吗替麦考酚酯对肺动脉高压大鼠血管结构及细胞因子和受体的影响

目的 观察吗替麦考酚酯对野百合碱诱导的肺动脉高压(PAH)大鼠肺动脉压力、碱性成纤维细胞生长因子(bFGF)、内皮素-1及受体的影响。方法 建立野百合碱诱导的PAH大鼠模型。分为4组：正常对照组;野百合碱组;低剂量治疗组;高剂量治疗组,每组各8只。通过Masson染色显示肺泡内动脉血管壁肌化情况;测定收缩期肺动脉压力(SPAP)、右心室肥厚指数(RVI)、血清及肺匀浆中bFGF和受体、肺匀浆中内皮素-1及受体水平,各组间差异采用方差分析及q检验,方差不齐采用秩和检验。结果 ①高、低剂量治疗组与野百合碱组相比,SPAP[(40±13),(53±10)与(68±10) mm Hg]及RVI (0.36±0.06,0.38±0.03与0.44±0.05)均降低(P＜0.05);②高、低剂量治疗组与野百合碱组相比,血清bFGF均降低[(2.3±1.9),(2.7±1.3)与(6.9±5.4) pg/ml,P＜0.05];③高、低剂量治疗组与野百合碱组相比,肺泡内动脉血管壁肌化程度改善及肺小血管中肌性动脉数量减少。结论 吗替麦考酚酯抑制血管肌化、降低SPAP和RVI,其机制可能通过抑制bFGF、内皮素-1及受体的表达抑制平滑肌增殖,从而达到缓解PAH。     

结缔组织病相关肺动脉高压模型的建立

目的 通过成年SD大鼠腹腔一次性注射野百合碱,构建结缔组织病相关肺动脉高压模型方法的可行性.方法 实验组一次性腹腔注入1％野百合碱溶液,剂量为50 mg/kg,对照组腹腔注入同体积2:8无菌乙醇和0.9％氯化钠注射液.2、4周后通过计算机控制多功能生理仪行血流动力学检测,通过肺组织病理学观察异硫氰酸荧光素( FITC).凝集素灌注和抗α.平滑肌肌动蛋白(α-SMA)荧光标记了解肺血管重构情况.2组间比较采用t检验.结果 腹腔注射1％野百合碱溶液4周后,模型动物肺动脉测压[肺动脉收缩压(PASP)(41±6) mm Hg,肺动脉舒张压(PADP)(24.3±3.8) mm Hg,平均肺动脉压(mPAP)(29.8±4.2) mm Hg],与对照组[PASP (23±3) mm Hg;PADP (8.5±2.4) mm Hg;mPAP (17.1±2.5) mm Hg]比较,明显升高(P＜0.05),实验组肺组织病理学检查显示肺小动脉管壁增厚、管腔狭窄,肺小动脉管壁厚度指数(TI) 0.723±0.034和面积指数(AI) 0.912±0.203明显高于对照组(0.314±0.023和0.414±0.021)(P＜0.05).结论 SD大鼠腹腔注射野百合碱4周后,可形成肺动脉高压模型,该模型与临床结缔组织病相关肺动脉高压的病理生理相接近,且稳定、可靠、经济.     

