Recombinant human thrombomodulin inhibits arterial neointimal hyperplasia after balloon injury
Recombinant human thrombomodulin inhibits arterial neointimal hyperplasia after balloon injury
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DOI：
10.1016/j.jvs.2003.12.030
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发表时间：
2004-05-01
影响因子：
4.3
通讯作者：
Nelson, PR
中科院分区：
文献类型：
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作者：
Li, JM;Singh, MJ;Nelson, PR
目的：平滑肌细胞增殖是损伤引起的内膜增生和复发性狭窄的主要病理生理因素。我们已经证明重组人血栓调节蛋白（rTM）在体外抑制凝血酶诱导的动脉平滑肌细胞增殖。 4本研究的目的是探讨rTM对体内新生内膜增生的影响。方法。采用兔股动脉球囊损伤模型。使用 2F 动脉取栓导管对双侧股浅动脉进行去内皮化。手术过程中静脉注射 rTM（145 微克/公斤；循环中 2.0 微克/毫升）或 Tris 盐酸载体对照，然后停止给药（A 组）或每天给药两次，持续 48 小时（B 组）。第4天、第1、2、4周处死家兔，并采用原位灌注固定和石蜡包埋制备股动脉标本。使用数字成像计算机面积测定法对管腔、内膜、中膜和整个动脉面积进行定量。计算内膜-中层和管腔-全动脉比率。还通过光学显微镜、扫描和透射电子显微镜、免疫组织化学和免疫组织荧光染色评估了损伤引起的炎症反应。 结果：在缓冲液对照组中，股动脉球囊损伤后的新生内膜增生在2周时明显，并在4周时明显（P < .0001）。 rTM 输注在第 2 周和第 4 周均显着抑制内膜增生 (P < .0001)。在 A 组中，rTM 在第 2 周和第 4 周时使内膜-中膜比率分别降低了 27% 和 39%。延长rTM给药（B组）在2周和4周时分别抑制增生57%和30%，但与较短的暴露相比未能达到显着效果。与缓冲液对照组相比，rTM 输注显着抑制血栓形成（8.1 倍）（P = .012）。 rTM 对管腔面积或管腔与全动脉比率没有显着影响，但治疗后的动脉表现出明显较少的代偿性扩张 (P = 0.045)，根据整个动脉面积对内膜增生减少的反应进行测量。 rTM 给药可抑制血小板粘附和中性粒细胞浸润，达到统计学显着性水平 (P = .0675)。 结论：全身静脉注射 rTM 显着减少球囊损伤后兔股动脉的新生内膜增生并改善通畅性。除了表现出抗血栓和抗增殖作用外，rTM 还可能激发抗炎机制，并可能以多维作用改变血管重塑，以抑制动脉损伤后复发性狭窄。
Objective: Smooth muscle cell proliferation is a major pathophysiologic factor in injury-induced neointimal hyperplasia and recurrent stenosis. We have demonstrated that recombinant human thrombomodulin (rTM) inhibits thrombin-induced arterial smooth muscle cell proliferation in vitro. The purpose 4 this study was to investigate the effect of rTM on neointimal hyperplasia in vivo.Methods. A rabbit femoral artery balloon injury model was used. Bilateral superficial femoral arteries were deendothelialized with a 2F arterial embolectomy catheter. rTM (145 mug/kg; 2.0 mug/mL in circulation) or Tris-hydrochloride vehicle control was administered intravenously during the procedure, then either discontinued (group A) or administered twice daily for an additional 48 hours (group B). Rabbits were euthanized at 4 days and at 1, 2, and 4 weeks, and femoral artery specimens were prepared with in situ perfusion fixation and paraffin embedding. Luminal, intima, media, and whole artery areas were quantitated with digital imaging computerized planimetry. Intima-media and lumen-whole artery ratios were calculated. The injury-induced inflammatory reaction was also evaluated with light microscopy, scanning and transmission electron microscopy, and immunohistochemical and immunohistofluorescence staining.Results: In the buffer control group, neointimal hyperplasia after femoral artery balloon injury was evident at 2 weeks, and was pronounced at 4 weeks (P < .0001). Infusion of rTM significantly inhibited intimal hyperplasia at both 2 and 4 weeks (P < .0001). In group A, rTM reduced the intima-media ratio by 27% and 39% at 2 and 4 weeks, respectively. Extended administration of rTM (group B) resulted in inhibition of hyperplasia by 57% and 30% at 2 and 4 weeks, respectively, but failed to reach significance compared with the shorter exposure. rTM infusion significantly inhibited thrombosis (8.1-fold) compared with the buffer control group (P = .012). rTM had no significant effect on lumen area or lumen-whole artery ratio, but treated arteries demonstrated significantly less compensatory dilatation (P = .045), as measured by whole artery area in response to less intimal hyperplasia. rTM administration inhibited platelet adhesion and inhibition of neutrophil infiltration to a degree that approached statistical significance (P = .0675).Conclusions: Systemic intravenous administration of rTM significantly decreases neointimal hyperplasia and improves patency in the rabbit femoral artery after balloon injury. In addition to exhibiting antithrombotic and antiproliferative effects, rTM may also invoke an anti-inflammatory mechanism, and may alter vascular remodeling in a multidimensional role to inhibit recurrent stenosis after arterial injury.