皮肤溃疡中血小板源性生长因子及其受体基因表达的变化

目的:观察血小板源性生长因子(PDGF)两亚基(PDGF-A和PDGF-B)和两种受体(PDGFR-α和PDGFR-β)在正常皮肤和溃疡组织中基因表达和蛋白含量变化的规律,探讨其与溃疡形成的关系.方法:收集8例难愈性皮肤溃疡患者的溃疡组织和正常皮肤组织,提取各组织的总RNA后,分离mRNA,用逆转录-多聚酶链反应(RT-PCR)方法检测PDGF-A、PDGF-B、PDGFR-α和PDGFR-β基因在不同组织中的表达量.结果:在正常皮肤组织内,PDGFR-α和PDGFR-β的基因表达较强,分别为(12.1±2.6)%和(13.8±4.6)%,而在溃疡组织中这两种受体的基因表达水平显著降低,分别为(5.0±1.2)%和(4.7±1.7)%,差异均有显著性(P均＜0.05).溃疡组织中PDGFR-α和PDGFR-β的基因表达量分别是正常皮肤的41.3%和34.1%;而PDGF-A和PDGF-B基因表达水平在正常皮肤和溃疡组织内差异不显著(P均＞0.05).结论:溃疡创面难愈性修复可能与PDGFR-α和PDGFR-β基因表达水平下降,引起PDGF与受体结合发生障碍相关.     

大鼠野百合碱肺高压模型基质金属蛋白酶-1、基质金属蛋白酶-9 mRNA的表达

目的 观察基质金属蛋白酶(MMP)-1、-9在大鼠野百合碱肺高压模型中的表达.方法 SD大鼠24只,随机分为野百合碱注射组(MCT)和对照组(Con).MCT组给予野百合碱60 mg/kg单次右侧皮下注射.饲养6周后,采集肺组织样本进行肺小动脉形态学测量,原位杂交和逆转录-聚合酶链反应(RT-PCR)检测.结果 MCT组肺小动脉横断面的厚度指数(TI)及面积指数(AI)的均值都高于Con组(TI:0.41±0.13比0.13 ±0.07,P＜0.05;AI:0.64±0.15比0.23 ±0.11,P＜0.05).MMP-1、-9主要分布于肺小动脉内皮细胞和外膜成纤维细胞,MCT组肺组织中MMP-1、-9mRNA转录水平高于对照组(0.72±0.13比0.28±0.01,P＜0.05;0.85±0.15比0.39±0.12,P＜0.05).结论 MMP-1、-9活性表达的增强,参与了肺高压肺血管重构的机制.     

下肢动脉硬化闭塞症血管壁炎性因子的表达

目的 定量分析下肢动脉核因子(NF)-κB和血小板源性生长因子(PDGF)的表达,探讨其在下肢动脉硬化闭塞症患者血管壁的表达及相互关系.方法 对病例组19例终末期动脉硬化的下肢动脉和对照组3例正常下肢动脉NF-κB和PDGF的表达进行实时定量聚合酶链反应(RT-qPCR)分析.结果 病例组患者动脉壁NF-κB(35.42±5.69)和PDGF-A(34.38±5.80)、PDGF-B(33.95±5.92) mRNA的相对表达量均高于对照组(P＜0.05),且NF-κB与PDGF-A(r=0.926)和NF-κB与PDGF-B(r=0.925)之间均存在线性正相关(P＜0.05).结论 下肢动脉硬化闭塞症患者血管壁存在NF-κB和PDGF高表达,并且两者表达相关.     

