肺动脉高压动物模型的理论研究及其制备特点

背景:建立肺动脉高压动物模型,对其深入研究有助于推动临床对肺动脉高压诊治水平的不断提高。目的:总结与探讨各种肺动脉动物模型的制备、病理生理学特点以及对临床肺动脉高压的模拟性。方法:应用计算机检索PubMed数据库1975-01/2009-09期间相关文章,检索词为"pulmonary hypertension、animal model",同时检索中国期刊全文数据1990-01/2009-09期间的相关文章,检索词为"肺动脉高压,动物模型"。纳入外科手术制作肺动脉高压动物模型的研究、药物注射制作肺动脉高压动物模型的研究、有新生内膜形成的肺动脉高压动物模型研究、肺动脉高压动物模型与临床肺动脉高压患者的病理生理对比的研究、肺动脉高压动物模型的药物干预研究。结果与结论:已知的肺动脉高压动物模型建立方法包括.外科手术建立分流术、野百合碱注射、低氧吸入法等经典方法,以及近年报道的几种有新生内膜产生的重度肺动脉高压模型。此类模型建立经过了不断地改进,为了解肺动脉高压的细胞及分子病理学机制提供了帮助,但尚不明确这些模型能在多大程度模拟临床肺动脉高压的细胞和分子发生机制,因此仍不清楚哪类模型更能代表临床肺动脉高压的病理机制。     

慢性血栓栓塞性肺动脉高压病例——与子宫肌瘤相关?

目的:通过分析2例慢性血栓栓塞性肺动脉高压(chronic thromboembolic pulmonary hypertension, CTEPH)的女性病人的病例报告以及循证国内外研究结果,提高对罕见的与子宫肌瘤相关的CTEPH的认识,提高肺动脉高压的诊治水平.方法:病例报告及文献检索.结果:既往有子宫肌瘤的女性肺动脉高压患者,临床发现肺动脉血栓形成,诊断为CTEPH,CTEPH发病可能与子宫肌瘤相关.结论:慢性血栓栓塞性肺动脉高压和/或肺动脉高压可能是子宫肌瘤一种罕见的并发症.在临床实践中应考虑其可能性,尽早给予病人子宫肌瘤剔除术治疗及抗血栓治疗,提高治疗水平.     

肺动脉高压治疗的进展

肺动脉高压治疗的进展同济医科大学（武汉４３００３０）王迪浔肺动脉高压除病因治疗，如由肺栓塞引起的阻塞性肺动脉高压用溶栓及抗凝治疗，各种类型的肺动脉高压用血管舒张药均有不同程度的降压作用，说明在发病机制中均存在肺血管收缩因素。用血管舒张药的主要副作用为...     

慢阻肺引发肺动脉高压预后评价与ET-1、H2S、NO的相关性研究

目的探讨慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)引发肺动脉高压(pulmonary arterial hypertension,PAH)预后评价与内皮素(ET-1)、内源性硫化氢(H_2S)和一氧化氮(NO)的相关性研究。方法选取2016年1月至2017年12月本院确诊的慢阻肺并发肺动脉高压患者120例,按肺动脉压水平分为并发轻度PAH组(45例)、中度PAH组(42例)、重度PAH组(33例),选取COPD不并发肺动脉高压的患者为对照组(40例)。分别检测各组受试者外周静脉血中ET-1、H_2S和NO表达水平。结果与对照组相比,慢阻肺并发PAH患者血浆内ET-1水平显著升高,H_2S和NO水平显著降低(P <0. 05);随着疾病程度的加重,患者血清内各指标变化趋势更为显著(P <0.05)。与治疗前相比,各组患者血清内ET-1水平显著降低,H_2S和NO水平显著升高(P<0.05)。与对照组相比,慢阻肺并发PAH患者FEV_1/FVC(%)及FEV_1%预计值显著降低(P<0.05)。随着疾病程度的加重,患者FEV_1/FVC(%)及FEV_1%预计值降低更为明显(P<0.05)。与治疗前相比,患者FEV_1/FVC(%)及FEV,%预计值显著升高(P<0.05)。血浆H_2S、NO水平与FEV_1/FVC(%)、FEV_1%预计值呈显著正相关(P<0.05),ET-1水平则与其呈明显负相关(P<0.05)。血浆H_2S、NO水平与患者肺动脉压力呈显著负相关(P<0.05),ET-1水平则与其呈明显正相关(P <0.05)。血浆H_2S水平和NO水平与呼吸系统评分、循环系统评分、躯体功能评分、认知功能评分、社会功能评分及生活质量评分呈显著正相关,ET-1水平与呼吸系统评分、循环系统评分、躯体功能评分、认知功能评分、社会功能评分及生活质量评分呈负相关。结论慢阻肺并发肺动脉高压患者体内ET-1、H_2S和NO表达水平与肺功能及病情变化密切相关,可作为监测病情严重程度的良好指标。     

