低氧性肺动脉高压发生机制中气体信号分子的病理生理学意义

低氧性肺动脉高压(hypoxie pulmonary hyper-tension)是临床众多心肺疾病发生发展过程中重要的病理生理环节.低氧性肺血管结构重建是低氧性肺动脉高压的重要病理基础[1],其主要特征为肺动脉中膜平滑肌细胞增生、肥大,中膜增厚;非肌型动脉及部分肌型动脉肌化,形成肌型动脉以及血管壁中细胞外基质增多.低氧性肺血管收缩是肺动脉高压的始动环节和主要病理过程,后期以肺血管结构重建为主要病理生理改变.因此积极寻找低氧性肺动脉高压的发病机制,对引导其治疗有积极的推动作用.     

新生儿低氧性肺动脉高压的发病机制研究

新生儿低氧性肺动脉高压较为常见且病死率较高.其发病机制与肺动脉内皮功能障碍和(或)平滑肌细胞表型改变、功能障碍有关.急性缺氧时,肺动脉内皮一氧化氮合酶下调,一氧化氮合成减少,平滑肌细胞对一氧化氮的敏感性下降;内皮素生成增加,内皮素a受体基因表达增加,平滑肌表面分布密度增加;一氧化氮-内皮素-1轴失衡,使出生后肺动脉舒张过程受损,血管紧张度增高.低氧查影响新生儿血管平滑肌细胞表型转变为合成表型优势,与低氧发牛时机密切相关;缺氧状态持续影响了氧敏感基因转录因子的活性,进一步导致肺动脉平滑肌细胞增殖肥大,血管壁结构重建,加重肺动脉高压.内皮与平滑肌细胞之间也通过相互作用影响各自功能.因此,了解其发生机制,对探讨新生儿肺动脉高压的治疗措施有重要意义.     

一氧化氮对低氧性肺血管结构重建的调节作用

低氧性肺动脉高压是临床众多疾病发生发展过程中的重要病理生理环节,低氧性肺血管结构重建作为慢性低氧性肺动脉高压形成中重要的病理生理机制,近年来受到越来越多的重视。然而,低氧性肺血管结构重建的发生机制尚未完全清楚。一氧化氮(NO)是一种新型的细胞信使分子,由L-精氨酸(L-Arg)和氧分子在一氧化氮合酶(NOS)及其辅因子的作用下产生,近年来人们对其在调节低氧性肺血管结构重建     

新生儿持续肺动脉高压诊治

新生儿持续肺动脉高压(persistent pulmonary hypertension of the newborn,PPHN)是指生后肺血管阻力持续性增高,肺动脉压超过体循环动脉压,使由胎儿型循环过渡至正常"成人"型循环发生障碍,引起心房及(或)动脉导管水平血液的右向左分流,临床出现严重低氧血症等症状。此病病因复杂,病死率高,是导致新生儿死亡的主要原因之一。PPHN的治疗目的是降低肺动脉压力,维持体循环压力,纠正右向左分流,改善血氧饱和度。2003年全国新生儿学组制订了PPHN的诊治常规,使对该病的诊治得到统一的认识。本文主要论述PPHN的发病机制及治疗进展。     

吸入一氧化氮治疗新生儿持续性肺动脉高压研究进展

新生儿持续性肺动脉高压(persistent pulmonary hypertension of the newborn,PPHN)是胎儿从宫内生活过渡到宫外生活期间,肺动脉压力及肺血管阻力持续升高导致血液经过卵圆孔和(或)动脉导管的右向左分流,临床表现为严重紫绀、进行性低氧血症的严重新生儿疾病。最新研究报道PPHN发病率为2/1 000活产婴儿,病死率为11.6%[1]。临床研究[2]和Meta分析[3]证实吸入一氧化氮(inhaled     

