放射治疗对兔髂动脉粥样硬化狭窄成形术后再狭窄的影响

目的：探讨^32P液体球囊血管近距离照射预防血管成形术后再狭窄的量效关系及其抑制再狭窄发生的可能机制。方法：24只大耳白兔，采用髂动脉内膜损伤加高脂饲养6周，建立兔双侧髂动脉粥样硬化狭窄模型，随机选择一侧髂动脉血管成形术并分别给与9．1Gy、21.8Gy和33．4Gy^32P液体球囊血管照射治疗，另一侧髂动脉灌注造影剂，作为自身对照。术后5周行血管造影并取材进行光镜观察、电镜观察、核因子-κB（NF—κB）、胰岛素样生长因子-1（IGF-1）免疫组织化学染色，用计算机图像分析测量新生内膜面积、中膜面积、管腔面积及免疫组化染色阳性面积百分比。结果：对照组血管段内膜明显增生，管腔明显狭窄；9．1Gy组未观察到明显的生物效应；21．8Gy组血管壁平滑肌细胞增殖和迁移明显受抑，管腔面积无明显丢失；33．4Gy组管腔重度狭窄，内膜严重增厚，中膜平滑肌明显萎缩变薄，4例血管腔内血栓形成。结论：^32P液体球囊在一定的吸收剂量范围内确可安全有效地防止血管成形术后再狭窄形成，其机制可能为是抑制新生内膜形成和管腔面积丢失；抑制NF-κB及其靶基因的活化，从而抑制血管平滑肌细胞的增殖、迁移，促进平滑肌细胞凋亡以及抑制血管负性重塑。     

32P放射性球囊血管内照射预防血管成形术后再狭窄的剂量学研究

目的探讨32P液体球囊血管内照射预防血管成形术后再狭窄的量效关系,及其抑制再狭窄发生的可能机制. 方法取24只大耳白兔,建立兔双侧髂动脉粥样硬化狭窄模型,随机选择一侧髂动脉血管成形术并分别给予9.1Gy、21.8Gy和33.4Gy32P液体球囊血管照射治疗,另一侧作为自身对照.术后5周行血管造影并取材进行光镜、电镜观察,增殖细胞核抗原(PCNA)、抑癌基因P53免疫组织化学染色,用计算机图像分析其组织形态学改变. 结果9.1Gy组未观察到明显的生物效应;21.8Gy组血管壁平滑肌细胞增殖和迁移明显受抑,管腔面积无明显丢失;33.4Gy组管腔重度狭窄,内膜严重增厚,中膜平滑肌明显萎缩变薄,4例血管腔内血栓形成.结论32P液体球囊在一定的吸收剂量范围内确可安全有效地防止血管成形术后再狭窄形成,其机制可能为抑制新生内膜形成和管腔面积丢失;促进平滑肌细胞凋亡以及抑制血管负性重塑.     

32P放射性球囊血管内照射预防血管成形术后再狭窄的实验研究

目的 探讨^32P液体球囊血管内近距离照射预防血管成形术后再狭窄的量效关系，及其抑制再狭窄发生的可能机制。方法 取36只新西兰白兔，随机分为3组，每组12只，球囊扩张法损伤髂动脉，一侧给予^32P液体球囊内照射治疗，预计吸收剂量分别为10、20和40Gy，以对侧髂动脉作对照，灌注生理盐水。术后于不同时间点取材，行HE染色、TUNEL染色观察血管病理变化及平滑肌细胞凋亡情况。用计算机图像分析其组织形态学改变。结果 对照组血管内膜明显增生，管胖变窄。10Gy组未观察到明显的生物效应；20Gy组血管壁平滑肌细胞增殖和迁移明显受抑。管腔面积略减小，可见较多的凋亡细胞；40Gy组中膜平滑肌明显萎缩变薄，4例血管腔内血栓形成。结论 ^32P液体球囊在一定的吸收剂量范围内可安全有效地防止血管成形术后再狭窄形成，其机制可能与促进平滑肌细胞凋亡、抑制新生内膜形成有关。     