急性放射性皮肤溃疡中血小板源性生长因子及其受体的表达

目的观察不同创面血小板源性生长因子(PDGF)A及其受体(PDGFR)α的动态表达,探讨急性放射性皮肤溃疡难愈合的机制。方法应用γ射线单次照射Wistar大鼠,制作急性放射性皮肤溃疡模型(照射组,55只),以皮肤全层切割伤模型大鼠作为创伤对照(创伤组,55只),另取5只正常大鼠作为对照组。采用免疫组织化学及原位逆转录-聚合酶链反应(RT-PCR)等方法,观察不同时相点各组大鼠创面内PDGF-A、PDGFR-α和PDGF-AmRNA的表达。结果对照组大鼠皮肤中PDGF-A及PDGFR-α表达为阴性;创伤组大鼠炎症反应期及肉芽组织期(伤后3~9d)PDGF-A的积分吸光度(IA)值为20.0±1.6、28.3±1.0;照射组炎症反应期及肉芽组织期(伤后14~28d)其PDGF-A的IA值各为14.0±1.2、20.3±1.2,PDGF-A及PDGFR-α和PDGF-AmRNA的表达较创伤组明显减弱,至瘢痕形成期(伤后55d)时表达进一步减弱。结论急性放射性皮肤溃疡内PDGF-A及PDGFR-α的表达减弱,可能是创面难愈合的机制之一。     

人体退变椎间盘中PDGF-A、PDGFR-α的表达及生物学意义

目的 观察人体退变椎间盘组织中血小板源性生长因子-A(PDGF-A)、血小板源性生长因子受体-α(PDGFR-α)的表达,探讨其生物学意义.方法 免疫组化(S-P)法分别检测PDGF-A、PDGFR-α、增殖细胞核抗原(PCNA)在正常对照组(A组,n=17)、退变椎间盘组(B组,n=51)中的表达;TUNEL法检测两...     

转移生长因子-β、碱性成纤维细胞生长因子诱导人成骨细胞表达血小板衍生生长因子BmRNA的研究

目的　探讨转移生长因子（TGF）-β、碱性成纤维细胞生长因子（bFGF）对人成骨细胞血小板衍生生长因子（PDGF）-B mRNA表达的影响及其意义。方法　体外分离培养人成骨细胞。在体外培养的成骨细胞中分别加入10、20、40、80、160 μg/L梯度浓度的PDGF-BB培养细胞24 h,以摄取3H-TdR为细胞增殖指标检测细胞增殖状况。以4 μg /L的TGF-β和10 μg/L的bFGF培养细胞24 h,寡核苷酸探针检测细胞PDGF-B mRNA的表达。 结果　10～160 μg/L的PDGF-BB可促进成骨细胞增殖（P＜0.05）。在普通培养条件下,细胞不表达PDGF-B mRNA;当培养体系中加入TGF-β和bFGF,可见PDGF-B mRNA的表达。 结论　PDGF-B基因的表达可能是骨组织生长的储备因素,TGF-β和bFGF可诱导成骨细胞表达PDGF-BB。     

血小板源性生长因子在肾脏疾病的研究进展

血小板源性生长因子(Platelet-derived growth factor,PDGF)系统,包含4个亚型(PDGF-A、B、C、D)和2个受体PDGFR-α、β.PDGF在绝大多数肾脏细胞都有表达,调节众多病理生理事件,如促进细胞DNA合成;诱导细胞进行有丝分裂;促进多种细胞外基质的积聚;产生抗炎因子和炎症介质前体;提高组织渗透性;调节血流动力学等.几乎只要有PDGF组成表达发生改变就会导致人类肾脏疾病.对PDGF的组成、信号转导、在肾脏的分布及表达、与肾脏疾病的关系等的研究具有重要意义.     

血小板源性生长因子在肾脏疾病的研究进展

血小板源性生长因子(Platelet-derived growth factor,PDGF)系统,包含4个亚型(PDGF-A、B、C、D)和2个受体PDGFR-α、β.PDGF在绝大多数肾脏细胞都有表达,调节众多病理生理事件,如促进细胞DNA合成;诱导细胞进行有丝分裂;促进多种细胞外基质的积聚;产生抗炎因子和炎症介质前体;提高组织渗透性;调节血流动力学等.几乎只要有PDGF组成表达发生改变就会导致人类肾脏疾病.对PDGF的组成、信号转导、在肾脏的分布及表达、与肾脏疾病的关系等的研究具有重要意义.     

血小板源性生长因子在肾脏疾病的研究进展

血小板源性生长因子(Platelet-derived growth factor,PDGF)系统,包含4个亚型(PDGF-A、B、C、D)和2个受体PDGFR-α、β.PDGF在绝大多数肾脏细胞都有表达,调节众多病理生理事件,如促进细胞DNA合成;诱导细胞进行有丝分裂;促进多种细胞外基质的积聚;产生抗炎因子和炎症介质前体;提高组织渗透性;调节血流动力学等.几乎只要有PDGF组成表达发生改变就会导致人类肾脏疾病.对PDGF的组成、信号转导、在肾脏的分布及表达、与肾脏疾病的关系等的研究具有重要意义.     