N-proBNP对慢性心衰患者发生肺动脉高压的预测价值

目的 探讨N-proBNP对慢性心力衰竭患者合并肺动脉高压的预测价值。方法 选取我院心脏科住院的140例心力衰竭患者,根据是否发生肺动脉高压,分为心衰合并肺动脉高压组110例及心衰未合并肺动脉高压组30例,收集临床资料及实验室指标,分析N-ProBNP水平对心衰发生肺动脉高压预测价值。结果 与未发生肺动脉高压相比,合并肺动脉高压组中N-proBNP、尿酸、总胆红素、心率、心功能分级差异有统计学有意义（P＜0.05）。相关性分析显示,尿酸、总胆红素、心率、红细胞分布宽度、N-proBNP与肺动脉高压之间存在正相关（r=0.237、0.355、0.225、0.259、0.357,P＜0.05）,将其进行多元线性回归分析发现,总胆红素及N-proBNP与肺动脉高压独立相关。ROC曲线显示,N-proBNP对心衰合并肺动脉高压有很好的预测价值,曲线下面积为0.678。结论 N-ProBNP对心衰肺动发生脉高压有很好的预测价值。     

一种可逆转肺动脉高压基因治疗的发现

某高校Alberta研究小组在寻找肺动脉高压(PAH)(一种由细胞无限制生长导致的致命性的肺动脉压增高)最佳治疗方案的时候发现了重要的新信息.该病在短期内可导致心力衰竭及死亡,但目前该病治疗方法有限.     

一种可逆转肺动脉高压基因治疗的发现

某高校Alberta研究小组在寻找肺动脉高压（PAH）（一种由细胞无限制生长导致的致命性的肺动脉压增高）最佳治疗方案的时候发现了重要的新信息。该病在短期内可导致心力衰竭及死亡，但目前该病治疗方法有限。     

血清NSE在HIE患儿中的应用探讨

新生儿缺氧缺血性脑病（hypoxic ischemic encephalopathy，HIE）是围产期缺氧所致的严重并发症，其发病率和病死率都较高，部分患儿可遗留严重的神经系统后遗症。因此寻找早期诊断HIE脑损伤程度的指标和方法，对判断病情严重程度、预后及指导临床治疗均具有重要意义。有文献报道，测定血清神经元特异性烯醇化酶（neuron specmcenolase，NSE）对缺氧缺血性脑损伤的诊断有一定意义。为此，我们应用放射免疫分析（RIA）对98例HIE患者血清NSE水平进行了检测，以探讨在HIE中的变化及临床意义。     

移植骨髓间充质干细胞预防野百合碱诱导的肺动脉高压

背景：干细胞移植治疗肺动脉高压有一定疗效。 目的：观察骨髓间充质干细胞移植治疗肺动脉高压的效果及并探讨其作用机制。 方法：采用密度梯度离心法体外培养、纯化、扩增获得大鼠骨髓间充质干细胞,经荧光染料标记后备用。大鼠皮下注射野百合碱建立肺动脉高压模型,建模后1周将大鼠随机分为3组,干细胞移植组和肺动脉高压组大鼠皮下注射野百合碱建立肺动脉高压模型,1周后干细胞组大鼠经舌下静脉注射骨髓间充质干细胞悬液,肺动脉高压组注射等量不含干细胞的培养液,对照组皮下注射等量生理盐水。 结果与结论：移植后2周,与野百合碱诱导的肺动脉高压大鼠相比干细胞移植组血流动力学参数及右心室与体质量之比明显改善(P < 0.05);肺血管重构程度减轻(P < 0.05)。荧光显微镜下发现干细胞组移植的骨髓间充质干细胞在大鼠体内能存活至少2周,部分干细胞能转化为血管平滑肌细胞。说明静脉移植骨髓间充质干细胞能明显改善野百合碱造成的肺动脉高压大鼠肺血管和右心室结构的损伤。     