CX3CL1/fractalkine在野百合碱诱导大鼠肺动脉高压中的表达变化

目的 观察CX3CL1/fractalkine(FKN)在野百合碱诱导的肺动脉高压大鼠模型中的变化并探讨其在肺动脉高压发生、发展中的作用.方法 将30只SPF级雄性Sprague-Dawley(SD)大鼠随机分为溶剂对照组(C组)、野百合碱2周组(M2组)和野百合碱3周组(M3组).测量并比较各组肺动脉平均压(mPAP)、右心室平均压(mRVP)、颈动脉平均压(mCAP)、右心室游离壁(RV)和左心室加室间隔(LV+S)重量比.光镜、电镜下分别观察肺细小动脉显微、超微结构变化,测定肺细小动脉管壁面积/管总面积(WA/TA)、肺细小动脉中膜厚度(PAMT)反映肺血管重塑情况,酶联免疫吸附试验测定血浆可溶性FKN(sFKN)浓度,免疫组织化学法测定肺小动脉FKN含量,逆转录聚合酶链反应测定肺组织中FKN mRNA的表达.结果 ①M2组[(20.58±3.54) mm Hg、( 18.14±2.47) mm Hg、(29.83±4.07)％]、M3组[(26.04±5.03) mm Hg、(22.17±5.63) mm Hg、(59.52±12.86) ％] mPAP、mRVP、RV/( LV+S)均显著高于C组[(12.93±1.93) mm Hg、(11.66±1.81) mm Hg、(23.33±2.90)％](P值均＜0.01),反映体循环的mCAP在各组之间差异无统计学意义.M2组[0.74±0.09、(27.36±2.02)μm]、M3组[0.87±0.04、(36.48±3.81)μm] WA/TA和PAMT均较C组[0.45±0.07、(13.91±1.51)μm]显著增高(P值均＜0.01).②M2组血浆sFKN浓度和肺组织FKN mRNA相对含量[(677.76±101.75) ng/L、0.49±0.09]高于C组[(412.09±57.38) ng/L、0.11±0.06],M3组血浆sFKN浓度和肺组织FKNmRNA相对含量[(1078.02±254.05) ng/L、0.64±0.04]高于M2组及C组(P值均＜0.01).③M2组、M3组动脉管壁FKN蛋白(0.192±0.006、0.198±0.019)较C组(0.171±0.010)升高(P值均＜0.01),M2组与M3组之间差异无统计学意义.sFKN与PAMT、RV/( LV+S)呈正相关(r值分别为0.796、0.710,P＜0.01),FKN mRNA与PAMT、RV/(LV+S)呈正相关(r值分别为0.934,0.757,P＜0.01).结论 FKN及其介导的炎症反应在野百合碱诱导的肺动脉高压形成和发展及肺动脉重塑过程中可能起重要作用.     

瑞舒伐他汀对野百合碱诱导大鼠肺动脉高压的干预及机制研究

目的探讨瑞舒伐他汀干预野百合碱诱导大鼠肺动脉高压的作用及可能机制。方法 48只雄性SD大鼠随机分为正常对照组(n=8)和野百合碱组(n=40),正常对照组予皮下注射生理盐水,野百合碱组一次性皮下注射1%野百合碱50mg/kg,4周后再随机分为肺动脉高压组(n=16)、瑞舒伐他汀低剂量组[2mg/(kg·d),n=12]、瑞舒伐他汀高剂量组[10mg/(kg·d),n=12],瑞舒伐他汀低剂量组和高剂量组于野百合碱注射第4周末起每日给予瑞舒伐他汀灌胃,正常对照组、肺动脉高压组仅予生理盐水灌胃,干预4周。观察各组大鼠的一般情况,各组干预结束后测量平均右心室压力(mRVP)、平均肺动脉压力(mPAP)和右心室肥厚指数(RVHI);HE染色观察肺小动脉管壁厚度与血管外径之比(WT%)和管壁面积占血管总面积的百分比(WA%);Western blot法检测骨形成蛋白Ⅱ型受体(BMPR-Ⅱ)、Smad4蛋白在肺动脉中的表达水平。结果瑞舒伐他汀能降低mRVP[瑞舒伐他汀低剂量组(24.58±1.38)、瑞舒伐他汀高剂量组(21.56±3.05)比肺动脉高压组(35.28±2.81)mmHg,均P<0.05],降低mPAP[瑞舒伐他汀低剂量组(30.26±1.57)、瑞舒伐他汀高剂量组(27.88±2.17)比肺动脉高压组(41.23±2.63)mmHg,均P<0.05],减轻肺小动脉管壁厚度(P<0.01)、右心室肥厚程度(均P<0.05),上调肺动脉BMPR-Ⅱ和Smad4蛋白的表达(均P<0.05)。结论瑞舒伐他汀缓解已经形成的肺动脉高压,减轻右心室肥厚,可能是通过上调BMPR-Ⅱ、Smad4蛋白的表达来实现的。     

