西罗莫司给药方式对静脉移植物内膜增生的影响

Administration of sirolimus affects vein graft neointima hyperplasia

目的:比较西罗莫司口服给药(商品名:雷帕鸣)和局部缓释给药两种不同方式对静脉移植血管内膜增生的影响,探讨其优缺点。方法:健康家兔24只,建立颈外静脉-颈总动脉移植模型,随机分为4组:空白对照组、Pluronic F-127对照组、局部缓释西罗莫司组和口服西罗莫司组。观察静脉移植血管内膜增生厚度及管腔狭窄程度,内膜及中层平滑肌细胞增殖细胞核抗原表达程度及细胞凋亡水平。结果:与空白对照组相比,局部缓释西罗莫司组和口服西罗莫司组血管内膜增生受到明显抑制内膜厚度分别为(90.11±10.99)μm,(29.38±10.45)μm和(18.29±9.03)μm,管腔再狭窄程度减轻(管腔面积/总面积分别为0.58±0.11,0.80±0.16,0.77±0.16),平滑肌细胞增殖受到抑制(细胞增殖指数分别为31.03%±6.80%,20.32%±9.19%和16.22%±5.85%),细胞凋亡水平增加(调亡指数分别为16.27%±6.49%,33.39%±7.05%和33.42%±7.11%),局部缓释西罗莫司组与口服西罗莫司组差异无统计学意义。结论:局部缓释西罗莫司与口服西罗莫司均可以有效抑制静脉移植血管内膜增生。局部缓释给药方式由于对全身影响小而推荐作为首选给药方式。以上研究结果为临床应用提供了实验依据。

Objective： To investigate the effect of Sirolimus on vein graft neointima hyperplasia via oral administration compared with local delivery, and find out an effective and safe way to provide support for clinical application. Methods： A rabbit external jugular vein-to-common carotid artery model was established. Twenty-four healthy rabbits were divided into 4 groups at random： blank-control group, F-127 control group, group 3 that received locally applied slow-releasing Sirolimus with F-127, group 4 that received oral Sirolimus （ the commercial name Rapamune）. The ratio of intima to medium thickness and restenosis rate （ratio of lumina to lumina plus intima area） were measured, PCNA positive cells by immunohistochemical staining were detected to indicate the degree of cell proliferation, and apoptosis cells detected by TUNEL. Results： Compared with blank-control group, neointima hyperplasia was inhibited significantly in group 3 and group 4 [ intima thickness were （90.11±10.99μm versus （ 29.38±10.45 ）μm （ 18.29 ±9.03） μm respectively]. Re-stenosis rate was reduced （lumina area/ total area ratio were 0. 58 ±0.11 versus 0.80 ±0.16, 0.77±0.16, respectively）. Proliferation of VSMC was inhibited （cell proliferation indexes were 31.03% ±6.80% versus 20.32%±9.19%, 16.22% ± 5.85%, respectively） and cell apoptosis level raised （ cell apoptosis indexes were 16. 27% ± 6.49% versus 33.39% ±7.05%, 33.42% ± 7. 11%, respectively）. There was no significant difference between group 3 and group 4. Conclusion： Both locally applied slow-releasing Sirolimus and oral Rapamune could inhibit vein graft neointima hyperplasia; Administration via local delivery was preferred for little side-effect on the whole body. This conclusion provides support for clinical application.