外周血中性粒细胞/淋巴细胞比值在慢性阻塞性肺病相关肺动脉高压患者中的预后价值

目的：探讨外周血中性粒细胞/淋巴细胞比值(neutrophil/lymphocyte ratio,NLR)对慢性阻塞性肺病(chronic obstructive pulmonary disease,COPD)相关肺动脉高压患者预后的评判价值。方法：选择2013年1月至2014年3月收治入上海交通大学医学院附属新华医院急诊科的200例COPD相关肺动脉高压(pulmonary hypertension,PH)患者为研究对象,对其进行至少2年的生存随访,随访终点为全因死亡,按照生存情况分为生存组和死亡组;记录各组入院24 h的一般临床资料,血常规[C反应蛋白(C-reactive protein,CRP)、中性粒细胞计数(neutrophils count,NEU)及淋巴细胞计数(lymphocyte count,LYM)并计算两者间比值(NLR)]、肌酐、尿素氮、胆红素、WHO肺动脉高压功能分级、肺动脉收缩压等;绘制受试者工作特征(receiver operating characteristic,ROC)曲线,分析NLR预测患者预后的临床价值;并以Kaplan-Meier法绘制观察指标不同水平下的生存曲线,进行生存分析。COX回归分析各指标提示预后的价值。结果：死亡组患者NLR,CRP,WHO肺动脉高压功能分级、肺动脉收缩压、尿素氮、肌酐、中性粒细胞计数高于生存组,淋巴细胞计数低于生存组,差异均具有统计学意义(P<0.05)。根据ROC曲线分析,NLR的ROC曲线下面积(AUC)为0.720(P<0.01),高于肌酐(AUC=0.716)、中性粒细胞计数(AUC=0.655)、肺动脉收缩压(AUC=0.652)及CRP(AUC=0.643)。当NLR截断值为4.7时,其灵敏度为74.2%,特异度为72.0%。Kaplan-Meier生存曲线分析显示,NLR值水平较高组预后明显差于水平较低组(P<0.01)。单因素Cox回归分析提示NLR是提示患者不良预后的危险因素,多因素Cox回归分析(P>0.05)。结论：NLR水平与COPD相关肺动脉高压患者临床预后呈明显相关;NLR水平越高则提示病情较重,预后较差。     

Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases

Pulmonary arterial hypertension is a severe complication of connective tissue diseases. It is currently well established that pulmonary arterial hypertension associated with connective tissue diseases such as systemic sclerosis is frequently less responsive or even refractory to pulmonary vasodilator therapies. In that setting, pulmonary venoocclusive disease is believed to contribute to treatment failures. We therefore hypothesized that pulmonary arterial hypertension associated with connective tissue diseases may be associated with obstructive lesions of pulmonary veins. Lung samples from 8 patients with pulmonary arterial hypertension associated with connective tissue disease (4 limited systemic sclerosis, 2 systemic lupus erythematosus, 1 mixed connective tissue diseases, and 1 rheumatoid arthritis) were studied by light microscopy and analyzed by immunohistochemistry (5 postmortem samples, 3 explants after lung transplantation). Findings were compared with 29 pulmonary arterial hypertension cases from patients displaying neither connective tissue diseases nor associated conditions. We found that (a) 6 (75%) of 8 patients with pulmonary arterial hypertension associated with connective tissue diseases showed significant obstructive pulmonary vascular lesions predominating in veins/preseptal venules, as compared with 5 (17.2%) of 29 non-connective tissue diseases control pulmonary arterial hypertension; (b) lesions of small muscular arteries were consistently present in pulmonary arterial hypertension associated with connective tissue diseases, showing mostly intimal fibrosis and thrombotic lesions; and (c) 6 of 8 lung samples from patients with pulmonary arterial hypertension associated with connective tissue diseases revealed perivascular inflammatory infiltration. In conclusion, our study highlights the fact that pulmonary arterial hypertension complicating the course of connective tissue diseases may be characterized by a more frequent involvement of pulmonary veins and may thus explain why these patients are less prone to respond to specific pulmonary arterial hypertension treatment as compared with idiopathic pulmonary arterial hypertension.     

