大鼠慢性栓塞性肺动脉高压模型的建立和肺血管重构的研究

Established of rat model with chronic thromboembolism pulmonary hypertension and investigation of vascular remodeling

目的探讨妥善建立大鼠栓塞性肺动脉高压模型的方法,研究肺血管重构和右心室的改变。方法雄性Wistar大鼠141只,随机分为12组,采血加入凝血酶200 U/ml,体外制备栓子,经颈静脉注入栓子,制备肺栓塞模型,2周后同法进行二次栓塞,全程腹腔注射纤溶抑制剂氨甲环酸,达目标时间后用右心导管法测平均肺动脉压（mPAP）;开胸取肺组织,HE染色及弹力纤维染色,观察肺组织和肺血管结构的变化;用病理图像分析软件测定肺动脉相对中膜厚度（PAMT）和管壁面积/管总面积（WA/TA）;取心脏组织测定右心室游离壁（RV）和左心室加室间隔（LV＋S）的重量比即右心室肥大指数（RVHI）。结果①动物模型成功率85.1%（120/141）;②4周组至12周组肺动脉压明显升高（P均〈0.01）,8周后RVHI较对照组明显增高（8周组P〈0.05;12周组P〈0.01）;③8周和12周组肺小动脉结构出现明显变化：中膜平滑肌细胞明显增生,PAMT和WA/TA值明显增大（P均〈0.01）,管壁增厚,管腔狭窄,肺动脉有显著重构;④mPAP、RVHI与PAMT有明显相关性（r分别为0.681和0.690,P均〈0.01）;mPAP、RVHI与WA/TA有明显相关性（r分别为0.677和0.794,P均〈0.01）。结论用二次栓塞并应用氨甲环酸抑制纤溶,成功制备了大鼠栓塞性肺动脉高压模型;模型组大鼠出现明显肺动脉重构,继之出现右心室重构;栓塞时间越长肺动脉高压越明显;肺动脉重构与肺动脉高压之间有显著相关关系。

Objective To find a way to establish the model of chronic thromboembolism of pulmonary hypertention（CTEPH） in rats and to investigate the pulmonary vascular remodeling. Methods Male Wistar rats were randomly divided into two control group and ten of pulmonary thromboembolism（PTE） groups. Model of PTE was established by injecting thrombi to jugular vein two times in two weeks and each rat underwent peritoneal injection with tranexamic acid one time a day during experiment to prevent thrombolysis;to measure the mean pulmonary artery pressure（mPAP） using right cardiac atheterzation and to evaluate the right ventricular hypertrophy index （RVHI） by scalling the weight ratio of right ventricle to left ventricle plus septum; to oberserve the changes of structure in pulmonary artery and in lung, including relative medial thickness of small pulmonary arteries（PAMT） and vessel wall area /total area （WA/TA）. Results （1） Percentage of success in model was 85.1% （120/141）;Q mPAP, WA/TA and PAMT were higher respectively in 4 week group to 12 week group than that in control group（all P d0.01） ; （3）RVHI was elevated in 12 week group（ P 〈0.01）;（4）There were positive correlations between mPAP,RVHI and PAMT （ r =0. 681 and 0. 690, P 〈0.01, respectively ）. There were also positive correlations between mPAP, RVHI and WA/TA （ r = 0. 677 and 0. 794, P 〈0.01 respectively）. Conclusions The rat model of CTEPH was established by injecting thrombi through jugular vein two times in two weeks and peritoneal injection with tranexamic acid one time a day during experiment to prevent thrombolysis, varied degree mPAP, RVHI,WA/TA and PAMT are evident at different times after embolization, pulmonary vascular remodeling is related to pulmonary hypertension in CTEPH rat model.