肺动脉高压大鼠肺组织肝细胞生长因子和c-met表达的变化

目的 观察肺动脉高压大鼠肺内肝细胞生长因子(HGF)及其受体(c-met)表达的变化.方法 雄性SD大鼠80只,7周龄,体重180～250 g,采用随机数字表法,将其随机分为2组(n=40):对照组(C组)和肺动脉高压组(PH组).PH组经左侧开胸行左肺切除术,手术结束后关胸,待自主呼吸恢复后拔除气管导管,2周后颈部皮下注射野百合碱60 mg/kg,制备肺动脉高压模型;C组仅开胸,2周后颈部皮下注射等容量生理盐水.分别于注射野百合碱前1 d(基础值)、注射野百合碱后7、14、21和28 d时,各取8只大鼠,监测肺动脉压(mPAP),计算右心室与左心室+室间隔质量比[RV/( LV+S)],计算肌型肺小动脉血管中膜相对厚度(RWT1和RWT分别表示直径为50～100 μm和100-150μm的血管中膜相对厚度).采用RT-PCR法检测肺组织HGF mRNA和c-met mRNA的表达,采用Western blot法检测肺组织HGF蛋白和c-met蛋白的表达,采用ELISA法检测肺组织转化生长因子-β(TGF-β)含量.结果 与C组比较,PH组注射野百合碱后14、21和28 d时mPAP、RV/ (LV+S)和RWT2升高,HGF蛋白表达下调,注射野百合碱后7、14、21和28 d时RWT1升高,肺组织HGF mRNA表达下调,TGF-β含量升高(P＜0.01),c-met mRNA及其蛋白表达差异无统计学意义(P＞0.05).结论 肺组织HGF合成不足可能参与了肺动脉高压的形成,其机制与肺组织TGF-β含量升高有关.     

二氯乙酸盐对肺动脉高压大鼠肺组织KV1.5表达的影响

目的 探讨二氯乙酸盐对肺动脉高压大鼠肺组织Kv1.5表达的影响.方法 雄性SD大鼠32只,8周龄,体重200～250 g,采用随机数字表法,将大鼠随机分为4组(n=8):正常对照组(C组)、二氯乙酸盐对照组(D组)、肺动脉高压组(PAH组)和二氯乙酸盐治疗组(PD组).采用左肺切除术联合皮下注射野百合碱60mg/kg的方法制备肺动脉高压模型.PD组于皮下注射野百合碱后,给予二氯乙酸盐80mg/kg灌胃,1次/d,连续28 d,PAH组给予等量生理盐水;D组不制备模型,给予相同剂量二氯乙酸盐灌胃.于皮下注射野百合碱后28 d时测定肺动脉压(PAP),随后处死,取肺组织,计算肺小动脉中膜厚度百分比和右心室肥厚指数,采用Western blot法检测增殖细胞核抗原(PCNA)和Kv1.5蛋白的表达水平,采用RT-PCR法检测Kv1.5 mRNA的表达水平.结果 与C组比较,PAH组和PD组PAP、中膜厚度百分比及右心室肥厚指数升高,肺组织Kv1.5 mRNA及其蛋白表达下调,PCNA表达上调(P＜0.05),D组上述指标差异无统计学意义(P＞0.05);与PAH组比较,PD组PAP、中膜厚度百分比及右心室肥厚指数降低,肺组织Kv1.5mRNA及其蛋白表达上调,PCNA表达下调(P＜0.05).结论 二氯乙酸盐减轻大鼠肺动脉高压与上调肺组织Kv1.5表达,抑制肺血管重构有关.

