病理生理学系课件

病理生理学系

DepartmentofPathophysiology

高远生应激Stress

对各种刺激的非特异性全身性反应称为应激(stress)或应激反应(stressresponse)

第一节概念(Concept)二、应激原(Stressor)

外环境因素(externalfactors)

高温，严寒，低氧，创伤等

内环境因素(internalfactors)

器官功能紊乱，心率失常，低血糖等

心理社会环境因素(psychosocialfactors)

职业竞争，沮伤，恐惧，激怒，惊喜等

良性应激(eustress);

劣性应激(distress)问题：应激?应激原?第二节应激反应的基本表现(Manifestationsofstressresponse)

神经-内分泌反应细胞体液反应神经-内分泌反应兰斑-去甲肾上腺素/交感-肾上腺髓质轴(Locusceruleus-norepinephrine/sympathetic-adrenalmedullaaxis,LC/NE)下丘脑-垂体-肾上腺皮质系统(Hypothalamus-pituitary-adrenalcortexsystem,HPA)其他内分泌反应(Neuroendocrineresponsesinstress)兰斑-去甲肾上腺素/交感-肾上腺髓质轴(Locusceruleus-norepinephrine/sympathetic-adrenalmedullaaxis,LC/NE)兰斑：位于桥脑与中脑交界处后侧的核团，含约20，000去甲肾上腺素能神经元应激原兰斑兴奋交感神经系统兴奋肾上腺素去甲肾上腺素Fight-or-FlightResponse急性应激反应生理意义：

促进多种激素的分泌

支气管扩张→供氧量

血液重分布→保证心、脑、骨骼肌的供血心功能增强→组织供血

糖元、脂肪分解

→能量供应持续时间过长对机体的不利影响:心肌耗氧量应激性心功能异常外周血管持续收缩应激性高血压,组织缺血血小板数目

粘附聚集诱发DIC分解代谢能量过度消耗下丘脑-垂体-肾上腺皮质系统(Hypothalamus-pituitary-adrenalcortexsystem,HPA)AdrenalglandPain,fearInfectionhemorragehypoglycemiaCentralnervoussystemCRH(ng)HypothalamusAnteriorpituitaryACTH(mg)Cortisol(mg)CRH:corticotropin-releasinghormone

（促肾上腺皮质激素释放激素）ACTH:adrenocorticotropichormone

（促肾上腺皮质激素）PhilipShowalterHench

EdwardCalvinKendall

In1849ThomasAddisonofScotlandin1849discoveredtheconnectionbetweentheadrenalglandsandAddison'sdisease.In1894,anEnglishphysicianraisedhisownson'sbloodpressurebymeansofwateryextractsfromadrenlaglands.

Duringtheearly1930's,EdwardC.Kendallsuccessfullyisolated5differentcompoundsfromtheadrenalcortex.In1936,Thadeus

Reichsteinisolatedasmanyas7substances.OnApril29,1948,KendallproducedafewgramsofcompoundE.PhilipS.HenchjoinedwithKendallatthispoint,andtogethertheydiscoveredthatcompoundEcouldbesuccessfullyusedtotreatpatientswithrheumatoidarthritis.Thewonderdrughadfinallyarrivedanditwaschristened"cortisone"onJuly1,1949.In1950,Kendall,ReichsteinandHenchwereawardedtheNobelPrize.

TheNobelPrizeinPhysiologyorMedicine1950“fortheirdiscoveriesrelatingtothehormonesoftheadrenalcortex,theirstructureandbiologicaleffects”BenefitsGCsareused:endocrinedisorders,rheumaticdisorders,collagendiseases,dermatologicdiseases,allergicstates,ophthalmicdiseases,respiratorydiseases,hemotologicdisorders,neoplasticdiseases,edematousdiseases,gastrointestinaldiseases,etc.Specificexamplesincluderheumatoidarthritis,tuberculosis,Addison'sdiseaseandsevereasthma.GCsalsohelpedtomakeorgantransplantsarealityduetoitsabilitytominimizethedefensereactionofthebodytowardsforeignproteins.ProblemsThemajorriskisthespreadofbacterialinfectionduetodiminishedresistance.Depressionandpepticulcersoccasionallyoccur.Psychicderangementsmayappearrangingfromeuphoria,insomnia,moodswingsandpersonalitychanges,tofrankpsychoticmanifestations.Athighdosage,moonfaceandbuffalohumpcanalsooccur.Inaddition,cataractsandglaucomamaydevelopinpredisposedpatientsifusedforaprolongedperiodoftime.

