慢性阻塞性肺疾病合并肺动脉高压诊治的新认识

肺动脉高压是COPD的重要合并症.一般而言,COPD患者出现严重气流受限时可发生肺动脉高压,常伴有慢性低氧血症,其主要病理生理过程为慢性肺泡性低氧,也可能有其他发病机制的参与.COPD合并肺动脉高压时的平均肺动脉压＞20 mm Hg(1 mm Hg=0.133 kPa),COPD合并重度肺动脉高压时的平均肺动脉压＞35 mm Hg[1].由于肺泡低通气造成的肺泡性低氧一般是肺动脉高压产生的主要原因,临床上低氧血症可导致COPD患者发生严重的肺动脉高压和右心衰竭[2].     

缺氧诱导因子1与心血管疾病的关系

缺氧诱导因子1(HIF1)是一种在体内广泛存在的bHLH转录因子,由α和β亚单位组成.HIF1对机体氧稳态的调节有重要意义.近年研究发现,HIF1与心血管发育调控、缺血性心脏病、肺动脉高压有密切关系.     

慢性阻塞性肺疾病和低氧性肺动脉高压诊治进展

按照最新的分类诊断标准,临床上将肺动脉高压(PH)分为5类,其中肺部疾病和(或)低氧所致的肺动脉高压属于肺动脉高压的第3类[1],相关的疾病包括慢性阻塞性肺疾病(COPD)、间质性肺疾病、其他伴有限制性和阻塞性混合型通气障碍的肺部疾病、睡眠呼吸暂停、肺泡低通气、慢性高原缺氧和肺发育异常等.我们在此探讨COPD合并肺动脉高压的临床特征及治疗进展.     

缺氧诱导因子1与心血管疾病的关系

缺氧诱导因子1（HIF1）是一种在体内广泛存在的bHLH转录因子，由α和β亚单位组成。HIF1对机体氧稳态的调节有重要意义。近年研究发现，HIF1与心血管发育调控、缺血性心脏病、肺动脉高压有密切关系。     

低氧诱导因子与低氧性肺动脉高压形成机制的相关研究

低氧诱导因子(hypoxia inducible factor-1,HIF-1)是细胞为适应缺氧环境和各种病理刺激所表达的核心调控因子,可调控多种与低氧条件下细胞生存相关靶基因的转录和信号的转导,在低氧性肺动脉高压、白血病、炎症、肿瘤等多种疾病的发生发展过程中起着重要的作用.近年来研究发现,HIF-1与低氧性肺动脉高压形成机制中离子通道的紊乱、血管活性物质的失衡、炎症的加重、肺血管的重塑等密切相关.本文将对低氧诱导因子的结构特征及其与低氧性肺动脉高压形成机制的最新研究概况作一综述.     

炎症反应在慢性阻塞性肺疾病伴发肺动脉高压中的作用

炎症反应在慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)伴发肺动脉高压的发生、发展中起着重要作用.气道存在炎症时,激活的炎症细胞释放肿瘤坏死因子a(TNF-α)、白介素6(IL-6)和IL-8等多种细胞因子,共同参与气道壁、肺泡壁的结构破坏和重塑.这些气道炎症反应不仅影响已存在缺氧的COPD伴肺动脉高压患者,也可影响尚不存在缺氧的COPD伴肺动脉高压患者,可能是早期COPD患者肺动脉重塑及血流动力学改变的始动环节.     

miRNA-214靶向HIF1AN对肺动脉平滑肌细胞增殖和迁移的影响

目的研究miR-214在肺动脉高压发病机制中的调控作用。方法应用逆转录聚合酶链式反应(qRT-PCR)方法检测miR-214在肺动脉高压患者血清及缺氧诱导肺动脉平滑肌细胞中表达;通过EdU渗入法以及划痕实验研究miR-214对肺动脉平滑肌细胞增殖及迁移的影响;对miR-214靶基因预测并验证。结果肺动脉高压患者血清中miR-214显著高于正常人血清(p0.001);经过缺氧处理肺动脉平滑肌细胞明显促进miR-214表达(p0.01);miR-214促进缺氧条件下的肺动脉平滑肌细胞增殖、迁移;双荧光素酶报告系统证明miR-214能够与缺氧诱导因子1α抑制因子(HIF1AN)的3'-UTR结合;HIF1AN为miR-214在肺动脉平滑肌细胞中的靶向基因。结论miR-214可能通过靶基因HIF1AN参与肺动脉高压调节机制。     

