靶向纳米载体包封西地那非对肺高压大鼠肺血管重构的影响  

Effect of targeted nanoparticles embedded with sildenafil on the vascular remodeling in rats with pulmonary arterial hypertension

作　　者：祝玉玲 俞春芳 孙青[1] 杨军[2] 缪明星[3] 何伟[3] 李冰冰[1] ZHU Yuling;YU Chunfang;SUN Qing;YANG Jun;MIAO Mingxing;HE Wei;LI Bingbing(Department of Anesthesiology,Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing University Medical School,Nanjing 210008,China)

机构地区：[1]南京大学医学院附属鼓楼医院麻醉科,210008 [2]南京大学医学院附属鼓楼医院病理科,210008 [3]中国药科大学

出　　处：《临床麻醉学杂志》2018年第12期1218-1222,共5页Journal of Clinical Anesthesiology

基　　金：国家自然科学基金(81470242);江苏省六大人才高峰(2016-WSN-147);南京市卫生青年人才培养工程(QRX17013)

摘　　要：目的观察包封西地那非的靶向纳米载体对野百合碱肺高压大鼠肺动脉压力、肺小血管中膜增殖以及右心室心肌肥厚的治疗作用。方法雄性SD大鼠42只,随机分为六组,每组7只。除对照组(CON组)外,其余各组皮下注射野百合碱60mg/kg,4周后分别经尾静脉注射西地那非8mg/kg(SIL组)、靶向纳米空载体(GL组)、普通纳米载体包封西地那非(L-SIL组)和靶向纳米载体包封西地那非(GL-SIL组)干预2周,CON组与模型组(MCT组)则给予等体积的生理盐水。2周后,开胸测量大鼠平均肺动脉压(mPAP)并处死动物取心肺组织,进行HE染色,测定肺小血管中膜厚度比例(WT),右心室心肌细胞的面积。采用免疫组织化学法检测肺血管中膜α-平滑肌肌动蛋白(α-SMA)含量。采用活体荧光示踪观察靶向纳米载体的组织分布。结果与CON组比较,MCT组、GL组、SIL组和L-SIL组mPAP明显升高(P<0.05)。与MCT组比较,GL-SIL组mPAP明显降低(P<0.05)。与CON组比较,MCT组、SIL组、GL组和L-SIL组WT明显增加(P<0.05),α-SMA表达明显增高(P<0.05)。与MCT组比较,GL-SIL组WT和α-SMA的表达明显降低(P<0.05)。与CON组比较,MCT组、SIL组、GL组和L-SIL组心肌细胞面积明显增大(P<0.05)。但GL-SIL组明显小于MCT组(P<0.05)。结论靶向纳米载体包封西地那非可明显降低肺动脉高压大鼠的平均肺动脉压力,改善肺血管中膜增殖和右心室肥大,与其具有良好的肺组织靶向性相关。Objective To explore the possible efficacy of glucose modified nanoparticles embedded with sildenafil on amelioration of pulmonary hypertension and pulmonary vascular remodeling in rats treated with monocrotaline.Methods Forty-two male Sprague-Dawley rats were randomly divided into 6 groups with 7 rats for each group.All rats,except in Control group(group CON),were subjected to 60 mg/kg monocrotaline subcutaneous injection.After 4 weeks MCT insult,the rats received intravenous injection of sildenafil 8mg/kg(group SIL),glucose modified nanoparticles(group GL),conventional nanoparticles embedded with sildenafil(group L-SIL),glucose modifiednanoparticles embedded with sildenafil(group GL-SIL)every other day for 2 weeks.The same volume of normal saline was substituted for drugs in the groups CON and MCT.The right lower lobes of the lungs were fixed in neutralformaldehyde for morphometric analysis and assessment of the medial thickness of pulmonary arterioles wall.The expressions ofα-smooth muscle actin(α-SMA)were detected with immunohistochemistry assay.The cardiomyocyte volume of right ventricle was also measured under the high-resolution microscope.Ex vivo fluorescence imaging of DiR-loaded nanoparticles in the main tissues collected from rats at 4h after intravenous injection.Results Compared with group CON,the mPAP,WT,expressions ofα-SMA and cardiomyocyte volume of right ventricle in groups MCT,SIL,GL and L-SIL were significantly increased(P < 0.05).Compared with group MCT,the mPAP,WT,expressions ofα-SMA and cardiomyocyte volume of right ventricle in group GL-SIL were significantly reduced(P<0.05).The intensity of fluorescent of lung tissue was higher in DiR-loaded glucose modified nanoparticles compared with conventional nanoparticles after 4h injection.Conclusion Glucose modified nanoparticles embedded sildenafil can effectively inhibit the increase in mPAP,percentage of medial thickening and cardiomyocyte hypertrophy of right ventricle induced by MCT in rats,which might be associated with high affinity to

关 键 词：肺动脉高压 纳米载体 西地那非 

分 类 号：R965[医药卫生—药理学]