肺动脉高压PPT课件

Pathogenic Mechanism of Pulmonary Hypertension Role of Ca2+ and Ion Channels and NO,1,Certain problems related to distribution of blood flow and other hemodynamics are special to the pulmonary circulation and are especially important for gas ex-change in the lungs. The present discussion is concerned specially with these special features of the pulmonary circu1ation,2,PHYSIOLOGIC ANATOMY OF THE PULMONARYCIRCULATORY SYSTEM,3,Pulmonary vessels,The pulmonary artery extends only 5 centimeters beyond the apex of the right ventricle and then divides into the right and left main branches, which supply blood to the two respective lungs.,4,The pulmonary artery is also thin, with a wall thickness about twice that of the venae cavae and one third that of the aorta. The pulmonary arterial branches are very short, and all the pulmonary ateries, even the smaller arteries and arterioles, have larger diameters than their counterpart systemic arteries.,5,This,combined with the fact that the vessels are very thin and distensible,gives the pulmonary arterial tree a large compliance, averaging almost 7ml/mm Hg, which is similar to that of the entire systemic arterial tree. This large compliance allows the pulmonary arteries to accommodate about two thirds of the stroke volume output of the right ventricle.The pulmonary veins, like the pulmonary arteries, are short, but their distensibility characteristics are similar to those of the veins in the systemic circulation,6,Bronchial Vessels,Blood also flows to the lungs through small bronchial arteries that originate from the systemic circulation, amounting to about l to 2 percent of the total cardiac output. This bronchial arterial blood is oxygenated blood, in contrast to the partially deoxygenated blood in the pulmonary arteries.It supplies the supporting tssues of the lungs, including the connective tissue, septa, and large and small bronchi.,7,PRESSURES IN THE PULMONARY SYSTEM,Pulmonary arterial pressure averages about 25mm Hg in the normal human being; the diastolic pulmonary arterial pressure, about 8mm Hg; and the mean pulmonary arterial pressure,15mm Hg.,Pulmonary arterial pressure,8,Pulmonary Capillary Pressure,The mean pulmonary capillary pressure, has been estimated by indirect means to be about 7mm Hg. The importance of this low capillary pressure is related to fluid exchange functions of the pulmonary capillaries.,9,Left Atrial and Pulmonary Venous Pressures.,The mean pressure in the left atrium and the major pulmonary veins averages about 2mm Hg in the recumbent human being,varying from as low as l mm Hg to as high as 5mm Hg.,10,BLOOD VOLUME