Development and Characterization of an Inducible Rat Model of Chronic Thromboembolic Pulmonary Hypertension
Development and Characterization of an Inducible Rat Model of Chronic Thromboembolic Pulmonary Hypertension
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DOI：
10.1161/hypertensionaha.116.07247
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发表时间：
2016-05-01
期刊：
影响因子：
8.3
通讯作者：
Pelzer, Theo
中科院分区：
文献类型：
--
作者：
Arias-Loza, Paula-Anahi;Jung, Pius;Pelzer, Theo
慢性血栓栓塞性肺动脉高压（CTEPH）是PH的一个实体，不仅限制了患者的生活质量，而且还导致显著的发病率和死亡率。治疗的选择是肺动脉内膜切除术。然而，许多患者不符合肺动脉内膜切除术的条件，或在肺动脉内膜切除术后存在残余血管病变，需要特定的血管扩张剂治疗。目前，还没有可用的CTEPH特定小动物模型可用作鉴定靶向分子途径和测试新治疗方案的工具。因此，我们生成并标准化了一种大鼠模型，该模型不仅类似于CTEPH的功能和组织学特征，而且还模拟血栓纤维化。肺栓塞方案包括3次连续尾静脉注射纤维蛋白原/胶原蛋白覆盖的聚苯乙烯微球与凝血酶的组合，并给予10周龄雄性Wistar大鼠。第三次栓塞后，大鼠出现CTEPH的特征性特征，包括右心室收缩压升高、右心室心肌细胞肥大、肺动脉重塑、血清脑钠肽水平升高、血栓纤维化和肺细胞纤维化病变形成。目前的动物模型似乎适用于CTEPH病理生理学的详细研究，并允许对CTEPH的新药理学疗法进行临床前试验。
Chronic thromboembolic pulmonary hypertension (CTEPH) is an entity of PH that not only limits patients quality of life but also causes significant morbidity and mortality. The treatment of choice is pulmonary endarterectomy. However numerous patients do not qualify for pulmonary endarterectomy or present with residual vasculopathy post pulmonary endarterectomy and require specific vasodilator treatment. Currently, there is no available specific small animal model of CTEPH that could serve as tool to identify targetable molecular pathways and to test new treatment options. Thus, we generated and standardized a rat model that not only resembles functional and histological features of CTEPH but also emulates thrombi fibrosis. The pulmonary embolism protocol consisted of 3 sequential tail vein injections of fibrinogen/collagen-covered polystyrene microspheres combined with thrombin and administered to 10-week-old male Wistar rats. After the third embolism, rats developed characteristic features of CTEPH including elevated right ventricular systolic pressure, right ventricular cardiomyocyte hypertrophy, pulmonary artery remodeling, increased serum brain natriuretic peptide levels, thrombi fibrosis, and formation of pulmonary cellular-fibrotic lesions. The current animal model seems suitable for detailed study of CTEPH pathophysiology and permits preclinical testing of new pharmacological therapies against CTEPH.