局部缓释紫杉醇抑制犬人工血管移植术后吻合口内膜增生的初步研究

The pilot study of the effect of paclitaxel by local slow delivery on intimal hyperplasia of vascular anastomosis after vascular graft bypass

目的探索预防周围动脉人工血管旁路移植术(VGB)后吻合口内膜增生(IH)性再狭窄的新方法。方法取大型杂种犬5只,全麻后行双侧髂股动脉 VGB,并结扎、切断人工血管桥之间的自体动脉。同一犬随机选取一侧人工血管(VG)及远近端吻合口喷紫杉醇-生物蛋白胶(FG)混合物,另一侧喷 FG 作为对照。4周后取出两侧包括远近端吻合口在内的 VG,对吻合口进行肉眼、病理组织学及电镜检查,测量内膜厚度及内膜面积,并进行免疫组化检查。结果5只实验犬两侧 VG 均通畅,远近端吻合口可见新生内膜。实验侧吻合口新生内膜厚度和内膜面积均显著小于对照侧(P<0.05)。扫描电镜检查示:实验侧吻合口可见覆盖一层完整的内皮细胞(EC),EC 排列规则整齐,其表面有较少血液成分附着。对照侧 EC 排列不规则,并见大量血液成分附着。吻合口新生内膜透射电镜检查示:对照侧细胞丰富,细胞类型单一,主要为典型的平滑肌细胞(VSMC);基质为规则密集排列的胶原纤维。实验侧可见多种类型的细胞;基质中胶原纤维稀疏,并可见大量异物颗粒。结论以FG 作为载体,在 VG 吻合口外局部应用小剂量紫杉醇可以起到抑制吻合口 IH 的作用。紫杉醇能够从吻合口外渗透至吻合口内,并能在内膜中停留至少4周以上。近期安全有效。

Objective To develop a new way to prevent restenosis in the anastomotic site due to intimal hyperplasia after vascular graft bypass （VGB） in peripheral arteries. Methods Five mongrel dogs received bilateral iliac-femoral VGB and their arteries between the graft were ligated and cut off under general anaesthesia. The mixture of the paclitaxel and fibrin gel（FG） were randomly sprayed onto one side of grafts including distal and proximal anastomotic site, and the fibrin gel served as control were sprayed onto the other one. The bilateral grafts including distal and proximal anastomotic site were harvested four weeks postoperationally and the anastomotic sites were observed grossly, pathologically and by electron microscopy. The intimal thickness and area of each anastomotic site were measured, then the data were analysed statistically. Results The bilateral grafts of all dogs were patent and the neointima of all anastomotic sites have been seen grossly. The neointimal thickness and area of the experimental side were significantly reduced compared with the control side （ P 〈 O. 05 ）. Scanning electron microscopy showed that the anastomotic intima of the experimental side was covered with one layer of intact and regular endothelium cells with deposition of little blood components, but the anastomotic intima of the control side was covered with irregular endothelium cells and deposited with a lot of blood cells and fibrins. Transmission electron microscopy showed the anastomotic intima of the control side that rich in vascular smooth muscle cells and the matrix of the intima was composed of regular collagenous fibers, and that of the experimental side consisted of several types of cells with a lot of foreign particles in the matrix. Conclusion It is safe and effective to locally use low dose of paclitaxel carried by FG in the prevention of vascular anastomotic site intimal hyperplasia. Paclitaxel molecules can penetrate the graft wall and stay in the anastomotic intima more than four weeks postoperationally.