OF THE LUNGS,The blood volume of the lungs is about 450 ml, about 9 percent of the total blood volume of the circulation system. Approximately 70 milliliters of this is in the pulmonary capillaries, and the remainder is divided about equally between the arteries and the veins,11,Lungs as a blood reservoir of normal to 2 times of normal,Shift of blood between the pulmonary and systemic circulatory system as a result of cardiac pathology.,12,BLOOD FLOW THROUGH THE LUNGS AND ITS DISTRIBUTION,Factors that control cardiac output-mainlyperipheral factors also control pulmonary blood.For adequate aeration of the blood to occur,it is important for the blood to be distributed to those segments of the lungs where the alveoli are best oxygenated,13,Mechanism,Effect of Diminished Alveolar Oxygen on Local Alveolar Blood Flow-Automatic Control of Pulmonary Blood Flow Distribution.,14,When the concentration of oxygen in the alveoli decreases below normal-especially when it falls below 70 per cent of normal (below 73mm Hg Po2)-the adjacent blood vessels constrict during the ensuing 3 to10minutes, with the vascular resistance increasing more than five fold at extremely :low oxygen levels.,Hypoxia Pulmonary Vasoconstriction, HPV,15,This is opposite to the effect observed in systemic vessels, which dilate rather than constrict in response to low oxygen.,16,Significance,Providing an automatic control system for distributing blood now to the pulmonary areas in proportion to their degrees of ventilation.,17,Pulmonary Microcirculation,组成,Composition,由肺毛细血管、肺毛细血管前终末微动脉、微动脉,以及毛细管后的终末微静脉和微静脉所组成的灌流系统,18,Morphology Characteristics,在体循环，根据口径、结构和管壁的厚度，将血管 分为动脉、静脉、小动脉、小静脉、微动脉、微静脉和毛细血管。其中小动脉和小静脉是体循环阻力形成的主要部位。而在肺循环中则不存在相当于体循环中的小动脉和小静脉的结构。肺的大血管直接移行为毛细血管。,(一) Difference from systematic system,19,对于同样口径的血管，肺循环，血管管壁薄、管腔大, 管壁平滑肌少，其中层平滑肌层要比体循环血管薄许多。,肺动脉与肺静脉之间的组织结构差异不如体循环动脉和静脉的差异明显,肺的毛细血管前微动脉多以直角形式自母支发出。此种解剖学排列特点, 使供应肺泡的血流不致因呼吸运动的牵张和回缩作用而受影响,肺泡壁毛细血管网和体循环毛细血管网的形态也存在差 异.肺毛细血管则是互相吻合成为一个六边形的毛细血管网，没有明显的起点和终点，而且并非所有的毛细血管都在同一个平面,20,肺微循环的血流动力学特征,肺泡毛细血管血压肺微循环的血管阻力 肺毛细血管血流及其分布,21,气体交换的原理气体交换的过程气体交换的影响因素,22,肺微循环的功能,-组织液的生成与回流功能,肺泡组织液的生成与回流肺水肿的发生与微循环,23,膜片钳技术的基本原理,离子通道研究的基本方法之一：,Part two,24,一、细胞膜离子的转运方式,主动转运： 钠-钾泵、钙泵继发性主动转运：钠-钙交换被动转运：各种离子通道,25,离子通道简介,细胞膜或细胞器膜上的特殊蛋白质 通道分子构型变化表现开放和关闭两种基本状态； 通道分子的随机运动：开放和关闭状态是随机的；,26,单个通道电流 （随机量） 大量同类通道的电流（统计量）,通道开放时，特定离子顺电化学梯度被动 转运形成单通道电流。