肺动脉高压血管重构与磷酸二酯酶关系进展

肺动脉高压（Pulmonary Artery Hypertension,FAH）是一种由于肺动脉血流受限而引发的综合征,其可引起PVR（肺血管阻力）病态增加以及最终引起右心衰。根据发病诱因可分为特发性PAH、家族性PAH、缺氧性PAH及结缔组织病引起的PAH;感染因素如艾滋病等引起的PAH;     

内皮素受体拮抗剂治疗肺动脉高压的研究进展

肺动脉高压（PAH）是一种在中国发病率及病死率都较高的疾病。可根据其病因是否明确而分为特发性和继发性两大类。内皮素（ET）是引起细胞增殖的重要物质,抑制其作用具有控制PAH的作用。现已发现ET有ET-1,ET-2和ET-3三类,肺是ET-1作用和代谢最重要的器官。随着有关ET与PAH关系研究的不断深入,为临床应用内皮素受体拮抗提供了理论基础。理想的内皮素受体拮抗剂应特异性地针对ETA受体,而保留ETB受体的舒张血管和清除ET-1的作用。目前一些内皮素受体拮抗剂已上市或进入Ⅲ期临床试验阶段。所以,ET参与低氧性肺动脉高压和肺血管重构的形成,阻断ET与其受体结合的内皮素拮抗剂对低氧性肺动脉高压具有较好的预防和治疗作用。     

妊娠合并肺动脉高压妊娠结局分析及护理体会

肺动脉高压（pullnonaryarterialhypertension，PAH）是一种由多种心、肺或肺血管本身疾病引起，以肺血管阻力进行性升高为主特征，可致右心负荷增大、右心功能不全、肺血流减少而引起一系列临床表现的疾病。肺动脉高压患者妊娠期易发生低氧血症，可影响胎儿生长发育，甚至出现宫内窘迫及新生儿窒息。低体重及早产（包括医源性早产）发生率高，分别为40％及28％～57％，新生儿窒息率约15％。分娩期低氧血症可导致宫缩乏力，常引起产程延缓及停滞，宫缩乏力性产后出血亦较多见。分娩期前后，     

肺血管重构与磷酸二酯酶关系的新进展

肺动脉高压（pulmonary artery hypertension, PAH）是一大类以肺动脉压和肺循环阻力升高为特征的严重疾病。根据发病诱因可分为特发性PAH、家族性PAH、缺氧性PAH及结缔组织病引起的PAH;感染因素如艾滋病等引起的PAH;以及因先天性心脏病左向右分流引起的PAH;急、慢性肺动脉栓塞引起的PAH等。各类PAH的发病机制大部分未明,但其共同特征是肺动脉压及肺血管阻力升高、右心室后负荷增加,从而导致右心衰竭甚至死亡。不同发病原因的PAH进展过程中,都会出现肺血管收缩和肺血管重构相同的病理学特征。     

肺动脉高压与免疫炎症反应

肺动脉高压（PAH）是一大类以肺动脉压进行性升高为特点的肺血管疾病。目前广泛采用的PAH血流动力学定义为：静息状态下肺动脉平均压〉25mmHg，或运动状态下〉30mmHg。而相应的肺毛细血管嵌压小于15mmHg。由于现代医疗技术的进步与发展，人们对肺动脉高压的认识也日趋深入。2003年威尼斯第三届世界PAH会议上，新指南将肺动脉高压分为肺动脉性高压（PAH）、左心疾病伴发肺动脉高压、     

钙通道阻滞剂及L－精氨酸对肺动脉高压的影响

采用常压间竭低氧模型，观察了钙通道拮抗剂尼群地平（Ｎｉｔ）、硝苯吡啶（Ｎｉｆ）、内皮依赖性血管舒张因子（ＥＤＲＦ）合成前体Ｌ－精氨酸（Ｌ－Ａ）对大鼠慢性低氧性肺动脉高压的预防作用。结果提示：三者均能预防低氧性肺动脉高压形成和减轻低氧引起的右室肥大；Ｎｉｔ、Ｎｉｆ与Ｌ－Ａ比较无显著性差异（Ｐ＞０．０５）；Ｎｉｔ对低氧性肺动脉高压的降压作用较Ｎｉｆ稍好。     

