肺动脉平滑肌细胞与肺动脉高压

肺动脉高压(PAH)的主要病理生理变化是肺血管收缩和肺血管重塑.肺动脉平滑肌细胞(PASMC)是肺血管的主要成分,PASMC的增殖和凋亡失衡势必导致肺血管收缩和肺血管重塑;许多细胞因子和生长因子、内源性气体分子及细胞膜离子通道也参与了PAH的调控.     

钾离子通道在肺动脉高压中的作用研究进展

肺动脉高压(PAH)是多种因素引起的肺血流动力学异常,以肺血管阻力进行性升高为临床特征的一组疾病.近年研究表明,肺动脉平滑肌细胞膜上的钾离子通道与PAH时的肺血管收缩和血管重构关系密切,现就钾离子通道在PAH中的作用研究进展作一综述.     

肺动脉高压发病机制研究进展

肺动脉高压(PAH)是一种以肺血管重构为主要病理变化特征的疾病,表现为肺小血管增殖、重塑及原位血栓形成,发生过程是一个复杂的病理生理过程,其发病机制尚未完全明了.关于其发病的基因多态性研究已基本明确,同时内皮系统分泌的各种血管活性物质的研究也较深入全面,近年来离子通道等方面的研究亦为PAH的发病机制揭开一条新路.对于PAH的进一步研究应着重于其基因组、蛋白质组学及信号传导等方面,为有效治疗PAH提供思路.现就上述几个方面作一综述.     

肺动脉高压大鼠模型肺血管维甲酸受体的变化

目的阐明维甲酸受体(retinoic acid receptor,RAR)变化与肺动脉高压发病机制的关系,并评价全反式维甲酸(all-trans retinoic acid,atRA)对肺高压肺血管重建过程的逆转作用。方法选择3周龄SD大鼠72只,将其平均分为3组,试验组1为野百合碱(Monocrotaline,MCT)诱导建立SD大鼠肺动脉高压模型;试验组2为MCT诱导建立SD大鼠,同时给予atRA 10 mg/(kg.d)灌胃;对照组为生理盐水组。分别于实验第7、14、21、28天每组取6只大鼠,测肺动脉压力后处死;实时定量RT-PCR检测主动脉、肺动脉及肺组织中RAR受体数量与mRNA水平。结果肺动脉高压时,肺血管中RAR各亚型(α、β、γ)转录水平均有下降,且随肺动脉高压加重下降更为明显。结论 RAR可能参与了肺动脉高压的发病机制。     

先天性心脏病合并肺动脉高压的药物治疗进展

先天性心脏病合并肺动脉高压(PAH)是儿科最常见的心血管疾病之一.传统治疗药物包括α1、α2-受体阻滞剂、钙通道阻滞剂、腺苷和镁离子等,目前治疗上已从单纯的对症降压治疗转向逆转肺血管重构治疗,临床上出现了前列环素、内皮素受体拮抗剂、磷酸二酯酶抑制剂、一氧化氮及其供体等治疗药物.近年来,PAH治疗又出现了以下三大研究热点:钾通道开放剂、5-羟色胺载体抑制剂和羟甲基戊二酰辅酶A还原酶抑制剂,但尚处于动物实验阶段,需进一步研究以得出正确的结论,提高PAH的治疗水平.     

儿童肺动脉高压的研究现状与未来

肺高压( pulmonary hypertension,PH)指肺循环压力超出正常,可由多种心、肺等疾病引起,严重者可导致右心室负荷增大、右心功能不全,引起一系列临床表现.肺动脉高压(pulmonary arterial hypertension,PAH)是指肺动脉压力和阻力增加,是PH的一种类型[1].当今广泛采用的PAH血流动力学定义为:在海平面静息状态下,右心导管测定肺动脉平均压(mPAP)高于25 mm Hg(1 mm Hg=0.133 kPa),肺毛细血管楔压(pulmonary capillary wedge pressure,PCWP)低于或等于15 mm Hg或肺血管阻力(pulmonary vascular resistance,PVR)大于3 Wood单位[1-2].来自法国的一项注册研究显示,PAH的患病率为15/百万[3],其中儿童患病率为3.7/百万[4].目前我国尚无儿童PAH的流行病学数据,儿童PAH注册登记研究尚待开展.     

