缺氧性肺动脉高压新生大鼠肺血管重塑的研究

Pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension

摘要:

目的：通过建立新生大鼠缺氧性肺动脉高压（hypoxia-induced pulmonary hypertension，HPH）模型，探讨HPH新生大鼠发病过程中肺血管重塑的变化。方法：将96只新生Wistar大鼠随机分为2组：缺氧组和常氧对照组，缺氧组建立新生大鼠HPH模型。分别于缺氧3、5、7、10、14、21 d 取缺氧组及对照组同日龄新生大鼠各8只测定其平均肺动脉压（mean pulmonary arteria pressure，mPAP）、右心室肥大指数（right ventricle hypertrophy index，RVHI），血管重塑指标MT%、MA%，观察肺血管超微结构。结果：缺氧组大鼠在缺氧3、5、7、10、14、21 d mPAP持续上升，明显高于对照组（P<0.05）；随着缺氧时间的延长，差异更为显著。缺氧7 d后MT%、MA%、RVHI明显高于对照组（P<0.05）；随着缺氧时间的延长，差异同样更为显著。透射电镜显示，缺氧7 d后大鼠肺小动脉内膜增厚，内皮细胞增生、变性，细胞器增多；细胞外基质见胶原纤维沉积；出现肺血管重塑改变。结论：新生大鼠缺氧3～5 d肺动脉压力增高，处于肺血管痉挛阶段；缺氧7 d后肺血管出现重塑，右心室肥厚，出现不可逆变化；随着缺氧时间延长，上述变化加剧。

Abstract:

OBJECTIVE: To study the changes of pulmonary vascular remodeling in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH) in neonatal rats. METHODS: Ninety-six newborn Wistar rats were randomly divided into an HPH group (hypoxia exposure) and a control group (room air exposure). The mean pulmonary arteria pressure (mPAP), right ventricle hypertrophy index (RVHI), and vascular remodeling indexes MT% and MA% were measured 3, 5, 7, 10, 14 and 21 days after exposure (n=8 each time point). The ultrastructure of pulmonary vascular was observed under a transmission electron microscope. RESULTS: mPAP in the HPH group 3, 5, 7, 10, 14 and 21 days after hypoxia exposure increased compared with the control group (P<0.05). With the prolonged hypoxia time, mPAP in the HPH group increased more significantly. MT%, MA% and RVHI increased significantly in the HPH group after 7 days of hypoxia exposure in a time-dependent manner compared with the control group (P<0.05). The transmission electron microscopy demonstrated that small pulmonary arterials became thickened, endothelial cell hyperplasia and degeneration, and organelles increased in the HPH group after 7 days of hypoxia exposure. Besides, collagen deposition in the extracellular matrix and the changes of pulmonary vascular remodeling were observed. CONCLUSIONS: mPAP increases between 3 and 5 days of hypoxia exposure, resulting from pulmonary vascular spasm caused by hypoxia. After hypoxia of 7 days, the mPAP increases more significantly, pulmonary vascular remodeling occurs, and right ventricle becomes irreversibly hypertrophic. These changes may be intensified as the prolonged hypoxia time.