肺血管重塑与低氧性肺动脉高压

肺血管重塑和肺动脉高压密切相关,慢性缺氧是肺血管重塑和肺动脉高压的一个常见原因.肺血管重塑以纤维母细胞、平滑肌细胞和内皮细胞增殖为最大特征,并导致管腔闭塞.了解肺血管重塑特征和机制对于预防或者逆转肺动脉高压具有重要的意义.     

低氧诱导因子-1在低氧性肺动脉高压中的研究进展

低氧性肺动脉高压(HPH)是由缺氧引起的肺动脉压力进行性升高的肺血管疾病。低氧诱导因子-1(HIF-1)是维持细胞氧稳态的核心转录因子,可促进细胞糖代谢模式的转变、调节细胞膜表面离子通道活性、调节肺血管收缩及舒张因子活性等,在HPH的发生和发展中具有重要作用。现对HIF-1及其下游信号分子在HPH发生和发展中的作用机制进行综述,有助于为HPH的治疗提供新的理论依据和治疗靶点。     

肺动脉平滑肌细胞与低氧性肺血管重塑形成机制

低氧条件下肺血管收缩、重塑,继而导致肺血管的持续对抗,其中以中膜增厚为主的肺血管重塑是导致低氧性肺动脉高压持续不可逆性病理改变的重要因素.肺动脉平滑肌细胞是肺动脉中膜的主要构成部分,慢性缺氧条件下由于各种活性介质及细胞生长因子稳态的失衡,肺动脉平滑肌细胞聚集、增殖、肥大及分泌胞外基质;另外,肺动脉平滑肌细胞通过各种信号通路与内膜的内皮细胞及外膜的成纤维细胞相互作用,在低氧性肺血管重塑过程中起着至关重要的作用,本文将对肺动脉平滑肌细胞与低氧性肺血管重塑形成机制的最新研究概况作一综述.     

碱性成纤维细胞生长因子在低氧性肺动脉高压大鼠肺内表达…

OBJECTIVE: To evaluate the role of bFGF in the development of hypoxic pulmonary hypertension. METHOD: Rat models with chronic hypoxia induced pulmonary hypertension were established, the pulmonary hemodynamics were measured and the pulmonary arterioles change were studied with morphometric analysis under light microscopes, immunohistochemical staining with monoclonal antibody against human recombinant bFGF was performed in the paraffin section of rat lung. RESULT: (1) The mean pulmonary artery pressure (mPAP), and the ratio of the thickness of pulmonary arteriolar wall to external diameter of pulmonary arterioles (MT%) were 3.96 +/- 0.47 kPa and 33.8% +/- 3.5% in rats exposed to hypoxia for 3 weeks respectively, both were significant higher than those in normal control group, P < 0.01. (2) The positive staining for bFGF in the wall of pulmonary arterioles in hypoxic rats was stronger than that of control group (P < 0.01), there was a statistical relationship between increase of staining for bFGF and MT% in rats exposed to hypoxia. CONCLUSION: (1) Hypoxia can induce formation of pulmonary hypertension and structual remodeling of pulmonary arterioles. (2) bFGF may modulate the structure remodeling of pulmonary arterioles in chronic hypoxic pulmonary hypertension.     

HERG基因在低氧性肺动脉高压大鼠肺小动脉平滑肌中的表达

用地高辛标记延迟整流性钾通道基因ＨＥＲＧ的ｃＤＮＡ为探针,通过原位杂交法检测正常和低氧性肺动脉高压（ＨＰＨ）大鼠肺小动脉平滑肌ＨＥＲＧ的表达。目的在于探讨慢性低氧导致肺动脉平滑肌细胞膜去极化,引起肺动脉高压是否与ＨＥＲＧ基因表达改变有关,及其在ＨＰＨ...     

蛋白激酶C与低氧性肺动脉高压

蛋白激酶C（PKC）是细胞膜后住处转导通路之一，在细胞的生长、增殖、代谢等各方面发挥重要作用。了解CK信息通道在低氧性肺动脉高压发病中的作用，有助于探索低氧性肺动脉高压新的防治方法。     

血管内皮生长因子和低氧性肺动脉高压

血管内皮生长因子（ＶＥＧＦ）是一重要的有丝分裂原及通透性因子,具有促进内皮细胞增殖,新生血管形成,增加微血管通透性等功能。本重点介绍了ＶＥＧＦ及其受体的特性以及在低氧性肺动脉高压形成中的意义和调节。为从基因水平治疗肺动脉高压提供一新的途径。     

香烟烟雾刺激诱导肺动脉高压动物模型的构建

目的 探讨利用单纯香烟烟雾刺激造模能否有效构建肺动脉高压疾病模型.方法 把20只清洁级SD大鼠,随机分为对照组(9只)、肺动脉高压(模型)组(11只),用香烟烟雾刺激的方法诱导肺动脉高压模型.在造模满4个月时检测各组大鼠血流动力学指标,取肺组织制作病理切片,比较两组大鼠的肺血管重构程度.结果 与对照组相比,模型组右室收...     

