组明显多于C组和D组。内膜厚度、内膜增生程度、管腔狭窄程度结果分别为:1周A组12.69±1.68μm,0.73±0.05,0.025±0.003;B组17.52±2.01μm,0.86±0.06,0.027±0.004;C组21.92±1.85μm,1.06±0.09,0.036±0.006;D组26.45±3.86μm,1.18±0.08,0.041±0.005。2周A组24.61±2.91μm,0.86±0.06,0.047±0.003;B组37.28±2.78μm,1.17±0.09,0.060±0.004;C组46.52±2.25μm,1.41±0.08,0.073±0.003;D组52.07±3.29μm,1.45±0.05,0.081±0.006。4周A组61.09±6.84μm,1.38±0.08,0.106±0.007;B组63.61±8.25μm,1.40±0.07,0.107±0.010;C组80.04±7.65μm,1.64±0.07,0.129±0.011;D组84.45±9.39μm,1.68±0.10,0.138±0.014。6周A组65.27±5.25μm,1.46±0.07,0.113±0.005;B组65.82±7.12μm,1.45±0.05,0.112±0.011;C组84.45±6.39μm,1.69±0.09,0.135±0.007;D组87.27±8.96μm,1.76±0.05,0.140±0.012。均为A组、B组小于C组和D组(P<0.05)。内膜的增殖指数、凋亡指数和外膜的增殖指数、凋亡指数结果分别为:1周A组4.83±1.96,30.51±4.01,14.61±2.17,9.23±1.40;B组8.01±2.18,29.27±5.18,20.25±3.18,6.93±1.05;C组9.09±1.27,19.21±3.16,26.80±3.13,3.89±1.11;D组12.25±2.13,28.71±4.17,19.01±4.12,3.83±1.34。2周A组18.92±3.73,36.16±2.27,22.31±3.94,10.72±2.32;B组19.16±3.26,32.41±3.74 , 30.51±4.01 , 5.13±2.22; C组25.97±2.17 , 29.24±2.11 ,37.81±4.50,5.94±1.79;D组27.06±2.91,27.15±2.51,42.71±3.60,5.21±1.91。4周A组10.17±1.21,11.73±3.21,20.00±3.16,5.19±1.83;B组11.18±2.01,11.23±2.15,21.13±2.62,4.99±1.41;C组15.01±2.03,11.04±2.84,24.64±2.98,4.15±2.31;D组15.96±2.44,12.21±3.68,28.70±2.08,4.86±1.69。6周A组6.67±2.10,5.69±2.31,2.51±1.53,3.84±1.41;B组6.67±1.81,5.04±1.71,2.47±1.51,3.53±1.34;C组6.88±2.01,5.99±2.13,3.40±0.98,3.74±1.03;D组8.21±2.27,6.01±2.03,3.28±1.09,3.64±1.08。术后1、2、4周的细胞增殖指数均为A组、B组小于C组和D组(P<0.05),术后1、2周内膜、中膜细胞凋亡指数A组和B组均大于C组和D组(P<0.05)。透射电镜观察到A组、B组相对于C组和D组粗面内质网、高尔基体、核糖体等合成细胞器含量明显减少。
结论:局部应用5-FU可抑制移植静脉平滑肌细胞增殖,诱导术后早期平滑肌细胞凋亡,有效地减轻内膜增生,降低移植静脉管腔再狭窄程度。
第二部分自体静脉外支架对移植静脉内膜增生影响的实验研究
1963年,Parsonne等首先报道了于移植静脉周围应用外支架(external stent)能够减轻移植静脉的内膜增生,有效地预防移植静脉狭窄,之后许多学者通过实验研究证实应用外支架是一种很有前景的预防移植静脉狭窄的措施。外支架的作用是对抗移植静脉移植后的早期扩张,通过刺激新生外膜形成或直接对抗作用使移植静脉管腔内的血流动力学特性更加接近动脉,从而减少因血流动力学改变所引发的一系列病理改变。目前应用的外支架多为人工合成材料,植入体内可引发慢性炎症、局部感染、静脉外膜纤维化等不良反应,而且其弹性和顺应性与动脉差异很大,因此并不能充分发挥减少移植静脉血流动力学改变的作用。我们选用自体相容性好、弹性和顺应性与动脉相近的自体静脉作为移植静脉的外支架,在移植静脉外周放置单层和双层自体静脉外支架,通过动物实验观察自体静脉外支架能否对抗移植静脉的早期扩张,抑制平滑肌细胞增生,预防移植静脉再狭窄的发生。
目的:探讨自体静脉外支架对动脉缺损静脉移植后内膜增生的影响。