Glucocorticoids生理意义：提高抵抗力

允许作用(permissiveeffects)

儿茶酚胺儿茶酚胺胰高血糖素代谢反应心血管反应糖皮质激素Oncatecholamineaction:Inducingphenylalanine-N-methyltransferase，therate-limitingenzymeinepinephrinesynthesis.Inhibitingcatecholaminereuptake,decreasingperipherallevelsofcatechol-O-methyltransferaseandmonoamineoxidaseIncreasingthebindingcapacityandaffinityofb-adrenergicreceptors,receptor-Gproteincoupling,andcatecholamine-inducedcAMPsynthesis.Onmetabolicaction:Increasinginthecapacityoftheliverforgluconeogenesis,primarilybyenhancingtheactivityofphosphoenolpyruvatecarboxykinaseandglucose6-phosphatase.Increasingsubstratesforgluconeogenesis,primarilyaminoacidsreleasedfrommuscleandotherperipheraltissues,andglycerolreleasedfromadiposetissueMechanismsofthepermissiveeffects

稳定溶酶体膜

抑制炎性介质与细胞因子的生成与释放

促进蛋白质的糖异生糖皮质激素:有利作用糖皮质激素增多的不利影响:

负氮平衡

免疫功能过低

应激性胃粘膜病变其他内分泌反应(Otherendocrineresponses)

胰高血糖素和胰岛素胰高血糖素，胰岛素

→血糖调节水盐代谢的激素

肾素,血管紧张素Ⅱ,醛固酮及ADH

→维持血容量及BP问题：兰斑-去甲肾上腺素/交感-肾上腺髓质轴?下丘脑-垂体-肾上腺皮质系统?二、应激的细胞体液反应(Cellularandhumoralresponsesinstress)热休克蛋白

(Heatshockprotein,Hsp)急性期反应蛋白

(Acutephaseprotein,AP)(一)热休克蛋白(Heatshockprotein,Hsp)应激反应时细胞新合成或合成增加的一类高度保守的蛋白质，在细胞内发挥作用，属非分泌型蛋白

Hsp的概念：HSP的基本组成：结构性Hsp

正常时即存在于细胞内诱生的Hsp

由各种应激原诱导生成HSP的基本功能：结构性Hsp

分子伴娘。HSP控制新生蛋白质正确的三维结构和定位诱生的Hsp

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、保护作用

(二)急性期反应蛋白(Acutephaseprotein,AP)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速升高，这些蛋白质被称为急性期反应蛋白，属于分泌型蛋白AP的概念：AP的主要构成及来源：

构成50%：铜蓝蛋白，补体C3，补体C4<5倍：纤维蛋白原，纤溶酶原激活物抑制物-1

1-蛋白酶抑制剂，1-抗糜蛋白酶结合珠蛋白5-100倍：甘露糖结合蛋白，脂多糖结合蛋白>1000倍：C反应蛋白，血清淀粉样A蛋白

来源

主要由肝细胞合成AP的生物学功能：抗感染（调理素作用,促进吞噬细胞功能:C反应蛋白;补体作用:C反应蛋白,补体C3)

抗炎症（C反应蛋白：抑制中性新粒细胞激活)

促凝血作用（纤维蛋白原，纤溶酶原激活物抑制物-1；C反应蛋白：促进单核细胞组织因子表达)

抗损伤(1-蛋白酶抑制剂，1-抗糜蛋白酶）

结合与运输功能（铜蓝蛋白，结合珠蛋白）问题：Hsp与AP的基本功能?

