过表达ACE2基因的骨髓间充质干细胞对肺动脉高压大鼠的干预作用

目的:探讨过表达血管紧张素转化酶2(ACE2)的大鼠骨髓间充质干细胞(BM-MSCs)对野百合碱(MCT)诱导的肺动脉高压(PAH)大鼠模型的干预作用。方法:原代提取BM-MSCs并进行纯化、鉴定,使用携带ACE2基因的慢病毒载体感染MSC制备ACE2-MSC,并检测ACE2的基因与蛋白表达水平;实验动物选用健康、雄性、8周龄的SD大鼠,随机分为正常对照组(Control组)、MCT诱导的肺动脉高压组(PAH组)、转导ACE2的间充质干细胞组(ACE2-MSCs组)以及空病毒载体的间充质干细胞组(null-MSCs组)。于造模后第4周(28d)测定各组大鼠平均肺动脉压力(mPAP)及右心室肥厚指数(RV/LV+S);肺组织标本作HE染色并计算肺动脉管壁厚度指数(TI)及面积指数(AI);Western Blot检测肺组织中ACE2、ACE蛋白表达水平。结果:成功制备能在体外稳定过表达ACE2的ACE2-MSCs;造模后第4周(28d),ACE2-MSCs组的mPAP、RV/LV+S、TI、AI均较PAH组及null-MSCs组有所下降(P0.05),但仍高于Control组(P0.05);造模后第4周(28d),ACE2-MSCs组肺组织中ACE2、ACE2/ACE蛋白表达水平较PAH组及null-MSCs组有所升高(P0.05),但仍低于Control组(P0.05)。结论:过表达ACE2的大鼠BM-MSCs能有效降低PAH大鼠平均肺动脉压力,改善肺血管与右心室重构,抑制肺部炎症及调节RAS平衡。     

气道内滴注肝细胞生长因子对野百合碱诱导肺动脉高压大鼠的干预研究

目的 通过气道内滴注腺病毒转染肝细胞生长因子（adenovirus hepatocyte growth factor,Ad-HGF）干预野百合碱（monocrotaline,MCT）诱导的肺动脉高压（pulmonary hypertension,PAH）模型大鼠,观察Ad-HGF干预对平均肺动脉压（mean pulmonary artery pressure,mPAP）等指标的影响.方法 选用健康雄性SD大鼠40只,随机[采用随机单位（区）组设计方法]分为4组：正常对照组（normal,NOR组）10只,MCT诱导PAH组（PAH组）10只、单次和重复肝细胞生长因子（hepatocyte growth factor,HGF）干预治疗组（HGF和THGF组）各10只.NOR组和PAH组：气道内滴注0.2 mL磷酸盐缓冲液;HGF组和THGF组：气道内滴注0.2 mL Ad-HGF 1次和一周后重复一次共2次.再饲养两周后,测定各组大鼠的肺动脉压,计算右心室肥厚指数;苏木素伊红染色观察肺动脉管壁等;酶联免疫吸附（ELISA）法测定肺组织匀浆中HGF浓度.结果 与PAH组大鼠比较,HGF组和THGF组大鼠的mPAP、右心室肥厚指数、肺动脉管壁指数和面积指数明显降低,肺苏木素伊红染色肺小动脉管壁厚度减少,管腔面积增大,血管周围炎症细胞浸润减轻,肺组织匀浆HGF浓度明显升高,差异有统计学意义（P＜0.05）,且低于NOR组水平.结论 经气道内滴注转染Ad-HGF,能明显降低但不能完全逆转MCT诱导PAH大鼠的mPAP,减少肺小动脉管壁厚度,减轻右心室肥厚程度,从而达到延缓PAH进程的作用.     

