病理生理学系课件

病理生理学系病理生理学系Department of Department of PathophysiologyPathophysiology高远生高远生应激Stress 对各种对各种刺激刺激的的非特异性非特异性全身性反应全身性反应称为应激称为应激(stress)stress)或应激反应或应激反应(stress stress response)response)第一节第一节 概念概念 (Concept)二、应激原二、应激原(Stressor)(Stressor)v 外环境因素外环境因素(external factorsexternal factors)高温，严寒，低氧，创伤等高温，严寒，低氧，创伤等v 内环境因素内环境因素(internal factorsinternal factors)器官功能紊乱，心率失常，低血糖等器官功能紊乱，心率失常，低血糖等v 心理社会环境因素心理社会环境因素(psychosocial factorspsychosocial factors)职业竞争，沮伤，恐惧，激怒，惊喜等职业竞争，沮伤，恐惧，激怒，惊喜等 良性应激良性应激(eustress);劣性应激劣性应激(distress)问题：问题：应激应激?应激原应激原?第二节第二节 应激反应的基本表现应激反应的基本表现(Manifestations of stress response)v 神经神经-内分泌反应内分泌反应v 细胞体液反应细胞体液反应神经神经-内分泌反应内分泌反应兰斑兰斑-去甲去甲肾上腺素肾上腺素/交感交感-肾上腺髓质轴肾上腺髓质轴(Locus c(Locus ceruleuseruleus-n-norepinephrineorepinephrine/sympathetic-adrenal medulla axis,LC/NE)sympathetic-adrenal medulla axis,LC/NE)下丘脑下丘脑-垂体垂体-肾上腺皮质系统肾上腺皮质系统(Hypothalamus-pituitary-adrenal cortex(Hypothalamus-pituitary-adrenal cortex system,HPA)system,HPA)其他内分泌反应其他内分泌反应(Neuroendocrine responses in stress)兰斑兰斑-去甲去甲肾上腺素肾上腺素/交感交感-肾上腺髓质轴肾上腺髓质轴(Locus(Locus ceruleusceruleus-norepinephrinenorepinephrine/sympathetic-adrenal medulla axis,LC/NE)sympathetic-adrenal medulla axis,LC/NE)兰斑：兰斑：位于桥脑与中脑交界处后侧的核团，含约位于桥脑与中脑交界处后侧的核团，含约2020，000000去甲肾上腺素能神经元去甲肾上腺素能神经元应激原应激原兰斑兰斑兴奋兴奋交感神经交感神经系统兴奋系统兴奋肾上腺素肾上腺素去甲肾上腺素去甲肾上腺素Fight-or-Flight Response急性应激反应急性应激反应生理意义：生理意义：v 促进多种激素的分泌促进多种激素的分泌v 支气管扩张支气管扩张供氧量供氧量 v 血液重分布血液重分布保证心、脑、骨骼肌的供血保证心、脑、骨骼肌的供血v 心功能心功能增强增强组织供血组织供血 v 糖元、脂肪分解糖元、脂肪分解 能量供应能量供应 持续时间过长对机体的不利影响持续时间过长对机体的不利影响:心肌耗氧量心肌耗氧量 应激性心功能异常应激性心功能异常外周血管外周血管持续收缩持续收缩应激性高血压应激性高血压,组织缺血组织缺血血小板数目血小板数目 粘附聚集粘附聚集 诱发诱发DICDIC分解代谢分解代谢 能量过度消耗能量过度消耗下丘脑下丘脑-垂体垂体-肾上腺皮质系统肾上腺皮质系统(Hypothalamus-pituitary-adrenal cortex(Hypothalamus-pituitary-adrenal cortex system,HPA)system,HPA)AdrenalglandPain,fearInfectionhemorragehypoglycemiaCentralnervoussystemCRH(ng)HypothalamusAnteriorpituitaryACTH(m mg)Cortisol(mg)CRH:corticotropin-releasing hormone （促肾上腺皮质（促肾上腺皮质激素释放激素释放激素）激素）ACTH:adrenocorticotropic hormone （促（促肾上腺皮质激素）肾上腺皮质激素）Philip ShowalterHench Edward CalvinKendall In 1849 Thomas Addison of Scotland in 1849 discovered the connection between the adrenal glands and Addisons disease.In 1894,an English physician raised his own sons blood pressure by means of watery extracts from adrenla glands.During the early 1930s,Edward C.Kendall successfully isolated 5 different compounds from the adrenal cortex.In 1936,Thadeus Reichstein isolated as many as 7 substances.On April 29,1948,Kendall produced a few grams of compound E.Philip S.Hench joined with Kendall at this point,and together they discovered that compound E could be successfully used to treat patients with rheumatoid arthritis.The wonder drug had finally arrived and it was christened cortisone on July 1,1949.In 1950,Kendall,Reichstein and Hench were awarded the Nobel Prize.The Nobel Prize in Physiology or Medicine 1950“for their discoveries relating to the hormones of the adrenal cortex,their structure and biological effects”BenefitsGCs are used:endocrine disorders,rheumatic disorders,collagen diseases,dermatologic diseases,allergic states,ophthalmic diseases,respiratory diseases,hemotologic disorders,neoplastic diseases,edematous diseases,gastrointestinal diseases,etc.Specific examples include rheumatoid arthritis,tuberculosis,Addisons disease and severe asthma.GCs also helped to make organ transplants a reality due to its ability to minimize the defense reaction of the body towards foreign proteins.ProblemsThe major risk is the spread of bacterial infection due to diminished resistance.Depression and peptic ulcers occasionally occur.Psychic derangements may appear ranging from euphoria,insomnia,mood swings and personality changes,to frank psychotic manifestations.At high dosage,moon face and buffalo hump can also occur.In addition,cataracts and glaucoma may develop in predisposed patients if used for a prolonged period of time.Glucocorticoids生理意义：生理意义：提高抵抗力提高抵抗力v 允许作用允许作用 (permissive effects)儿茶酚胺儿茶酚胺儿儿 茶茶 酚酚 胺胺胰高血糖素胰高血糖素代代 谢谢 反反 应应心血管反应心血管反应糖皮质激素糖皮质激素On catecholamine action:Inducing phenylalanine-N-methyltransferase，the rate-limiting enzyme in epinephrine synthesis.Inhibiting catecholamine reuptake,decreasing peripheral levels of catechol-O-methyltransferase and monoamine oxidaseIncreasing the binding capacity and affinity of -adrenergic receptors,receptor-G protein coupling,and catecholamine-induced cAMP synthesis.On metabolic action:Increasing in the capacity of the liver for gluconeogenesis,primarily by enhancing the activity of phosphoenol pyruvate carboxykinase and glucose 6-phosphatase.Increasing substrates for gluconeogenesis,primarily amino acids released from muscle and other peripheral tissues,and glycerol released from adipose tissueMechanisms of the permissive effectsv 稳定溶酶体膜稳定溶酶体膜v 抑制炎性介质与细胞因子的生成与释放抑制炎性介质与细胞因子的生成与释放 v 促进蛋白质的糖异生促进蛋白质的糖异生糖皮质激素糖皮质激素:有利作用有利作用糖皮质激素增多的不利影响糖皮质激素增多的不利影响:v 负氮平衡负氮平衡v 免疫功能过低免疫功能过低v 应激性胃粘膜病变应激性胃粘膜病变其他内分泌反应其他内分泌反应(Other endocrine responses)v 胰高血糖素和胰岛素胰高血糖素和胰岛素 胰高血糖素胰高血糖素，胰岛素，胰岛素 血糖血糖 v调节水盐代谢的激素调节水盐代谢的激素 肾素肾素,血管紧张素血管紧张素 ,醛固酮醛固酮 及及ADHADH 维持血容量及维持血容量及BPBP问题：问题：兰斑兰斑-去甲肾上腺素去甲肾上腺素/交感交感-肾上腺髓质轴肾上腺髓质轴?下丘脑下丘脑-垂体垂体-肾上腺肾上腺皮质系统皮质系统?二、应激的细胞体液反应二、应激的细胞体液反应(Cellular and(Cellular and humoralhumoralresponses in stress)responses in stress)v热休克蛋白热休克蛋白 (Heat shock protein,Hsp)(Heat shock protein,Hsp)v急性期反应蛋白急性期反应蛋白 (Acute phase protein,AP)(Acute phase protein,AP)(一一)热休克蛋白热休克蛋白(Heat shock protein,(Heat shock protein,HspHsp)应激反应时细胞应激反应时细胞新合成或合成新合成或合成增加增加的一类的一类高度保守高度保守的蛋白质，在的蛋白质，在细胞内发挥作用，属细胞内发挥作用，属非分泌型非分泌型蛋白蛋白 HspHsp的概念：的概念：HSPHSP的基本组成：的基本组成：结构性结构性HspHsp 正常时即存在于细胞内正常时即存在于细胞内 诱生的诱生的HspHsp 由各种应激原诱导生成由各种应激原诱导生成HSPHSP的基本功能：的基本功能：结构性结构性HspHsp 分子伴娘。分子伴娘。HSPHSP控制新生蛋白质控制新生蛋白质 正确的三维结构和定位正确的三维结构和定位 诱生的诱生的HspHsp 与应激时受损蛋白质的修复或移与应激时受损蛋白质的修复或移除有关，在蛋白质水平起防御、保除有关，在蛋白质水平起防御、保护作用护作用 (二二)急性期反应蛋白急性期反应蛋白(Acute phase protein,(Acute phase protein,AP)AP)应激时由于感染、炎症或组织损应激时由于感染、炎症或组织损伤等原因使血浆中某些蛋白质浓度迅伤等原因使血浆中某些蛋白质浓度迅速升高，这些蛋白质被称为速升高，这些蛋白质被称为急性期反急性期反应蛋白应蛋白，属于，属于分泌型蛋白分泌型蛋白APAP的概念：的概念：APAP的主要构成及来源：的主要构成及来源：v 构成构成50%50%：铜蓝蛋白，铜蓝蛋白，补体补体C3C3，补体，补体C4C4510001000倍：倍：C C反应蛋白，血清淀粉样反应蛋白，血清淀粉样A A蛋白蛋白v 来源来源 主要由肝细胞合成主要由肝细胞合成APAP的生物学功能：的生物学功能：v 抗感染抗感染（调理素作用调理素作用,促进吞噬细胞功能促进吞噬细胞功能:C:C反应蛋反应蛋 白白;补体作用补体作用:C:C反应蛋白反应蛋白,补体补体C3)C3)v 抗炎症抗炎症 （C C反应蛋白：反应蛋白：抑制中性新粒细胞激活抑制中性新粒细胞激活)v 促促凝血凝血作用作用（纤维蛋白原，纤溶酶原激活物抑（纤维蛋白原，纤溶酶原激活物抑 制物制物-1-1；C C反应蛋白：促进单核细胞反应蛋白：促进单核细胞组织因子表达组织因子表达)v 抗损伤抗损伤 (1-1-蛋白酶蛋白酶抑制剂，抑制剂，1-1-抗糜蛋白酶）抗糜蛋白酶）v 结合与运输功能结合与运输功能（铜蓝蛋白，铜蓝蛋白，结合珠结合珠蛋白）蛋白）问题：问题：HspHsp与与APAP的的基本功能基本功能?三、应激时机体的功能代谢变化三、应激时机体的功能代谢变化(Functional and metabolic Functional and metabolic responses in stress)responses in stress)(一一)中枢神经系统中枢神经系统(Central nervous system,CNS(Central nervous system,CNS)去甲肾上去甲肾上腺素腺素适度适度紧张，专注程度升高紧张，专注程度升高过度过度焦虑、害怕、愤怒焦虑、害怕、愤怒HPA兴奋兴奋适度适度维持良好的认知维持良好的认知学习能力和良好的情绪学习能力和良好的情绪过度或过度或不足不足抑郁、厌食、自杀倾向抑郁、厌食、自杀倾向(二二)免疫系统免疫系统(Immunity)(Immunity)急性应激急性应激外周吞噬细胞外周吞噬细胞，补体补体，C C反应蛋白反应蛋白 过强过久或过强过久或慢性应激慢性应激GCGC和儿茶酚胺抑制免疫功能，诱和儿茶酚胺抑制免疫功能，诱发自身免疫病发自身免疫病(三三)心血管系统心血管系统(The cardiovascular system)(The cardiovascular system)v 基本变化基本变化 HR,心肌收缩力心肌收缩力,心输出量心输出量,BP v 机制机制 交感交感-肾上腺髓质系统兴奋，儿茶酚胺释放肾上腺髓质系统兴奋，儿茶酚胺释放v 代偿意义代偿意义 维持循环血量和维持循环血量和BP,保证心保证心,脑等重要器官的脑等重要器官的 血液供应血液供应(四四)消化系统消化系统(The digestive system)(The digestive system)应激时交感应激时交感-肾上腺髓质兴奋，导致：肾上腺髓质兴奋，导致：胃肠血管收缩、血流量胃肠血管收缩、血流量 胃肠粘膜糜烂胃肠粘膜糜烂,溃疡溃疡,出血出血(应激性应激性 溃疡溃疡)(五五)血液系统血液系统(The blood)(The blood)v急性应激急性应激 白白细细胞胞、血血小小板板数数目目及及粘粘附附力力，凝凝血因子血因子 等等抗感染、抗损伤及抗出血抗感染、抗损伤及抗出血v 慢性应激慢性应激 单核吞噬细胞对单核吞噬细胞对红细胞破坏红细胞破坏 贫血、贫血、低色素血症、红细胞寿命缩短等低色素血症、红细胞寿命缩短等(六六)泌尿生殖系统泌尿生殖系统 (The urinary system)(The urinary system)交感交感-肾上腺肾上腺髓质兴奋髓质兴奋肾素肾素-血管紧张素血管紧张素-醛固酮系统激活醛固酮系统激活肾血管收缩肾血管收缩肾小球肾小球滤过率滤过率ADH重吸收水重吸收水少少尿尿促性腺激素释放激素分泌促性腺激素释放激素分泌 (七七)生殖系统生殖系统(The reproductive system)(The reproductive system)问题：问题：应激时应激时心心血管系统血管系统的的变化变化?(Stress related injuries and diseases)应激性应激性疾病疾病应激起主要致应激起主要致病作用病作用应激性溃疡应激性溃疡应激相应激相关疾病关疾病应激是疾病发应激是疾病发生的重要原因生的重要原因和诱因和诱因原发性高血压、动原发性高血压、动脉粥样硬化、冠心脉粥样硬化、冠心病、溃疡性结肠炎、病、溃疡性结肠炎、支气管哮喘支气管哮喘一、全身适应综合征一、全身适应综合征(G(General adaptation syndromeeneral adaptation syndrome，GAS)GAS)Selye于于1946年提出年提出 v 定义定义应激原持续作用于机体，产生一个应激原持续作用于机体，产生一个动态动态的连续过程的连续过程并最终导致并最终导致内环境紊乱和疾内环境紊乱和疾病病，称为，称为全身适应综合征全身适应综合征v 分期分期 警觉期警觉期(the alarm stage)the alarm stage)抵抗期抵抗期(the resistance stagethe resistance stage)衰竭期衰竭期 (the exhaustion stage the exhaustion stage)(一一)警觉期警觉期(The alarm stage)(The alarm stage)v保护防御机制的快速动员期保护防御机制的快速动员期v交感交感-肾上腺髓质系统兴奋、肾上肾上腺髓质系统兴奋、肾上腺皮质激素腺皮质激素v有利于机体增强抵抗或回避损伤有利于机体增强抵抗或回避损伤的能力的能力(二二)抵抗期抵抗期(The resistance stage)(The resistance stage)v警觉反应逐步消退警觉反应逐步消退v出现以肾上腺皮质激素分泌增多出现以肾上腺皮质激素分泌增多为主的适应反应为主的适应反应v适应、抵抗能力增强适应、抵抗能力增强 (三三)衰竭期衰竭期 (The exhaustion stage)(The exhaustion stage)v抵抗能力耗竭抵抗能力耗竭v肾上腺皮质激素持续肾上腺皮质激素持续，但受体，但受体的数量和亲和力的数量和亲和力v内环境明显失衡内环境明显失衡v出现应激相关的疾病出现应激相关的疾病问题：问题：全身适应全身适应综合征综合征？分期？分期？病人在遭受各类病人在遭受各类重伤、重病和重伤、重病和其他应激其他应激情况下，出现情况下，出现胃、十二指胃、十二指肠粘膜的急性病变肠粘膜的急性病变，主要表现为胃、主要表现为胃、十二指肠粘膜的十二指肠粘膜的糜烂、浅溃疡、渗糜烂、浅溃疡、渗血血等，少数溃疡可较深或穿孔。等，少数溃疡可较深或穿孔。二、应激性溃疡二、应激性溃疡(Stress ulcer)(Stress ulcer)Multiple stress ulcers of the stomach,highlighted by the dark digested blood in their bases.发生机制发生机制(Mechanisms)(Mechanisms)v 胃、十二指肠粘膜缺血胃、十二指肠粘膜缺血 v 胃腔内胃腔内H H+向粘膜内的反向弥散向粘膜内的反向弥散 v 酸中毒，酸中毒，胆汁逆流胆汁逆流Five-year-old Scott was transported to our pediatric emergency department at 7:05 AM.His pajamas were covered with blood,and he was pale and anxious.His mother said that he had had a tonsillectomy 9 days ago.She also stated that Scott had been seen in our emergency department 2 days before because he was vomiting blood.At that time,he was kept overnight and discharged to home the next day.Scott had begun to vomit bright red blood again during the night.Scott was taken to the operating room within an hour of his arrival in the emergency department.No active tonsillar bleeding was found.He received a blood transfusion and was transported to the pediatric ICU.Only then did upper GI endoscopy performed reveal four or five multiple gastric stress ulcers on the greater curvature of the stomach,with one actively bleeding gastric ulcer.Scott did well and was discharged home the next day,with plans for close follow-up.What did we learn from this case?We were humbled to be reminded that the obvious answer is not always the correct one.Later,we learned that even though he was not physically or mentally abused,Scott had a very troubled 5 years of life.His mother was a drug addict and he was shuffled between different family members.Undoubtedly this factor could have contributed to a stress ulcer.As practitioners,we tend to think of ulcers as an adult disease,but children may be affected more than we think by social situations.(Maycock MA.A five-year-old boy with hematemesis.Journal of Emergency Nursing.22:454-456,1996).三、应激与心血管疾病三、应激与心血管疾病(Stress and cardiovascular diseases)(Stress and cardiovascular diseases)v原发性高血压原发性高血压 (essential hypertension)essential hypertension)v冠心病冠心病 (coronary artery disease)coronary artery disease)v心律失常心律失常 (arrhythmia)arrhythmia)In a Finnish study:812 factory workers,foundry work,heavy engineering to precision engineering,and clerical and administrative work.All free from cardiovascular diseases at baseline,followed for a mean of 25.6 years.Data were gathered by questionnaires,interviews and clinical examinations to explore the degree of responsibility at work,task difficulty and mental load.Questions on job control concerned decision authority and skill discretion.Pace of work,physical and mental load,satisfaction with income,fairness of supervision,job security and promotion prospects were also assessed.After adjustment for age and sex,participants with high job strain(high demands at work and low job control)had double the cardiovascular mortality risk.The risk was more than doubled for employees with effort-reward imbalance(low salary,lack of social approval,and few career opportunities relative to efforts required at work).High job strain and high effort-reward imbalance were also associated with increased cholesterol concentration and body mass index.(Kivimaki M,et al.Br Med J 325:857-60,2002).Stress and cardiovascular diseases致死性心律紊乱主要是致死性心律紊乱主要是心室纤颤心室纤颤,机制：机制：v儿茶酚胺兴奋儿茶酚胺兴奋 受体受体心室纤颤的阈值心室纤颤的阈值v心肌电活动异常心肌电活动异常v儿茶酚胺兴奋儿茶酚胺兴奋 受体使冠脉收缩痉挛受体使冠脉收缩痉挛v交感激活交感激活血液粘度血液粘度血栓形成血栓形成心肌心肌缺血缺血四、应激与内分泌功能障碍四、应激与内分泌功能障碍(Disorders of endocrine function in stress)(Disorders of endocrine function in stress)v生长激素（生长激素（急性急性应激应激：生长激素生长激素；慢性慢性应应激激：CRHCRH生长抑素生长抑素生长激素生长激素).).v甲状腺素（甲状腺素（急性急性应激应激：甲状腺素甲状腺素；慢性慢性应应激激:GC&GC&生长抑素生长抑素TSHTSH甲状腺素甲状腺素,GCGC抑制抑制T T4 4转化为转化为T T3 3).).v性性激素激素:(:(急性急性&慢性慢性应激应激性激素性激素).).问题：问题：应激性溃疡应激性溃疡?形成机制形成机制?(Pathophysiological basis of prevention and treatment of stress related diseases)v 尽快消除或撤离主要致病应激原尽快消除或撤离主要致病应激原v 避免给病人新的应激刺激避免给病人新的应激刺激v 恰当的心理治疗、护理恰当的心理治疗、护理v 及时识别、治疗应激性损伤及时识别、治疗应激性损伤Vocabularystress(应激应激);stressor(应激原应激原)locus ceruleus-norepinephrine/sympathetic-adrenal medulla axis(LC/NE,兰斑兰斑-去甲肾上腺素去甲肾上腺素/交感交感-肾上腺髓质轴肾上腺髓质轴)hypothalamus-pituitary-adrenal cortex system,(HPA,下丘脑下丘脑-垂体垂体-肾上腺皮质系统肾上腺皮质系统)heat shock protein(HSP,热休克蛋白热休克蛋白)acute phase protein(AP,急性期反应蛋白急性期反应蛋白)general adaptation syndrome(GAS,全身适应综全身适应综合征合征)the alarm stage(警觉期警觉期););the resistance stage (抵抗期抵抗期););the exhaustion stage(衰竭期衰竭期)stress ulcer(应激性溃疡应激性溃疡)Thanks!Thanks!谢谢！谢谢！