硫化氢对低氧性肺动脉高压大鼠肺动脉增殖细胞核抗原及Bcl-2的调节作用

目的　探讨硫化氢 (H2 S)对低氧性肺动脉高压 (HPH)大鼠肺动脉结构重建和肺动脉平滑肌细胞增殖、凋亡的调节作用。方法　选取体重 180～ 2 0 0g的健康雄性Wistar大鼠 2 4只 ,随机分为常氧组、低氧组、低氧 硫氢化钠 (NaHS)组。监测其血液动力学变化及肺动脉结构重建 ,采用免疫组织化学方法检测增殖细胞核抗原 (PCNA)和Bcl 2凋亡蛋白表达 ,并对肺动脉平滑肌细胞增殖与凋亡进行定位和半定量分析。结果　低氧组大鼠平均肺动脉压 (mPAP)明显升高 (P <0 .0 1) ,右室 / (左室 室间隔 )比值显著增加 (P <0 .0 1) ,肺动脉相对中膜厚度 (RMT)和相对中膜面积 (RMA)增加 (P均 <0 .0 1) ;NaHS可明显降低肺动脉压力及抑制肺动脉重建 (P <0 .0 1)。低氧组大鼠肺小动脉平滑肌细胞PCNA和Bcl 2凋亡蛋白表达分别较对照组增高 (P <0 .0 1) ;NaHS可明显下调肺小动脉平滑肌细胞PCNA和Bcl 2蛋白表达 (P <0 .0 1)。结论　新型气体信号分子H2 S可降低肺动脉压力 ,抑制肺动脉平滑肌细胞增殖 ,在HPH及肺血管结构重建的形成中发挥重要作用     

新生儿持续肺动脉高压的病因及治疗

新生儿持续肺动脉高压(persistent pulmonary hypertension of the newborn,PPHN)指生后肺血管阻力持续性增高,肺动脉压超过体循环动脉压,使由胎儿型循环过渡至正常"成人"型循环发生障碍,而引起的心房及(或)动脉导管水平血液的右向左分流,临床出现严重低氧血症等症状.以下将对PPHN的病因及治疗进行讨论.     

吸入一氧化氮治疗新生儿严重低氧性呼吸衰竭38例疗效观察

低氧性呼吸衰竭一直是新生儿临床上的重要难题.其共同的病理生理学特点是肺血管持续收缩导致持续肺动脉高压(PPHN)和右向左分流,这类患儿对一般机械通气和肺表面活性物质反应不良,是导致治疗失败或死亡的重要原因[1].     

新生儿持续肺动脉高压的治疗进展

新生儿持续肺动脉高压(persistent pulmonary hypertension of the newborn,PPHN)是指生后肺血管阻力持续性增高,肺动脉压超过体循环动脉压,胎儿型循环过渡到新生儿型循环发生障碍所导致的危重急症,多见于足月儿或过期产儿。按病因分为原发性及继发性,原发性为不明原因的PPHN,继发性常见于胎粪吸入综合征或新生儿呼吸窘迫综合征等。按发病机制分为肺血管发育不全、肺血管发育不良     

新生儿窒息后的肺栓塞(文摘)

本文描述了用通气灌注肺扫描(Ventilation-Perfusion lung Scan)诊断肺栓塞的两个新生儿病例,其中一例伴有持续肺高压(PPHN)征象。 PPHN与明显的心血右向左分流和全身性低氧血症有关。其机制可能是先天肺循环异常,低氧酸中毒或血管活性物质的释放引起血管收缩所致。尸检提示:血栓栓塞可导致呼吸困难和PPHN。本文试图说明围产期新生儿窒息和随后出现的呼吸困难与肺性栓塞症的关系。     

Persistent pulmonary hypertension of the newborn

In utero, fetal pulmonary vascular resistance (PVR) is high, but rapidly falls after birth. Expansion of the lungs, increase in oxygenation, release of vasoactive mediators, growth factors and remodeling of the vascular wall, all contribute to the reduction in PVR. Persistent pulmonary hypertension of the newborn (PPHN) is defined as a failure of the pulmonary vasculature to relax at birth, resulting in hypoxemia. PPHN is in fact a variety of disorders that have a common presentation. Some of the pathophysiological mechanisms and the therapeutic approaches are discussed below.     

肺动脉高压病因学最新研究进展

肺动脉高压(pulmonary arterial hypertension,PAH)是一组少见的、预后不良的疾病,以进行性增高的肺动脉压力和阻力为特征.其病理变化包括肺血管收缩与重构、肺血管平滑肌和内皮细胞的异常增殖、血栓形成等.PAH的发病机制复杂,最新研究表明肺动脉高压病因包括骨形成蛋白Ⅱ型受体(BMPR2)和活化素受体样激酶(ALK1)等遗传基因变异以及过氧化物酶增殖物激活受体(PPAR)、Rho激酶信号通路等的异常.这为肺动脉高压的治疗和预防提供了更多的理论依据.     