瑞舒伐他汀干预野百合碱诱导大鼠肺动脉高压的实验研究

目的 探讨他汀类药物改善内皮细胞功能、抗增殖等降脂外作用在防治肺动脉高压中的作用及可能机制.方法 雄性SD大鼠,体重(255.7±12.5)g,皮下注射野百合碱诱导大鼠形成肺动脉高压,肺动脉高压形成前后分别接受瑞舒伐他汀预防和治疗.预防实验:32只SD大鼠随机分为4组,分别为瑞舒伐他汀低剂量(2 mg·kg-1·d-1)预防组(n=8)、瑞舒伐他汀高剂量(10 mg·kg-1·d-1)预防组(n=8)、肺动脉高压4周组(n=8)和正常对照4周组(n=8),野百合碱注射当日起预防组每日予瑞舒伐他汀灌胃至第4周末,正常对照组、肺动脉高压4周组仅予生理盐水灌胃.治疗实验:52只SD大鼠随机分为4组,分别为瑞舒伐他汀低剂量(2 mg·kg-1·d-1)治疗组(n=12)、瑞舒伐他汀高剂量(10 mg·kg-1·d-1)治疗组(n=12)、肺动脉高压8周组(n=20)和正常对照8周组(n=8),野百合碱注射4周后治疗组每日予瑞舒伐他汀灌胃至第8周末,正常对照组、肺动脉高压8周组仅予生理盐水灌胃.比较各组生存率、平均肺动脉压(mPAP)、肺小动脉管壁厚度、右心室肥厚程度,比较肺小动脉增殖细胞核抗原(PCNA)、内皮型一氧化氮合酶(eNOS)蛋白表达水平,比较肺组织Rho激酶1(ROCK-1)、eNOS mRNA表达水平.结果 预防实验大鼠均存活,肺动脉高压形成之后瑞舒伐他汀治疗能改善生存率(瑞舒伐他汀低剂量治疗组、瑞舒伐他汀高剂量治疗组与肺动脉高压8周组比较为58%、75%比30%,P均＜0.05);肺动脉高压形成之前和之后瑞舒伐他汀预防和治疗均能降低mPAP[预防实验:瑞舒伐他汀低剂量预防组、瑞舒伐他汀高剂量预防组与肺动脉高压4周组比较为(27.53±3.43)mm Hg(1 mm Hg=0.133 kPa)、(25.72±1.76)mm Hg比(36.05±2.45)mm Hg,P均＜0.01;治疗实验:瑞舒伐他汀低剂量治疗组、瑞舒伐他汀高剂量治疗组与肺动脉高压8周组比较为(30.39±3.17)mm Hg、(27.59±1.99)mmHg比(40.68±1.39)mm Hg,P均＜0.01],减轻肺小动脉管壁增厚、右心室肥厚程度(P均＜0.01),下调肺小动脉平滑肌细胞PCNA表达(P均＜0.01),上调内皮细胞eNOS表达(P均＜0.05),抑制ROCK-1基因表达(P均＜0.05),有一定的剂量依赖性(P均＜0.05).结论 瑞舒伐他汀防治肺动脉高压可能是通过抑制ROCK-1基因表达,抑制肺动脉平滑肌增殖和恢复内皮细胞功能等机制来实现的.