慢性阻塞性肺疾病并肺动脉高压的实验动物模型研究现状

借助实验动物模型研究慢性阻塞性肺疾病(COPD)并肺动脉高压形成的机制,一直是COPD研究工作中的一大热点。用于反映COPD并肺动脉高压形成的动物模型有多种,其中低氧性肺动脉高压动物模型最为常用。导致COPD并肺动脉高压形成的因素很多,在疾病发展的过程中各种细胞生长因子、炎症因子和炎症细胞同时存在,相互影响。低氧、炎症因素和基因多态性均被纳入不同模型中进行研究。用单一因素诱发的肺动脉高压模型很难复制出人类COPD并肺动脉高压的病理、生理改变。     

COPD肺动脉高压诊断和治疗的进展

肺动脉高压(指平均肺动脉压力大于20mmHg)是一种常见的临床病症,它可由多种原因引起。慢性阻塞性肺疾患(COPD)合并的肺动脉高压是继发性肺动脉高压的一种,这里简称 COPD 肺动脉高压。肺动脉高压的产生明显影响 COPD 病人的病程和预后。近年来,有关 COPD 肺动脉高压诊断和治疗的研究越来越多,并不断取得新进展。     

血管内皮生长因子与慢性阻塞性肺疾病继发肺动脉高压的关系

血管内皮生长因子(vascular endothelial growth factor,VEGF)是一种重要的血管内皮细胞丝裂原和通透因子.肺血管的重塑与慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)继发肺动脉高压密切相关.VEGF贯穿于COPD发展的全过程,在COPD的不同时期呈现不同的表达水平,发挥不同的生物学作用.气道炎症、低氧等因素可以在COPD早期促进VEGF及其受体的表达上调从而导致肺血管重塑的发生发展,VEGF也可以对COPD后期继发肺动脉高压时的重度肺血管重塑起到一定的修复作用.通过阐述VEGF、COPD肺血管重塑及继发肺动脉高压之间的相互关系,可以对COPD继发肺动脉高压的诊断和治疗提供新的思路.     

Pulmonary diseases and heart function

The most severe cardiac sequel to lung disease is the load on the right ventricle due to pulmonary hypertension with the development of a cor pulmonale. This is characterized by hypertrophy and/or dilatation of the right ventricle because of a primary impairment of lung function and/or lung structure. The most important pathomechanisms for the development of pulmonary hypertension are vessel obliteration, mechanical lesions, primary vascular or extra-vascular inflammation and hypoxic vasoconstriction. Chronic obstructive pulmonary disease (COPD) is one of the most important reasons for chronic cor pulmonale. A further very common reason is obstructive sleep apnea syndrome, especially if combined with a COPD. In this case, the prevalence of cor pulmonale can reach 80%. The development of a chronic cor pulmonale is the most striking negative prognostic factor for these patients. Only 30% of COPD patients with cor pulmonale survive longer than 5 years, and only early detection of the disturbances to respiration which might potentially lead to cor pulmonale and their subsequent therapy are able to improve the patient's prognosis. Furthermore, pulmonary diseases may also have an impact on the left heart side in terms of an impairment of left heart function or by inducing severe arrhythmias . Thus, lung diseases may have both a significant impact on right and left heart performance.     

Cor pulmonale: an overview

Chronic cor pulmonale involves the enlargement of the right ventricle as a result of pulmonary hypertension due to pulmonary disorders involving the lung parenchyma, bellows function, or ventilatory drive. The right ventricular hypertrophy that occurs in chronic cor pulmonale is a direct result of chronic hypoxic pulmonary vasoconstriction and subsequent pulmonary artery hypertension, leading to increased right ventricular work and stress. We discuss methods by which hypoxic vasoconstriction and reduction in the pulmonary vascular bed lead to the development of pulmonary artery hypertension. This article reviews the interaction of the pulmonary vasculature and right ventricle in the non-diseased state as well as during disease exacerbations. Ventricular dependence and its contribution to the pathophysiology of right ventricular failure are also reviewed. In addition, we provide an overview of specific disease states that can result in the development of chronic cor pulmonale including chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep apnea, alveolar hypoventilation disorders, and primary pulmonary hypertension. We also review the current diagnostic studies used to evaluate and study cor pulmonale.     

核因子κB与慢性阻塞性肺疾病继发的肺动脉高压

核因子κB是一种多功能核转录因子,能调节多种参与炎症免疫反应的细胞因子、炎症介质,黏附分子及蛋白酶类的基因转录过程,从而控制它们的生物合成.肺动脉高压是临床常见的病理生理过程,致病的原因有很多,但慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是最常见的病因.COPD是一种以气道气流受限且不完全可逆为特征的疾病,气道炎症是COPD重要病理基础,而且在肺血管重构中有很重要的作用,肺血管重构进一步导致COPD继发肺动脉高压.通过阐述核因子κB、COPD气道炎症、肺血管重构之间相互作用的机制,可以对COPD继发的肺动脉高压的治疗提供新的思路和方法.     