Abstract：

Objective To investigate the effect of dichloroacetate on the expression of Kv1.5 in a rat model of pulmonary arterial hypertension (PAH) .Methods Thirty-two male SD rats weighing 200-250 g were randomly divided into 4 groups ( n = 8 each): normal control group (group C), dichloroacetate control group (group D),PAH group, and PAH + dichloroacetate group (group PD). PAH was induced by left lung resection combined with subcutaneous injection of monocrotaline 60 mg/kg in PAH and PD groups. In group PD, dichloroacetate 80 mg/kg was given through a gastric tube into stomach once a day for 28 consecutive days after monocrotaline injection,while the equal volume of normal saline was given instead of dichloroacetate in group PAH. Group D only received dichloroacetate 80 mg/kg through a gastric tube into stomach once a day for 28 consecutive days. Pulmonary arterial pressure (PAP) was measured at day 28 after monocrotaline injection. The rats were then sacrificed and lung tissues were removed to calculate the percentage of thickness of the tunica media of pulmonary artery and right venicular hypertrophy index and to determine the proliferating cell nuclear antigen (PCNA) and Kv1.5 protein expression (by Western blot) and Kv1.5 mRNA expression (by RT-PCR).Results Compared with group C, the PAP,percentage of thickness of the tunica media, right ventricular hypertrophy index were significantly increased, Kv1.5 mRNA and protein expression was down-regulated and PCNA expression was up-regulated in groups PAH and PD ( P ＜ 0.05). Compared with group PAH, the PAP, percentage of thickness of the tunica media, right ventricular hypertrophy index were significantly decreased, Kv1.5 mRNA and protein expression was up-regulated and PCNA expression was down-regulated in group PD (P ＜ 0.05). There was no significant difference in the indexes mentioned above between group C and group D ( P ＞ 0.05). Conclusion Dichloroacetat alleviates PAH through upregulating Kv1.5 expression in lung tissues and inhibiting pulmonary vascular remodeling in rats.     

两种大鼠肺动脉高压模型肺血管重塑的血流动力学、组织学和体视学指标变化

目的 构建大鼠颈动静脉分流型(CA-JV)和野百合碱诱导型(MCT)肺动脉高压模型,观察两种肺动脉高压模型肺血管重塑的血流动力学、组织学和体视学指标改变.方法 36只Spargue-Dawley大鼠,对照组、CA-JV和MCT肺动脉高压模型各12只,MCT组6周,其余两组12周后测定右心室收缩压(RVSP),并取左下肺组织测定肺小动脉横截面厚度指数(TI)和面积指数(AI)以及肺小动脉纤维比例.结果 大鼠分流型与药物型肺动脉高压模型中RVSP(37.69±3.00、43.99±4.60)、TI(0.43±0.16、0.41±0.13)和AI(0.65±0.19、0.64±0.15)和肺小动脉纤维比例(33.59±7.58、30.33±7.24)均较对照组均显著升高,药物型模型RVSP升高更明显(P<0.05),分流型模型肺小动脉纤维比例更高(P<0.05).结论 两种肺动脉高压模型均可以造成大鼠血流动力学变化和肺血管结构改变,不同模型肺血管重塑存在不同特点.     

盐酸戊乙奎醚对野百合碱致大鼠肺动脉高压的抑制作用

目的探讨盐酸戊乙奎醚是否能够减缓野百合碱导致的大鼠肺动脉高压及是否能够预防或缓解肺血管重构。方法 3~4周龄健康雄性SD大鼠30只,体重90~100g,随机均分为正常对照组(C组)、野百合碱肺高压组(M组)、盐酸戊乙奎醚组(P组),每组10只。M组和P组腹腔注射野百合碱60mg/kg建造大鼠肺动脉高压模型,C组腹腔注射等容量生理盐水。P组大鼠于建模前15min时腹腔注射盐酸戊乙奎醚2mg/kg,建模第2天腹腔注射盐酸戊乙奎醚1mg/kg,C组和M组在相应时点腹腔注射等容量生理盐水,连续使用3周。在建模后第21天,三组大鼠检测血流动力学(肺动脉压、右心室压);处死大鼠前采集静脉血以备血液生化检测:ELISA法检测一氧化氮(NO)含量、内皮素-1(ET-1)含量。处死大鼠后留取左肺组织行病理切片以观察肺组织病理形态学变化,取右肺组织于-80℃冻存以备后续检测。结果 M组和P组右心室SBP、平均肺动脉压、肺动脉SBP和肺动脉DBP明显高于C组(P0.05);P组右心室SBP、平均肺动脉压、肺动脉SBP和肺动脉DBP明显低于M组(P0.05)。M组肺小动脉明显增厚,肺小动脉管腔狭窄甚至闭塞,肺组织炎性细胞浸润非常明显。P组肺小动脉壁增厚减轻,肺组织炎性细胞浸润减轻。M组大鼠血清中NO含量明显低于,ET-1的含量明显高于C组(P0.05);P组大鼠血清中NO含量明显高于M组和C组(P0.05),ET-1含量明显高于C组,但明显低于M组(P0.05)。结论使用野百合碱成功建造了大鼠肺动脉高压模型,NO含量降低、ET-1含量增加可能与野百合碱致大鼠肺动脉高压的形成有关;盐酸戊乙奎醚减缓野百合碱致大鼠肺动脉高压模型的肺动脉压力的升高、改善肺小动脉壁增厚可能与增加NO含量、降低ET-1含量有关。     

