腹主动脉瘤动物模型的研究现状与转化应用

Creation and translational relevance of abdominal aortic aneurysm animal models

随着我国人口老龄化趋势加剧,腹主动脉瘤(abdominal aortic aneurysm, AAA)发病率逐渐升高。由于动脉瘤破裂后死亡率极高,该病已经成为危害我国人群健康的重要疾病之一。在组织病理学上,AAA表现为中膜平滑肌细胞耗竭、弹力纤维断裂和退化、细胞外基质降解和血管局部炎症反应等。目前,临床上AAA的治疗多以血管内介入治疗为主,缺乏药物治疗手段,这也与致病机制迄今未被完全阐明有关。目前AAA动物模型主要以啮齿类实验动物(小鼠、大鼠)为主,也有部分中、大型实验动物(如兔、豚鼠、犬和猪等)。在造模方法上,主要包含弹性蛋白酶动脉腔内灌注法、血管紧张素Ⅱ输注法、氯化钙涂抹法和血管组织移植法等。部分药物或手术AAA模型由于前期诱导刺激的停止,诱导后动脉瘤病变趋于稳定。开发允许AAA持续发展,甚至可以在人为刺激下诱导破裂的,更符合人动脉瘤发展规律的模型是今后的造模研究方向之一。实验动物模型是阐明AAA发病机制、开发治疗动脉瘤新药和评价相关治疗策略安全性的重要研究工具。因此,本文综述了目前常用的AAA造模方法和其在临床前转化研究中的应用。

Population aging in China has led to an increase in the incidence of abdominal aortic aneurysm(AAA).AAA rupture is one of the most severe life-threatening diseases,with high mortality.The main histopathological features of AAA include elastin degradation,smooth muscle cell depletion,extracellular matrix digestion,and mural leukocyte accumulation.Clinically,drug therapy is still lacking,and open/endovascular repair remains the most effective treatment strategy for AAA management.Notably however,the detailed molecular mechanism of AAA remains unclear,representing an important bottleneck affecting the development of potential drug targets.Animal models are the most powerful tools for clarifying the pathogenesis of AAA,and although some medium-to-large laboratory animal models(e.g.,rabbits,guinea pigs,dogs,pigs)have been established for AAA studies,rodent models(mice and rats)are still the main models used in this field.Current method of inducing AAA include intra-infrarenal aortic infusion of elastase,subcutaneous infusion of angiotensinⅡ,periaortic calcium chloride painting,and decellularized aortic xenografting;however,AAA tends to stabilize in most models after ceasing pre-induced stimulation(medical or surgical),and there remains a need for ideal animal models that maintain continuous aortic dilation and even rupture.AAA animal models are helpful for elucidating the pathogenesis of AAA,screening new drug targets,and promoting clinical translation.This review aims to discuss the application of current AAA modeling method and their translational relevance.