钙通道阻滞剂及L—精氨酸对肺动脉高压的影响

采用常压间竭低氧模型，观察了钙通道拮抗剂尼群地平（Ｎｉｔ）、硝苯吡啶（Ｎｉｆ）、内皮依赖性血管舒张因子（ＥＤＲＦ）合成前体Ｌ－精氨酸（Ｌ－Ａ）对大鼠慢性低氧性肺动脉高压的预防作用。结果提示：三者均能预防低氧性肺动脉高压形成和减轻低氧引起的右室肥大：Ｎｉｔ、Ｎｉｆ与Ｌ－Ａ比较无显著性差异（Ｐ＞０．０５）；Ｎｉｔ对低氧性肺动脉高压的降压作用较Ｎｉｆ稍好。     

低氧性肺动脉高压大鼠肺内血管内皮生长因子分布和水平的变化

肺血管结构重建是低氧性肺动脉高压的重要特征之一。血管内皮生长因子（ＶＥＧＦ）具有明显的促内皮细胞有丝分裂和血管形成的作用，体外实验已证实低氧可引起肺组织中ＶＥＧＦ及其受体的表达增多［１］。为探讨ＶＥＧＦ在低氧性肺动脉高压发病中的作用，我们观察了低氧性...     

肺动脉高压的诊断进展

肺循环高压相关术语及分类 肺循环高压（pulmonary hypertension）（肺高压）由多种心、肺或肺血管本身疾病所引起，表现为肺循环的压力和阻力增加，包括肺动脉高压（pulmonary arterial hypertension，PAH）、肺静脉高压和混合性PAH，可引起一系列临床表现，最终导致右心功能衰竭（心衰）。     

结缔组织病相关肺动脉高压的研究进展

肺动脉高压（pulmonary arterial hypertension,PAH）是一组以肺动脉平均压（mean pulmonary arterial pressure,mPAP）升高为特征的临床一病理生理综合征。肺血管重塑引起肺循环血流动力学改变,最终导致右心衰竭,作为具有潜在破坏力的慢性肺循环疾病,PAH一直是临床诊治的难点。     

电压依赖性钾离子通道在肺动脉高压发病过程中的作用

肺动脉高压是一种肺血流受限引起肺血管阻力和压力持续性增高,最终导致右心衰竭甚至死亡的综合征.病理生理学改变主要为肺血管收缩、重塑及原位血栓形成.研究表明,钾离子通道尤其电压依赖性钾离子通道功能与表达水平的降低是引起肺血管平滑肌细胞增殖和凋亡异常、肺血管重塑的关键因素.本文着重论述近年来有关电压依赖性钾离子通道与肺动脉高...     

缺氧诱导丝裂原因子与肺动脉高压

缺氧诱导丝裂原因子（hypoxia—induced mitogenic factor,HIMF）是近年来从慢性缺氧致肺动脉高压小鼠模型的肺组织中发现的一种分泌型蛋白,于肺组织中被缺氧诱导表达,因其能促进小鼠肺微血管平滑肌细胞的增殖而得名,是肺组织特异性生长因子,又名发现于炎症区域1（found in inflammatory zone1,FIZZ1）或抵抗素样分子α（resistin-like molecule—α,RELM—α）。HIMF／FIZZ1／RELM—α具有促有丝分裂、血管收缩、血管再生和诱导细胞迁移、趋化性、抗细胞凋亡、炎症因子样作用等多种生物学功能。研究发现HIMF通过引起肺血流动力学改变,血流阻力增加,肺动脉压增高等不同的方式参与肺血管收缩及重塑。HIMF的各种生物学特性证明其和肺动脉高压,尤其是慢性缺氧性肺动脉高压的发病机制有密切的联系,而这对肺动脉高压的治疗是非常重要的。下面就HIMF与肺动脉高压的相互联系作一归纳、总结。     

交感神经系统在肺动脉高压发生发展过程中的作用

肺动脉高压（pulmonary arterial hypertension,PAH）是各种原因所致的一种慢性肺血管性疾病,主要表现为肺动脉重构和肺血管阻力进行性增加,最后导致右心室功能衰竭和死亡,预后极差。PAH时交感神经表现为过度激活,交感激活后可以通过多种机制参与肺动脉重构及加重右心室功能紊乱。干预交感神经可以改善PAH的预后,其原因与改善PAH的右心室功能和肺动脉重构密切相关,但是不良反应也较多,交感神经系统参与PAH发生发展的确切机制尚不完全知道,仍需进一步研究。     

