目的 研究淫羊藿苷改善缺氧性肺动脉高压（hypoxic pulmonary hypertension，HPH）作用与趋化因子C-X3-C基元配体1（chemokine C-X3-C motif ligand 1，CX3CL1）介导的炎症反应的关系。方法 将40只C57BL/6J雄性野生型（wide type，WT）小鼠随机分为对照组、WT模型组和WT＋淫羊藿苷（10、20 mg/kg）组，20只雄性CX3CL1^—/—小鼠分为CX3CL1^—/—模型组和CX3CL1^—/—＋淫羊藿苷（20 mg/kg）组。除对照组外，各组均于含氧量为10%的低氧环境中连续饲养21 d，于低氧饲养7 d后ig淫羊藿苷2周。采用小动物超声仪检测小鼠肺动脉血流速度和右心室血流动力学，测量右心室肥厚指数（right ventricular hypertrophy index，RVHI）；采用苏木素-伊红（HE）和Masson染色观察小鼠肺小动脉重构情况；采用ELISA法检测小鼠血清中肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）和白细胞介素-1β（interleukin-1β，IL-1β）水平；采用Western blotting检测小鼠肺组织CX3CL1和核因子-κB（nuclear factor-κB，NF-κB）通路相关蛋白表达情况。结果 与对照组相比，WT模型组小鼠肺动脉血流速度明显降低（P<0.05），RVHI显著增大（P<0.05），右心室收缩末期直径、收缩末期容积和每博输出量升高（P<0.05），右心室短轴缩短率和射血分数降低（P<0.05），肺小动脉重构明显。与WT模型组相比，淫羊藿苷能够增加WT小鼠肺动脉血流速度（P<0.05），降低RVHI、右心室收缩末期直径、收缩末期容积和每博输出量（P<0.05），升高右心室短轴缩短率和射血分数（P<0.05），肺小动脉重构明显改善，同时，淫羊藿苷降低血清IL-1β和TNF-α水平以及肺组织CX3CL1蛋白表达水平（P<0.05），抑制NF-κB通路相关蛋白表达水平（P<0.05）。与WT模型组相比，CX3CL1^—/—模型组小鼠肺动脉血流速度、肺小动脉重构、右心室血流动力学均有改善（P<0.05），血清IL-1β和TNF-α水平降低（P<0.05）。敲除CX3CL1^—/—后，淫羊藿苷（20 mg/kg）对HPH小鼠的改善作用减弱甚至消失。结论 淫羊藿苷能够通过抑制CX3CL1介导的炎症反应改善小鼠HPH。

Objective To study the relationship between ameliorative effect of icariin on hypoxic pulmonary hypertension (HPH) and inflammation mediated by chemokine chemokine C-X3-C motif ligand 1 (CX3CL1). Methods Forty C57BL/6J male wild type (WT) mice were randomly divided into control group, WT model group and WT + icariin (10, 20 mg/kg) group; And twenty male CX3CL1^−/− mice were divided into CX3CL1^−/− model group and CX3CL1^−/− + icariin (20 mg/kg) group. Except for control group, mice were exposed to hypoxia environment with oxygen content of 10% for 21 d, and were ig icariin for two weeks after 7 d of hypoxic feeding. Pulmonary artery blood flow velocity and right ventricular hemodynamics of mice were detected by ultrasound, and right ventricular hypertrophy index (RVHI) was measured; HE and Masson staining were used to observe the remodeling of pulmonary artery; Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels in serum was detected by ELISA; Western blotting was used to detect CX3CL1 and nuclear factor-κB (NF-κB) pathway-related protein expressions in lung of mice. Results Compared with control group, pulmonary artery blood flow velocity of mice in WT model group was significantly decreased (P < 0.05), RVHI was significantly increased (P < 0.05), right ventricular end-systolic diameter, end-systolic volume and output per stroke were increased (P< 0.05), right ventricular short axis shortening rate and ejection fraction were decreased (P < 0.05), and pulmonary arteriole remodeling was obvious. Compared with WT model group, pulmonary artery blood flow velocity of mice was increased by icariin (P< 0.05), RVHI, right ventricular end-systolic diameter, end-systolic volume and output per stroke were reduced (P < 0.05), right ventricular short axis shortening rate and ejection fraction were increased (P < 0.05), and pulmonary arteriole remodeling was significantly improved; IL-1β and TNF-α levels in serum and CX3CL1 protein expression in lung tissue were decreased by icariin (P < 0.05), NF-κB pathway related protein expressions were inhibited (P < 0.05). Compared with WT model group, pulmonary artery blood flow velocity, pulmonary arteriolar remodeling, and right ventricular hemodynamics in mice of CX3CL1^−/− model group were improved (P < 0.05), IL-1β and TNF-α levels in serum were decreased (P < 0.05). After knockout of CX3CL1^−/−, ameliorating effect of icariin (20 mg/kg) on ​​HPH mice was attenuated or even disappeared. Conclusion Icariin can improve HPH in mice through inhibiting inflammation mediated by CX3CL1.

R285.5

遵义医科大学博士启动基金资助项目（F-951）；遵义医科大学基础药理教育部重点实验室开放课题（JCYL-K-015）；遵义市科技局与遵义医学院联合基金资助项目（遵市科合社字[2018]03号）