人源性脐带间充质干细胞治疗实验性肺动脉高压所致右心衰竭的疗效观察

目的 拟通过建立MCT诱导的PAH大鼠模型,观察人脐带间充质干细胞（UC-MSCs）干预对大鼠PAH和右心衰竭的治疗效应。方法 实验动物分为3组（空白对照组、PAH组和UC-MSCs组）,在MCT腹腔注射1周后进行干预,UC-MSCs组舌下静脉注射UC-MSCs悬液,空白对照组和PAH组舌下静脉注射等量生理盐水。第4周大鼠行右心超声心动图、右心导管测压、右心肥厚指数以及肺组织病理等检测。结果 与对照组相比,PAH组大鼠右心室游离壁厚度(RVWT)和右心室内径(RVID)显著增大,肺动脉血流加速时间与射血时间比值（PAT/PET）显著下降,右心收缩压（RVSP）和右心肥厚指数(RVHI)显著增高,肺小动脉血管壁厚度（WT）明显增厚。与PAH组相比,UC-MSCs组RVWT和RVID显著减小,PAT/PET明显升高,RVSP和RVHI明显降低,WT明显变薄。结论 利用MCT腹腔注射成功制备PAH大鼠模型,经舌下静脉注射UC-MSCs可以显著降低肺动脉压力,改善右心功能,逆转肺血管重构。     

褪黑素干预动脉性肺动脉高压大鼠的实验研究

目的探讨褪黑素(MEL)干预对野百合碱(MCT)诱导的动脉性肺动脉高压(PAH)大鼠肺动脉压及肺组织环氧合酶-2(COX-2)表达情况的影响。方法 36只大鼠按随机数表法分为对照组、造模组(MCT)、干预组(MCT+MEL)。造模组和干预组分别按2.5 ml/kg(50 mg/kg,溶于无水乙醇+生理盐水混合液)规格腹膜内注射MCT溶液。对照组按2.5 ml/kg接受腹膜内注射溶媒。造模后第1～28天,干预组予以MEL 10 ml/kg (10 mg/kg,溶于无水乙醇+生理盐水混合液)腹膜内注射,1次/d,对照组和造模组予以单位等体积溶媒腹膜内注射,1次/d。测量并记录3组大鼠平均肺动脉压(mPAP)、右心室肥厚指数(RVHI)、肺小动脉管壁厚度占血管外径的百分比(WT%)、肺小动脉血管壁面积占血管总面积的百分比(WA%)及肺小动脉COX-2平均光密度值(AOD)。应用SPSS 22.0统计软件对数据进行分析。结果与对照组比较,造模组大鼠mPAP、RVHI、WT%、WA%、AOD显著升高;与造模组比较,干预组大鼠上述指标均有不同程度降低,但仍高于对照组,差异均具有统计学意义(P0.001)。相关性分析显示,AOD与mPAP、RVHI、WT%、WA%呈显著正相关(r依次为0.836、0.749、0.823、0.821,P均0.01)。结论 MEL能够降低MCT诱导的PAH大鼠的肺动脉压,改善肺血管重塑,这可能与其抑制COX-2表达水平有关。     

肝素对低氧诱导肺动脉高压大鼠肺血管外膜重塑干预作用的研究

目的 探讨肝素对低氧诱导肺动脉高压(PAH)大鼠肺动脉外膜重塑的干预作用及机制. 方法 将60只健康雄性SD大鼠随机分为A、B、C三组,各20只;A组正常饲养,B组作低氧处理4周,C组作低氧处理4周后给予肝素处理.测定各组大鼠平均肺动脉压(mPAP)、右心室肥厚指数[RV/(LV S)]、PaCO2和PaO2.用免疫组化SP法检测肺动脉外膜巨噬细胞及其单核细胞趋化蛋白-1(MCP-1);用RT-PCR一步法检测肺组织中的MCP-1mRNA. 结果 B组mPAP、RV/(LV S)、PaCO2显著高于A组(P<0.05),C组显著低于B组(P<0.01),而PaO2则相反.肺动脉外膜单视野平均巨噬细胞数目(MAM)、巨噬细胞MCP-1蛋白及肺组织MCP-1 mRNA的表达B组显著高于A组(P<0.05),C组显著低于B组(P<0.01). 结论 MCP-1可能参与了缺氧诱导的肺动脉外膜重塑,促进了PAH的发生、发展.肝素封闭了MCP-1的作用,抑制肺血管结构外膜重建,减轻肺动脉高压.     