血管内放射治疗对血管成形术后再狭窄及核因子-кB活性的影响

目的:观察32P液体球囊血管近距离照射预防血管成形术后再狭窄的量效关系及其对核转录因子核因子-кB (NF-кB)活性的影响,以探讨其防治再狭窄的可能作用机制.方法:24只大耳白兔,建立兔双侧髂动脉粥样硬化狭窄模型,随机选择一侧髂动脉血管成形术并分别给予9.1Gy组、21.8Gy组和33.4Gy 组32P液体球囊血管照射治疗(每组n=8),另一侧髂动脉灌注造影剂,作为自身对照(对照组,n=24).术后5周行血管造影并取材进行光镜观察、NF-кB、胰岛素样生长因子-1(IGF-1)免疫组织化学染色,用计算机图像分析测量新生内膜面积、中膜面积、管腔面积及免疫组化染色阳性面积百分比.结果:①光镜观察: 9.1Gy组:与对照组比病变无明显差异;21.8Gy组:内弹力膜完整无明显断裂;管腔轻度狭窄,新生内膜面积明显减小,内膜层泡沫样细胞及脂质沉积均不明显;中膜平滑肌呈轻度增厚, 排列轻度紊乱;33.4Gy组:内弹力膜破坏,管腔明显狭窄,内膜可见大量泡沫细胞及脂质沉积,大量炎性细胞浸润及细胞外基质不定形物质沉积,中膜平滑肌明显萎缩变薄,其中4例血管腔内可见血栓形成.②免疫组化染色:9.1Gy组:NF-кB、IGF-1蛋白表达与对照组无明显差异(P>0.05);21.8Gy组:NF-кB、IGF-1蛋白表达量中等,呈灶状散在分布于内皮细胞、平滑肌细胞及泡沫细胞,与对照组相比有明显差异(P<0.01);③33.4Gy组:NF-кB、IGF-1蛋白少量表达,呈散在性分布,明显低于9.1Gy组和21.8Gy组(P<0.01).结论:32P液体球囊在一定的吸收剂量范围内确可安全有效地防止血管成形术后再狭窄形成,其机制可能为抑制NF-кB及其靶基因的活化,从而抑制血管平滑肌细胞的增殖、迁移.     

血管内近距离照射对兔髂动脉术后中膜平滑肌细胞凋亡的影响

目的观察血管内近距离照射（BT）对血管成形术后动脉中膜平滑肌细胞（SMC）凋亡的影响，并观察其量效关系，初步探讨其防治再狭窄的可能机制。方法24只大耳白兔随机分为3组，选择一侧行髂动脉血管成形术并分别给予9．1Gy、21．8Gy和33．4Gy^32 P液体球囊血管内照射治疗，对侧作为对照。术后5周，重复血管造影观察靶血管再狭窄程度，应用三磷酸脱氧尿嘧啶缺口末端标记法（TUNEL法）检测中膜平滑肌细胞凋亡的情况。结果血管造影显示9．1Gy组狭窄与对照血管段无明显差异（P〉0．05）；21．8Gy组为仅轻度狭窄（P〈0．05）；33．4Gy组为重度狭窄（P〈0．05）。TUNEL阳性率在21．8Gy组和33．4Gy组均高于自身对照组（P〈0．01）。3个照射剂量组间，21．8Gy组作用最明显（P〈0．01）。结论^32P放射性液体球囊血管内照射治疗在一定剂量范围内可防止血管成形术后再狭窄的形成，促进血管中膜平滑肌细胞凋亡可能是其作用机制之一。     