,27,细胞膜离子通道分类,电压门控通道 （voltage-gated channel)Na, K , Ca, Cl敏感元件：带电荷基团受体激活通道 (ligand-gated channel)第二信使激活通道（Second-messenger gated channel)Ca, cAMP, cGMP, IP3,G protein,（一）、激活方式,机械门控通道,KATP KACh,28,（二）、离子通透性选择性; 非选择性（三）、 通道特性激活快慢，单通道电流幅值大小, 药理学特性等 （四）、分子结构特点,29,二、 膜片钳研究方法简介 1 膜片钳研究方法的基本原理 2 膜片钳方法的优点 3 记录膜电流的几种基本方式及其特点 4 膜片钳研究方法的其它应用,30,Erwin Neher(埃尔温内尔，德国）: Ion Channels for Communication Between and within Cells Neuron,1991 : Nobel Prize,1976-1981 Erwin Neher and Bert Sakmann,31,膜片钳技术的应用,细胞膜通道电流细胞分泌药理学病理生理学神经科学脑科学植物细胞的生殖生理,32,膜片钳的工作模式,电压钳模式 （Voltage clamp , VC)电流钳模式 ( Current clamp, CC),33,1) 膜内向外记录方式,单通道活动人工模拟细胞内环境 （PH, ATP, 特定成分)有利于从细胞内侧研究通道的调控VC =-VM,34,2) 膜外向外记录方式,记录单通道活动； 电极内液相当于细胞内环境； 改变浴液，从外侧研究药物对单通道的作用； VC =VM,35,3) 全细胞记录方式,记录的电流反映大量多种通道活动的总和； 用适当方法区分出某种电流药理学方法电流特性 细胞内成分受电极内液影响 改变浴液，研究对某一通道电流的作用； VC =VM,36,4) 细胞贴附式记录方式,记录单通道活动对细胞内成分无影响改变浴液，研究对某一通道电流的作用； VC = - VM+VRMP; VM =VRMP - VC,VRMP,VC,0mV,37,4 膜片钳研究方法的其它应用,记录膜电位及动作电位（电流钳） 记录胞吐事件（分泌）,38,Pathogenic Mechanism of Pulmonary Hypertension Role of NO, Ca2+ and Ion Channels,Jun Wang,10,Part three,39,肺动脉高压 (Pulmonary Arterial Hypertension, PAH),40,基本概念,以肺血管阻力进行性升高为主要特征 既可来源于肺血管自身病变，也可继发于其他心肺疾患。 病因广泛，患病率高，危害严重。 诊断标准:海平面状态 静息时sPAP超过30mmHg，或mPAP超过25mmHg 活动时mPAP大于30mmHg 肺毛细血管嵌压20mmHg 鉴别毛细血管前/后肺动脉高压, 诊断IPAH的必要条件,41,Pulmonary hypertensionis defined as:mean PAP 25 mmHg at rest 30 mmHg on exercise,14,wedge PAP 15 mmHg,42,PAP = CO PVRPAP, Pulmonary Artery PressureCO, Cardiac OutputPVR, Pulmonary Vascular Resistance,Human PA tree,PVR,PAP,43,Right ventricular hypertrophyRight heart failureDyspnea, disability, syncope, death,Consequences of pulmonary hypertension,44,新的临床分类与观点,1.原发性. 1.原发性肺动脉高压不再应用散发性 特发性 （IPAH）家族性 家族性 （FPAH）相关因素所致 相关因素所致 2.肺静脉高压 2.左心疾病性PAH 3.呼吸系统相关性 3.肺疾病和/或低氧血症性4.慢4. 4.性栓栓塞性 4.慢性血栓和/或栓塞性PAH 5.影响肺血管结构的其他疾病 5.混合因素,1998（埃维安） 2003（威尼斯）,45,新的临床分类（2003，威尼斯）,肺动脉高压( pulmonary arterial hypertension, PAH) 特发性 （idiopathic PAH, IPAH） 家族性 (familial PAH, FPAH) 相关因素 (associated, APAH) 胶原血管病(Collagen vascular disease) 先天性体-肺分流 (Congenital systemic to pulmonary shunts) 各种类型(large, small, repaired or non repaired) 门脉高压(Portal hypertension) HIV感染(HIV infection) 药物/毒素(Drugs and toxins) 其他(Other) 糖原蓄积症 (glycogen storage disease)，高雪病(gaucher disease)，遗传性出血性毛细血管扩张症(hereditaryhemorrhagic telangiectasia)，血红蛋白病(hemoglobinopathies)，骨髓增生异常(myeloproliferative disorders)，脾切除(splenectomy) 肺静脉和/或毛细血管病变所致(Associated with significant venous or capillary involvement) 肺静脉闭塞病(Pulmonary veno-occlusive disease) 肺毛细血管瘤(Pulmonary capillary hemangiomatosis),46,新的临床分类（2003，威尼斯）,肺静脉高压(Pulmonary venous hypertension) 左房/左室性心脏病(Left-sided atrial or ventricular heart disease) 左心瓣膜病(二尖瓣或主动脉瓣) (Left-sided valvular heart disease) 低氧血症相关的PAH (Pulmonary hypertension associated with hypoxemia) 慢性阻塞性肺疾病(COPD) 间质性肺疾病(Interstitial lung disease) 睡眠呼吸障碍(Sleep-disordered breathing) 肺泡低通气病变(Alveolar hypoventilation disorders) 慢性高原缺氧暴露(Chronic exposure to high