风湿性心脏病二尖瓣狭窄合并肺动脉高压者血管力学特性的变化

目的　探讨风湿性心脏病(风心病)二尖瓣病变合并肺动脉高压(肺高压)的肺血管力学特性的变化规律。方法　借助右心导管技术和利用压力波形面积确定动脉顺应性的改进方法,测定肺血流动力学和肺血管顺应性。结果　①二尖瓣狭窄(MS)为主合并肺高压组的肺动脉血管零压(C     

不同数目骨髓间充质干细胞移植对大鼠肺动脉高压的作用及内皮素-1表达的影响

目的探讨不同数目骨髓间充质干细胞(mesenchymal stem cells,MSCs)移植对野百合碱(MCT)诱导大鼠肺动脉高压的治疗作用,以及对内皮素-1(endothelin-1,ET-1)表达的影响。方法成年雄性Wistar大鼠40只(体重180～250 g),按随机数字表法分为4组,每组10只。A组:大鼠腹腔注射MCT 60 mg/kg,经颈外静脉注入1×106MSCs;B组:大鼠腹腔注射MCT 60 mg/kg,经颈外静脉注入5×105MSCs;MCT组:大鼠腹腔注射MCT60 mg/kg和等量磷酸盐缓冲液(PBS);对照组:大鼠腹腔注入等量生理盐水和等量PBS。MSCs移植4周后测定右心室收缩压(RVSP),计算心室比,即右心室/(左心室+室间隔)[RV/(LV+VS)];观察肺组织形态学改变;检测肺组织ET-1基因表达和血清ET-1的含量。结果 MSCs移植4周后,A组RVSP和RV/(LV+VS)与MCT组比较明显降低[(35.8±4.2)mm Hg vs.(47.2±10.1)mm Hg,P<0.01;(0.357±0.032)vs.(0.452±0.056),P<0.01];而B组与MCT组比较差异无统计学意义(P>0.05)。A组肺小动脉中膜厚度较MCT组明显变薄[(19.7%±3.0%)vs.(26.8%±3.6%),P<0.01];而B组则差异无统计学意义。逆转录酶-聚合酶链反应(RTase-PCR)检测结果显示,MCT组肺组织ET-1 mRNA表达最强,A组肺组织ET-1 mRNA与MCT组比较明显减弱,B组表达与MCT组接近。A组血清ET-1含量与MCT组比较明显减少。结论 MSCs静脉移植对MCT诱导的肺动脉高压具有抑制作用,并能减少肺组织ET-1的mRNA表达及血清ET-1浓度。采用1×106MSCs移植具有较好的治疗作用。     

法舒地尔对肺血管重构的肺动脉高压大鼠的影响

目的 观察法舒地尔对发生肺血管重构的肺动脉高压(PAH)大鼠的影响.方法 将32只雄性Wistar大鼠随机均分为4组:对照3周组,模型3、6周组及治疗组;予野百合碱建模;治疗组于3周后予法舒地尔腹腔内注射.于3、6周末测定各组大鼠右心室收缩压(RVSP)、内皮素-1(ET-1)、N端脑钠素前体(NT-proBNP)、肺小动脉病理等.结果 (1)造模后RVSP随时间升高(31.2±7.6)、(43.3±8.3)、(56.9±6.9)mm Hg(1 mm Hg=0.133 kPa),治疗组(47.3±6.3)mmHg较模型6周组明显降低.(2)ET-1、NT-proBNP与RVSP呈正相关(r=0.721、0.454).(3)病理:造模后肺动脉平滑肌增生,管壁狭窄,至6周时近于闭塞,治疗组则明显好转.结论 对于已发生肺血管重构的PAH大鼠,法舒地尔能阻止肺动脉高压进展,ET-1、NT-proBNP可成为较理想的评估指标.