Abstract：

Objective To investigate the effects of rosuvastatin on monocrotaline (MCT)-induced pulmonary artery hypertension in rats. Methods Pulmonary arterial hypertension was induced by a single subcutaneous injection of monocrotaline (50 mg/kg) in rats. In the prevention protocol, 32 male SpragueDawley rats were randomly divided into four groups ( n = 8 each): low-dose rosuvastatin prevention group (2 mg · kg-1 · d-1 ), high-dose rosuvastatin prevention group ( 10 mg· kg-1 · d-1 ), pulmonary arterial hypertension group, normal control group. Beginning on the MCT injection day, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group received vehicle by garage. In the treatment protocol, 52 male Sprague-Dawley rats were randomly dividedinto four groups (n = 13 each): low-dose rosuvastatin treatment group (2 mg · kg-1 · d-1), high-dose rosuvastatin treatment group( 10 mg · kg-1 · d-1), pulmonary arterial hypertension group, normal control group. Four weeks after MCT injection, rats were treated with rnsuvastatin by daily gavage for 4 weeks.Normal control group and pulmonary arterial hypertension group received vehicle by gavage. At the end of study, survival rates, mean pulmonary arterial pressure (mPAP), wall thickness of small pulmonary artery and right ventricular hypertrophy among groups were compared. The expression levels of proliferating cell nuclear antigen (P CNA) and endothelial nitricoxide synthase (eNOS) protein in small pulmonary artery,the expression levels of Rho kinase 1 ( ROCK-1 ) and eNOS mRNA in lung tissue were also detected. Results All rats in the prevention protocol survived. Rosuvastatin treatment improved survival in the treatment protocol (58%, 75% vs. 30%, P ＜0. 05 ). Rosuvastatin therapy in both preventment or treatment protocols significantly lowered mPAP [prevention protocol: ( 27.53 ± 3.43 ), ( 25.72 ± 1.76 ) vs. ( 36. 05 ± 2. 45 )mm Hg(1 mm Hg =0. 133 kPa), P ＜0.01; treatment protocol: (30. 39 ±3. 17), (27.59 ±1.99) vs.(40. 68 ± 1.39) mm Hg, P ＜0. 01], reduced thickening of small pulmonary artery wall (P ＜0. 01 ) and right ventricular hypertrophy ( P ＜ 0. 01 ). Rosuvastatin also inhibited PCNA expression of SMC ( P ＜0. 01 ), restored eNOS expression of EC ( P ＜ 0. 05) and inhibited ROCK-1 mRNA expressions in lung tissue (P ＜ 0. 05 ). Conclusions Rosuvastatin therapy reduced mPAP in monocrotaline-induced pulmonary arterial hypertension rat model and this effect is linked with inhibition of ROCK-I expression, inhibition of smooth muscle cell proliferation and restoration of endothelial cell functions.     

多廿烷醇对野百合碱诱导的肺动脉高压大鼠肺动脉重构的影响

目的观察多廿烷醇对野百合碱诱导的肺动脉高压(PAH)大鼠的平均肺动脉压(MPAP)与肺动脉重构的影响及可能的机制。方法雄性SD大鼠60只随机数字法分为正常对照组、PAH组、多廿烷醇组,每组20只。野百合碱(40mg/kg)一次性腹腔注射建立大鼠PAH模型,多廿烷醇组以多廿烷醇[10 mg/(kg·d)]灌胃,对照组和PAH组给予等量的生理盐水灌胃4周。肺动脉导管法测定大鼠MPAP;称重法测右心室肥厚指数(RVHI);HE染色观察肺小动脉病理形态改变,测定肺小动脉管壁厚度占血管外径的百分比(WT%)、肺小动脉管壁总面积占血管总面积的百分比(WA%);TUNEL染色法观察肺小动脉内皮细胞凋亡情况;Western blot法测肺组织凋亡相关蛋白Bax、Bcl-2表达;酶联免疫吸附试验测定血清白细胞介素6(IL-6)和肿瘤坏死因子α(TNF-α)水平。结果与正常对照组相比,PAH组MPAP[(33.91±4.72)比(17.57±3.44)mm Hg]、RVHI[(69.25±8.42)%比(24.91±2.82)%]、肺小动脉WT%[(66.53±10.01)%比(32.08±4.98)%]和WA%[(86.52±4.97)%比(52.96±6.65)%]增加(均P0.01);与PAH组相比,多廿烷醇组MPAP[(26.94±6.02)比(33.91±4.72)mm Hg]、RVHI[(55.27±9.89)%比(69.25±8.42)%]、肺小动脉WT%[(41.66±10.47)%比(66.53±10.01)%]和WA%[(64.10±12.80)%比(86.52±4.97)%]减少(均P0.01)。与正常对照组相比,PAH组大鼠肺小动脉内皮细胞凋亡增多,PAH组肺组织凋亡蛋白Bax表达增加,抗凋亡蛋白Bcl-2表达减少,Bax与Bcl-2比值增加;与PAH组相比,多廿烷醇组大鼠肺小动脉内皮细胞凋亡减少,肺组织Bax表达减少,Bcl-2表达增加,Bax与Bcl-2比值减少(均P0.01)。与正常对照组相比,PAH组大鼠血清细胞因子IL-6、TNF-α水平升高;与PAH组相比,多廿烷醇组血清IL-6、TNF-α水平降低(均P0.01)。结论多廿烷醇改善野百合碱诱导的PAH大鼠的MPAP及肺血管重构,可能与其减少细胞凋亡、抑制炎症反应有关。     