altitude),47,新的临床分类（2003，威尼斯）,慢性血栓和/或栓塞性 (PH due to chronic thrombotic and/or embolic disease) 肺动脉近端血栓栓塞(Thromboembolic obstruction of proximal pulmonary arteries) 肺动脉远端血栓栓塞(Thromboembolic obstruction of distal pulmonary arteries) 肺栓塞(Pulmonary embolism) 肿瘤、寄生虫、异物等(tumor, parasites, foreign material) 其他复杂疾病(Miscellaneous) 结节病(Sarcoidosis) 组织细胞增生症X (histiocytosis X) 淋巴管瘤病 (Lymphangiomatosis) 肺静脉压迫性病变(compression of pulmonary vessels) 淋巴结肿大，肿瘤，纤维素性纵隔炎 (adenopathy, tumor, fibrosing mediastinitis),48,新的临床分类与观点 新分类方法的特点,名词的变化 废弃PPH，代之以IPAH，FPAH：具有家族遗传倾向者 概念的扩展 对先天性体-肺分流进行重新分类 肺疾病和/或低氧血症性替代呼吸系统相关性 慢性血栓和/或栓塞性替代慢性血栓栓塞性 将肺静脉闭塞症（PVOD）和肺毛细血管瘤（PCH）归入肺静脉和/或毛细血管病变所致肺动脉高压 更新了肺动脉高压的危险因素及相关因素的分类标准 突出了易患因素的研究 增加了药物和毒素相关的危险因素 充分体现治疗靶点,49,CLASSIFICATION (updated 3rd WSPAH-Venice 2003),50,流行病学,美国 ：PPH发病率：30-50/百万死亡率：3.1/10万 欧洲 :特发性：39.2% 家族性： 3.9%减肥药相关：9.5%结缔组织病相关：15.3%先心病相关：11.3%门脉高压相关：10.4%HIV感染相关：6.2%,51,流行病学,PAH是结缔组织疾病（CTD）重要的并发症 进行性系统性硬化，9-33% CREST综合征的患者大约有60%继发PAH SLE合并PAH的发病率为4%14% 从诊断PAH起两年内总体病死率达25%50%。 类风湿性关节炎（RA） 在65岁以上的人群中PAH发病率高达5% 没有其他心肺基础疾病的RA患者中有21%合并PAH。,52,流行病学,慢性肝病和门脉高压容易发生PAH， 美国NIH门脉高压患者中有8%存在PAH 肝移植患者PAH发生率分别为4-5% HIV感染者PAH发生率 美国0.5%； 瑞士和法国5年PAH发生率分别为0.57%和0.1-0.2% 在HIV感染者中，静脉注射药物吸毒者PAH约占42%-56%。 减肥药物 阿米雷司、氟苯丙胺、右苯丙胺等可能导致PAH 抑制食欲药物和PAH存在明显相关关系，相对危险为6.3 服药时间大于3月相对危险估计23.1 欧美国家报道新型食欲抑制剂芬氟拉明与PAH有关,53,病理学改变,肺动脉病变 主要见于IPAH、FPAH和APAH。 中膜增生肥厚、内膜增生、外膜增厚 丛样病变（complex lesions） 肺静脉病变 主要见于肺静脉闭塞症 弥漫性、不同程度的闭塞，可为完全性或偏心性阻塞 毛细血管扩张、突出变形，肺小动脉中膜肥厚和内膜纤维化 细胞胞浆及细胞间质中含铁血黄素沉积,肺小叶间隔渗出 肺微血管病变：也称肺毛细血管瘤 以肺内毛细血管局限性增殖为特征，呈全小叶和部分小叶分布 异常增生的毛细血管可穿过动静脉壁，侵犯肌层，引起管腔狭窄 巨噬细胞和型肺上皮细胞含铁血黄素沉积,肌层肥厚和内膜增生,54,病理生理和发病机制,几个重要的路径 前列环素路径(Prostacyclin Pathway) 内皮素路径（Endothelin Pathway) 一氧化氮（Nitric Oxide Pathway） 鸟苷酸环化酶（Guanylate Cyclase） 磷酸二酯酶（Phosphodiesterases）,55,病理生理和发病机制,几种重要介质变化 前列环素水平下降，血栓素A2升高 ETA受体和ETS受体的激活介导ET-1 NO的水平和NO合酶的水平下降 血小板和肺组织5-HT与5-HTT水平增加 肾上腺髓质素和血管活性肠肽（VIP）水平下降 血管内皮生长因子及其受体表达增加 氧化剂应激（Oxidant Stress） 人类疱疹病毒属（Human Herpesvirus）,56,NORMAL,HYPERTENSION,Thromboxane,A,2,Endothelin,-,I,Angiotensin,II,5,-,hydroxytryptamine,Prostacyclin,Nitric oxide,ANP,Adrenomedullin,Thromboxane,A,2,Endothelin,I,Angiotensin,II,5,-,hydroxytryptamine,Prostacyclin,Nitric oxide,ANP,Adrenomedullin,Vasoconstrictors,Vasodilators,Vasoconstrictors,Vasodilators,Low resting tone,Vasoconstriction &,vascular remodelling,57,Inhibits Smooth muscle contraction Smooth muscle proliferation Platelet aggregation Platelet/monocyte adhesion LDL oxidation Expression of adhesion molecules Endothelin production,NO effects in the Vascular System,58,59,eNOS Transcriptional regulation Post-translational modifications Protein-protein interactions Caveolin, GPCR, hsp90 Dimerization