YC-1 attenuates hypoxia-induced pulmonary arterial hypertension in mice

BackgroundPulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and elevation of pulmonary arterial pressure, leading to right ventricular failure and eventual death. Currently, no curative therapy for PAH is available, and the overall prognosis is very poor. Recently, direct activators of soluble guanylyl cyclase (sGC) have been tested as a novel therapeutic modality in experimental models of pulmonary arterial hypertension (PAH).ObjectiveIn this study, we used in vitro and in vivo models to evaluate the therapeutic potential of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), a dual functioning chemical, as a direct activator of guanylyl cyclase and an inhibitor of hypoxia-inducible factor-1.MethodsWe analyzed the effects of YC-1 on cell proliferation and the levels of p21 and p53 in human pulmonary artery smooth muscle cells (HPASMCs) under hypoxia. We also determined the effects of YC-1 on expression of endothelin-1 (ET-1) and phosphorylation status of endothelial nitric oxide synthase (eNOS) at Ser¹¹⁷⁹ in human pulmonary artery endothelial cells (HPAECs) under hypoxia. In mice, hypoxic PAH was induced by exposure to normobaric hypoxic conditions for 28 days. To assess preventive or therapeutic effects, randomized mice were subjected to once daily i.p. injections of YC-1 for the entire hypoxic period (5 mg/kg) or for the last seven days of a 28-day hypoxic period (5 and 10 mg/kg). On day 28, we measured the right ventricular systolic pressure (RVSP) and determined the degrees of right ventricular hypertrophy (RVH) and vascular remodeling.ResultsIn HPASMCs, YC-1 inhibited hypoxia-induced proliferation and induction of p53 and p21 in a concentration-dependent manner. Also, YC-1 suppressed the hypoxia-induced expression of ET-1 mRNA and dephosphorylation of eNOS at Ser¹¹⁷⁹ in HPAECs. In the preventive in vivo model, a daily dose of 5 mg/kg YC-1 significantly prevented the elevation of RVSP, development of RVH, and pulmonary vascular remodeling, which were caused by hypoxic exposure. In the therapeutic model, YC-1 at daily doses of 5 and 10 mg/kg alleviated RVH and pulmonary vascular remodeling but did not prevent the elevation of RVSP.ConclusionsOur results indicate that YC-1 prevents the development of hypoxia-induced PAH in a preventive model and alleviates RVH and pulmonary vascular remodeling in a therapeutic model. Therefore, these data imply that YC-1 has therapeutic potential for use in a single or combination therapy for PAH.     

Exercise physiology and pulmonary arterial hypertension

The lungs are the only organ that receives the entire cardiac output with every stroke. The pulmonary circulation is normally a high-flow, low-resistance, low-pressure system that carries blood into the pulmonary microcirculation. In pulmonary artery hypertension (PAH)vascular remodeling contributes to a sustained elevation of pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) as a result of vascular remodeling characterized largely by vascular smooth muscle cell proliferation and medial hypertrophy, and endothelial cell proliferation resulting in lumen obliteration. The loss of pulmonary arterial compliance and development of elevated PVR puts an excessive burden on the right ventricle due to the increased workload necessary to overcome the downstream pressure, ultimately leading to right-sided heart failure. The functional status of the pulmonary circulation and the levels of PVR and PAP ultimately determine the outcome of patients with PAH. Study of the pressure–flow relationships in the pulmonary vascular bed will provide an improved appreciation of the pathophysiology of pulmonary hypertension.     

肺动脉平滑肌细胞:肺动脉高压的关键治疗靶点

肺动脉高压(PAH)是一种进展快、预后欠佳、死亡率高的心血管疾病。研究表明,肺血管重构是PAH发生发展的重要病理基础,而肺动脉平滑肌细胞的增殖和肥大是PAH肺血管重构的主要病理改变。在PAH时,肺血管平滑肌细胞由收缩表型向增殖状态的合成表型转化,主要表现为肺血管平滑肌细胞的增殖和肥大。上述病理改变最终导致肺血管管腔狭窄,管壁僵硬,进而促进PAH的发生发展。本文对肺动脉平滑肌细胞在PAH中的关键作用及作用机制进行阐述,为临床防治PAH提供新靶点和新策略。     

Low-molecular-weight heparin inhibits hypoxic pulmonary hypertension and vascular remodeling in guinea pigs