ATP敏感性钾通道与低氧性肺动脉高压

研究证明肺血管上存在ATP敏感性钾通道（KATP通道），该通道参与了膜静息电位和血管紧张性的调节。在低氧性诱导的肺动脉高压中，KATP通道参与了血管收缩和重构的病理过程。了解KATP通道的结构和其生物学特性，对认识低氧性肺动脉高压的形成机制和发展新的临床治疗手段有重要意义。     

Dynamic aspects of regulatory lung peptides in chronic hypoxic pulmonary hypertension.

Male Sprague-Dawley rats were placed in hypobaric hypoxia for 17-21 d (FIO2 10%) to establish pulmonary hypertension (PH) and control rats were kept in normobaric room air. Right mean atrial and ventricular pressures (PRA, PRV) were recorded, left ventricular (LV) blood was collected, and lungs were perfused with heparinized saline. Hearts were removed to evaluate right ventricular (RV) hypertrophy (RV/(LV+septum)%). Peptides were quantitated with radioimmunoassay in lung tissue extracts and plasma. Wet lung weight, PRA, PRV, and RV/(LV+S)% were higher and body weight was lower in hypoxia rats, and lung morphometry revealed increased arterial medial thickness (MT/OD%) and elastification of arterioles and capillaries. Lung tissue CGRP, PYY, gamma 2-MSH, and SOM were higher in PH rats and ANP was unchanged. Blood AVP, CGRP, PYY, VIP, and SOM were reduced in PH rats and ANP was unchanged. Lung levels of PYY and SOM correlated significantly with the time in hypoxia and with all parameters examined and CGRP and gamma 2-MSH correlated with all but medial thickness. PYY had the highest correlation of the peptides with body weight, PRV, and RV/(LV+S)%, and SOM the highest with time in hypoxia, wet lung weight, PRA, MT/OD%, and elastification of arterioles and capillaries. Blood peptides correlated inversely with these parameters. ANP had the overall weakest correlations and CGRP, PYY, and SOM had the highest. SOM correlated the highest with arterial medial hypertrophy, PRV, RV hypertrophy, and elastification of peripheral capillaries. VIP correlated the highest of the blood peptides with body weight and wet lung weight. Statistically significant correlations do not necessarily imply causal relationships. The putative roles of these peptides in pulmonary function are discussed.     

慢性低氧性肺动脉高压大鼠肺动脉内PTEN蛋白表达的变化

目的 通过观察慢性低氧性肺动脉高压大鼠肺动脉内人第10号染色体缺失的磷酸酶及张力蛋白同源的基因（PTEN）蛋白表达水平的变化,初步探讨PTEN在慢性低氧性肺动脉高压的发生、发展过程中所起的作用.方法 将6周龄健康雄性SD大鼠,随机分为正常对照组、低氧1d、3d、7d、14d和21d组,除对照组外,其他各组先建立慢性低氧肺动脉高压大鼠模型,然后检测各组大鼠右心室收缩压（right ventricle systolic pressure,RVSP）和右心室肥厚指数（right ventricle hypertrophy index,RVHI）,采用HE染色观察肺动脉病理学改变,采用Western blot技术检测肺动脉内PTEN蛋白的表达水平.结果 ①与正常对照组（23.76±0.82）mmHg相比,低氧暴露1d、3d、7d、14 d、21d后RVSP均明显上升（P＜0.05）;RVHI低氧3d、7d、14 d、21d组均较正常对照组（100％）明显上升（P＜0.05）;低氧暴露3d、7d和21d组肺动脉中膜明显增厚、管腔明显变小.②PTEN和p-PTEN在正常对照组和低氧各组均有表达.低氧各组肺动脉内PTEN蛋白的表达较对照组下降,但差异无统计学意义（P＞0.05）;而p-PTEN蛋白与PTEN总蛋白表达量的比值随低氧时间的延长有上升趋势,且在慢性低氧21d组（1.71±0.25）较正常对照组（1.00）明显增高（P＜0.05）.结论 PTEN蛋白表达的降低和p-PTEN蛋白表达的增高可能参与了大鼠慢性低氧性肺动脉高压的发生和发展过程.     

大鼠缺氧肺动脉高压模型肺组织信号转导与转录激活因子的表达

目的　通过观察大鼠常压缺氧肺动脉高压模型肺组织信号传导与转录活化因子(STATs)的表达水平 ,探讨其在低氧性肺动脉高压 (HPH)形成过程中参与的可能机制。方法　健康成年雄性Wistar大鼠 6 0只 ,随机分为缺氧组和健康对照组 ,缺氧组大鼠复制HPH模型。用逆转录 (RT) 聚合酶链反应 (PCR)和Northernblot检测 2组大鼠肺组织STATsmRNA的表达水平 ,免疫组化检测大鼠肺组织STATs蛋白的含量。结果　RT PCR扩增显示 ,缺氧 1周大鼠肺组织STAT 1、STAT 2、STAT 3、STAT5mRNA表达水平升高 ,缺氧 2周表达水平最高 ,缺氧 3周表达水平降低 ,但明显高于健康对照组 ;且缺氧 2周的表达水平高于其他缺氧时间 (P <0 0 5 ) ;STAT 4未检出。Northernblot显示 ,缺氧 2周大鼠肺组织STAT 1、STAT 3、STAT 5mRNA表达高于其他缺氧时间 (P <0 0 1)。缺氧 3周大鼠肺组织STAT3和STAT 5组化染色可见 ,肺泡壁细胞、支气管壁细胞、小血管壁细胞及巨噬细胞的胞核呈紫蓝色 ;图像定量分析显示 ,缺氧 3周大鼠肺组织STAT 3和STAT 5蛋白表达含量最高 ,缺氧 4周含量降低 ,但仍高于健康对照组 (P <0 0 1)。结论　大鼠常压缺氧肺动脉高压模型肺组织STATsmRNA和蛋白表达增高 ,提示STAT可能参与了HPH的发病机制。     

