硫化氢对肺动脉高压大鼠肺血管重塑及其抑制因子的影响

目的 探讨硫化氢（H2S）对肺动脉高压（PH）大鼠肺血管重塑及其抑制因子的影响。方法 30只雄性SD大鼠，通过随机数字表方式分为对照组10只、模型组10只及H2S干预组10只，其中模型组通过野百合碱诱导建立PH模型，H2S干预组在模型组基础上，对大鼠腹腔注射NaHS（56 μmol/kg），对照组注射等剂量的生理盐水。制作模型4周后，测定各组大鼠血流动力学指标，计算右心室肥厚指数(RVHI)，通过HE染色检测肺血管病理形态学变化，应用Western blotting及Real-time PCR检测丝裂原激活蛋白激酶（MAPK）家族中p38、c-Jun氨基末端激酶（JNK）蛋白的表达及表达含量。结果 各组血流动力学、RVHI、管壁厚度占血管直径百分比（WT%）、肺血管壁面积占血管截面积百分比（WA%）、p38 mRNA和JNK mRNA差异比较，具有统计学意义（P＜0.05）。其中模型组及H2S干预组平均体循环动脉压(MSAP)、平均肺动脉压(MPAP)、RVHI、WT%、WA%、p38mRNA和JNK mRNA表达水平均显著高于对照组（P＜0.05），而H2S干预组MSAP、MPAP、RVHI、WT%、WA%、p38mRNA和JNK mRNA水平均显著低于模型组（P＜0.05）。肺动脉形态图显示，与对照组相比，模型组及H2S干预组的血管管壁厚度均增加，管腔变狭窄，但H2S干预组管厚度及管腔狭窄度均较模型组明显减轻；Western blotting显示，模型组及H2S干预组p38、JNK蛋白表达量均高于对照组，而H2S干预组p38、JNK蛋白表达量均低于模型组。结论 H2S可改善PH大鼠血流动力学、右心室肥厚指数；减轻肺动脉血管管壁增厚及管腔狭窄，抑制大鼠肺血管重构，其作用机制可能与H2S下调MAPK信号通路上JNK及p38蛋白的表达有关。

Effects of hydrogen sulfide on pulmonary vascular remodeling and its inhibitors in rats with pulmonary hypertension

Objective To explore the effects of hydrogen sulfide on pulmonary vascular remodeling and its inhibitors in rats with pulmonary hypertension( PH). Methods Thirty male SD rats were randomly divided into control group( 10 rats),model group( 10 rats) and H2S intervention group( 10 rats),PH model was induced by Lilium Wilfordii in model group,on the basis of model group,rats in H2S intervention group were injected with Na HS( 56 μmol/kg)intraperitoneally,while rats in control group were injected with normal saline at the same dose. Four weeks later,the hemodynamic parameters were measured,the right ventricular hypertrophy index( RVHI) was calculated,the pathological changes of pulmonary vessels were detected by HE staining,and the expressions of p38 and c-Jun N-terminal kinase( JNK)proteins in the mitogen-activated protein kinase( MAPK) family were detected by Western blotting and Real-time PCR.Results There were significant differences in hemodynamics,RVHI,wall thickness as a percentage of vessel diameter( WT) %,pulmonary vessel wall area as a percentage of vascular cross-sectional area( WA) %,p38 and JNK in each group( P<0. 05). The expression levels of MSAP,MPAP,RVHI,WT%,WA%,p38 mRNA and JNK mRNA in the model group and H2S intervention group were significantly higher than those in the control group( P<0. 05),while the levels of MSAP,MPAP,RVHI,WT%,WA%,p38 mRNA and JNK mRNA in H2S intervention group were significantly lower than those in the model group( P<0. 05). The pulmonary artery morphology showed that the wall thickness and lumen stenosis of the model group and the H2S intervention group increased compared with the control group,but the lumen thickness and lumen stenosis of the H2S intervention group were significantly reduced compared with the model group;Western blotting showed that the expressions of p38 and JNK in model group and H2S intervention group were higher than those in control group,while the expressions of p38 and JNK in H2S intervention group were lower than those in model group. Conclusion H2S can improve hemorheology,right ventricular hypertrophy index,alleviate pulmonary artery wall thickening and lumen stenosis,and inhibit pulmonary vascular remodeling in PH rats. Its mechanism may be related to the down-regulation of JNK and p38 protein expression in MAPK signaling pathway by H2S.