192Ir血管内照射防止兔球囊血管成形术后再狭窄

目的　旨在检验1 92 Ir血管内照射对兔球囊血管成形术后再狭窄的作用。方法　建立兔髂动脉粥样硬化模型 ,对病变血管行球囊成形术 ,同时随机分为对照组、10Gy照射组和 18Gy照射组。以导管导入1 92 Ir放射性导丝对照射组动物的扩张处进行血管内照射。 4周后处死动物 ,取出血管标本 ,进行病理组织学分析。结果　 18Gy照射组最终管腔面积较对照组及 10Gy照射组大 (P <0 0 5 ) ,18Gy照射组内膜面积较小 (P <0 0 5 )。结论　提示1 92 Ir血管内照射可防止球囊血管成形术后再狭窄 ,其效果与照射剂量相关 ,其机制涉及抑制新生内膜增殖。     

32P液体球囊血管内照射预防血管介入治疗后再狭窄的实验研究

目的观察血管内液体球囊放射治疗对血管介入治疗后再狭窄的影响，为其临床应用提供实验依据；同时通过放射治疗效应来探讨放射治疗防止再狭窄发生的可能机制。方法兔髂动脉经球囊过度扩张损伤后，一侧经３２Ｐ液体球囊血管内照射作治疗，另一侧未经治疗作对照。用计算机图像分析方法观察血管组织形态学的变化；免疫组化方法测定增殖细胞核抗原（ＰＣＮＡ）阳性细胞以了解血管内膜增殖过程。结果兔髂动脉经球囊过度扩张损伤后，血管内膜可明显增生，ＰＣＮＡ染色为强阳性；经３２Ｐ液体球囊照射后的对侧损伤髂动脉，内膜增生明显受抑，ＰＣＮＡ染色为弱阳性，外弹力板围绕面积均增加，管腔面积无明显变化。结论３２Ｐ液体球囊确可防止再狭窄的形成，其机制可能是通过抑制平滑肌细胞增殖和改善血管重塑形成。     

血管内32P放射治疗减少血管损伤后内膜增生的实验研究

目的　研究血管内放射源照射对损伤血管增生反应的影响。方法　 30只常规喂养新西兰大白兔 ,用大于血管直径的球囊过度扩张兔双髂动脉 (球囊 /血管 =1 5 4∶1) ,造成血管壁损伤 ,同时在扩张的球囊中灌注放射性3 2 P进行一侧损伤血管内照射 ,一侧血管单纯扩张作自身对照。按不同照射剂量分成三组 :10Gy、2 0Gy和 40Gy ,每组 10只。在扩张前后进行血管造影 ,4周后再次血管造影同时处死动物取双髂动脉作平滑肌细胞、弹力纤维和胶原纤维染色 ,观察血管受损后放射对血管腔径及其管壁增生的影响。结果　 4周后血管造影显示 ,三组兔髂动脉扩张损伤后均发生一定程度的狭窄反应 (P <0 0 0 1)。血管内照射一侧与对照侧比较 ,血管狭窄程度无明显差异 (P >0 0 5 )。病理组织分析 ,10Gy组照射一侧血管内膜增生与对照侧比较无差异 (P >0 0 5 ) ,而 2 0Gy和 40Gy二组照射一侧血管内膜增生较对照侧血管减少 (P <0 0 0 1,P <0 0 4) ,但二组间比较内膜增生减少无差异 (P >0 0 5 )。结论　过度扩张兔髂动脉可产生再狭窄样反应 ,血管内放射在 2 0Gy到 40Gy照射剂量时能减少血管损伤后内膜增生 ,但血管损伤后狭窄程度未受影响。     