粉防己碱对肺动脉高压大鼠中NLRP3炎性小体表达研究

目的:研究肺动脉高压大鼠中NLRP3炎性小体的表达情况,探究粉防己碱对肺动脉高压的保护作用。方法:36只雄性SD大鼠,随机分为3组:正常对照组(control)、肺动脉高压组(MCT)、粉防己碱组(Tet)。对照组单剂量给予0.9%氯化钠腹腔注射,其余两组单剂量给予野百合碱腹腔注射后正常饲养21d;而后Tet组每天给予粉防己碱药物灌胃,其余两组则每天给予0.9%氯化钠灌胃21d后留取组织标本,测量肺动脉压力(右室收缩压,right ventricular systolic pressure,RVSP),计算右心室/(左心室+心室壁)[RV/(LV+S)]比值,行HE染色观测各组形态学变化,免疫组化及western blot检测各组NLRP3、caspase-1及白细胞介素-1β(IL-1β)的表达水平。结果:(1)与对照组相比,MCT及Tet组RVSP、RV/(LV+S)值均明显增高(P0.05);与MCT组相比,Tet组又明显下降(P0.05)。(2)病理组织学检测结果显示,粉防己碱可减轻PAH模型大鼠肺小动脉内膜增生,减少肺组织炎性细胞浸润;(3)免疫组化及western blot结果显示,粉防己碱可抑制NLRP3、caspase-1、IL-1β的表达。结论:粉防己碱可以抑制NLRP3炎性小体的活化,减轻肺动脉高压大鼠肺组织的炎性浸润,对肺动脉高压具有一定的逆转作用。     

间歇性低压低氧预适应延缓大鼠低氧性肺动脉高压发展并改善肺动脉舒张

目的 观察间歇性低压低氧预适应对大鼠低氧性肺动脉高压（HPH）及肺动脉舒张功能的影响。方法 将24只雄性SD大鼠随机分为:对照组、HPH组、间歇性低压低氧预适应组,每组8只。对照组动物常规饲养10周;HPH组动物先在同一室内常规饲养6周,然后按低压低氧法建立HPH模型（给予持续低压低氧4周）;间歇性低压低氧预适应组动物先给予预适应实验:HPH 1周,再放置同一室内常规饲养1周,如此重复循环3个周期共6周,然后按低压低氧法建立HPH模型（方法同HPH组）。分组模型建立后,用右心导管法测定肺动脉平均压（mPAP）、右心室平均压（mRVP）;称重测量右心室/（左心室+室间隔）〔RV/(LV+S)〕、右心室/体质量（RV/BW）;HE染色高倍镜下观察肺小动脉显微结构改变;取大鼠左、右肺动脉干制备血管环,行离体血管灌流实验,观察不同浓度乙酰胆碱和硝普钠的舒张血管作用。结果 与对照组比,HPH组大鼠的mPAP、mRVP、RV/(LV+S)、RV/BW均显著增高（P<0.01）;病理切片显示低氧后大鼠肺动脉平滑肌和弹力纤维层增生,血管壁增厚,管腔狭窄、变形;且低氧后大鼠肺动脉血管环对乙酰胆碱的舒张作用显著降低（P<0.01）。与HPH组比,经间歇性低压低氧预适应处理的大鼠mPAP、mRVP、RV/(LV+S)、RV/BW均显著降低（P<0.05）;病理切片显示肺动脉平滑肌和弹力纤维层增生及血管壁增厚有所缓解;且肺动脉血管环对乙酰胆碱的舒张作用显著增强（P<0.05）。结论 间歇性低压低氧预适应可增强大鼠肺动脉对低压低氧环境的耐受能力,延缓肺动脉高压和右心重构的发展,并改善肺动脉内皮功能。     