Heme, zinc, BH4,Factors Affecting NO Bioavailability,eNOS activity Calcium, substrate, co-factors, phosphorylation eNOS subcellular localization Naturally occurring inhibitors Superoxide and other scavengers,Factors Affecting NO Bioavailability,60,Reduced NO Bioavailability,Endothelial Dysfunction,?,61,AtherosclerosisSystemic Arterial HypertensionPulmonary Arterial HypertensionCoronary Artery Disease/RestenosisThromboembolic DiseaseInflammationPeripheral Vascular DiseaseSickle Cell Diseaseet, al,Reduced NO Bioavailability in:,62,Oral PDE5i pulmonary vasodilation oral PDE5i intrapulmonary selectivity Clinical Effectiveness of PDE5-Inhibition in PAH Combination therapies PDE5i in Hypoxia- induced pulmonary hypertension PDE-5 Inhibition in pulmonary venous hypertension ? Antiproliferative and cardiotropic effects of PDE-5 Inhibitors,Phosphodiesterase-5 Inhibition in PH,63,Oral PDE5i pulmonary vasodilation oral PDE5i intrapulmonary selectivity Clinical Effectiveness of PDE5-Inhibition in PAH Comparison of currently available PDE5i Combination therapies PDE5i in Hypoxia- induced pulmonary hypertension PDE-5 Inhibition in pulmonary venous hypertension ? antiproliferative and cardiotropic effects of PDE-5 Inhibitors,Phosphodiesterase-5 Inhibition in PH,64,65,Oral PDE5i pulmonary vasodilation oral PDE5i intrapulmonary selectivity Clinical Effectiveness of PDE5-Inhibition in PAH Comparison of currently available PDE5i Combination therapies PDE5i in Hypoxia- induced pulmonary hypertension PDE-5 Inhibition in pulmonary venous hypertension ? antiproliferative and cardiotropic effects of PDE-5 Inhibitors,Phosphodiesterase-5 Inhibition in PH,Oral PDE5i pulmonary vasodilation oral PDE5i intrapulmonary selectivity Clinical Effectiveness of PDE5-Inhibition in PAH Combination therapies PDE5i in Hypoxia- induced pulmonary hypertension PDE-5 Inhibition in pulmonary venous hypertension ? antiproliferative and cardiotropic effects of PDE-5 Inhibitors,Phosphodiesterase-5 Inhibition in PH,66,Oral PDE5i pulmonary vasodilation oral PDE5i intrapulmonary selectivity Clinical Effectiveness of PDE5-Inhibition in PAH Comparison of currently available PDE5i Combination therapies PDE5i in Hypoxia- induced pulmonary hypertension PDE-5 Inhibition in pulmonary venous hypertension ? antiproliferative and cardiotropic effects of PDE-5 Inhibitors,Phosphodiesterase-5 Inhibition in PH,67,Oral PDE5i pulmonary vasodilation oral PDE5i intrapulmonary selectivity Clinical Effectiveness of PDE5-Inhibition in PAH Comparison of currently available PDE5i Combination therapies PDE5i in Hypoxia- induced pulmonary hypertension antiproliferative