脂肪间充质干细胞在野百合碱诱导的肺动脉高压大鼠肺血管内的定植

目的观察移植不同细胞数量的脂肪间充质干细胞(ADMSC)及移植后不同时间内ADMSC在野百合碱诱导的肺动脉高压(PAH)大鼠肺血管内的定植情况。方法实验分两部分:(1)不同时间细胞定植(时效):160只SD大鼠随机分为正常肺动脉压对照组1(Ctrl1)、肺动脉高压组1(PAH1)、正常肺动脉压移植组1(Ctrl1-ADMSC)和肺动脉高压移植组1(PAH1-ADMSC)。PAH1和PAH1-ADMSC腹腔注射野百合碱。Ctrl1-ADMSC和PAH1-ADMSC于野百合碱注射2周后移植1×10~6/mL ADMSC。各组分别于移植1、3、7、14和21d后测定肺动脉平均压(mPAP)。取肺组织切片并予滂胺天空蓝和二脒基苯基吲哚(DAPI)染色,观察ADMSC在肺血管的定植。(2)不同数量细胞移植与定植的关系(量效):80只SD大鼠随机分为正常肺动脉压移植组2(Ctrl2-A)、肺动脉高压移植组2(PAH2-A)。PAH2-A腹腔注射野百合碱。2周后各移植5个不同细胞数量(A0:0、A1:5×10~5、A2:1×10~6、A3:5×10~6、A4:1×10~7/mL)的ADMSC,21d后观察mPAP及ADMSC的定植。结果(1)PAH1-ADMSC中肺血管中定植的ADMSC呈时间依赖性减少[1~21d分别为(12.00±3.29)、(7.00±1.69)、(5.50±1.41)、(4.13±1.25)、(1.75±0.71)个]。与PAH1比较,PAH1-ADMSC的mPAP在移植7d后降低[(23.36±2.47)比(27.37±2.18)mm Hg,P0.05]。(2)PAH2-A中肺血管定植的细胞数呈细胞数量依赖性增加[0、(3.13±1.25)、(7.00±2.00)、(13.25±1.91)、(22.00±8.05)个];对比移植细胞数为0的PAH大鼠,移植(1~5)×10~6时,PAH大鼠的mPAP显著降低[(28.6±3.0)、(26.0±1.7)比(39.8±1.8)mm Hg,P0.05]。结论ADMSC可定植于肺血管内,并降低野百合碱诱导的PAH大鼠的mPAP;最佳移植数为(1~5)×10~6/mL。     

肺小动脉楔入造影对先天性心脏病患儿肺动脉高压的评估价值

目的通过对肺小动脉行肺小动脉楔入造影(PWA),分析PWA对先天性心脏病(CHD)相关肺动脉高压(PAH)的评估价值。方法对50例CHD患儿进行心导管及PWA检查,根据肺动脉压力分为肺动脉压力、阻力正常组[A组,15例,肺平均动脉压(m PAP)≤25 mm Hg(1 mm Hg=0.133 k Pa)、全肺阻力(PVR)300 dyne·s·cm~5],肺动脉压力升高、阻力正常组(B组,24例,m PAP25 mm Hg、PVR300 dyne·s·cm~5),肺动脉压力、阻力均升高组(C组,11例,m PAP25 mm Hg、PVR≥300 dyne·s·cm5)。观察肺小动脉逐渐变细速率(ROT)、肺循环时间(PCT)、肺毛细血管充盈度(BH)与血流动力学指标的相关性。结果 C组肺小动脉ROT显著小于A组[(8.16±2.14)mm比(18.70±2.25)mm]、B组[(8.16±2.14)mm比(13.83±3.45)mm],差异均有统计学意义(P=0.000);B组和C组的ROT与m PAP无相关性,C组ROT与PVR负相关(相关系数r=-0.606,P0.05)。C组PCT指数显著大于A组[(1.50±0.37)s/m~2比(1.08±0.23)s/m~2]、B组[(1.50±0.37)s/m~2比(1.22±0.32)s/m~2],差异均有统计学意义(P0.05);B组和C组PCT指数与m PAP无相关性,C组PCT指数与PVR正相关(相关系数r=0.783,P=0.01)。三组患者毛细血管充盈度比较,差异均有统计学意义(F=23.697,P=0.000),其中B组、C组与A组相比毛细血管充盈度显著减少(P0.05)。结论 PWA能定量评估CHD相关PAH患者的肺血管床。     