放射性液体球囊血管内照射防治血管成形术后再狭窄的实验研究

目的　评定放射性液体球囊防治血管成形术后再狭窄的有效性、安全性和可行性,并观察其剂量效应关系,初步探讨其作用机制。方法　18只日本大耳白兔髂动脉经球囊过度扩张损伤后,一侧行32P或90Y放射性液体球囊血管内照射作治疗,另一侧以假源（充盈造影剂的液体球囊）未经治疗作对照。5周后重复血管造影观察血管影像学改变;原位固定取材后,分析血管断面组织形态学的变化;免疫组化方法观察增殖细胞核抗原（PCNA）阳性细胞以了解血管壁细胞的增殖情况;行胶原染色显示细胞外基质的合成情况。结果　造影可见兔髂动脉经球囊过度扩张损伤后未经治疗的靶血管段明显狭窄,平均狭窄程度达77%;血管壁吸收剂量为24Gy的靶血管段无明显狭窄或仅轻度狭窄(平均狭窄程度为12%),16Gy者为30%,8Gy者为76%。兔髂动脉病理切片行HE染色和弹力纤维染色,经计算机图像分析可见血管壁吸收剂量为24Gy和16Gy的靶血管段外弹力板围绕面积,内弹力板围绕面积,新生内膜面积,管腔面积分别与其自身对照相比具有统计学意义（P＜0.01）;8Gy者与其自身对照血管段相比无统计学意义（P＞0.05）。行PCNA染色可见对照血管段,血管壁吸收剂量为8Gy、16Gy及24Gy血管段PCNA阳性细胞百分率分别为(84±5)%、(77±3)%、(44±5)%和(21±6)%,除对照血管段和8Gy血管段之间差异无显著性(P＞0.05)外,其余各组间差异均有非常显著性（P＜0.01）,且存在剂量效应关系。未发现与放射治疗相关的不良病理改变。结论　放射性液体球囊在一定的吸收剂量范围内确可安全有效地防治血管成形术后再狭窄的形成,表现为抑制新生内膜形成和管腔面积丢失,且存在一定的剂量效应关系;其作用机制可能是通过抑制血管壁过度扩张后细胞的增殖,分泌功能和改善血管重塑形成。     

32P液体球囊血管内照射对血管损伤后管壁基质金属蛋白酶9表达的影响

目的观察血管内液体球囊放射治疗对血管成形术后再狭窄的影响,同时通过观察放射治疗效应探讨放射治疗防止再狭窄发生的可能机制.方法雄性Wistar大鼠72只,体重300～350 g,随机分为两组,胸主动脉经球囊损伤(损伤组),球囊损伤加32P液体球囊血管内照射(照射组,按照射剂量分为20 Gy亚组和28Gy亚组).使用原位杂交方法测定管壁基质金属蛋白酶9(MMP-9)mRNA表达;采用免疫组化的方法测定增殖细胞核抗原(PCNA)表达阳性细胞;用计算机图像分析方法观察血管组织形态学的变化,并对原位杂交和免疫组化的结果进行定量分析.结果照射组与损伤组相比第14天外弹力板围绕面积、管腔面积明显增大,且随照射剂量的增加而增大;第1,3,7天管壁MMP-9 mRNA表达率明显降低,降低程度随照射剂量增加而增大.结论32P液体球囊可防止再狭窄的形成,其机制之一可能是通过抑制管壁MMP-9 mRNA表达,从而抑制血管重塑.     

External beam radiation after stent implantation increases neointimal hyperplasia by augmenting smooth muscle cell proliferation and extracellular matrix accumulation.

