New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis.
New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis.
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DOI：
10.4103/2045-8932.105031
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发表时间：
2012-10
影响因子：
2.6
通讯作者：
Bogaard HJ
中科院分区：
文献类型：
--
作者：
Nicolls MR;Mizuno S;Taraseviciene-Stewart L;Farkas L;Drake JI;Al Husseini A;Gomez-Arroyo JG;Voelkel NF;Bogaard HJ
尽管进行了治疗，但严重的血管增生性肺动脉高压(PAH)仍然是一种发病率高、生存期短的疾病。需要针对PAH患者的新的治疗策略，在药物开发之后，临床前研究最好在出现肺血管闭塞性疾病和右心衰竭的动物模型中进行。十年前描述的严重肺动脉高压和右心衰竭的大鼠模型仍在接受研究，并为肺血管病变的性质和心脏对肺循环改变的适应机制提供了洞察。这种大鼠模型是基于血管内皮生长因子受体阻断与Su5416和慢性低氧相结合的；使用这种肺动脉高压诱导策略导致了细胞凋亡依赖的代偿性血管细胞生长的概念的发展。尽管在实验设计中经常采用慢性低氧，但慢性低氧不是血管闭塞性肺动脉高压发生的必要条件。左全肺切除联合Su5416在常氧条件下也会导致严重的肺动脉高压。类似地，重度PAH的免疫功能不全部分可以在无胸腺大鼠(缺乏T淋巴细胞)中模拟。在常氧条件下饲养的这些大鼠，用VEGFR受体阻滞剂治疗会导致血管增生性肺动脉高压；这些动物的心肺疾病可以通过调节性T细胞(Treg)的免疫重建来预防。最后，慢性缺氧可以被HIF-1α的另一个刺激物：卵清蛋白(OVA)所取代。OVA免疫大鼠可增加肺组织HIF-1α蛋白的表达，而Su5416处理的大鼠可导致致死性肺动脉高压。最后，我们假设这些模型也可能对“反向翻译”有用；也就是说，在Su5416 VEGFR抑制剂模型中已被识别的肺血管细胞死亡和生长的机制以及免疫和骨髓细胞的修饰影响可以为人类PAH中迄今未描述的过程提供信息。
In spite of treatment, severe angioproliferative pulmonary arterial hypertension (PAH) remains a disease characterized by great morbidity and shortened survival. New treatment strategies for patients with PAH are needed, and after drug development, preclinical studies are best conducted in animal models which present with pulmonary angio-obliterative disease and right heart failure. A rat model of severe pulmonary hypertension and right heart failure, described a decade ago, continues to be investigated and provide insight into the nature of the lung vascular lesions and mechanisms of cardiac adaptation to an altered lung circulation. This rat model is based on the combination of VEGF receptor blockade with Su5416 and chronic hypoxia; use of this pulmonary hypertension induction strategy led to developing the concept of apoptosis-dependent compensatory vascular cell growth. Although, often employed in experimental designs, chronic hypoxia is not necessary for the development of angio-obliterative pulmonary hypertension. Left pneumonectomy combined with Su5416 also results in severe pulmonary hypertension in normoxic conditions. Similarly, the immune insufficiency component of severe PAH can be modeled in athymic rats (lacking T-lymphocytes). In these rats housed under normoxic conditions, treatment with the VEGFR receptor blocker results in angioproliferative pulmonary hypertension; cardiopulmonary disease in these animals can be prevented by immune reconstitution of regulatory T-cells (Tregs). Finally, chronic hypoxia can be replaced with another stimulator of HIF-1α: Ovalbumin (Ova). Immunization of rats with Ova increases lung tissue HIF-1α protein expression, and in Su5416-treated rats causes lethal pulmonary hypertension. Finally, we postulate that these models may also be useful for “reverse translation”; that is, the mechanisms of lung vascular cell death and growth and the modifying influences of immune and bone marrow cells that have been identified in the Su5416 VEGFR inhibitor models can be informative about heretofore undescribed processes in human PAH.