Abstract：

Objective To investigate the effects of Rho kinase inhibitor fasudil on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) with vascular remodeling in rats. Methods Thirty-two male Wistar rats were randomly and equally divided into control group ( C3 ), MCT-PAH 3- and 6-week model groups (H3, H6 ) and fasudil-treated group (F6). The right ventricle systolic pressure( RVSP), right ventricle/left ventricle and septum[RV/( LV + S)], plasma endothelin-1 and NT-proBNP were measured; small pulmonary arterial morphometry, ratio of vascular wall thickness to vascular external diameter (WT) and ratio of vascular wall area to the total area (WA) were also observed. Results ( 1 )The RVSP was highest in H6 group, followed by F6 group, H3 group, and C3 group[(56. 9 ±6. 9), (47. 3±6.3), (43.3±8.3) and (31.2±7.6) mm Hg (1 mm Hg=0. 133 kPa)]. But no significant difference was found between H3 and F6 groups; (2) The levels of plasma ET-1 and NT-proBNP were positively associated with RVSP, RV/(LV +S), WT and WA (r for ET-1 was 0.721, 0.607, 0.652, 0.707,P＜0.01; r for NT-proBNP was 0. 454, 0. 330, 0. 365, 0. 398,P ＜0. 05); (3) Pathematological assessment showed that the thickness and muscularization of small pulmonary artery were increased in H3 group as compared with C3 group, most significantly in H6 group, and those were significantly decreased in F6 group as compared with H6 group. Conclusion Fasudil can improve the MCT-induced PAH with vascular remodeling in rats. The plasma ET-1 and NT-proBNP could be used as good makers to evaluate the severity of PAH.     

肺动脉灌注抗肿瘤坏死因子-α抗体减轻体外循环的肺损伤

目的 探讨经肺动脉灌注抗肿瘤坏死因子-α抗体（TNF-αAb）对体外循环（CPB）肺损伤的保护作用及机制。 方法 健康新西兰大白兔40只,体重2.0～2.5 kg,雌雄不拘,随机分为4组,每组10只。Ⅰ组：CPB ＋单纯肺动脉灌注液;Ⅱ组：CPB ＋肺动脉灌注TNF-αAb;Ⅲ组：单纯CPB组;Ⅳ组：单纯开胸。测定4组CPB前、后左、右心房血液中性粒细胞计数、肿瘤坏死因子-α （TNF-α）、丙二醛（MDA）含量及氧合指数;取肺组织样本,在光学显微镜和电子显微镜下观察其病理变化和超微结构改变,并动态观察肺组织含水量、TNF-α mRNA表达及凋亡指数变化。 结果 与Ⅳ组比较,CPB后Ⅰ～Ⅲ组血浆中性粒细胞计数、TNF-α、MDA含量、肺组织TNF-α mRNA表达、凋亡指数均显著升高（P＜0.05）;肺组织含水量增加,而氧合指数显著下降（P＜0.05）,肺组织病理形态学发生改变。与Ⅱ组比较,CPB后Ⅰ组、Ⅲ组血浆TNF-α含量显著升高［主动脉开放5 min： （220.43±16.44） pg/ml vs. （185.27±11.78） pg/ml,P＜0.05; （249.99±14.09） pg/ml vs. （185.27±11.78） pg/ml,P＜0.05］,凋亡指数均显著升高（CPB停止即刻：60.7‰±13.09‰ vs. 37.9‰±7.78‰,P＜0.05;59.6‰±7.74‰ vs. 37.9‰±7.78‰,P＜0.05）,血浆中性粒细胞计数、MDA含量、肺组织TNF-α mRNA表达亦显著升高（P＜0.05）,肺组织含水量增加,而氧合指数显著下降（P＜0.05）,肺组织病理形态学改变明显。与Ⅰ组比较,Ⅲ组上述指标仅在CPB30 min显著升高（P＜0.05）,氧合指数显著下降（P＜0.05）。 结论 TNF-αAb经肺动脉灌注可明显抑制CPB期间炎性肺损伤,并减少肺组织细胞凋亡的发生。     