方法:选用36只5月龄雄性新西兰大白兔,体重2.8~3.0kg,随机分为A组、B组和C组(n=12)。切取右侧颈外静脉6cm,等分为三段,远心段均用作移植静脉,B组以中段作为自体外支架,A组以近心段套叠中段做成双层自体外支架。游离左侧颈总动脉,中间切除长约0.5cm,建立动脉缺损模型,将移植静脉远近端倒置后吻合于动脉缺损,通血后行移植静脉外径测量。分别于术后2、4周切取移植静脉,行HE染色、Masson染色观察移植静脉管壁组织学变化,PCNA免疫组化染色观察移植静脉平滑肌细胞增殖情况。
结果:通血后移植静脉直径A组1.62±0.31mm,B组2.21±0.40mm,C组2.65±0.58mm,A组
第三部分抑制外周组织粘连对移植静脉内膜增生影响的实验研究
移植静脉植入后均与外周组织间存在明显的粘连,粘连机制是移植静脉外膜滋养血管长入、从外周组织获得血运的途径。如果采取措施阻止外周粘连,阻止外膜滋养血管长入,屏蔽移植静脉从周围组织获得血运,可能导致内膜缺血,而内膜缺血促进促有丝分裂原的产生,是内膜增生的重要原因。Fogelstrand和Zhang等学者通过动物实验研究发现外周组织来源的平滑肌细胞也是导致移植静脉内膜增生的重要细胞来源,外周组织源性平滑肌细胞通过外周组织粘连迁移至移植静脉,参与内膜增生的形成,阻断外周组织的粘连可以抑制内膜增生。因此,阻止外周组织粘连对移植静脉内膜增生可以产生两种相反的作用机制,究竟哪一种机制占主导地位,抑制周围组织粘连将对内膜增生产生怎样的影响是一个需要探究的课题。透明质酸钠局部应用可以抑制粘连的发生,而且透明质酸钠为液性,局部应用后不通过改变移植静脉的生物力学机制影响内膜增生。因此,我们设计采用移植静脉周围应用透明质酸钠的方法抑制移植静脉周围组织粘连,与常规移植静脉对照,揭示其抑制外周组织粘连对移植静脉平滑肌细胞增殖、细胞因子(PDGF)的表达和分布以及对内膜增生的影响。
目的:探讨抑制外周组织粘连对移植静脉平滑肌细胞增殖、细胞因子(PDFG)的表达和分布以及对内膜增生的影响。
方法:选用24只5月龄雄性新西兰大白兔,体重2.8~3.0kg,随机分为A组、B组(n=12)。切取右侧颈外静脉3cm,游离左侧颈总动脉,中间切除长约1cm,建立动脉缺损模型,将切取静脉远近端倒置后用9-0无损伤缝线端端吻合于动脉缺损,吻合结束后A组动物用透明质酸钠凝胶0.2ml涂布于移植静脉外膜及两个吻合口。分别于术后1、2、4周行移植静脉切取前肉眼观察,切取移植静脉后行HE染色、Masson染色观察移植静脉管壁组织学变化,PCNA免疫组化染色、PDGF免疫组织化学染色观察移植静脉平滑肌细胞增殖和PDFG的表达、分布情况。
结果:术后1、2、4周肉眼观察B组移植静脉周围均有明显粘连,A组术后1、2周无粘连,术后4周有轻度粘连。HE染色、Masson染色、PCNA免疫组化染色和PDGF免疫组化染色观察到:术后2、4周A组移植静脉内膜厚度小于B组,术后1、2、4周A组增殖细胞均少于B组,术后1周A组外膜无PDGF阳性细胞,B组外膜内见阳性的炎性细胞;术后2、4周A组内膜、中膜和外膜PDGF阳性细胞均少于B组。内膜厚度、内膜增生程度、管腔狭窄程度结果分别为:1周A组25.51±3.93μm,1.18±0.07,0.041±0.005;B组26.18±4.16μm,1.19±0.09,0.042±0.006。2周A组44.27±2.53μm,1.22±0.06,0.062±0.003;B组50.99±3.76μm,1.40±0.03,0.078±0.004。4周A组69.85±6.76μm,1.49±0.07,0.114±0.009;B组84.43±6.41μm,1.69±0.09,0.137±0.007。术后2、4周A组的内膜厚度、内膜增生程度、管腔狭窄程度均小于B组(P<0.05)。内膜、中膜的增殖指数结果分别为:1周A组7.43±2.21,21.53±3.24;B组11.41±2.01,28.63±4.48。2周A组20.01±3.21,35.81±3.41;B组26.78±4.14,42.63±4.15。4周A组11.41±2.01,22.09±2.65;B组15.52±2.37,28.64±3.90。术后2、4周A组的内膜和中膜增殖指数均小于B组(P<0.05)。内膜、中膜外膜的PDGF表达率结果分别为:1周A组7.67±1.61,19.59±3.66,2.46±1.53;B组7.60±2.42,20.58±4.39,10.25±2.31。2周A组11.37±2.55,19.81±3.09,12.90±3.26;B组19.45±3.48,30.63±5.16,30.47±5.84。4周A组6.15±1.94,11.09±2.83,10.19±2.44;B组10.51±2.03,18.64±3.21,26.51±3.84。术后1周A组外膜PDGF表达率低于B组(P<0.05),术后2、4周A组的内膜、中膜和外膜PDGF表达率均小于B组(P<0.05)。