波生坦对慢性低氧性肺动脉高压大鼠右心室肥厚及缝隙连接蛋白(Cx)43表达的影响

目的:研究波生坦(bosentan,BST)对慢性低压低氧性肺动脉高压(HPH)大鼠右心室肥厚及缝隙连接蛋白43(Cx43)表达量的影响。方法:将24只实验动物随机分为正常组、HPH组、安慰剂组和BST治疗组,每组各6只。正常组:常压常氧下饲养6周;其他3组大鼠置于低压低氧仓内8h/d,共6周,从第4周开始,每天给BST治疗组大鼠BST(100mg/kg)灌胃,安慰剂组生理盐水灌胃。6周后,所有大鼠测定血流动力学指标:如平均肺动脉压力(mPAP)、右心室收缩压(RVSP)、右心室收缩压上升最大速率(dp/dtmax),以及右心室肥厚度[如右心室质量/(左心室质量+室间隔质量),RV/(LV+S)]和右心室质量/体质量(RW/BW)。收集动脉血检测血浆内皮素-1(ET-1)和一氧化氮(NO)水平。Masson染色观察心肌胶原纤维容积百分比的变化,免疫组化染色法和Westernblot观察Cx43的变化。结果:BST治疗组大鼠的mPAP、RVSP、RV/(LV+S)、RW/BW及心肌胶原纤维容积百分比均较HPH组显著降低(P0.05),但血浆NO、ET-1的水平和心肌Cx43表达量显著升高(P0.05)。结论:BST在降低肺动脉压力的同时,还可抑制右心室肥厚和Cx43表达量的降低。     

基质金属蛋白酶-2在低氧性肺动脉高压大鼠肺血管中的表达及辛伐他汀对其影响

目的观察基质金属蛋白酶-2(MMP-2)在低氧性肺动脉高压大鼠肺血管中的表达,及辛伐他汀对其表达的调节作用。方法采用随机分组方法将30只雄性SD大鼠分为对照组、低氧组和预防组,每组10只,低氧组和预防组给予低氧处理,建立大鼠低氧性肺动脉高压模型,且预防组于低氧前给予辛伐他汀灌胃,对照组不做任何处理。3周后观察大鼠平均肺动脉压(mPAP)、右心室肥厚指数即右心室/(左心室+室间隔)和肺血管形态学指标的变化。采用免疫组织化学染色方法检测大鼠肺小动脉MMP-2表达。结果低氧组大鼠mPAP、右心室肥厚指数、肺血管形态学指标和肺小动脉MMP-2染色强度均高于对照组,差异有统计学意义(P<0.01);而预防组上述指标低于低氧组,差异有统计学意义(P<0.01)。结论 MMP-2在低氧性肺动脉高压大鼠肺血管中的表达增加,辛伐他汀可抑制其表达,预防低氧性肺动脉高压的形成。     

肺动脉高压对右心重构及右心室AT_1R、TGF-β1、ERK1/2蛋白表达的实验研究

目的:探讨肺动脉高压(pulmonary arterial hypertension,PAH)对大鼠右心重构及右心室AT1R,TGF-β1及ERK1/2蛋白的表达。方法:选取体质量250~260g的健康雄性SD大鼠12只,随机分为:对照组(n=6)、PAH右心重构组(n=6)。对照组和PAH右心重构组分别予以0.9%氯化钠液和野百合碱(MCT)60 mg/kg单次注射于大鼠颈背部皮下,饲养6w建立模型。应用超声生物显微镜测定其右心室前壁厚度(RVAWd)及右心室射血分数(RVEF),应用右心导管测定肺动脉平均压(mPAP)。处死后分别称量右心室(RV)和左心室+室间隔(LV+SP)质量,计算右心室肥厚指数(RVHI)。天狼猩红染色计算心肌组织胶原容积分数(CVF)。应用Western blot测定右心室AT1R,TGF-β1,ERK1/2蛋白表达。结果:与对照组相比,野百合碱诱导6w后,PAH右心重构组的RVAWd、mPAP、RVHI及CVF均高于对照组,差异有统计学意义,分别为RVHI[(25.01±1.20)vs.(40.57±4.17)%],mPAP[(16.56±1.98)vs.(29.46±2.47)mmHg],RVAWd[(0.65±0.09)vs.(1.17±0.08)mm],RVEF[(54.15±4.60)vs.(62.63±9.54)%],均为P0.01;PAH右心重构组右心室心肌组织AT1R、TGF-β1及ERK1/2蛋白表达显著高于对照组(均为P0.05)。结论:肺动脉高压对大鼠右心重构及右心室AT1R、TGF-β1及ERK1/2蛋白表达显著上调。     