OBJECTIVES: We sought to examine the effects of high volume external beam radiation (EBR) after stent implantation on neointimal hyperplasia, smooth muscle cell (SMC) proliferation, presence of inflammatory cells and expression of extracellular matrix (ECM). BACKGROUND: Endovascular irradiation has been shown to reduce restenosis rates after angioplasty in preliminary trials, but conflicting results have been reported for the effects of external beam irradiation. METHODS: Forty-three Palmaz-Schatz stents were implanted into iliac arteries of New Zealand White rabbits. The arteries were externally irradiated after stent implantation with a single dose of 8 Gy (at day 3) or 16 Gy in two fractions (8 Gy at days 3 and 4) by means of a linear accelerator. In the control rabbits, no radiation was applied after stent implantation. Smooth muscle cells, macrophages and ECM were studied by immunohistochemistry at one and 12 weeks after stent implantation. Collagen type I and biglycan messenger ribonucleic acid (mRNA) levels were assessed by Northern blot analysis at one week. Neointimal cell densities and arterial lumen stenosis were measured by histomorphometry at 12 weeks. RESULTS: At 1 week, SMC proliferation at the site of stent implantation was increased after EBR with 8 and 16 Gy (26 +/- 5%, 32 +/- 3% vs. 17 +/- 8%; p < 0.01, 16 Gy vs. control). External beam radiation with 8 and 16 Gy augmented SMC proliferation proximal and distal to the angioplasty site (11 +/- 3%, 14 +/- 3 vs. 6 +/- 1%; p < 0.01, 16 Gy vs. control). Collagen type I and biglycan mRNA levels were elevated in stented arteries after EBR with 16 Gy. At 12 weeks, a marked decrease in neointimal cell density (248 +/- 97 vs. 498 +/- 117 SMCs/0.1 mm2 neointima; p < 0.005 vs. control) was noted after EBR with 16 Gy. Irradiation with 8 and 16 Gy increased arterial lumen stenosis compared with nonirradiated control rabbits (45 +/- 7%, 55 +/- 9% vs. 33 +/- 7%; p < 0.05, 8 Gy and p < 0.001, 16 Gy vs. control). CONCLUSIONS: High volume external beam radiation at doses of 8 or 16 Gy causes restenosis by augmenting proliferative activity at and adjacent to the site of stent implantation, and by dose-dependent up-regulation of extracellular matrix expression. The study suggests that excessive matrix accumulation is an important determinant of failure of radiation therapy to prevent restenosis.     

血管腔内放疗对经皮腔内冠状动脉成形术后再狭窄的防治

目的 :观察血管腔内放疗对经皮腔内冠状动脉成形术 (PTCA)后再狭窄的防治作用。方法 :选用家兔经颈外动脉插管对其颈总动脉实行了 PTCA,术后给予血管腔内放疗 (核通后装治疗计划 ) ,放射源中心轴外 3m m为处方剂量点 ,分别照射 10 Gy、2 0 Gy和 30 Gy。术后 4、12、2 4周取颈总动脉行病理检查。结果 :对照组PTCA后 4周 ,可见管腔狭窄 ,内膜不规则增厚 ,新生内膜内见大量棱形平滑肌细胞 ,排列紊乱 ,部分内弹力膜断裂。 10 Gy剂量放疗组未见有新生内膜 ,管腔无狭窄 ,内弹力膜完整 ,管壁略变薄。 2 0 Gy或 30 Gy放疗组管腔变大 ,管壁明显变薄 ,胶原组织和平滑肌细胞数量减少。 12周的病理结果与 2 4周时无明显差异。结论 :血管腔内放射治疗可明显抑制血管损伤后的组织增生 ,且抑制程度与剂量相关。     

Vascular stenting in normal and atherosclerotic rabbits. Studies of the intravascular endoprosthesis of titanium-nickel-alloy

Percutaneous transluminal balloon angioplasty would be more effective if the rate of recurrent stenosis were reduced. To evaluate the prevention of restenosis after percutaneous transluminal angioplasty, intravascular endoprosthetic stents of titanium-nickel-alloy were implanted transluminally in seven normal and 21 atherosclerotic rabbits. In normal rabbits, a 3.5-mm diameter stent was implanted in the aorta and a 2.5-mm diameter stent in the right iliac artery, which were followed with serial angiograms from 6 weeks (n = 7) to 8 months (n = 4). There was a mean stenosis of 13.1% in the 2.5-mm and 13.6% in the 3.5-mm stent. There was no significant narrowing compared with the adjacent control segments of artery; histopathology showed a thin, fibrous neointima with smooth muscle cells. Each atherosclerotic rabbit was balloon dilated at two separate stenotic sites; each site was 2.0 cm in length. The aortic site (with 28.8 +/- 13.8% mean stenosis [+/- SD]) was dilated with a 3.5-mm balloon, and the iliac site (with 36.5 +/- 14.2% stenosis) was dilated with a 2.5-mm balloon. In each site, an intravascular stent of corresponding diameter and 7-mm length was implanted in one half of the dilated segment, assigned randomly, and the other half served as the angioplasty control. Angiographically observed restenosis rates and the corresponding histopathology were similar in the atherosclerotic segments that had angioplasty alone versus the atherosclerotic segments that had angioplasty plus stenting. The mean neointimal thickness in the aortas and iliac arteries, respectively, measured 247 +/- 181 microns (+/- SD) and 218 +/- 77 microns after 6 weeks (n = 8) versus 321 +/- 168 and 308 +/- 189 microns after 20 weeks (n = 5, p = NS). At 20 weeks follow-up, there was 29.1 +/- 29.8% (median, 16.4%) stenosis in the aortic stent versus 38.9 +/- 24.1% (median, 34.0%) stenosis in the percutaneous transluminal angioplasty control segment of aorta (n = 5, p = NS) and 81.4 +/- 25.5% stenosis in the iliac artery stent versus 89.3 +/- 15.3% stenosis in the PTA control segment of the right iliac artery (n = 5, p = NS). Comparing stenotic arterial segments treated with angioplasty alone with angioplasty plus intravascular stenting in the atherosclerotic rabbits showed that there was no significant difference in either the histopathologic changes or the restenosis rates.     