结论:局部应用透明质酸钠可以有效地抑制移植静脉外周粘连的形成,并在一定程度上减轻内膜增生;抑制外周组织粘连并不加重移植静脉内膜增生和管腔狭窄。
Autogenous vein graft has been more and more common in clinical practice since autogenous vein was first used for artery reconstruction by Gluck in 1898. Heretofore autogenous vein graft continues to be the primary method for the reconstruction of the artery defect and coronary artery bypass graft. However, the long-term therapeutic efficacy is always limited by the intimal hyperplasia and stenosis of vein graft. Raja reported that patency rate of vein graft was no more than 50% 10 years after surgery. So it is always a focus of study for the researcher of orthopaedics, vascular surgery and cardiac surgery to prevent intimal hyperplasia and stenosis of vein graft. Intimal hyperplasia is the result of remodeling for vein graft to adapt itself to a charged environment, the pathologic process comprised thrombogenesis, activating of endothelial cell, leukocyte adhesion, Leukocytic infiltrate,smooth muscle cells migration, proliferation and apoptosis, extracellular matrix formation and migration, activating cytokine and signal transducting, it is a complex and continuously changing pathogenesis influenced by multiple factor and interfered by multiple cytokine and gene. Accordingly, it has been being a pressing difficult problem to prevent the occurrence of stenosis of vein graft.
It is the critical way of preventing stenosis to inhibit the intimal hyperplasia of vein graft because intimal hyperplasia is the primary and leading pathological change of stenosis of vein graft. For this reason, we designed a project to answer 3 questions: First, to assess the effect of 5-Fluorouracil(5-FU) applied topically on intimal hyperplasia of the vein grafts; Second, to assess the effect of the autologous single-layer and double-layer venous external stents on intimal hyperplasia; Third, to assess the effect of preventing peripheral adhesion of vein graft on intimal hyperplasia.