盐敏感人群的血流动力学、水盐平衡与钠储存、血管功能障碍相关

正该研究对8名盐敏感和13名盐抵抗正常血压受试者的盐负荷和损耗引起的24h血流动力学变化进行评估。盐负荷后,与盐抵抗组人群比较,盐敏感组受试者由于总外周血管阻力[(1791±148)比(1549±66)dyn/(cm·s),P=0.05]较高,从而平均动脉压[(96.5±2.8)比(84.2±2.7)mm Hg,1 mm Hg=0.133kPa,P0.01]也增高;而两组人群心输出量差异无统计学意义[盐敏感(4.5±0.3)比盐抵抗(4.4±0.2)L/min]。盐损耗后,两组人群心输出量降幅差异无统计学意义,而盐抵抗组总外周血管阻力增     

依那西普在野百合碱诱导的大鼠肺动脉高压模型中作用的初步探讨

目的 应用重组人Ⅱ型肿瘤坏死因子受体抗体融合蛋白——依那西普(ECP)对野百合碱(MCT)诱导的大鼠肺动脉高压(PAH)模型进行干预,观察ECP在该模型中的疗效,并对其机制进行初步探讨.方法 用MCT建立动物模型,并用ECP对模型进行预防干预和治疗干预,分别在建模第2、4周时,通过右心导管技术测量大鼠的肺动脉平均压(mPAP),与模型组比较,判断干预是否有效;并通过肺脏病理组织苏木素-伊红(HE)染色进行肺小动脉血管壁增厚定量测定(R值),及免疫组织化学染色测定肿瘤坏死因子(TNF)-α和白细胞介素(IL)-6的表达量,探讨ECP的干预机制.结果 ECP预防组mPAP(14±6)mm Hg与2周模型组(29±8)mm Hg相比显著降低(P＜0.01),ECP治疗组mPAP(36±22)mmHg与4周模型组(66±28)mm Hg相比有下降趋势;肺脏病理组织HE染色显示ECP预防组测定的R值(0.273±0.019)与2周模型组(0.203±0.039)相比显著增高(P＜0.01),提示肺小血管壁厚度程度减轻;免疫组织化学染色显示野百合碱模型中大鼠肺组织中有大量炎性细胞浸润,并且有大量TNF-α和IL-6的表达,ECP预防组较2周模型组的TNF-α和IL-6染色减少.结论 ECP可降低MCT诱导的大鼠PAH模型的肺动脉压力,其机制与抑制巨噬细胞分泌炎症因子,减轻肺小动脉血管炎症和血管壁增厚程度相关.     