基于导管技术的肺动脉高压治疗进展

正肺动脉高压(pulmonary arterial hypertension,PAH)是一种以平均肺动脉压力、肺血管阻力持续升高以及运动耐量下降及死亡的疾病。2015年欧洲心脏病学会/欧洲呼吸病学会(ESC/ERS)发布的《肺动脉高压诊断和治疗指南》将PAH诊断标准定为:静息时右心导管测得的平均肺动脉压(mean pulmonary arterial pressure,mPAP)≥25 mmHg(1 mmHg=0.133 kPa),肺毛细血管楔压(pulmonary arterial wedge pressure,PAWP)≤15 mmHg,且肺血管阻力(pulmonary vascular resistance,PVR)3 Wood,PAH分为原发性肺高压、左心疾病相关     

儿童结缔组织病相关性肺动脉高压的诊断与治疗

肺动脉高压(pulmonary arterial hypertension,PAH)是指肺小动脉原发性疾病或其他疾病导致的肺动脉阻力增加,最终导致右心衰竭的一类病理生理综合征;表现为肺动脉压力升高而肺静脉压力正常.过去的10年里,PAH病理生理学和治疗都有了飞速发展.     

Rho激酶在缺氧性肺动脉高压大鼠不同阶段肺组织中的激活及意义

目的探讨缺氧性肺动脉高压(HPH)大鼠肺组织小G蛋白Rho相关激酶(Rho激酶)的表达及其抑制剂法舒地尔对HPH的影响。方法72只雄性SD大鼠。随机均分为对照组、缺氧模型组和法舒地尔干预组。测各组大鼠平均肺动脉压力(mPAP)、右心室肥厚指数(RVHI);采用逆转录酶-聚合酶链反应(RT-PCR)、免疫印迹法,从基因、蛋白质水平观察肺组织Rho激酶表达规律;免疫印迹法检测其底物肌球蛋白磷酸酶的磷酸化状态,作为该激酶功能活化的标志。结果Rho激酶mRNA和蛋白在HPH大鼠发生早期即明显上调,至模型后期仍维持较高水平;肌球蛋白磷酸酶磷酸化水平也较对照组显著增高(Pa<0.01),并与mPAP及RVHI均呈明显正相关(Pa<0.01);法舒地尔干预后mPAP、Rho激酶mRNA和蛋白、肌球蛋白磷酸酶磷酸化水平均明显降低。结论HPH大鼠肺组织中存在Rho激酶的表达上调与功能活化,提示Rho/Rho激酶信号通路在HPH发病机制中具起重要作用,其抑制剂法舒地尔有望用于肺动脉高压的治疗。     

BQ123对左向右分流肺动脉高压肺组织ET-1及其受体表达的影响

内皮素1(endothelin-1，ET-1)是一种强效缩血管肽和促血管平滑肌细胞(SMC)分裂原。研究发现，BQ123，是选择性ETA受体(ETAR)的拮抗剂，可拮抗ET-1促培养的肺动脉SMC增殖、肥大作用。我们用套管连接法制作左向右分流肺动脉高压(简称肺高压)模型，研究BQ123对肺高压大鼠肺组织ET-1及其受体表达的影响。     

骨髓间充质干细胞移植对肺动脉高压大鼠肺血管重构的影响

目的 探讨骨髓间充质干细胞(MSCs)移植对野百合碱诱导的肺动脉高压(PAH)大鼠肺血管重构的影响.方法 体外分离、培养并纯化SD大鼠骨髓MSCs.健康雄性SD大鼠随机分为3组:正常对照组(n＝15)、PAH组(n＝20)和MSCs移植组(n＝20).PAH组和MSCs移植组大鼠一次性项背部皮下注射野百合碱(50 mg·kg -1),复制PAH肺血管重建动物模型.3组大鼠在同等条件下饲养.3周后,MSCs移植组大鼠经舌下静脉注射5×109 L-1的经Hoechst 33342标记的MSCs细胞悬液1 mL,PAH组大鼠予等量低糖-Dulbecco改良Eagle's培养液(L-DMEM)注射,正常对照组不做任何处理.移植28 d,观察3组大鼠肺小动脉的显微结构及超微结构的改变.结果 PAH大鼠用MSCs移植28 d后,肺小动脉管壁厚度指标(WD/TD％、VA％)、放射性肺泡计数、肺非肌性小动脉肌化程度均较PAH组显著改善(P＜0.01)；其肺小动脉的重构及超微结构的血气屏障、线粒体、板层小体等改变均有明显改善.荧光显微镜观察到Hoechst 33342标记的MSCs在肺内定植,且分化成大量新生血管并形成侧支循环,肺动脉重构得到有效逆转.结论 MSCs移植可有效减轻并逆转肺动脉重构的进程,其作用机制是MSCs分化形成新生血管,建立了侧支循环,从而修复野百合碱诱导的肺损伤.     