Part 1 Inhibitory effects of topical application of 5-fluorouracil on intimal hyperplasia of the vein grafts in rabbits
The excessive proliferation and migration of vascular smooth muscle cell are the critical pathogenesis of intimal hyperplasia, so it is a immediate way of preventing intimal hyperplasia and stenosis to inhibit excessive proliferation and migration of vascular smooth muscle cell and to induce apoptosis and to regulate the remodeling of vein graft. 5-Fluorouracil(5-FU) is a antimetabolite belonging to miazines, it can inhibit cell proliferation and induce cell apoptosis, and it is very safe applied locally. Cragg reported that 5-Fluorouracil can effectively inhibit proliferation of vascular smooth muscle cell cultured in vitro. So, external jugular vein grafts was interposed into the carotid artery of rabbits and applied 5-Fluorouracil to test the effect of 5-Fluorouracil in inhibiting proliferation of vascular smooth muscle cell and inducing apoptosis of vascular smooth muscle cell in vivo and regulating the remodeling and preventing stenosis of vein graft.
Objective To assess the effect of 5-Fluorouracil(5-FU) applied topically on intimal hyperplasia of the vein grafts in rabbits.
Methods Sixty-four male New Zealand white rabbits, aged 5 months and weighing 2.8 to 3.0kg, were randomly divided into 4 groups: Group A, B, C and D (n=16 rabbits per group). Artery defect model was established by cutting about 1 cm artery from the middle part of the dissociated left common carotid artery. A section about 3 cm was cut from the right external jugular vein, and the harvested vein was inverted and end-to-end anastomosed to the artery defect with 9-0 non-traumatic suture. After anastomosis, the extima of the grafted veins in group A, B, and C was completely wrapped with cotton sheet (12mm×30mm×1mm in size) immersed by 5-FU at a concentration of 50.0, 25.0, and 12.5 mg/mL, respectively, and each vein was treated 5 times (1 minute at a time). In group D, the extima of the graft veins was treated with normal sal ine instead of 5-FU. The grafted veins were obtained 1, 2, 4, and 6 weeks after operation, HE staining and Masson staining were preformed for histological changes of grafted vein wall, proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and terminal deoxymudeotityl transferase mediated dUTP nick end labeling (TUNEL) staining were conducted for proliferation and apoptosis of smooth muscle cell of the grafted vein, and transmission electron microscope observation was performed for cellular ultrastructure.
Result The HE staining, Masson staining showed that the thickness of intima in group A and B was obviously less than that in group C and D at 1, 2, 4, and 6 weeks after operation. PCNA immunohistochemistry staining and TUNEL labeling staining showed that the proliferation cells in group A and B were less than that in group C and D at 1, 2, and 4 weeks after operation and the apoptotic cells in group A and B were more than that in group C and D at 1 and 2 weeks after operation. The thickness of the intima, the degree of intima hyperplasia, the degree of vessel lumen stenosis of four groups at different time points were as follows: at 1 week after operation, group A [(12.69±1.68)μm, 0.73±0.05, 0.025±0.003], group B [(17.52±2.01)μm, 0.86±0.06, 0.027±0.004], group C [(21.92±1.85)μm, 1.06±0.09, 0.036±0.006] and group D [(26.45±3.86)μm, 1.18±0.08, 0.041±0.005]; at 2 weeks after operation, group A [(24.61±2.91)μm, 0.86±0.06, 0.047±0.003], group B [(37.28±2.78)μm, 1.17±0.09, 0.060±0.004], group C [(46.52±2.25)μm, 1.44±0.08, 0.073±0.003], and group D [(52.07±3.29)μm, 1.45±0.05, 0.081±0.006]; at 4 weeks after operation, group A [(61.09±6.84)μm, 1.38±0.08, 0.106±0.007], group B [(63.61±8.25)μm, 1.40±0.07, 0.107±0.010], group C [(80.04±7.65)μm, 1.64±0.07, 0.129±0.011], and group D [(84.45±9.39)μm, 1.68±0.10, 