Lungenerkrankungen und Herzfunktion

The most severe cardiac sequel to lung disease is the load on the right ventricle due to pulmonary hypertension with the development of a cor pulmonale. This is characterized by hypertrophy and/or dilatation of the right ventricle because of a primary impairment of lung function and/or lung structure. The most important pathomechanisms for the development of pulmonary hypertension are vessel obliteration, mechanical lesions, primary vascular or extra-vascular inflammation and hypoxic vasoconstriction. Chronic obstructive pulmonary diesease (COPD) is one of the most important reasons for chronic cor pulmonale. A further very common reason is obstructive sleep apnea syndrome, especially if combined with a COPD. In this case, the prevalence of cor pulmonale can reach 80%. The development of a chronic cor pulmonale is the most striking negative prognostic factor for these patients. Only 30% of COPD patients with cor pulmonale survive longer than 5 years, and only early detection of the disturbances to respiration which might potentially lead to cor pulmonale and their subsequent therapy are able to improve the patient’s prognosis. Furthermore, pulmonary diseases may also have an impact on the left heart side in terms of an impairment of left heart function or by inducing severe arrhytmias. Thus, lung diseases may have both a significant impact on right and left heart performance.     

Chronic obstructive pulmonary disease and the early stage of cor pulmonale: A perspective in treatment with pulmonary arterial hypertension-approved drugs

Cor pulmonale is right ventricular hypertrophy and/or dilation caused by pulmonary hypertension (PH) due to diseases affecting the lung function and structure. Recently, the definition of PH was revised from a mean pulmonary arterial pressure (mPAP) >25 mmHg to an mPAP >20 mmHg based on the Nice statement; this might expedite the detection of cor pulmonale. However, the only treatment for cor pulmonale for the past 3 decades has been to maintain the lung function and oxygen saturation.Chronic obstructive pulmonary disease (COPD) is the leading cause of cor pulmonale. Cor pulmonale in COPD is generally known to occur due to loss of vascular bed and chronic hypoxic pulmonary vasoconstriction (HPV) due to alveolar wall destruction. However, a recent study suggested that in some patients with COPD, the pulmonary vascular alterations include components that are primary lesions of the pulmonary artery. These alterations may be similar to the remodeling that occurs in pulmonary arterial hypertension (PAH). Although, there is no evidence supporting the treatment of COPD patients with PH using drugs approved for PAH, such drugs may be effective in the treatment of a selected group of COPD patients, whose disease includes PAH-like vascular components.To distinguish these patients, it is necessary to understand the histopathology of COPD and renew our understanding of the concept of cor pulmonale, which treats the heart and lung as a single unit. Herein, we review the recent histopathological concepts of COPD with respect to the progression of cor pulmonale.     

Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease

Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). The increase in pulmonary artery pressures is often mild to moderate. However, 5-10% of patients with advanced COPD may suffer from severe pulmonary hypertension and present with a progressively downhill clinical course because of right heart failure added to ventilatory handicap. The prevalence of clinically significant severe pulmonary hypertension in COPD is roughly estimated to be of 1-2/1,000. The cause of pulmonary hypertension in COPD is generally assumed to be hypoxic pulmonary vasoconstriction leading to permanent medial hypertrophy. However, recent pathologic studies point rather at extensive remodeling of all layers of the pulmonary arterial walls. These aspects account for minimal reversibility with supplemental oxygen. There may be a case for pharmacologic treatment of pulmonary hypertension in selected patients with advanced COPD and right heart failure. However, it will be a challenge for randomized controlled trials to overcome the difficulties of the diagnosis of right ventricular failure and the definition of a relevant primary endpoint in pulmonary hypertensive patients with COPD.     

Cor pulmonale in chronic obstructive pulmonary disease. Circulatory pathophysiology and management

The development of pulmonary hypertension and right ventricular failure in COPD patients signals a poor prognosis. In hypoxic patients, long-term oxygen therapy prolongs life and appears to prevent or lessen the progression of pulmonary hypertension. However, oxygen therapy does not benefit and is not indicated for all COPD patients, and even in those patients who improve with oxygen, there remains a need to further improve survival. Therefore, there continues to be active investigations into pharmacologic agents that might reduce pulmonary hypertension or improve right ventricular function. Although many agents appear to have salutary acute effects, it has been more difficult to establish evidence for sustained hemodynamic benefits from chronic drug therapy. Furthermore, some effective agents may not provide additive benefit when combined with standard supplemental oxygen use, although the available data are limited. Clearly, further research is necessary to identify which COPD patients, if any, may benefit from either beta-agonists or vasodilators for the treatment or prevention of cor pulmonale at some time during the natural history of their disease.