钙通道在肺动脉高压发病机制中的研究进展

肺动脉高压是一类严重的进展性疾病,最终导致患者右心衰竭,甚至死亡。肺血管收缩、肺血管重构、血栓形成和血管硬化等诸多原因导致肺动脉高压的发生。众多研究表明,Ca~(2+)信号在维持血管张力和调控血管平滑肌细胞增殖、凋亡等过程中发挥了重要作用,而这一信号转导机制主要由钙通道来调节操纵。文章综述钙通道在肺动脉高压发病机制中的研究进展。     

Fatal pulmonary arterial hypertension in an infant girl with incontinentia pigmenti

We report the case of an infant girl with incontinentia pigmenti (IP) complicated by fatal pulmonary arterial hypertension (PAH). She was diagnosed with IP, based on the presence of specific skin lesions, neonatal seizures, hypereosinophilia and a maternal family history of IP. At the age of 2 months, she was diagnosed with PAH on systolic heart murmur due to tricuspid valve regurgitation. Despite several treatments for PAH but not including epoprostenol, severe PAH persisted and she died of pulmonary hypertensive crisis at the age of 5 months. On postmortem histopathology the pulmonary artery had severe intimal thickening, with occlusion or stenosis of the vascular lumen of the small pulmonary arteries as well as partial plexiform lesions, all of which were compatible with PAH. Modulation of nuclear factor‐κB signaling may be involved in the development of PAH in IP.     

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目的 探讨雾化吸入伊洛前列素进行急性血管扩张试验的价值.方法 研究对象为2007年2月至2008年5月在广东省心血管病研究所住院的50例先天性心脏病合并肺动脉高压患儿,对所有患儿进行左右心导管检查,之后肺动脉内注射酚妥拉明或雾化吸入伊洛前列素进行急性血管扩张试验,试验后重复左右心导管检查.根据Fick公式计算血流动力学参数.综合判断肺动脉高压性质,将惠几分成两组:动力组和梗阻组.动力组患儿进行手术治疗,术后定期随访并修正术前诊断.结果 酚妥拉明会显著增高受试者的心率,而伊洛前列素对心率的影响较轻微;酚妥拉明和伊洛前列素都能够降低平均肺动脉压力和肺血管阻力,升高肺循环血流量;酚妥拉明同时会降低平均主动脉压力和体循环阻力,升高体循环血流量,而伊洛前列素对体循环没有明显的影响.在使用伊洛前列素的急性血管扩张试验中,平均肺动脉压力、肺血管阻力/体循环阻力和肺循环血流量/体循环血流量等参数的变化在动力组和梗阻组中差异无统计学意义(P值分别为0.016、0.024和0.030).而使用酚妥拉明的急性血管扩张试验中,平均肺动脉压力和肺血管阻力两项参数的变化在动力组和梗阻组中差异有统计学意义(P值分别为0.017和0.004).结论 在先天性心脏病合并肺动脉高压的患儿中,使用酚妥拉明或伊洛前列素进行急性血管扩张试验都能够有效区分动力性与梗阻性肺动脉高压.酚妥拉明用药前后,肺循环和体循环的压力、阻力和血流量都有明显变化.而伊洛前列素雾化吸入以影响肺循环为主,可以保持相对平稳的血流动力学,在安全性上优于酚妥拉明.     

肺动脉去神经治疗肺动脉高压研究进展

肺动脉去神经治疗(pulmonary artery denervation,PADN)可阻断局部肺动脉交感神经,降低肺动脉高压(pulmonary arterial hypertension,PAH)血流动力学参数,改善肺血管重塑及右心室心肌肥厚、纤维化,进而改善心室功能。前期基础实验已确定肺动脉交感神经在肺动脉内膜位置,并证实PADN对PAH动物模型安全有效,可能通过抑制交感神经系统和肾素-血管紧张素-醛固酮系统发挥作用。PADN已开展成人临床应用研究,取得良好临床效果。在此基础上正初步探索PADN在儿童PAH中应用的可能性。     

Biological serum markers in the management of pediatric pulmonary arterial hypertension