0.138±0.014]; at 6 weeks after operation, group A [(65.27±5.25)μm, 1.46±0.07, 0.113±0.005], group B [(65.82±7.12)μm, 1.45±0.05, 0.112±0.011], group C [(84.45±6.39)μm, 1.69±0.09, 0.135±0.007], and group D [(87.27±8.96)μm, 1.76±0.05, 0.140±0.012]. Group A and B were inferior to group C and D in terms of the above three parameters 1, 2, 4 and 6weeks after operation (P<0.05). Cell proliferation index and cell apoptosis index of intima and that of media were as follows: at 1 week after operation, group A (4.83±1.96, 30.51±4.01, 14.61±2.17, 9.23±1.40), group B (8.01±2.18, 29.27±5.18, 20.25±3.18, 6.93±1.05), group C (9.09±1.27, 19.21±3.16, 26.80±3.13, 3.89±1.11) and group D (12.25±2.13, 28.71±4.17, 19.01±4.12, 3.83±1.34); at 2 weeks after operation, group A (18.92±3.73, 36.16±2.27, 22.31±3.94, 10.72±2.32), group B (19.16±3.26, 32.41±3.74, 30.51±4.01, 5.13±2.22), group C (25.97±2.17, 29.24±2.11, 37.81±4.50, 5.94±1.79), and group D (27.06±2.91, 27.15±2.51, 42.71±3.60, 5.21±1.91); at 4 weeks after operation, group A (10.17±1.21, 11.73±3.21, 20.00±3.16, 5.19±1.83), group B (11.18±2.01, 11.23±2.15, 21.13±2.62, 4.99±1.41), group C (15.01±2.03, 11.04±2.84, 24.64±2.98, 4.15±2.31), and group D (15.96±2.44, 12.21±3.68, 28.70±2.08, 4.86±1.69); at 6 weeks after operation, group A (6.67±2.10, 5.69±2.31, 2.51±1.53, 3.84±1.41), group B (6.67±1.81, 5.04±1.71, 2.47±1.51, 3.53±1.34), group C (6.88±2.01, 5.99±2.13, 3.40±0.98, 3.74±1.03), and group D (8.21±2.27, 6.01±2.03, 3.28±1.09, 3.64±1.08). Group A and B were inferior to group C and D in terms of cell proliferation index of intima and media 1, 2 and 4 weeks after operation (P<0.05). Group A and B were superior to group C and D in terms of cell apoptosis index of intima and media 1 and 2 weeks after operation (P<0.05). Transmission electron microscope observation showed that the synthetic cell organelles such as rough endoplasmic reticulum, golgi apparatus, and ribosome in group A and B were obviously less than those in group C and D.
Conclusion Topical application of 5-FU can inhibits proliferation of vascular smooth muscle cell and induces cell apoptosis of vascular smooth muscle cell, so that it can effectively inhibit intima hyperplasia and stenosis of the vein grafts.
Part 2 The effects of the autologous venous external stents on intimal hyperplasia of the vein grafts in rabbits
In 1963, Parsonne first reported that external stent can inhibit intimal hyperplasia and stenosis of vein graft. After that, many researcher proved that the application of external stent was a promising and effective means of preventing stenosis of vein graft. External stent can counteract the early distension of vein grafted, and it made hemodynamic index of vein graft approaching that of the host artery by the means of prevoking neoadventitia forming and its counteraction, so that the pathologic process induced by the change of hemodynamic index was inhibited. At present the material of most external stent is artificial synthetics, which was likely to evoke inflammation, local infection and adventitial fibrosis of vein graft if implanted. In addition, the mechanical properties of artificial synthetics were far from artery, so this kind of external stents cannot enough inhibit the change of hemodynamic index of vein grafted. Accordingly, the autologous venous external stents, whose mechanical properties were approaching the artery and unlikely to trigger reject reaction, were selected and tested. Single-layer and double-layer venous external stents were applied to vein graft in rabbits to test the effect of autologous venous external stents in counteracting the early distension of vein
grafted and preventing intimal hyperplasia and stenosis of vein graft. Objective To assess the effect of the single-layer and double-layer autologous venous external stents on intimal hyperplasia of the vein grafts in rabbits.