and cardiotropic effects of PDE-5 Inhibitors,Phosphodiesterase-5 Inhibition in PH,68,Oral PDE5i pulmonary vasodilation oral PDE5i intrapulmonary selectivity PDE5i in Hypoxia- induced pulmonary hypertension Clinical Effectiveness of PDE5-Inhibition in PAH Comparison of currently available PDE5i Combination therapies antiproliferative and cardiotropic effects of PDE-5 Inhibitors,Phosphodiesterase-5 Inhibition in PH,69,dysfunction of ion channelmutation of receptor abnormal transporterabnormal hormonal and agonist,SMC and /or EC /Fibroblast,Mechanism of PAH is related to,16,70,Hypoxic pulmonary vasoconstriction (HPV),Adaptive mechanism Sustained HPV,Intrinsic property of PASMC,Pulmonary hypertension Right heart failure Death,18,71,Disturbed Ca2+ homeostasis plays a key role in vasoconstriction and PA remodeling,25,72,Is cytosolic Ca2+ elevated in PASMC from PAH patients? What is the mechanism of Ca2+ regulationin PASMC ? How Ca2+cyt is increased in PASMC from IPAH patients?,26,73,activation of receptor-operated (or ligand-gated) Ca channels (ROCs) activation of SOCs that are opened by depletion of Ca from intracellular stores; activation of voltage-dependent Ca channels (VDCC) that are opened by membrane depolarization; activation IP3 receptor-mediated Ca release from the IP3-sensitive SR; activation of ryanodine receptor-mediated Ca release from SR,In PASMC, increased Ca2+cyt may occur by,74,VDCC blockers takes effect in some cases VDCC current is bigger in some PAH cases,Why does VDCC open during PAH ?,Voltage-Gated Ca2+ Channel,29,75,Voltage-Gated Kv Channel,Role of Kv channel in membrane potentialDown regulation of Kv gene expressionReduced function of Kv channelMutation of Kv channel,31,76,PAP,PVR,vasoconstriction,Vascular remodeling,In situ thrombosis,Ca2+i,Ca2+i sensitization,Em depo,adventitial,(hypertrophy),medial,intimal,fibroblast Macrophage transdifferentiation,Proliferation apoptosis,EC proliferation Plexiform lesion SMC/EC migration,platelets and EC,Ion channel,43,77,病理生理和发病机制,遗传机制 骨形态生成蛋白受体-2（BMPR-2） 转化生长因子（Transforming Growth Factor） 5-羟色胺转运子（Serotonin Transporter） 一氧化氮合酶（ec-NOS） 氨甲酰合成酶基因 激活素受体样激酶-1（activin-receptor-like kinase 1,ALK-1） 内皮因子（endoglin）,78,Current treatment,Conventional DiureticsWarfarinDigoxinDisease targeted(Calcium antagonists)ProstanoidsBosentan,79,诊断手段,肺动脉高压判别技术的发展血流动力学 无创超声心动图 有创压力测定 急性药物试验 病理、病因识别技术的提高,80,诊断策略,结合临床表现和危险因素识别可疑患者（疑诊） 血流动力学检查明确是否存在肺动脉高压（确诊） 病因学分析和临床归类（求因） 临床评估和功能评价（评估）,81,结合临床表现和危险因素 识别可疑PAH患者（疑诊）,临床表现： 肺动脉高压表现 右心衰竭表现 相关疾病伴随症状：皮疹、红斑、关节肿痛等 常规检查 心电图：右心室肥厚、右心房扩大 胸部X线：肺门动脉扩张伴远端外围分支纤细（“截断”征）、右心扩大；排除基础肺病、左心疾病所致或肺静脉闭塞症 动脉血气分析：PaO2正常或稍低于正常；PaCO2常降低。,82,