Neonatal thyrotoxicosis and persistent pulmonary hypertension necessitating extracorporeal life support

We report a case of neonatal Graves' disease involving an infant with severe persistent pulmonary hypertension (PPHN) associated with neonatal thyrotoxicosis that necessitated extracorporeal membrane oxygenation. Hyperthyroidism, although uncommon in the newborn period, has been associated with pulmonary hypertension among adults. The exact mechanisms responsible for this effect on pulmonary vascular pressure are not well understood. Recent studies have provided evidence that thyrotoxicosis has direct and indirect effects on pulmonary vascular maturation, metabolism of endogenous pulmonary vasodilators, oxygen economy, vascular smooth muscle reactivity, and surfactant production, all of which may contribute to the pathophysiologic development of PPHN. Therefore, because PPHN is a significant clinical entity among term newborns and the symptoms of hyperthyroidism may be confused initially with those of other underlying disorders associated with PPHN (eg, sepsis), it would be prudent to perform screening for hyperthyroidism among affected newborns.     

Persistent pulmonary hypertension of the newborn

Failure of the normal circulatory adaptation to extrauterine life results in persistent pulmonary hypertension of the newborn (PPHN). Although this condition is most often secondary to parenchymal lung disease or lung hypoplasia, it may also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance with resultant right-to-left shunting of blood and hypoxemia. Although the preliminary diagnosis of PPHN is often based on differential cyanosis and labile hypoxemia, the diagnosis is confirmed by echocardiography. Management strategies include optimal lung recruitment and use of surfactant in patients with parenchymal lung disease, maintaining optimal oxygenation and stable blood pressures, avoidance of respiratory and metabolic acidosis and alkalosis, and pulmonary vasodilator therapy. Extracorporeal membrane oxygenation is considered when medical management fails. Although mortality associated with PPHN has decreased significantly with improvements in medical care, there remains the potential risk for neurodevelopmental disability which warrants close follow-up of affected infants after discharge.     

Persistent pulmonary hypertension in preterm-infants

Persistent pulmonary hypertension of the newborn (PPHN) is a cyanotic syndrome that occurs primarily in full-term and postmature infants and causes right-to-left shunts at the atrial or ductal levels or both. Term babies with PPHN show structural changes in pulmonary vascular smooth muscle as a result of chronic prenatal distress. It is our opinion that in preterm babies the PPHN syndrome also exists. In this group of patients the potential pathways to the persistence of high pulmonary vascular resistence are only functional vascular changes precipitated by acute perinatal stress. The cyanosis of PPHN is rapidly regredient in preterm infants and clinical resolution occurs promptly if the diagnosis is correct and the treatment is started as early as possible in centers capable of extensive monitoring and neonatal supportive care to minimize the risks of Tolazoline therapy.     

缺氧性肺动脉高压新生大鼠肺血管重塑的研究

目的：通过建立新生大鼠缺氧性肺动脉高压（hypoxia-induced pulmonary hypertension,HPH）模型,探讨HPH新生大鼠发病过程中肺血管重塑的变化。方法：将96只新生Wistar大鼠随机分为2组：缺氧组和常氧对照组,缺氧组建立新生大鼠HPH模型。分别于缺氧3、5、7、10、14、21 d 取缺氧组及对照组同日龄新生大鼠各8只测定其平均肺动脉压（mean pulmonary arteria pressure,mPAP）、右心室肥大指数（right ventricle hypertrophy index,RVHI）,血管重塑指标MT%、MA%,观察肺血管超微结构。结果：缺氧组大鼠在缺氧3、5、7、10、14、21 d mPAP持续上升,明显高于对照组（P<0.05）;随着缺氧时间的延长,差异更为显著。缺氧7 d后MT%、MA%、RVHI明显高于对照组（P<0.05）;随着缺氧时间的延长,差异同样更为显著。透射电镜显示,缺氧7 d后大鼠肺小动脉内膜增厚,内皮细胞增生、变性,细胞器增多;细胞外基质见胶原纤维沉积;出现肺血管重塑改变。结论：新生大鼠缺氧3～5 d肺动脉压力增高,处于肺血管痉挛阶段;缺氧7 d后肺血管出现重塑,右心室肥厚,出现不可逆变化;随着缺氧时间延长,上述变化加剧。     

Effect of blood pressure cuffs on neonatal circulation: Their potential application to newborns with persistent pulmonary hypertension