Preventive treatment with atorvastatin ameliorates endothelial dysfunction of small pulmonary arteries in monocrotaline-induced pulmonary hypertensive rats

This study examined the effects of preventive atorvastatin (Ator) treatment on vasodilatation of small pulmonary arteries (SPAs) in monocrotaline (MCT)-induced pulmonary hypertensive rats. SD rats were randomly assigned to: normal control (Ctr), pulmonary arterial hypertension (PAH), PAH treated with 5 mg/kg/d Ator (LAtor), or 10 mg/kg/d Ator (HAtor). PAH was induced by MCT injection (40 mg/kg, i.p.). Mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RVHI%), endothelium-dependent relaxations (EDdRs), and endothelium-independent relaxations (EDiRs) were determined. Four weeks after MCT injection, mPAP was higher in PAH group compared to that in Ctr group, and this effect was suppressed by Ator treatment (PAH: 32.19 ± 0.91 mm Hg vs. LAtor: 19.13 ± 1.01 mm Hg, HAtor: 17.55 ± 0.20 mm Hg, p < 0.05). Similar trend of changes in RVHI% was found in the same way. EDdRs of SPA rings in PAH group were markedly decreased 2 and 4 weeks after MCT injection, while in Ator treated groups, the impairment can only be detected 4 weeks after MCT injection. There were no differences in EDiRs among all groups 1 week after MCT injection. However, 2 weeks and 4 weeks after MCT injection, EDiRs were significantly impaired, while in HAtor and LAtor groups, EDiR was only impaired 4 weeks but not 2 weeks after MCT injection. Preventive treatment with atorvastatin for 2 weeks ameliorated endothelium-dependent and endothelium-independent vasodilative dysfunction in small pulmonary artery rings of MCT-induced PAH rats. It suggests that MCT-induced damage of endothelial function was progressing, and Ator was only beneficial in the early stage of MCT-induced PAH.     

Urantide alleviates monocrotaline induced pulmonary arterial hypertension in Wistar rats

Pulmonary arterial hypertension (PAH) is a serious disorder with poor prognosis. Urotensin II (UII) has been confirmed to be powerful vasoconstrictor than endothelin-1, which may play an important role in PAH development. The aim of this study is to observe the effects of urantide, a UII receptor antagonist, on monocrotaline (MCT) induced PAH in rats. 60 male Wistar rats were divided into six groups. For early treatment experiment, rats were divided into normal control group, MCT(4w) model group (MCT + saline × 3 wks from the 8th day of MCT injection) and urantide early treatment group (MCT + urantide 10 μg/kg/d × 3 wks, 1 week after MCT injection once). For late treatment experiment, rats were divided as controls, MCT(6w) model group (MCT + saline × 2 wks, 4 weeks after MCT injection once) and urantide late treatment group (MCT + urantide 10 μg/kg/d × 2 wks, 4 weeks after MCT injection once). At the end of experiments, mean pulmonary arterial pressures (mPAP) and mean blood pressure (MBP) of rats in each group were measured by catheterization. Right ventricular weight ratio was also weighed. Relaxation effects of urantide on intralobar pulmonary arterial rings of normal control and MCT(4w) model rats were investigated. Pulmonary artery remodeling was detected by hematoxylin and eosin (HE) staining and immunohistochemistry analysis. Serum nitric oxide (NO) levels in all six groups were assayed by ELISA kits. Urantide markedly reduced the mPAP levels of MCT induced PAH in both early and late treatment groups. It didn't change the MBP. Urantide dose-dependently relaxed the pulmonary arterial rings of normal control and MCT(4w) model rats. Moreover, N(G)-Nitro-l-arginine Methyl Ester (l-NAME) blocked the dilation response induced by urantide. In addition, urantide inhibited the pulmonary vascular remodeling remarkably. Serum NO level elevated in both early and late treatment rats with urantide infusion. These results suggest that urantide effectively alleviated MCT induced rats PAH may through relaxing pulmonary arteries and inhibiting pulmonary vascular remodeling. NO pathway might be one of the mechanisms in urantide induced pulmonary artery dilation. Thus, it is expected that urantide may be a novel therapy for PAH.     