Gene transfer of hepatocyte growth factor with prostacyclin synthase in severe pulmonary hypertension of rats

Objective: Hepatocyte growth factor (HGF) is a multi-potent growth factor, which has anti-fibrotic effects for lung injuries. In this study, we investigated whether human HGF gene transfer may attenuate the medial hypertrophy of pulmonary arteries and enhance the ameliorating effect of prostacyclin in monocrotaline (MCT)-induced pulmonary hypertension in rats. Methods and results: The day before MCT injection, HVJ-liposome complex with the cDNA encoding HGF gene (H group), PGIS gene (P group), and both HGF and PGIS gene (HP group) were transfected to the liver of rats as drug delivery system for the lung. Rats transfected with control vector served as controls (C group). Twenty-eight days after MCT injection, histological examination showed marked thickening of medial wall of pulmonary arteries and right ventricular hypertrophy. Percent medial wall thickness (%WT) of peripheral pulmonary arteries, pressure ratio of the right ventricle (RV) to the left ventricle (LV), and weight ratio of the RV to the LV plus septum were significantly increased in the control. Percent medial wall thickness was significantly ameliorated in H group and HP group in comparison with C group. Pressure and weight ratio of RV to LV was significantly ameliorated in P group and HP group in comparison with C group, and was significantly ameliorated in HP group than P group. Conclusions: In vivo gene transfection with HGF gene attenuated the medial hypertrophy of pulmonary arteries and enhanced the ameliorating effect of prostacyclin for pulmonary hypertension in MCT rats. Thus, gene therapy with HGF and PGIS may be a promising strategy for severe pulmonary hypertension.     

Specific inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates vascular proliferation in monocrotaline-induced pulmonary hypertension in rats

OBJECTIVES: p38 mitogen-activated protein kinase is associated with many clinical entities characterized by inflammation. We postulated that inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates inflammation and the development of pulmonary hypertension in monocrotaline-treated rats. METHODS: Rats were divided into 4 groups: (1) the control group (daily 0.9% saline), (2) the FR group (daily FR167653, 2 mg . kg(-1) . d(-1)), (3) the MCT group (daily 0.9% saline the day after a single monocrotaline dose, 60 mg/kg), and (4) the MCT+FR group (daily FR167653, 2 mg . kg(-1) . d(-1), the day after a single MCT dose). Body weight, pulmonary artery pressure, and morphometric changes of the pulmonary artery with the histopathologic method were observed weekly for 4 weeks. Also, p38 mitogen-activated protein kinase activity and inflammatory cytokine expression in the lung were measured. RESULTS: Four weeks after monocrotaline administration, mean pulmonary artery pressure in the MCT+FR group was lower than in the MCT group (MCT+FR vs MCT: 24.7 +/- 1.9 vs 36.5 +/- 2.1 mm Hg; P < .05). In morphometric analysis the percentage of medial wall thickness and the percentage of muscularization in the MCT+FR group were reduced compared with those in the MCT group after 4 weeks (P < .05); however, the number of macrophages was not significantly different. p38 mitogen-activated protein kinase activity was significantly attenuated in the MCT+FR group compared with in the MCT group (7.2 +/- 0.52 vs 2.1 +/- 0.23 fold-increase, P < .05, at 1 week). Although mRNA levels of tumor necrosis factor alpha and interleukin 1beta were reduced in the MCT+FR group compared with in the MCT group (tumor necrosis factor alpha: 1.18 +/- 0.36 vs 3.05 +/- 1.12 fold-increase, P < .05, at 2 weeks; interleukin 1beta: 2.2 +/- 0.34 vs 4.4 +/- 1.09 fold-increase, P < .05, at 1 week), FR167653 did not suppress increased monocyte chemotactic protein 1 mRNA expression induced by monocrotaline (3.2 +/- 0.62 vs 3.1 +/- 0.42 fold-increase, at 1 week). CONCLUSION: FR167653 significantly attenuates the expression of inflammatory cytokines, ultimately preventing the progression of pulmonary hypertension. These results suggest that p38 mitogen-activated protein kinase might play a central role in the molecular events that underlie the development and progression of pulmonary hypertension.