肝细胞生长因子对低氧性肺动脉高压小鼠影响的初步研究

Effect of hepatocyte growth factor on mice with hypoxic pulmonary arterial hypertension: a preliminary study

摘要:

目的 探讨肝细胞生长因子（hepatocyte growth factor，HGF）在低氧性肺动脉高压（hypoxic pulmonary arterial hypertension，HPAH）小鼠中与治疗反应的关系，探索其成为治疗HPAH靶向药物新思路的可能性。 方法 将构建成功的HPAH模型小鼠随机分为HPAH组、HGF治疗组（重组小鼠HGF，1 mg/kg，尾静脉注射），另设置正常对照组，每组10只。5周后，采用心脏超声测定各组小鼠的三尖瓣峰值流速、右心室收缩压、右心室肥厚指数、右心室/体重比值；采用Griess法测定小鼠血清中一氧化氮含量；采用ELISA法检测小鼠血清中内皮素-1水平；采用透射电镜观察小鼠肺动脉超微结构改变。 结果 HPAH组三尖瓣峰值流速、右心室收缩压、右心室肥厚指数、右心室/体重比值均显著高于HGF治疗组及正常对照组（P<0.05）。透射电镜观察到HPAH组血管内皮细胞被大量破坏，小动脉内膜弹力膜排列紊乱，有断裂及缺失；HGF治疗组血管内皮细胞结构基本完整，动脉内膜弹力膜结构基本正常。HPAH组小鼠血清一氧化氮和内皮素-1水平显著高于正常对照组和HGF治疗组（P<0.05）。 结论 提高血清HGF水平可有效缓解HPAH对小鼠心血管系统的影响，其机制可能与修复内皮细胞损伤，改善血管重构，恢复肺血管正常舒缩功能有关。

Abstract:

Objective To study the association between hepatocyte growth factor (HGF) and treatment response in mice with hypoxic pulmonary arterial hypertension (HPAH) and the possibility of HGF as a new targeted drug for HPAH. Methods After successful modeling, the HPAH model mice were randomly divided into two groups: HPAH group and HGF treatment group (tail vein injection of recombinant mouse HGF 1 mg/kg), with 10 mice in each group. Ten normal mice were used as the control group. After 5 weeks, echocardiography was used to measure tricuspid peak velocity, right ventricular systolic pressure, right ventricular hypertrophy index, and right ventricular/body weight ratio; the Griess method was used to measure the content of nitric oxide in serum; ELISA was used to measure the serum level of endothelin-1; transmission electron microscopy was used to observe changes in the ultrastructure of pulmonary artery. Results Compared with the HGF treatment and normal control groups, the HPAH group had significantly higher tricuspid peak velocity, right ventricular systolic pressure, right ventricular hypertrophy index, and right ventricular/body weight ratio (P<0.05). The transmission electron microscopy showed that the HPAH group had massive destruction of vascular endothelial cells and disordered arrangement of the elastic membrane of arteriolar intima with rupture and loss. The structure of vascular endothelial cells was almost complete and the structure of arterial intima elastic membrane was almost normal in the HGF treatment group. Compared with the normal control and HGF treatment groups, the HPAH group had significantly higher serum levels of nitric oxide and endothelin-1 (P<0.05). Conclusions Increasing serum HGF level can alleviate the impact of HPAH on the cardiovascular system of mice, possibly by repairing endothelial cell injury, improving vascular remodeling, and restoring the normal vasomotor function of pulmonary vessels.