槲皮素对野百合碱诱导的大鼠肺动脉高压的影响

目的:观察槲皮素对野百合碱(MCT)诱导的肺动脉高压大鼠的治疗效果。方法:30只成年雄性SD大鼠随机分成3组:MCT诱导的肺动脉高压组(MCT组)、治疗组和对照组。MCT组和治疗组一次性皮下注射MCT 50mg/kg,饲养21d;对照组一次性皮下注射等量0.9%氯化钠溶液,饲养21d。造模后治疗组以槲皮素100mg.kg-1.d-1灌胃20d;MCT组和对照组以0.9%氯化钠溶液2ml/d灌胃20d。20d后,测定3组大鼠平均肺动脉压(mPAP),计算右心室肥大指数(RVHI);光镜下观察大鼠肺组织形态学的改变及肺血管增殖细胞核抗原(PCNA)增殖度的变化,并计算肺中、小动脉管壁厚度占血管外径的百分比(WT%)和肺动脉管壁面积/管总面积的百分比(WA%)。结果:MCT组的mPAP、RVHI、肺中、小动脉WT%、WA%及PCNA增殖度均显著高于对照组及治疗组。结论:槲皮素可降低MCT所致的大鼠肺血管PCNA表达,抑制MCT诱导的肺部炎症、肺血管重建和肺动脉高压形成,对MCT所致的大鼠肺动脉高压具有治疗作用。     

改良心导管测定大鼠肺血管阻力的方法

目的 建立一种简单、可重复性强的测定正常及肺动脉高压大鼠肺血管阻力的方法.方法 雄性Sprague-Dawley( 180 ～ 200 g)大鼠45只,随机分为3组:正常对照组、低剂量野百合碱组(50 mg/kg)和高剂量野百合碱组(60 mg/kg).给予大鼠颈背部皮下一次性注射野百合碱建立肺动脉高压大鼠模型.大鼠肺动脉压力采用自制改良的末端呈圆弧形的PE- 50导管行右心导管法测定.心输出量利用热稀释法原理检测.肺血管阻力由平均肺动脉压力除心输出量得出.结果 三组大鼠肺动脉压力、心输出量及肺血管阻力的检测总成功率均分别为98％、100％和96％,组间差异无统计学意义.注射野百合碱21 d后,低、高剂量野百合碱组大鼠的平均肺动脉压均显著高于对照组[(43.1±0.8)mm Hg(1 mm Hg=0.133 kPa)、(54.8±2.2) mm Hg比(17.4±1.0) mm Hg,P均＜0.001],且高剂量组明显高于低剂量组(P＜0.001).低、高剂量野百合碱组大鼠心输出量均明显低于对照组[(77.5±6.9) ml/min、(71.0+6.7)ml/min比(126.8±3.9) ml/min,P均＜0.001],低、高剂量组间差异无统计学意义.低、高剂量野百合碱组大鼠肺血管阻力均显著高于对照组[(0.56±0.06) mm Hg·min-1·ml-1、(0.76±0.08)mm Hg·min-1·ml-1比(0.13±0.01)mm Hg- min-1·ml-1,P均＜0.001],且高剂量组明显高于低剂量组(P=0.01).结论 采用此方法检测大鼠肺血管阻力准确、可靠、操作性强,具有推广价值.     