RATIONALE: We have shown previously that antiproliferative unfractionated heparins block hypoxia-induced pulmonary arterial hypertension (PAH) and vascular remodeling, and hypothesized that low-molecular-weight heparins (LMWHs) would too. OBJECTIVES: To determine the potential role and mechanisms of dalteparin and enoxaparin (two LMWHs) in inhibiting hypoxic PAH and vascular remodeling. METHODS: Male Hartley guinea pigs were exposed for 10 days to normobaric 10% oxygen with dalteparin (5 mg/kg), enoxaparin (5 mg/kg), or with an equivalent volume of normal saline solution. Normoxic control animals (n = 5) received room air for 10 days. Bovine pulmonary artery smooth-muscle cells (PASMCs) were grown in 10% fetal bovine serum without heparin, with dalteparin (1 microg/mL) or with enoxaparin (1 microg/mL). MEASUREMENTS: Pulmonary arterial pressure (PAP), cardiac index, right ventricular heart weight divided by left ventricular plus septum weight (RV/LV+S), hematocrit, percentage of wall thickness of intraacinar vessels (%WT-IA), percentage of wall thickness of terminal bronchiole vessels (%WT-TA), and the percentage of thick-walled vessels (%Thick) were determined. In PASMCs, expression of p27 and cell growth were compared because in mice whole heparin depends on p27 for its antiproliferative action. MAIN RESULTS: In hypoxic animals, hematocrit, PAP, total pulmonary vascular resistance index, RV/LV+S, %WT-IA, %WT-TA, and %Thick all rose significantly vs normoxic control animals (p < 0.05); cardiac index was unchanged. Dalteparin but not enoxaparin significantly reduced PAP, total pulmonary vascular resistance index, and RV/LV + S (p < 0.05 vs hypoxia alone); inhibited PASMC growth; and upregulated p27 expression. Enoxaparin moderately reduced vascular remodeling, which did not translate into less pulmonary hypertension. CONCLUSIONS: Not all LMWHs are the same. Dalteparin was more effective than enoxaparin in inhibiting pulmonary hypertension and vascular remodeling in hypoxic guinea pigs.     

肺动脉高压治疗的最新进展

肺动脉高压是各种原因引起的肺动脉压力持续升高的临床综合征.若缺乏相应的治疗,将导致肺血管重塑,最终发展为右心衰竭,预后极差.但早期诊断及合理治疗可提高该病患者的生存率并改善患者的生存质量.近年,对肺动脉高压发病机制认识的不断深入推动了肺动脉高压治疗手段的发展,现将肺动脉高压治疗的最新进展综述如下.     

Hypoxia-induced pulmonary hypertension: different impact of iloprost, sildenafil, and nitric oxide

OBJECTIVES: Chronic alveolar hypoxia induces pulmonary hypertension, evident from elevated pulmonary artery pressure (PAP), pulmonary vascular resistance, right ventricular hypertrophy (RVH), and increased muscularization of the pulmonary vasculature. Additionally, the vasoconstrictor response to acute hypoxia (HPV) may be reduced in the remodeled vasculature. However, no direct comparison of different treatments on the various parameters characterizing pulmonary hypertension has been performed yet. Against this background, we compared the effects of inhaled NO, infused iloprost, a stable prostacyclin analogue, and oral sildenafil, a phosphodiesterase 5 inhibitor, on hypoxia-induced pulmonary hypertension. METHODS: Exposure of rabbits to chronic hypoxia (FiO(2)=0.10) for 42 days. Treatment with infused iloprost, oral sildenafil, and inhaled nitric oxide. RESULTS: We quantified PAP, pulmonary vascular resistance, RVH, vascular remodeling, vasoreactivity, and the strength of HPV. Chronic hypoxia resulted in an increase in (a) the right ventricle/(left ventricle+septum) ratio from 0.26+/-0.01 to 0.44+/-0.01, (b) PAP, and (c) the degree of muscularization from 14.0+/-4.0% to 43.5+/-5.3%. Treatment with iloprost and sildenafil, but not with NO, prevented the increase in muscularization. In contrast, RVH was strongly inhibited by sildenafil, whereas NO had some minor, and iloprost had no effect. Only iloprost reduced PAP compared to NO and sildenafil. The downregulation of HPV was abrogated only by NO. CONCLUSION: We demonstrated (a) that the parameters characterizing hypoxia-induced pulmonary hypertension are not functionally linked, (b) that the downregulation of HPV under chronic hypoxia can be prevented by inhaled NO but not by sildenafil and iloprost, and (c) that iloprost is particularly effective in preventing vascular remodeling and sildenafil in preventing RVH.