血管损伤致平滑肌细胞增殖的兔耳动脉狭窄模型及应用

为研究经皮冠状动脉腔内成形术后血管再狭窄的发生机理，本文选用新西兰家兔耳中央动脉，以物理性创伤诱发出血管壁平滑肌细胞增殖，从而造成实验性动脉管腔狭窄模型。利用该模型观察了血管内皮细胞生长因子和水蛭素联合应用对动脉再狭窄的影响。结果发现该模型血管狭窄程度、平滑肌细胞增殖、内膜增生及血栓形成等均与在体动脉再狭窄的病理改变一致。内皮细胞生长因子与水蛭素联合运用能防止血栓形成，但对平肖肌细胞增殖无影响。     

Endovascular brachytherapy for treatment of bilateral renal artery in-stent restenosis.

Percutaneous transluminal angioplasty of renal artery stenosis is an attractive alternative to surgical therapy. However, even with endovascular stenting, the overall rate of restenosis is 21%. While brachytherapy for coronary in-stent restenosis has proven efficacy, its use for renal artery in-stent restenosis has not been formally evaluated. We report a case of bilateral in-stent renal artery restenosis treated with endovascular brachytherapy.     

Altered endothelin-1 binding following balloon angioplasty of pig coronary arteries: effect of the ETA receptor antagonist, LU 135252.

OBJECTIVE: Since raised levels of endothelin-1 (ET-1) have been detected in the human coronary sinus following percutaneous transluminal angioplasty (PTCA) we investigated the role of ET-1 in the etiology of vascular restenosis. METHODS: Balloon angioplasty of coronary arteries was performed in pigs and the animals were treated with placebo or the endothelin (ETA) receptor antagonist LU 135252 (30 mg/kg/day). After 4 weeks vascular stenosis and the distribution of endothelin and its receptors was evaluated. RESULTS: The pronounced neointima formation in the control group (neointima:media ratio = 0.87 +/- 0.36) was significantly reduced by LU 135252 (0.43 +/- 0.30, P < 0.001). Angioplasty caused a significant increase in medial ETA (approximately 275%, P < 0.026) and ETB (approximately 250%, P < 0.001) binding to injured, compared with non-injured segments, an effect that was also reduced by LU 135252 (ETA = 11.5% increase; ETB = 14% increase). The neointima of control animals exhibited ET-1 like immunoreactivity as well as ETA and ETB binding sites. CONCLUSION: These data indicate that endothelin is locally-released from endothelial and vascular smooth muscle cells following angioplasty which binds to ETA and ETB receptor sites in the neointima and media. Since administration of the ETA antagonist LU 135252 markedly reduces neointima formation and medial ET binding, we conclude that vascular smooth muscle cell proliferation and subsequent neointima formation is mediated predominantly via ETA receptors. These data underscore the therapeutic potential of ETA antagonists in reducing the degree of restenosis following vascular injury.