A review of wave mechanics in the pulmonary artery with an emphasis on wave intensity analysis

Mean pulmonary arterial pressure and pulmonary vascular resistance (PVR) remain the most common haemodynamic measures to evaluate the severity and prognosis of pulmonary hypertension. However, PVR only captures the non‐oscillatory component of the right ventricular hydraulic load and neglects the dynamic compliance of the pulmonary arteries and the contribution of wave transmission. Wave intensity analysis offers an alternative way to assess the pulmonary vasculature in health and disease. Wave speed is a measure of arterial stiffness, and the magnitude and timing of wave reflection provide information on the degree of impedance mismatch between the proximal and distal circulation. Studies in the pulmonary artery have demonstrated distinct differences in arterial wave propagation between individuals with and without pulmonary vascular disease. Notably, greater wave speed and greater wave reflection are observed in patients with pulmonary hypertension and in animal models exposed to hypoxia. Studying wave propagation makes a valuable contribution to the assessment of the arterial system in pulmonary hypertension, and here, we briefly review the current state of knowledge of the methods used to evaluate arterial waves in the pulmonary artery.     

结缔组织病相关的肺动脉高压研究进展

肺动脉高压是结缔组织病（CTD）的严重并发症之一。结缔组织病中最常受累的是系统性硬化症（SSc）,而混合性结缔组织病（MCTD）、系统性红斑狼疮（SLE）及炎性肌病包括多肌炎和皮肌炎也常被累及。结缔组织病相关的肺动脉高压引起的原因不仅是肺动脉的病变,慢性血栓的形成,自身免疫反应和肺间质病变也是引起肺动脉高压的原因之一。由于其症状出现晚且不典型,预后甚差,死亡率高,因此对结缔组织病相关的肺动脉高压早期诊断,及时合理的治疗十分重要。     

The role of platelets in the development and progression of pulmonary arterial hypertension

Pulmonary arterial hypertension is a multifactorial disease characterized by vasoconstriction, vascular remodeling, inflammation and thrombosis. Although an increasing number of research confirmed that pulmonary artery endothelial cells, pulmonary artery smooth muscle cells as well as platelets have a role in the pulmonary arterial hypertension pathogenesis, it is still unclear what integrates these factors. In this paper, we review the evidence that platelets through releasing a large variety of chemokines could actively impact the pulmonary arterial hypertension pathogenesis and development. A recent publication revealed that not only an excess of platelet derived cytokines, but also a deficiency may be associated with pulmonary arterial hypertension development and progression. Hence, a simple platelet blockade may not be a correct action to treat pulmonary arterial hypertension. Our review aims to analyse the interactions between the platelets and different types of cells involved in pulmonary arterial hypertension pathogenesis. This knowledge could help to find novel therapeutic options and improve prognosis in this devastating disease.     

Scleroderma Lung Disease

Pulmonary involvement is second in frequency only to esophageal involvement as a visceral complication of systemic sclerosis (SSc) and has surpassed renal involvement as the most common cause of death. Interstitial lung disease and pulmonary vascular disease, particularly pulmonary arterial hypertension, are the most commonly encountered types of lung involvement. Chronic aspiration, airway disease, neuromuscular weakness, extrinsic pulmonary restrictive pathology, pleural effusions, pneumothorax, and lung cancer cause clinically significant disease and occur commonly enough to be routinely considered in the assessment of the SSc patient with respiratory symptoms. Affected patients have a significantly worse prognosis than patients with SSc who are free of pulmonary involvement.     

