辛伐他汀对野百合碱致肺动脉高压大鼠肺血管病变的影响

Simvastatin prevents the development of pulmonary hypertension in the rats through reduction of inflammation

目的探讨辛伐他汀早期干预对野百合碱致肺动脉高压（PH）大鼠肺血管病变的作用及其机制。方法32只Sprague-Dawley大鼠随机分为正常对照组、辛伐他汀对照组、PH模型组和辛伐他汀干预PH组，每组8只。PH模型组和辛伐他汀干预PH组大鼠皮下注射野百合碱80μg／g；2个对照组大鼠皮下注射等体积生理盐水。辛伐他汀干预PH组和辛伐他汀对照组大鼠自注射野百合碱或生理盐水当日开始以辛伐他汀2μg/g每日1次灌胃，连续21d。实验第21天测定各组大鼠肺动脉平均压（mPAP）；取肺组织观察肺小动脉周围炎症细胞浸润程度，记录炎性评分，采用病理图像分析系统测定肺小动脉壁面积／管面积比值和管壁厚／管外径比值，评价肺血管重构的严重程度；酶联免疫吸附试验测定肺组织匀桨白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α）和单核细胞趋化蛋白1（MCP-1）水平。结果PH模型组、辛伐他汀干预PH组和正常对照组大鼠mPAP分别为（5g±9）、（23±7）、（20±4）mmHg（1mmHg=0．133kPa）；肺小动脉周围炎性评分为（3．40±0．65）、（2．19±0．81）、（0．82±0．01）分；肺小动脉壁面树管面积比值为（0．560±0．086）、（0．442±0．061）、（0．408±0．049），管壁髟管外径比值为（0．368±0．055）、（0．325±0．045）、（0．302±0．035）；肺组织匀浆中IL-6为（765±179）、（264±127）、（59±26）pg／ml，TNF-α为（447±86）、（179±91）、（38±11）pg／ml，MCP-1为（4428±757）、（697±211）、（32±7）pg／ml。辛伐他汀干预PH组各项指标均明显低于PH模型组（P〈0．05或P〈0．01）。结论辛伐他汀可延缓野百合碱诱导的大鼠PH形成和肺血管重构，其作用机制可能与辛伐他汀抑制肺小动脉周围炎症和肺组织前炎性因子IL-6、TNF—α及MCP-1有关。

Objective To investigate the protection of simvastatin on monocrotaline （ MCT）-induce pulmonary hypertension （ PH ） and the mechanism thereof. Methods Tirty-two male Sprague-Dawley rats were randomly divided into 4 equal groups： PH group undergoing subcutaneous injection of MCT and then gastric infusion of normal saline （NS） once a day for 21 days, simvastatin control group undergoing subcutaneous injection of NS and then gastric infusion of simvastatin 2 μg/g once a day for 21 days, simvastatin intervention group undergoing subcutaneous injection of MTS and then gastric infusion of simvastatin 2 μg/g once a day for 21 days, and control group undergoing subcutaneous injection and gastric infusion of NS. Three weeks later the mean pulmonary arterial pressure （mPAP） was detected by right heart catheter. Then the rats were killed with their lungs taken out. Arterial wall area/vessel area （W/V） , and arterial wall thickness/vessel external diameter （T/D） were calculated. Perivascular inflammation was scored with the subjective scale of 0 （no） to 4 （severe）. Pulmonary interleukin （IL）-6, tumor necrosis factor α （ TNF-α）, and monocyte chemotactic protein 1 （ MCP-1 ） were tested by ELISA. Results The mPAP of the simvastatin intervention group was （23 ± 7 ）mm Hg, significantly lower than that of the PH group [ （34 ±9） mm Hg , P 〈0. 05], but not significantly different from that of the normal control group [ （20 ±4） mm Hg, P 〉 0. 05]. The W/V and T/D of the simvastatin intervention group were 0. 442 ± 0. 061 and 0. 325 ±0. 045 respectively, significantly lower than those of the PH group （0. 560 ±0. 086 and 0. 368 ± 0. 055 respectively, P 〈 0. 01 and P 〈 0. 05 ） . The perivascular inflammation score of the simvastatin intervention group was （2. 19 ±0. 81 ） , significantly lower than that of the PH group （3.40 ± 0. 65, P 〈 0. 05）, and the IL-6, TNF-α, and MCP-1 levels of the simvastatin intervention group [ （ 264 ± 127）, （179 ± 91 ）, and （697 ± 211 ） pg/ml respectively] were all significantly lower than those of the PH group [（765 ±179）, （447 ±86）, （4428 ±757） pg/ml respectively, all P 〈0.01]. Conclusion The protective effects of simvastatin against MCT-indueed PH may be associated with the inhibition of the perivaseular inflammation and lung IL-6, TNF-α, and MCP-1 levels.