Appropriate parameters are needed for the monitoring of children with pulmonary arterial hypertension (PAH). Various biologic markers seem to be of use in adults with PAH. No data are available on their value in children with PAH. In this study, the relation between serum markers, functional parameters, and hemodynamic variables in pediatric PAH and their ability to predict survival is determined. Serum N-terminal pro brain natriuretic peptide (NT-proBNP), uric acid, norepinephrine, and epinephrine were measured and correlated with invasive hemodynamics, functional parameters, and outcome in 29 pediatric patients with PAH who visited a tertiary reference center for pediatric PAH between 1997 and 2005. NT-proBNP correlated with functional class (R = 0.36; p = 0.03) and 6-min walking distance (6MWD) (R = -0.53; p < 0.001). Uric acid correlated with mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index (R = 0.63, p = 0.01; R = 0.71, p = 0.03, and R = -0.65, p = 0.007, respectively). After initiation of treatment, NT-proBNP decreased. This decrease correlated with an increased 6MWD. Finally, norepinephrine and NT-proBNP levels were highly predictive for mortality. In this series of children with PAH, biologic markers were correlated with hemodynamics and functional capacity, as parameters of disease severity. The data indicate that these markers can be used to monitor treatment effects and predict mortality in pediatric PAH.     

Comparison of Endothelial Biomarkers According to Reversibility of Pulmonary Hypertension Secondary to Congenital Heart Disease

The reversibility of pulmonary arterial hypertension (PAH) in children with congenital heart disease (CHD) is strongly associated with the degree of intimal proliferation, vessel narrowing, and number of circulating endothelial cells (CECs). Circulating endothelial cells may arise from either endothelial damage or accelerated turnover during vessel remodeling, but nothing is known about endothelial microparticles (EMPs) and other biomarkers reflecting endothelial alterations. This study aimed to document endothelial markers further according to the irreversibility of PAH secondary to CHD. The study investigated soluble markers of endothelial damage or activation (thrombomodulin, soluble endothelial protein C receptor, and soluble E-selectin), inflammation (interleukin-6), and angiogenic cytokine levels [vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)] in 26 patients with CHD, 16 with reversible PAH (median age, 2 years) and 10 with irreversible PAH (median age, 9 years). Endothelial activation/apoptosis was evaluated by measuring EMP levels. Plasma procoagulant activity also was measured. The results show that the levels of soluble markers indicating endothelial activation were not predictors of PAH irreversibility. Lower levels of PlGF were observed in reversible compared with irreversible PAH but were not associated with the CEC level, the mean pulmonary artery pressure (mPAP), or age. No significant difference in procoagulant activity or EMP level was found between irreversible and reversible PAH. Among a large panel of biomarkers reflecting endothelial activation, regeneration, and injury, the high CEC levels previously described proved to be the only marker allowing discrimination between reversible and irreversible PAH secondary to CHD.     

Pulmonary arterial hypertension in children: A Medical Update

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980’s, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients.     

Pulmonary arterial hypertension in children: A Medical Update

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980’s, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients.     

Clinical characteristics of pulmonary arterial hypertension associated with Down syndrome

The genetic abnormalities associated with Down syndrome (DS) are still being identified. Few studies have examined the roles of CRELD1 and GATA4 in cardiac abnormalities or their association with pulmonary artery histopathology. Children with DS have an elevated risk of pulmonary arterial hypertension (PAH). This increased risk is likely mainly due to genetic background, the structural characteristics of the pulmonary vascular wall, and certain heart diseases and partly due to pulmonary hypoplasia, upper and lower airway obstructive diseases, chronic infection, and neuromuscular underdevelopment. Exposure to increased left‐to‐right shunt flow increases sheer stress on endothelium and may induce endothelial dysfunction followed by irreversible remodeling of pulmonary arteries. Pathologic changes include endothelial cell proliferation and thickening of the pulmonary arterial wall due to mechanical responses to the thinner medial smooth muscle cell layer, which includes underdevelopment of alveoli. Production of prostacyclin and nitric oxide is diminished in DS, but endothelin‐1 and thromboxane are elevated. Perioperatively, patients with DS may experience pulmonary hypertensive crisis after intracardiac repair and prolonged PAH, and have a poorer response to nitric oxide inhalation. To better manage DS, it is crucial to systematically evaluate the systemic complications of DS. Cardiac catheterization data, particularly those regarding pulmonary arterial resistance, are essential in assessing severity and response to vasodilating agents, preventing postoperative crisis, and evaluating the possibility of intracardiac repair. Advanced therapy with pulmonary vasodilating agents appears effective. Operative risk is similar for individuals with and without DS, except among patients with a complete atrioventricular canal defect.