Charles River Laboratories, Preclinical Services Massachusetts, Shrewsbury, Massachusetts, United States of America.
PLoS One. 2010 Dec 13;5(12):e14314. doi: 10.1371/journal.pone.0014314.
Restenosis remains the main complication of balloon angioplasty and/or stent implantation. Preclinical testing of new pharmacologic agents preventing restenosis largely rely on porcine models, where restenosis is assessed after endothelial abrasion of the arterial wall or stent implantation. We combined endothelial cell denudation and implantation of stents to develop a new clinically relevant porcine model of restenosis, and used this model to determine the effects of an α4 integrin inhibitor, ELN 457946, on restenosis. Balloon-angioplasty endothelial cell denudation and subsequent implantation of bare metal stents in the left anterior descending coronary, iliac, and left common carotid arteries was performed in domestic pigs, treated with vehicle or ELN 457946, once weekly via subcutaneous injections, for four weeks. After 1 month, histopathology and morphometric analyses of the arteries showed complete healing and robust, consistent restenotic response in stented arteries. Treatment with ELN 457946 resulted in a reduction in the neointimal response, with decreases in area percent stenosis between 12% in coronary arteries and 30% in peripheral vessels. This is the first description of a successful pig model combining endothelial cell denudation and bare metal stent implantation. This new double injury model may prove particularly useful to assess pharmacological effects of drug candidates on restenosis, in coronary and/or peripheral arteries. Furthermore, the ELN 457946 α4 integrin inhibitor, administered subcutaneously, reduced inflammation and restenosis in stented coronary and peripheral arteries in pigs, therefore representing a promising systemic therapeutic approach in reducing restenosis in patients undergoing angioplasty and/or stent implantation.
再狭窄仍然是球囊血管成形术和/或支架植入术的主要并发症。新的预防再狭窄的药物的临床前测试主要依赖于猪模型，其中通过动脉壁的内皮细胞磨损或支架植入来评估再狭窄。我们将内皮细胞剥脱与支架植入相结合，开发了一种新的临床相关猪再狭窄模型，并使用该模型来确定α4 整合素抑制剂 ELN 457946 对再狭窄的影响。通过皮下注射每周一次，在家猪的左前降支、髂动脉和颈总动脉中进行球囊血管成形术内皮细胞剥脱和随后植入裸金属支架。1 个月后，对动脉进行组织病理学和形态计量学分析显示，支架内动脉完全愈合，并出现了强有力的、一致的再狭窄反应。用 ELN 457946 治疗导致新生内膜反应减少，冠状动脉内的面积狭窄百分比降低 12%，外周血管内降低 30%。这是首次成功描述将内皮细胞剥脱和裸金属支架植入相结合的猪模型。这种新的双重损伤模型可能特别有助于评估候选药物对再狭窄的药理作用，无论是在冠状动脉还是外周动脉。此外，皮下给予的 ELN 457946α4 整合素抑制剂可减少猪支架置入的冠状动脉和外周动脉的炎症和再狭窄，因此代表了一种有前途的系统治疗方法，可减少接受血管成形术和/或支架植入术的患者的再狭窄。