Methods Thirty-six male New Zealand white rabbits, aged 5 months and weighing 2.8 to 3.0kg, were randomly divided into 3 groups: Group A, B and C, with 12 rabbits in each group. First, a section about 6cm long of vein was cut from the right external jugular vein of each rabbit and severed to have 3 equal-length segments. Next, each distal segment prepared for anastomosis. The proximal segment invaginating middle segment in group A and only middle segment in group B were used for the external stent. Later, the left common carotid artery was separated from surrounding tissue, from it a section about 0.5 cm long was cut away. Finally, the vein graft was inverted and end-to-end anastomosed to the two ends of the artery with a 9-0 suture. After bloodstream re-established, the diameter of each vein graft was measured. At 2, 4 weeks postoperative,the graft veins were cut off and histologically examined by the means of HE staining and Masson staining. The smooth muscle cells(SMC) proliferation was studied by the immunohistochemical detection of proliferating cell nuclear antigen(PCNA).
Result After bloodstream re-established, the diameters of vein graft of group A, group B and group C were 1.62±0.31mm, 2.21±0.40mm and 2.65±0.58mm respectively. The diameter of vein graft of group A was smaller than of group B and group C, and that of group B was smaller than group C. (P<0.05). At 2 and 4 weeks after operation, HE staining, Masson staining and PCNA immunohistochemistry staining showed that the thickness of intima in group A and group B was obviously less than that in group C and the proliferation cells of intimal and media in group A and group B were less than that in group C. The thickness of the intima, the degree of intima hyperplasia, the degree of vessel lumen stenosis of 3 groups at different time points were as follows: at 2 week after operation, group A [(35.13±3.24)μm, 0.88±0.03, 0.046±0.004], group B [(44.53±3.55)μm, 1.08±0.02, 0.058±0.005] and group C [(51.62±4.72)μm, 1.21±0.04, 0.068±0.007]; at 4 weeks after operation, group A [(51.73±6.08)μm, 1.01±0.07, 0.076±0.008], group B [(69.29±6.33μm), 1.32±0.08, 0.101±0.009] and group C [(85.00±7.36)μm, 1.55±0.03, 0.134±0.003]. Group A was inferior to group B and C and Group B was inferior to group C in terms of the above three parameters 2 and 4weeks after operation (P<0.05). Cell proliferation index of intima and that of media were as follows: at 2 weeks after operation, group A (16.98±3.96, 28.39±6.02), group B (24.07±4.13, 36.41±6.93) and group C (29.90±4.68, 48.45±5.60); at 4 weeks after operation, group A (6.84±1.98, 15.65±5.12), group B (11.01±2.61, 23.31±4.30) and group C (14.96±4.14, 29.64±4.15). Group A and B were inferior to group C and Group B was inferior to group C in terms of cell proliferation index of intima and media 2 and 4 weeks after operation (P<0.05).
Conclusion The autologous venous two-layer external stents inhibit intimal hyperplasia and relieve the stenosis of the vein gratfs effectively. Part 3 The effects of inhibit perivascular adhesion on intimal hyperplasia of the vein grafts in rabbits
There was apparent adhesion between vein grafted and surrounding tissue. Perivascular adhesion was the way which vasa vasorum enter through to and hyperplasia if to prevent perivascular adhesion and vasa vasorum going in. However, Fogelstrand and Zhang et al reported that vascular smooth muscle cell derived from surrounding tissue played a very important role in intimal hyperplasia, which was proved by animal experiment. Vascular smooth muscle cell derived from surrounding tissue migrated to vein grafted through perivascular adhesion, so it can inhibit intimal hyperplasia to prevent perivascular adhesion. Accordingly, opposite actions on intimal hyperplasia were caused by preventing adhesion. It should be studied which action was dominant and what the effect of preventing adhesion on intimal hyperplasia was. Local application of sodium hyaluronate can prevent adhesion, but also it didn’t inflenced intimal hyperplasia of vein graft by biomechanical mechanism because it was liquid. For these reasons, sodium hyaluronate was applied locally to adventitia of vein graft in rabbits to test the effect of sodium hyaluronate on cell proliferation, expression and distribution of PDGF and intimal hyperplasia of vein graft.