碱性成纤维细胞生长因子在低氧性肺动脉高压大鼠肺内表达及分布变化的观察

目的探讨碱性成纤维细胞生长因子（ｂＦＧＦ）在慢性低氧性肺动脉高压中的作用。方法建立慢性低氧性肺动脉高压大鼠模型，测定肺血流动力学及肺小动脉显微形态计量学，用免疫组化方法观察ｂＦＧＦ在大鼠肺组织的表达和分布。结果缺氧组大鼠平均肺动脉压（ｍＰＡＰ）、肺小动脉壁厚度占血管外径的百分比（ＭＴ％）分别为３．９６±０．４７ｋＰａ、３４±４％，明显高于对照组（Ｐ＜０．０１）；肺小动脉壁ｂＦＧＦ染色明显强于对照组（Ｐ＜０．０１），并和ＭＴ％呈正相关。结论（１）慢性缺氧能导致肺小动脉重建及肺动脉高压。（２）ｂＦＧＦ参与了慢性低氧性肺动脉高压肺血管重建的调控。     

丹参对慢性低氧性肺动脉高压大鼠肺组织bFGF表达的影响

目的 观察丹参对慢性低氧性肺动脉高压大鼠肺组织碱性成纤维细胞生长因子(bFGF)表达的影响,探讨丹参阻抑肺腺泡内动脉(IAPA)重建的机制。方法 Wistar大鼠随机分为3组:正常对照组、慢性低氧组、低氧丹参治疗组。低氧大鼠置于常压低氧舱3周后,测定血流动力学;观察IAPA结构变化,用免疫组化检测肺组织bFGF表达;用氯胺T比色法测定肺组织羟田氨酸含量。结果 丹参能降低平均肺动脉压,减少肺组织羟脯氨酸含量(P<0.05,P<0.01),抑制IAPA平滑肌细胞增生,降低肺组织bFGF表达强度 结论(1)丹参能抑制IAPA平滑肌细胞增生及胶原沉积而阻抑IAPA的结构重建。(2)抑制bFGF表达是丹参调节IAPA平滑肌细胞增生的重要途径之一。     

波生坦对低氧性肺动脉高压大鼠肺动脉钙调节蛋白表达的影响

目的: 探讨波生坦（bosentan,BST）对低氧性肺动脉高压（HPH）大鼠肺动脉中钙调节蛋白（calponin,CPN）表达的影响。 方法: 40只健康SD大鼠随机分为正常组、模型组、安慰剂组和BST组,每组各10只。正常组常压常氧下饲养6周,其他组分别置于全自动调节的低压低氧仓中间断低氧(8 h/d),分别饲养3周、6周和6周。自第4周起,模型组常压常氧下饲养;安慰剂组和BST组大鼠在入仓前分别给予生理盐水（2 ml）和BST（100 mg/kg）灌胃。以6周为观察终点,经HE染色后,观察各组大鼠肺血管的形态学变化;应用图像采集处理系统检测各组大鼠中型及小型肺动脉的相对中膜厚度(RMT);用免疫组化染色法对各组大鼠肺动脉的CPN进行定位及半定量分析。结果: ①与其他组相比,安慰剂组大鼠肺动脉管壁增厚、管腔狭窄;BST组大鼠肺动脉管壁的厚度及管腔大小可恢复至正常组的状态;②各组大鼠肺动脉管壁中均有CPN表达,随着低氧时间的延长,CPN表达减少,BST组CPN表达与正常组相比无统计学差异。结论: BST可促进HPH大鼠肺动脉CPN的合成。     

Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension

We show that 1 of the type II bone morphogenetic protein (BMP) receptor ligands, BMP4, is widely expressed in the adult mouse lung and is upregulated in hypoxia-induced pulmonary hypertension (PH). Furthermore, heterozygous null Bmp4(lacZ/+) mice are protected from the development of hypoxia-induced PH, vascular smooth muscle cell proliferation, and vascular remodeling. This is associated with a reduction in hypoxia-induced Smad1/5/8 phosphorylation and Id1 expression in the pulmonary vasculature. In addition, pulmonary microvascular endothelial cells secrete BMP4 in response to hypoxia and promote proliferation and migration of vascular smooth muscle cells in a BMP4-dependent fashion. These findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH.