Transcript Hypoxia 缺 氧
Hypoxia 缺 氧 Concept of Hypoxia Deficiency Decrease Changes O2Delivery Cellular O2Utilization ATP Function Metabolism Structure 因组织供氧减少或用氧障碍引起细胞代谢、功 能和形态结构异常变化的病理过程称为缺氧。 The basic courses of respiration Taking Carry Transportation Utilization Parameters of blood oxygen 1. Partial pressure of oxygen，PO2 （氧分压） PO2 is the tension produced by oxygen molecules physically dissolved in plasma. Normal value PaO2：13.3kPa（100mmHg）0.3ml% PvO2：5.33kPa （40mmHg） Determinant factors PiO2 ，PAO2，gas diffusion Significance Determine O2 saturation of blood 2. Oxygen binding capacity，CO2max （氧容量） Maximal amount of oxygen that can be potentially bound by the haemoglobin is called oxygen binding capacity of haemoglobin (PO2 150mmHg, PCO2 40mmHg, 38℃) . Normal value 20ml%（8.92mmol/L） Determinant factors The quantity and quality of Hb. Significance Influence the ability of blood to carry O2（oxygen content）. 3. Oxygen content，CO2（氧含量） The total oxygen content of blood 100ml includes oxygen that is bound to haemoglobin an physically dissolved in plasma. Normal value CaO2:19ml% CvO2:12~14ml% Determinant factors PO2 and CO2max Significance CaO2: oxygen supplement CvO2: oxygen consumption 4. Oxygen saturation，SO2 （氧饱和度） SO2 is the percentage of haemoglobin present as oxyhaemoglobin. Normal value SaO2:93~98% SvO2:70~75% Determinant factors PO2 Significance Influence oxygen content Arteriovenous blood oxygen difference (A－VDO2) 19ml/dl A. O2 O2 14ml/dl O2 O2 5ml/dl O2 V. PiO2（氧分压） CO2 (氧含量) PaO2 （氧分压） ≈SO2 (氧饱和度) CO2max (氧容量) Oxygen–haemoglobin dissociation curve 100 Oxygen saturation % 90 80 2,3-DPG H+ , CO2 2,3-DPG Temperature H+, CO2 70 Temperature 60 50 Affinity normal 40 Affinity ↓ 30 Affinity ↑ 20 p50 10 0 10 20 30 40 50 60 70 PO2（mmHg) 80 90 100 Oxygen supply of tissue = CaO2 ×blood flow Oxygen consumption of tissue =（CaO2－ CvO2）×blood flow Classification Etiology Pathogenesis 发生缺氧的基本环节 Atmosphere Decreased PiO2 Ventilation & Diffusion External respiratory dysfunction Binding with Haemoglobin Transportation of gases in blood Venous-to-arterial shunts Taking and utilization of oxygen in tissue cells Hypotonic hypoxia Hypotonic hypoxia（低张性缺氧） Hypotonic hypoxia is characterized by the decrease of PaO2 ( ＜ 60mmHg ） , also called hypoxic hypoxia. Etiology Decreased PO2 of inspired air： Atmospheric hypoxia（大气性缺氧） Plateau （高原性缺氧) Altitude Atmosphere PiO2 PAO2 SaO2 m mmHg mmHg mmHg % 0 1000 2000 3000 4000 5000 6000 7000 8000 760 680 600 530 460 405 366 310 270 159 140 125 110 98 85 74 65 56 105 90 70 62 50 45 40 35 30 95 94 92 90 85 75 70 60 50 Altitude 3700 m (Tibet Lhasa Potala Palace) Altitude 1532 m (yellow mountain) Altitude 8848 m (The Himalayas ) External respiratory dysfunction： respiratory hypoxia （呼吸性缺氧） Venous-to-arterial shunts：tetralogy of Fallot 法洛氏四联症（tetralogy of Fallot ） Characteristics of blood O2 PaO2 ↓ CaO2 ↓ SO2 ↓ A-VdO2 CO2max N ↓/ N Cyanosis (紫绀)：Cyanosis is a bluish or purplish tinge to the skin and mucous membranes. Approximately over 5g/dL of unoxygenated hemoglobin in the capillaries generates the dark blue color appreciated clinically as cyanosis. O2 diffusion in tissue Atmosphere Decreased PiO2 Ventilation & Diffusion External respiratory dysfunction Hypotonic hypoxia Binding with Haemoglobin Abnormality of HB Transportation of gases in blood Venous-to-arterial shunts Taking and utilization of oxygen in tissue cells Hemic hypoxia Hemic hypoxia 血液性缺氧 Hemic hypoxia refers to the altered affinity of HB for oxygen or decrease in amount of HB in the blood, also can be termed as isotonic hypoxemia （等张性低氧血症）。 Etiology Anemia：贫血性缺氧（anemic hypoxia） Carbon monoxide poisoning ：碳氧血红蛋白（HbCO） Methemoglobinemia ：HbFe3+OH；肠源性紫绀 Carbon monoxide poisoning CO combines preferentially with hemoglobin to produce COHb, displacing oxygen and reducing systemic arterial oxygen (O2) content. CO binds reversibly to hemoglobin with an affinity 200230 times that of oxygen. Consequently, relatively minute concentrations of the gas in the environment can result in toxic concentrations in human blood. Possible mechanisms of toxicity include: Decrease in the oxygen carrying capacity of blood. Alteration of the dissociation characteristics of oxyhemoglobin, further decreasing oxygen delivery to the tissues. Decrease in cellular respiration by binding with cytochrome a3. Binding to myoglobin, potentially causing myocardial and skeletal muscle dysfunction. （2）一氧化碳中毒（Carbon monoxide poisoning） 吸入 CO CO + Hb 2，3-DPG生成↓ 碳氧血红蛋白（HbCO） 氧离曲线左移 Hb失去携O2能力 HbO2释放氧↓ CO + 1个Hb亚单位 组织缺氧 Hb产生变构 其余3个血红素结合的氧也不易释放 氧离曲线左移 ※CO与Hb的亲和力比O2大210倍，当 吸入的气体内含有0.1%CO时，血液中 的血红蛋白可能有50%转为HbCO。 Four binding sites Concentration 35 ppm (0.0035%) Symptoms Headache and dizziness within six to eight hours of constant exposure 100 ppm (0.01%) Slight headache in two to three hours 200 ppm (0.02%) Slight headache within two to three hours; loss of judgment 400 ppm (0.04%) Frontal headache within one to two hours 800 ppm (0.08%) Dizziness, nausea, and convulsions within 45 min; insensible within 2 hours 1,600 ppm (0.16%) Headache, tachycardia, dizziness, and nausea within 20 min; death in less than 2 hours 3,200 ppm (0.32%) Headache, dizziness and nausea in five to ten minutes. Death within 30 minutes. 6,400 ppm (0.64%) Headache and dizziness in one to two minutes. Convulsions, respiratory arrest, and death in less than 20 minutes. 12,800 ppm (1.28%) Unconsciousness after 2-3 breaths. Death in less than three minutes Concentration 0.1 ppm Source Natural atmosphere level 0.5 to 5 ppm Average level in homes 5 to 15 ppm Near properly adjusted gas stoves in homes 100 to 200 ppm Exhaust from automobiles in the Mexico City central area 5,000 ppm Exhaust from a home wood fire 7,000 ppm Undiluted warm car exhaust without a catalytic converter Table . COHb Levels and Symptomatology 10% Asymptomatic or may have headaches 20% Dizzyness, nausea, and syncope 30% Visual disturbances 40% Confusion and syncope 50% Seizures and coma 60% Cardiopulmonary dysfunction and death Methemoglobinemia, MHb • Definition: Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin (metHb) in the blood, in which the ferrous (2+) form of heme is oxidized to the ferric form (3+) thus making the heme moiety unable to bind oxygen. In addition, the remaining monomers of ferrous heme within a hemoglobin tetramer bind their oxygen more tightly causing a left shift of the oxygen dissociation curve and reduced oxygen delivery at the tissue level. Causes • Hereditary/Congenital: Hemoglobin M Cytochrome b5 reductase deficiency (NADH deficiency)—responsible for 95% of MetHgb reduction, NADPH deficiency of the HMP shunt Acquired: Multiple drugs and toxins including aniline dyes, benzene, chloroquine, dapsone, local anesthetic agents, reglan, naphthalene, nitrites (including NTG and NO), primaquine, phenazopyridine, and sulfonamides. Clinical presentation: • Chronic methemoglobinemia: chronically elevated levels of MetHgb often are asymptomatic or present with headache, fatiguability, or “slate blue skin” complaints. • Acquired (acute) methemoglobinemia: typically symptomatic due to lack of compensatory mechanisms: cyanosis, dyspnea, fatigue, lethargy, AMS, shock, seizures and death. Severity depends on percent methemoglobinemia. (1% is normal) 3-15% skin discoloration 20% cyanosis or asx 25-50%, HA, lightheaded, weak, chest pain, confusion 50-70% delirium, seizure, lactic acidosis >70% arrhythmia and death. Characteristics of blood O2 PaO2 N CaO2 ↓ /N SO2 N A-VdO2 CO2max ↓ /N ↓ Color of skin Anemia：Pale skin color HbCO：Classic cherry red skin is rare (ie, "When you're cherry red, you're dead"); pallor is present more often. HbFe3+OH：Bluish coloring, cyanosis 贫血的氧离曲线 70% 70% 20% normal methemoglobin concentration Note the chocolate brown color of methemoglobinemia. This dark hue imparts clinical cyanosis when methemoglobin levels are at 1.5 g/dL (approximately 10-15% methemoglobin concentration); however, a level of 5 g/dL of deoxygenated blood is required for similar effects. Therefore, when methemoglobin levels are relatively low, cyanosis may be observed without cardiopulmonary symptoms. Atmosphere Decreased PiO2 Ventilation & Diffusion External respiratory dysfunction Hypotonic hypoxia Binding with Haemoglobin Abnormality of HB Hemic hypoxia Transportation of gases in blood Venous-to-arterial shunts hypokinetic Taking and utilization of oxygen in tissue cells Circulatory hypoxia Circulatory hypoxia 循环性缺氧 Circulatory hypoxia refers to inadequate blood flow leads to inadequate oxygenation of the tissues. 1.Tissue ischemia：shock, heart failure 2.Tissue congestion：venous embolism Etiology Systemic：shock, heart failure Local：embolism, atherosclerosis Characteristics of blood O2 PaO2 N CaO2 N SO2 N A-VdO2 ↑ Color of skin Tissue ischemia ：pale Tissue congestion ：cyanosis CO2max N Atmosphere Decreased PiO2 Ventilation & Diffusion External respiratory dysfunction Hypotonic hypoxia Binding with Haemoglobin Abnormality of HB Hemic hypoxia Transportation of gases in blood Venous-to-arterial shunts hypokinetic Taking and utilization of oxygen in tissue cells Dysfunction of O2 utilization Circulatory hypoxia Histogenous hypoxia Histogenous hypoxia 组织性缺氧 Histogenous hypoxia refers to the tissue cell cannot make use of the O2 supplied to them. Etiology Tissue poisoning：histotoxic hypoxia cyanide, arsenide, sulphide Vitamin insufficiency：vitamin B1, B2, PP Mitochondrial damage：radiation, bacteria、uremia Characteristics of blood O2 PaO2 N CaO2 N SO2 N A-VdO2 ↓ CO2max N Color of skin Deceptively healthy pink to red skin color Functional and Metabolic Changes 急性严重缺氧时机体变化以失代偿和损 伤为主； 轻度缺氧时机体或细胞以代偿性调节为 主。 慢性缺氧时机体的代偿反应和缺氧性损 伤并存。 Compensatory reaction 代偿性反应 Respiratory system 急性缺氧时最主要的代偿反应-- 呼吸功能增强使肺通气量增加 PaO2＜60mmHg(8kPa) PaCO2 ↑ PaO2↑ 刺激外周化学感受器 刺激中枢化学感受器 PAO2和PaO2↑ C.O和肺血流量↑ 组织供氧↑ 静脉回流↑ 有利于氧的摄取和运输 窦神经、迷走神经 呼吸中枢(+) 呼吸加深加快 胸内负压↑ 肺通气变化与缺氧持续时间的关系 呼吸性碱中毒 【早期】 高原地区 中枢化学感受器兴奋性↓ 呼吸加深加快 肺通气量增加65% 呼吸加深加快 肺通气量增加5~7倍 【数日后】 高原地区 数日后 呼碱被纠正 中枢化学感受器（+）↑ 【长期居住】 肺通气量接近正常（肺通气量增加15%） 外周化学感受器对缺氧的敏感性↓ 机体对缺氧的耐受性↑ Circulatory system （1）心输出量增加 交感N（+） 心率↑；心肌收缩性↑；静脉回流↑ C.O ↑ （2）肺血管收缩（Kv通道为主） 缺氧 Kv通道开放↓ K+外流↓ 膜电位↑ 平滑肌(+)↑ Ca2+内流↑ 肺内合成释放缩血管物质大于扩血管物质 肺小动脉收缩 交感神经兴奋↑ （3）血液重分布 脑、心血管平滑肌以KCa 、KATP 通道为主。 （4）毛细血管增生 Hematologic system 1）红细胞增多 1）红细胞增多 急性缺氧 2）氧合血红蛋白解离曲线右移 脾脏、肝脏收缩，将储存血液释放入体循环，增加氧的摄 取和运输能力 缺氧时红细胞内2,3-DPG增多， 慢性缺氧 2,3-DPG增多使氧离曲线右移 血浆中ESF(EPO)增加，使红细胞数和Hb量明显增加 有利于HbO 2在组织部位释放出较多的氧 可增加血液的氧容量和氧含量 过度增加可使血粘度增加 当 paO2低于8kPa时，氧离曲线右移会明显影响肺部血液 对氧的摄取 2,3-DPG的生成与分解 Tissues and cells 细胞内呼吸功能增强：线粒体数目，呼吸酶活性 糖酵解增强 肌红蛋白增加：与氧的亲和力增加 低代谢状态 Hypoxia inducible factor-1(HIF-1) VEGF, EPO, glycolysis enzymes NATURE REVIEWS | Immunology volume 9 | September 2009 Hypoxia Injury 缺氧对机体的损伤性作用 Hypoxia / ischemia Mitochondrion ↓Oxidative phosphorylation ↓ATP ↓Na pump ↑Influx of Ca2+, H2O, and Na+ ↑Anaerobic glycolysis ↓Glycogen ↓pH Other effects Detachment of ribosome, etc. ↑Efflux of K+ ER swelling Cellular swelling Loss of microvilli Blebs Clumping of nuclear chromatin ↓Protein synthesis Lipid deposition Tissues and cells 缺氧引起机体功能和代谢障碍主要通过线粒 体途径引起能量代谢障碍导致细胞损伤 1）线粒体的变化 严重缺氧 线粒体损伤 ATP↓↓ 缺氧使线粒体损伤的原因 供氧障碍：损伤线粒体的功能和结构 线粒体用氧障碍：某些理化和生物因素可损伤线粒体 各种因素使得线粒体呼吸链中断 2）细胞膜变化 细胞缺氧 膜对离子的 通透性增高 ATP 消耗增多 Na+内流 钠泵功能障碍 K+外流 ATP减少 Ca2+内流 膜电位降低 细胞水肿 线粒体肿胀 溶酶体肿胀 各种酶代谢障碍 合成代谢障碍 加重能量代谢障碍 进入线粒体，使其功能发生障碍 和调钙蛋白激活磷脂酶，使膜磷脂分解 使自由基生成增加 3）溶酶体变化 溶酶体肿胀、破裂和释出大量溶酶体酶，引起细 胞及其周围组织的溶解、坏死。 Central nerve system 大脑是对缺氧最为敏感的器官， 缺氧最易使CNS功能发生障碍。 缺氧时CNS功能障碍的主要原因和机制： 神经细胞膜电位降低、神经介质合成减少、 ATP生成不足、酸中毒、细胞水肿、 细胞内游离Ca2+增多、溶酶体酶释放、 神经细胞的结构破坏等 急性缺氧、慢性缺氧、严重缺氧（PaO2<28mmHg) 可以产生严重程度不同的CNS功能障碍 高原脑水肿：重度高原反应并发症，CNS受损，颅内高压 机制 ：① 脑细胞水肿 ② 血脑屏障功能受损 ③ 脑静脉内血栓形成 Pathophysiology of hypoxic-ischemic brain injury in the developing brain. During the initial phase of energy failure, glutamate mediated excitotoxicity and Na+/K+ ATPase failure lead to necrotic cell death. After transient recovery of cerebral energy metabolism, a secondary phase of apoptotic neuronal death occurs. ROS = reactive oxygen species Summary of potential neuroprotective strategies Respiratory system 高原肺水肿（high altitude pulmonary edema, HAPE） 进入4000m高原后1～4d内出现 发病率：5.7％~17.7％ 临床表现：胸闷，咳嗽，发绀，呼吸困难，血性泡沫痰 体征：肺部湿罗音 发病机制 外周血管收缩，回心血量增加； 缺氧性肺血管收缩，肺动脉高压； 肺动脉收缩不均一引起超灌注→非炎性漏出； 肺毛细血管壁通透性增加。 中枢性呼吸衰竭 PaO2<30mmHg 抑制呼吸中枢 Circulatory system 心肌的收缩与舒张功能降低：心肌缺氧和酸中毒 心律失常：窦性心动过缓、引起期前收缩和各种心律失常， 包括引起心室纤维颤动致死。 静脉回流减少：严重、持久的缺氧使得外周血管扩张，血 液淤滞。 肺动脉高压：使得右室后负荷增加，引起右心室肥大代偿、 失代偿、心力衰竭。 Hematologic system 血液粘滞度增高 外周阻力增大 心脏后负荷增高 Oxygen Treatment 吸氧 对低张性缺氧最有效 提高血液性缺氧和循环性缺氧患者血液物理 溶解的氧 组织性缺氧治疗关键是解除呼吸链酶的抑制 Oxygen Intoxication 由于吸入气体氧分压过高，或长时间吸入高浓度氧， 使患者出现听觉或视觉障碍、恶心、抽搐、晕厥等神经症状， 部分患者出现溶血反应，或因引起严重呼吸衰竭致死，这样 一类临床综合征，称为氧中毒。 基本机制：氧中毒时可生大量氧自由基和活 性氧，导致组织细胞损伤。 肺型氧中毒： 吸入一个大气压左右的氧达8h时可发生肺型氧中毒。 脑型氧中毒： 吸入2～3个大气压以上的氧，可在短时内（6个大 气压氧吸入数分钟；4个大气压氧吸入数十分钟）引起脑 型氧中毒。 组织部位氧的弥散及其影响因素 物理溶解的氧 HbO2 血液 组织液 细胞内液 毛细血管动脉段PaO2（1） 100mmHg 血 流 速 度 （ 2 ） 组织 PtO2 30~40mmHg（3） 细胞（线粒体） ~5mmHg 弥散距离（4） (1) PaO2降低，组织部位O2弥散速度，单位时间的O2弥散量减少 (2) 血流速度减慢，血液中氧释放增多，但单位时间中组织获O2减少 (3) 组织氧分压降低，组织部位O2弥散速度，组织获得O2增多;反之亦然 (4) 弥散距离加大，单位时间中细胞获得O2可减少 返回 正常 100 20 20 血液性缺氧 （贫血） 80 15 氧 饱 和 度 % 60 10 血 氧 含 量 ml% 40 5 20 15 10 100 氧 饱 和 度 % 80 60 血 氧 含 量 5 ml% 40 20 0 0 20 40 60 80 氧分压（mmHg) 100 0 0 20 40 60 80 100 氧分压（mmHg) 返回 2,3-DPG的生成与分解 葡萄糖 6-磷酸葡萄糖 6-磷酸果糖 磷酸果糖激酶 1,6-二磷酸果糖 磷酸二羟丙酮 3-磷酸甘油醛 1,3-二磷酸甘油酸 乳酸 丙酮酸 2,3-DPG DPGP 2-磷酸烯醇式丙酮酸 3-磷酸甘油酸 2-磷酸甘油酸 返回 ISCHAEMIC AND HYPOXIC INJURY • cellular response to ischaemia: – – – – cesstion of blood flow --> lack of oxygen and glucose --> fall in mitochondrial ATP production --> depletion of cellular ATP --> • • • • • failure of membrane Na+/K+ ATPase pump – sodium and water enter cell --> – swelling of endoplasmic reticulum failure of membrane calcium pumps --> – free calcium enters cytoplasm – activates phospholipases – membrane damage --> – massive entry of calcium and water into cell and liberation of lysosomal enzymes failure of protein synthesis mitochondrial swelling switch to anaerobic metabolism --> – fall in intracellular pH --> activation of lysosomal enzymes because these have been liberated (see 2. failure of membrane calcium pumps above) --> necrosis • summary: hypoxia causes damage because ATP is not produced and therefore membrane pumps cannot work, in particular, cytosolic free calcium is a potent destructive agent