The synergistic therapeutic effect of hepatocyte growth factor and granulocyte colony-stimulating factor on pulmonary hypertension in rats

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure and vascular resistance. Despite advances in therapy for PAH, its treatment and prognosis remain poor. We aimed to investigate whether the transplantation of bone marrow mesenchymal stem cells (MSCs) overexpressing hepatocyte growth factor (HGF), alone or in combination with granulocyte colony-stimulating factor (G-CSF), attenuates the development of experimental monocrotaline (MCT)-induced PAH. Three weeks after MCT administration, rats were divided into the following groups: (1) untreated (PAH); (2) HGF treated; (3) MSCs administered; (4) HGF-MSCs treated; and (5) HGF-MSCs plus G-CSF treated. After 3 weeks, hemodynamic changes, histomorphology, and angiogenesis were evaluated. To elucidate the molecular mechanisms of vascular remodeling and angiogenesis, serum levels of transforming growth factor (TGF)-β and endothelin-1 (ET-1) were measured, and the gene and protein expression levels of vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinase-9 (MMP-9) were determined. Compared with the PAH, MSC, and G-CSF groups, the HGF and HGF+G-CSF groups exhibited significantly reduced right ventricular hypertrophy and mean pulmonary arterial pressure (P < 0.05). Histologically, vessel muscularization or thickening and collagen deposition were also significantly decreased (P < 0.05). The number of vessels in the HGF+G-CSF group was higher than that in the other groups (P < 0.05). The TGF-β and ET-1 concentrations in the plasma of pulmonary hypertensive rats were markedly lower in the HGF and HGF+G-CSF groups (P < 0.05). Furthermore, HGF induced the expression of VCAM-1, and HGF treatment together with G-CSF synergistically stimulated MMP-9 expression. Transplanted HGF-MSCs combined with G-CSF potentially offer synergistic therapeutic benefit for the treatment of PAH.     

槲皮素对肺动脉高压大鼠肺组织细胞凋亡的影响

目的:观察槲皮素对肺动脉高压肺组织细胞凋亡的影响。方法:将成年雄性SD大鼠30只,随机分为三组:正常对照组(对照组)、野百合碱(MCT)诱导的肺动脉高压组(MCT组)和槲皮素预防组(预防组),每组10只。MCT组及预防组给予野百碱造模,对照组仅以等量0.9%氯化钠液注射,预防组在造模同时每天给予槲皮素100mg/(kg.d)灌胃,21d后测肺动脉压力并计算右心肥大指数,肺组织切片用免疫组化法和免疫印迹法观察大鼠肺组织细胞凋亡(Bcl-2)情况。结果:MCT组大鼠肺动脉平均压力[MCT组(42.13±6.28)vs.对照组(14.57±1.59),P0.05;MCT组(42.13±6.28)vs.预防组(20.32±3.85),P0.05]、右心肥大指数[MCT组(0.593±0.100)vs.对照组(0.241士0.050),P0.05;MCT组(0.593±0.100)vs.预防组(0.290±0.065),P0.05]、肺组织细胞的Bcl-2蛋白相对表达量[MCT组(0.964±0.009)vs.对照组(0.684±0.014),P0.05;MCT组(0.964士0.009)vs.预防组(0.849±0.009),P0.05]显著高于对照组及预防组;同时预防组大鼠肺动脉压力[预防组(20.32士3.85)vs.对照组(14.57±1.59),P0.05]、右心肥大指数[预防组(0.290±0.065)vs.对照组(0.241±0.050),P0.05]、肺组织细胞的Bcl-2蛋白相对表达量[预防组(0.849±0.009)vs.对照组(0.684士0.014),P0.05]高于对照组。结论:槲皮素具有减缓MCT诱导肺动脉高压大鼠肺组织细胞凋亡的作用。     