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。     

二尖瓣形态对经皮球囊二尖瓣成形术近远期疗效的影响

目的 观察不同瓣膜形态的二尖瓣狭窄患者行经皮球囊二尖瓣成形术的近远期疗效.方法 根据Wilkins超声二尖瓣形态学积分,将385例二尖瓣狭窄患者分为＞8分组(125例)和≤8分组(260例).均采用改良Inoue法对患者行经皮球囊二尖瓣成形术.术后进行随访,并比较两组患者的临床疗效.结果 经皮球囊二尖瓣成形术成功370例,＞8分组经皮球囊二尖瓣成形术的成功率低于≤8分组(92.8％比97.7％,P＜0.05).术后6个月,两组患者各项超声心动图检查指标均较术前显著改善(均P＜0.05);与≤8分组(254例)比较,＞8分组(116例)经皮球囊二尖瓣成形术后左心房平均压、肺动脉收缩压、跨瓣压差及二尖瓣瓣口面积的改变值均较小[分别为(14.22±5.02)mm Hg(1 mm Hg=0.133 kPa)比(15.44±5.19) mm Hg、(26.13±9.27) mm Hg比(31.93±9.98)mm Hg、(9.21±4.11)mm Hg比(10.16 ±4.21)mm Hg和(1.02±0.15)cm2比(1.20±0.22)cm2,均P＜0.05].经皮球囊二尖瓣成形术成功且完成远期随访[(78±20)个月]的患者共353例,两组患者各项超声心动图检查指标均较术前显著改善(均P＜0.05);与≤8分组(245例)比较,＞8分组(108例)左心房平均压、肺动脉收缩压、跨瓣压差及二尖瓣瓣口面积的改变值均较小[分别为(13.28±5.06) mm Hg比(14.77±5.17)mm Hg、(21.19±9.17) mm Hg比(28.92±9.91) mm Hg、(7.30±4.40)mm Hg比(9.16±4.28)mm Hg和(0.92±0.17)cm2比(1.07±0.20)cm2,均P＜0.05],且再狭窄发生率较高(20.4％比8.2％,P＜0.05).结论 二尖瓣瓣膜形态是决定经皮球囊二尖瓣成形术疗效的关键因素之一.对于超声二尖瓣形态学积分低的患者,经皮球囊二尖瓣成形术成功率较高,术后近期及远期随访疗效较好,再狭窄发生率较低,治疗方案可优先选择经皮球囊二尖瓣成形术.     

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。     

肺动脉高压患者肺功能特点分析

目的 探讨国人肺动脉高压患者肺功能特点及其在肺动脉高压诊断中的价值.方法 连续入选经右心导管确诊的41例肺动脉高压患者为研究对象,所有患者均进行6分钟步行距离试验和肺功能检查,并与健康对照组比较其肺功能变化特点.结果 肺动脉高压组肺总量、肺活量和第1秒用力呼出量百分比对照组明显下降(分别为80.27±11.46和94.24±6.82;79.09±14.89和97.35±9.51;75.40±16.58和95.12±12.01,P＜0.001),残气量与肺总量比值较对照显著升高(分别为117.67±25.73和93.39±10.87,P＜0.001),第1秒用力呼出量与用力肺活量比值百分比与呼气中期流速百分比与对照组分别下降6.O%和19.4%(P=0.21和0.09),一氧化碳弥散量百分比与弥散量/肺泡通气量百分比较对照组分别下降36.6%和29.8%(P＜0.001),呼吸总阻力、总气道阻力和中心气道阻力和与对照组均无明显差异.有12.2%的患者肺功能检查结果完全正常.结论 特发性肺动脉高压、先天性心脏病相关性肺动脉高压和结缔组织病相关性肺动脉高压的肺功能改变相似,"动脉型"肺高压患者不仅可以存在不同程度外周气道阻塞性通气功能障碍,同时可合并弥散功能障碍,而肺阻力无明显变化.肺功能检查正常不能作为排除肺动脉高压的筛查手段.     

Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance caused by narrowing and loss of pulmonary microvasculature, which in its late stages becomes refractory to traditional therapies. We hypothesized that bone marrow-derived endothelial progenitor cells (EPCs), which normally function to repair and regenerate blood vessels, would restore pulmonary hemodynamics and increase microvascular perfusion in the rat monocrotaline (MCT) model of PAH. Mononuclear cells were isolated from the bone marrow of syngeneic Fisher-344 rats by Ficoll gradient centrifugation and cultured for 7 to 10 days in endothelial growth medium. Fluorescently labeled endothelial-like progenitor cells (ELPCs) engrafted at the level of the distal pulmonary arterioles and incorporated into the endothelial lining in the MCT-injured lung. The administration of ELPCs 3 days after MCT nearly completely prevented the increase in right ventricular systolic pressure seen at 3 weeks with MCT alone (31.5+/-0.95 versus 48+/-3 mm Hg, respectively; P<0.001), whereas injection of skin fibroblasts had no protective effect (50.9+/-5.4 mm Hg). Delayed administration of progenitor cells 3 weeks after MCT prevented the further progression of PAH 2 weeks later (ie, 5 weeks after MCT), whereas only animals receiving ELPCs transduced with human endothelial NO-synthase (eNOS) exhibited significant reversal of established disease at day 35 (31+/-2 mm Hg, P<0.005) compared with day 21 (50+/-3 mm Hg). Fluorescent microangiography revealed widespread occlusion of pulmonary precapillary arterioles 3 weeks after MCT, whereas arteriolar-capillary continuity and microvascular architecture was preserved with the administration of syngeneic ELPCs. Moreover, the delivery of ELPCs to rats with established PAH resulted in marked improvement in survival, which was greatest in the group receiving eNOS-transduced cells. We conclude that bone marrow-derived ELPCs can engraft and repair the MCT-damaged lung, restoring microvasculature structure and function. Therefore, the regeneration of lung vascular endothelium by injection of progenitor cells may represent a novel treatment paradigm for patients with PAH.     