Objective To assess the effect of sodium hyaluronate applied topically on cell proliferation, expression and distribution of PDGF and intimal hyperplasia of vein graft in rabbits.
Methods twenty-four male New Zealand white rabbits, aged 5 months and weighing 2.8 to 3.0kg, were randomly divided into 3 groups: Group A and B (n=12 rabbits per group). Artery defect model was established by cutting about 1 cm artery from the middle part of the dissociated left common carotid artery. A section about 3 cm was cut from the right external jugular vein, and the harvested vein was inverted and end-to-end anastomosed to the artery defect with 9-0 non-traumatic suture. After anastomosis, the adventitia and two anastomosis of the grafted veins in group A was applied 0.2ml sodium hyaluronate locally to. The grafted veins were obtained 1, 2 and 4 weeks after operation, HE staining and Masson staining were preformed for histological changes of grafted vein wall, proliferating cell nuclear antigen (PCNA) and platelet-derived growth factor (PDGF) immunohistochemistry staining were conducted for proliferation and expression and distribution of PDGF of the grafted vein.
Result The macroscopic observation showed that there was not apparent adhesion in group B at 1 and 2 weeks and was slight adhesion at 4 weeks after operation in group A and there was apparent adhesion in group B. HE staining, Masson staining showed that the thickness of intima in group A was obviously less than that in group B at 2 and 4 weeks after operation. PCNA and PDGF immunohistochemistry staining showed that the proliferation cells in group A was less than that in group B at 1, 2, and 4 weeks after operation and the positive cells of PDGF immunohistochemistry staining of intimal, media and adventitia in group A was less than that in group B at 1, 2 and 4 weeks after operation. The thickness of the intima, the degree of intima hyperplasia, the degree of vessel lumen stenosis of 2 groups at different time points were as follows: at 1 week after operation, group A [(25.51±3.93)μm, 1.18±0.07, 0.041±0.005] and group B [(26.18±4.16)μm, 1.19±0.09, 0.042±0.006]; at 2 weeks after operation, group A [(44.27±2.53)μm, 1.22±0.06, 0.062±0.003] and group B [(50.99±3.76)μm, 1.40±0.03, 0.078±0.004]; at 4 weeks after operation, group A [(69.85±6.76)μm, 1.49±0.07, 0.114±0.009] and group B [(84.43±6.41)μm, 1.69±0.09, 0.137±0.007]. Group A was inferior to group B in terms of the above three parameters 2 and 4weeks after operation (P<0.05). Cell proliferation index and cell apoptosis index of intima and that of media were as follows: at 1 week after operation, group A (7.43±2.21, 21.53±3.24) and group B (11.41±2.01, 28.63±4.48); at 2 weeks after operation, group A (20.01±3.21, 35.81±3.41) and group B (26.78±4.14, 42.63±4.15); at 4 weeks after operation, group A (11.41±2.01, 22.09±2.65) and group B (15.52±2.37, 28.64±3.90). Group A was inferior to group B in terms of cell proliferation index of intima and media 2 and 4 weeks after operation (P<0.05). The percentage of PDGF-positive cells of intima, media and adventitia was as follows: at 1 week after operation, group A (7.67±1.61, 19.59±3.66, 2.46±1.53) and group B (7.60±2.42, 20.58±4.39, 10.25±2.31); at 2 weeks after operation, group A (11.37±2.55, 19.81±3.09, 12.90±3.26) and group B (19.45±3.48, 30.63±5.16, 30.47±5.84); at 4 weeks after operation, group A (6.15±1.94, 11.09±2.83, 10.19±2.44) and group B (10.51±2.03, 18.64±3.21, 26.51±3.84). Group A was inferior to group B in terms of the percentage of PDGF-positive cells of intima, media and adventitia 2 and 4 weeks after operation (P<0.05) and Group A was inferior to group B that of adventitia 1 week after operation (P<0.05).
Conclusion Topical application of sodium hyaluronate prevents perivascular adhesion and inhibits intima hyperplasia. It doesn’t promote intima hyperplasia and stenosis of the vein graft to prevent perivascular adhesion.
引文
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