Vaskulopathien bei pulmonal-arterieller Hypertonie

Pulmonary arterial hypertension (PAH) is a term which has recently been redefined and includes idiopathic pulmonary arterial hypertension, familial pulmonary arterial hypertension PAH related to specific pathological conditions (e.g. connective tissue diseases), as well as PAH caused by veno-occlusive disease or capillary hemangiomatosis. The clinical manifestation seems to be related to a peculiar pathological anatomy involving small, muscular pulmonary arteries, capillaries and veins. In addition to common hypertrophy of the tunica media, other vascular compartments may also be affected by intimal thickening or adventitial fibrosis. Moreover, complex lesions, such as so called plexiform lesions and arteritis can be present in certain forms of the disease. While the recent identification of responsible gene mutations in subgroups of patients have shed some light on disease evolution, therapeutic strategies must currently rely on vasodilative and antimitogenic drugs acting on the intimal and medial level of the affected pulmonary vessels. The clinical outcome of patients suffering from PAH remains poor, underlining our need for a better comprehension of disease pathophysiology, and thus for the characterization of specific histomorphological patterns.     

肺动脉高压的血栓栓塞的机制

肺动脉高压是一种严重的临床疾病,常常并发血栓形成,其背后的机制可能与缺氧,内皮功能异常,炎症因子激活,血小板活化及凝血功能异常有关。本文拟探讨肺动脉高压患者的血栓形成机制,为临床治疗和预防肺动脉高压并发的血管栓塞提供理论依据。     

Pulmonary hypertension and human immunodeficiency virus infection: epidemiology,pathogenesis, and clinical approach

In recent years, the pathogenic role of human immunodeficiency virus (HIV) and the clinical manifestations of HIV-associated pulmonary arterial hypertension (HIV-PAH), which currently represents one of the most severe complications of HIV infection, have received more attention HIV-PAH occurs at all stages of the disease, and does not seem to be related to the degree of immune deficiency. Many of the symptoms in HIV-PAH result from right ventricular dysfunction: the first clinical manifestation is effort intolerance and exertional dyspnoea that will progress to the point of breathlessness at rest. Echocardiography is an extremely useful tool for the diagnosis of HIV-PAH, and Doppler echocardiography can be used to estimate systolic pulmonary artery pressure. Assessment of haemodynamic measures by catheterization remains, however, the best test for evaluating the response to therapy. Cardiac catheterization is mandatory to definitively diagnose the disease and exclude any underlying cardiac shunt as the aetiology. Recently, effective therapies for pulmonary arterial hypertension (PAH) have been available, including prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, allowing amelioration of symptoms and a better prognosis. However, HIV-PAH remains a progressive disease for which treatment is often unsatisfactory and there is no cure. As new efficient antiretroviral treatment is introduced, clinicians should expect to encounter an increasing number of cases of PAH in HIV-infected patients in the future.     

N-TproBNP as Biomarker in Systemic Sclerosis

Systemic sclerosis (SSc) is a connective tissue disorder characterized by tissue fibrosis affecting the skin and internal organs, fibroproliferative vasculopathy, and autoimmune activation. SSc still heralds a poor prognosis with significant morbidity and mortality. Early detection of organ involvement is critical as currently available treatments are most effective when started early. Many candidate biomarkers have been investigated in the past two decades. However, despite the enormous efforts, no accurate tool to predict the pattern of organ involvement and to assess disease activity has been yet identified. The N-terminal fragment of probrain natriuretic peptide (N-TproBNP) is a neurohormone released by ventricular myocytes in response to pressure overload. N-TproBNP is highly relevant for diagnosis, prognosis, and prediction of pulmonary arterial hypertension in SSc. Moreover, several studies support its potential benefit for cardiac assessment of scleroderma patients. Conversely, the role of N-TproBNP as surrogate marker of pulmonary fibrosis and skin involvement is much less clear. We provide an extensive review of the studies that have previously investigated the role of N-TproBNP as candidate biomarker in scleroderma manifestations, presenting also the findings of a recent study we conducted in a cohort of 87 SSc patients.