辛伐他汀抑制肺动脉高压大鼠肺动脉内COX-2的表达

目的: 探讨3-羟基-3-甲基戊二酰辅酶A还原酶（HMG-COA）抑制剂辛伐他汀对肺动脉高压（PAH）大鼠环氧合酶（COX-2）的影响。方法: 雄性SD大鼠30只,随机分为正常对照组、PAH模型组和辛伐他汀干预组,每组10只。用PM-8000型多参数监护仪及Elastin Van Gieson染色法,分别测定各组大鼠的平均肺动脉压力及肺小动脉新生内膜增殖度和平均血管阻塞计分（VOS）的改变。用免疫组化染色法和荧光定量PCR法,测定肺组织中的COX-2在蛋白和基因的水平上表达的差异。结果: PAH模型组大鼠的平均肺动脉压力、肺小动脉新生内膜增殖度和VOS的改变,均较正常对照组显著增加（P<0.05）,其COX-2在蛋白和基因的水平上的表达都明显高于正常对照组（P<0.05）。辛伐他汀干预后,大鼠的平均肺动脉压力、肺小动脉新生内膜增殖度和VOS,均较PAH模型组显著减少（P<0.05）,COX-2在蛋白和基因的水平上的表达都明显低于PAH模型组（P<0.05）。结论: 辛伐他汀可抑制肺动脉内COX-2的表达来抑制PAH形成。     

辛伐他汀对野百合碱诱导肺动脉高压大鼠Rho／Rock的影响

目的观察辛伐他汀在野百合碱（MCT）诱导的肺动脉高压（PAH）大鼠模型中对Rh0／Rock表达的影响,探讨辛伐他汀改善MCT所致PAH的机制。方法雄性SD大鼠30只随机均分为对照组、MCT模型组和辛伐他汀干预组（SS组）。测量各组大鼠干预后平均肺动脉压力（mPAP）、右心室肥厚指数（RVHI）;观测大体的组织形态病理改变,采用免疫组化和Westernblot检测肺组织中的PCNA、α-SMA、Rho／Rock的表达。结果与对照组及干预组相比,MCT组的mPAP及RVHI显著增加（P〈0．05）,PCNA、α—SMA、Rho／Rock的表达显著增多（P〈0．05）;与对照组相比,SS组的mPAP及RVHI差异无统计学意义（P〉0．05）;而PCNA、α—SMA、Rho／Rock的表达显著增多（P〈0．05）。结论辛伐他汀可有效减轻MCT诱导的PAH大鼠肺动脉压力,其机翩可能与辛伐他汀通过Rho／Rock信号通路改善肺动脉平滑肌增生重构有关。     

花生四烯酸细胞色素p450表氧化酶基因对野百合碱诱导的肺动脉高压大鼠IL-6,IL-8的影响

目的观察花生四烯酸色素p450表氧化酶基因CYP2J2过表达对野百合碱（MCT）诱导的肺动脉高压大鼠炎症细胞因子IL-6、IL-8、CRP和TNF-α表达的影响,探讨CYP2J2作用于肺动脉高压的机制。方法 ：选取8周龄250-280gSD大鼠60只随机分为正常对照组（n=30）和模型组（MCT组）（n=30）,模型组注射野百合碱（60mg/kg）造模。三周后分为6组：NS组（n=10）,pCDNA3.1（n=10）,pCDNA3.1-CYP2J2（n=10）,MCT＋NS（n=10）,MCT＋pCDNA3.1（n=10）,MCT＋pCDNA3.1-CYP2J2（n=10）,注射质粒三周后,检测大鼠平均肺动脉压（mPAP）,计算右心肥大指数（RVHl=RV/LV＋S）。ELISA法检测大鼠血清中IL-6、IL-8、CRP和TNF-α水平。RT-PCR检测大鼠肺组织中IL-6和IL-8的mRNA表达。结果 ：模型对照组mPAP、RVHI值、血清IL-6、IL-8、CRP和TNF-α水平及肺组织中IL-6和IL-8的mRNA表达均显著增高,与正常对照组相比有显著性差异（P〈0.01）;pCDNA3.1-CYP2J2治疗组mPAP、RVHI值、血清IL-6、IL-8、CRP和TNF-α水平及肺组织中IL-6和IL-8的mRNA表达均明显下调（P〈0.05）,但仍高于正常对照组（P〈0.05）。结论花生四烯酸色素p450表氧化酶基因可通过抑制MCT诱导大鼠肺动脉高压模型中肺组织炎性细胞因子的表达、下调大鼠炎性细胞因子的分泌达到对肺动脉高压的治疗作用。