心电图对肺动脉高压的诊断价值探讨

目的 参照右心导管检查结果,评价常规12导联心电图在肺动脉高压诊断中的应用价值.方法 入选超声心动图估测肺动脉收缩压≥36 mm Hg(1 mm Hg=0.133 kPa)的64例疑诊肺动脉高压患者为研究对象,右心导管检查前30 min行12导联心电图检查.根据右心导管检查结果排除肺动脉高压者26例,确诊肺动脉高压者38例(特发性肺动脉高压23例,结缔组织病相关性肺动脉高压15例).比较两组间心电图参数差异.通过ROC曲线计算心电图各指标诊断肺动脉高压的敏感性、特异性、阳性预测值及阴性预测值.采用Spearman相关性计算肺动脉高压组心电图参数与血液动力学指标相关性.结果 心电图诊断右心室肥大的各指标在肺动脉高压组中的发生率显著高于排除肺动脉高压组.Ⅰ导联S波振幅＞0.21 mV、QRS电轴＞87°、R_(v1) + S_(v5)＞0.76 mV诊断肺动脉高压的敏感性分别为89%、86%、84%,特异性分别为81%、92%、83%.采用Spearman相关性分析显示,QRS电轴与肺动脉平均压的相关性最高(r=0.75,P＜0.001);R_(v1) + S_(v5)与肺血管阻力的相关性最高(r=0.74,P＜0.001);R_(v1) + S_(v5)和I导联S波振幅与心指数相关性较高(r=-0.62,P＜0.001).结论 常规12导联心电图检查在肺动脉高压筛查中有重要价值,Ⅰ导联S波振幅＞0.21 mV、QRS电轴＞87°、R_(v1) + S_(v5)＞0.76 mV等右心室肥大征象时应考虑到肺动脉高压可能.QRS电轴、R_(v1) + S_(v5)以及Ⅰ导联S波振幅对评估肺动脉高压患者血液动力学受损的严重程度有临床意义.     

老年房间隔缺损患者介入治疗的临床分析

目的 探讨老年房间隔缺损患者的临床特征及行经导管封堵治疗的安全性和有效性.方法 入选2000年5月至2010年6月行经导管封堵治疗的(64.5±3.8)岁房间隔缺损患者82例.经导管封堵术中行右心导管检查.术后1d、1个月、3个月和6个月进行随访.分析老年房间隔缺损患者的临床特征,观察房间隔缺损封堵前后肺动脉压及心功能的改变情况.结果 82例房间隔缺损患者中,合并肺动脉高压37例,发生率为45.1％.封堵前的右心导管检查显示,患者肺动脉收缩压为(44.1±12.4)mm Hg(1 mm Hg=0.133 kPa),肺动脉平均压为(25.2 +6.8)mm Hg.1例重度肺动脉高压患者不适宜经导管封堵治疗,其余81例均成功行介入治疗,无手术相关并发症.36例封堵成功的肺动脉高压患者肺动脉收缩压由术前的(52.7±10.3)mm Hg下降至术后的(31.8 +6.3)mm Hg(P＜0.05),肺动脉平均压由术前的(30.9±4.7) mm Hg下降至术后的(21.8±3.4) mm Hg(P＜0.05).与术前比较,术后1d、1个月、3个月和6个月NYHA心功能分级改善.术后新发心房颤动6例.结论 老年房间隔缺损患者通常合并肺动脉高压.只要严格掌握适应证和规范操作,经导管封堵治疗老年房间隔缺损仍是一种安全有效的方法.