The contribution of vasoactive pharmacologic agents to the care of the infant with primary pulmonary hypertension of the newborn (PPHN) is hampered by their limited ability to act selectively on different vascular beds. In contrast, blood pressure (BP) cuffs decrease flow and increase resistance only in the extremities around which they are applied. They therefore offer a means of increasing systemic vascular resistance without affecting pulmonary vascular resistance, a hemodynamic effect that may be particularly desirable among PPHN patients receiving vasodilators. We studied the effect of BP cuffs on the circulation of nine healthy neonates and three infants with severe PPHN. Among the healthy neonates, inflation of the cuffs to 20 mmHg had no discernible hemodynamic effect. Inflation to systolic pressures, however, caused the left ventricular preejection period to increase from 36±9 ms to 45±10 ms, the end-diastolic dimension to increase from 1.80±0.16 cm to 1.92±0.16 cm, and the cardiac output to fall to 87±12% of baseline (allp<0.05)—changes indicative of an increase in systemic vascular resistance. Application of BP cuffs to the patients with PPHN was associated with 10–25 mmHg increases in transcutaneous arterial oxygen tensions. Administration of tolazoline to these patients while the cuffs were inflated resulted in additional 10–20 mmHg increases and did not precipitate hypotension. These observations suggest that BP cuffs can play a useful role in the management of patients with PPHN.     

Nitric oxide further attenuates pulmonary hypertension in magnesium-treated piglets

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) commonly appears as a complication of several pulmonary and non-pulmonary diseases. The hypoxia possibly inhibits Ca2+ +/- dependent K+ channels, thus resulting in membrane depolarization of pulmonary smooth muscle cells, which leads to the opening of Ca2+ channels and Ca2+ entry, resulting in contraction of the vascular smooth muscle. However, magnesium (Mg2+) is an antagonist of Ca2+. We studied the effect of magnesium sulfate on the treatment of hypoxia-induced pulmonary hypertension and compared to the site of action of nitric oxide (NO). METHODS: Zero-day-old piglets were used in each experiment. The effects of Mg2+ were tested in each hypoxic, normoxic and hyperoxic states. Once the desired physical state was achieved, Mg2+ was administered at a dose of 100 mg/kg approximately every 10 min. In order to determine the exact mechanism of the Mg2+, Nw-nitro-l-arginine (LNNA), a NO synthase-inhibitor, was administered simultaneously with Mg2+ in some of the experiments. RESULTS: There was a significant correlation between the percent reduction of the pulmonary arterial pressure (PAP) caused by magnesium and the level of oxygen (O2) present in the pulmonary artery. The greatest amount of reduction was seen in the hypoxic condition where the least amount of O2 is found. A further reduction in the PAP was seen when NO was given at the end of the Mg2+ trials. There was no significant reduction seen in the systemic arterial pressure. CONCLUSIONS: Inhaled NO further reduced the PAP in piglets already treated with Mg2+.     

Pulmonary vasodilator strategies in neonates with acute hypoxemic respiratory failure and pulmonary hypertension

The management of acute hypoxemic respiratory failure (AHRF) in newborns continues to be a clinical challenge with elevated risk for significant morbidities and mortality, especially when accompanied with persistent pulmonary hypertension of the newborn (PPHN). PPHN is a syndrome characterized by marked hypoxemia secondary to extrapulmonary right-to-left shunting across the ductus arteriosus and/or foramen ovale with high pulmonary artery pressure and increased pulmonary vascular resistance (PVR). After optimizing respiratory support, cardiac performance and systemic hemodynamics, targeting persistent elevations in PVR with inhaled nitric oxide (iNO) therapy has improved outcomes of neonates with PPHN physiology. Despite aggressive cardiopulmonary management, a significant proportion of patients have an inadequate response to iNO therapy, prompting consideration for additional pulmonary vasodilator therapy. This article reviews the pathophysiology and management of PPHN in term newborns with AHRF while highlighting both animal and human data to inform a physiologic approach to the use of PH-targeted therapies.     

Diagnosis and treatment of pulmonary hypertension in infancy

Normal pulmonary vascular development in infancy requires maintenance of low pulmonary vascular resistance after birth, and is necessary for normal lung function and growth. The developing lung is subject to multiple genetic, pathological and/or environmental influences that can adversely affect lung adaptation, development, and growth, leading to pulmonary hypertension. New classifications of pulmonary hypertension are beginning to account for these diverse phenotypes, and or pulmonary hypertension in infants due to PPHN, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). The most effective pharmacotherapeutic strategies for infants with PPHN are directed at selective reduction of PVR, and take advantage of a rapidly advancing understanding of the altered signaling pathways in the remodeled vasculature.