三、应激时机体的功能代谢变化

(Functionalandmetabolicresponsesinstress)

(一)中枢神经系统(Centralnervoussystem,CNS)去甲肾上腺素↑适度紧张，专注程度升高过度焦虑、害怕、愤怒HPA兴奋适度维持良好的认知学习能力和良好的情绪过度或不足抑郁、厌食、自杀倾向(二)免疫系统(Immunity)急性应激外周吞噬细胞，补体，C反应蛋白过强过久或慢性应激GC和儿茶酚胺抑制免疫功能，诱发自身免疫病(三)心血管系统(Thecardiovascularsystem)

基本变化

HR,心肌收缩力,心输出量,BP

机制

交感-肾上腺髓质系统兴奋，儿茶酚胺释放

代偿意义

维持循环血量和BP,保证心,脑等重要器官的血液供应(四)消化系统(Thedigestivesystem)应激时交感-肾上腺髓质兴奋，导致：

胃肠血管收缩、血流量胃肠粘膜糜烂,溃疡,出血(应激性溃疡)

(五)血液系统(Theblood)急性应激白细胞、血小板数目及粘附力，凝血因子等→抗感染、抗损伤及抗出血

慢性应激单核吞噬细胞对红细胞破坏

→贫血、低色素血症、红细胞寿命缩短等(六)泌尿生殖系统(Theurinarysystem)

交感-肾上腺髓质兴奋肾素-血管紧张素-醛固酮系统激活肾血管收缩肾小球滤过率↓ADH↑重吸收水↑少尿促性腺激素释放激素分泌↓

(七)生殖系统(Thereproductivesystem)

问题：应激时心血管系统的变化?

(Stressrelatedinjuriesanddiseases)第三节应激损伤与应激相关疾病应激性疾病应激起主要致病作用应激性溃疡应激相关疾病应激是疾病发生的重要原因和诱因原发性高血压、动脉粥样硬化、冠心病、溃疡性结肠炎、支气管哮喘

一、全身适应综合征(Generaladaptationsyndrome，GAS)

Selye于1946年提出

定义应激原持续作用于机体，产生一个动态的连续过程并最终导致内环境紊乱和疾病，称为全身适应综合征

分期警觉期

(thealarmstage)

抵抗期

(theresistancestage)

衰竭期

(theexhaustionstage)

(一)警觉期

(Thealarmstage)

保护防御机制的快速动员期交感-肾上腺髓质系统兴奋、肾上腺皮质激素↑有利于机体增强抵抗或回避损伤的能力(二)抵抗期

(Theresistancestage)警觉反应逐步消退出现以肾上腺皮质激素分泌增多为主的适应反应适应、抵抗能力增强

(三)衰竭期

(Theexhaustionstage)抵抗能力耗竭肾上腺皮质激素持续↑，但受体的数量和亲和力↓内环境明显失衡出现应激相关的疾病问题：全身适应综合征？分期？病人在遭受各类重伤、重病和其他应激情况下，出现胃、十二指肠粘膜的急性病变，主要表现为胃、十二指肠粘膜的糜烂、浅溃疡、渗血等，少数溃疡可较深或穿孔。二、应激性溃疡(Stressulcer)Multiplestressulcersofthestomach,highlightedbythedarkdigestedbloodintheirbases.发生机制

(Mechanisms)

胃、十二指肠粘膜缺血

胃腔内H+向粘膜内的反向弥散

酸中毒，胆汁逆流Five-year-oldScottwastransportedtoourpediatricemergencydepartmentat7:05AM.Hispajamaswerecoveredwithblood,andhewaspaleandanxious.Hismothersaidthathehadhadatonsillectomy9daysago.ShealsostatedthatScotthadbeenseeninouremergencydepartment2daysbeforebecausehewasvomitingblood.Atthattime,hewaskeptovernightanddischargedtohomethenextday.Scotthadbeguntovomitbrightredbloodagainduringthenight.Scottwastakentotheoperatingroomwithinanhourofhisarrivalintheemergencydepartment.Noactivetonsillarbleedingwasfound.HereceivedabloodtransfusionandwastransportedtothepediatricICU.OnlythendidupperGIendoscopyperformedrevealfourorfivemultiplegastricstressulcersonthegreatercurvatureofthestomach,withoneactivelybleedinggastriculcer.Scottdidwellandwasdischargedhomethenextday,withplansforclosefollow-up.

Whatdidwelearnfromthiscase?Wewerehumbledtoberemindedthattheobviousanswerisnotalwaysthecorrectone.Later,welearnedthateventhoughhewasnotphysicallyormentallyabused,Scotthadaverytroubled5yearsoflife.Hismotherwasadrugaddictandhewasshuffledbetweendifferentfamilymembers.Undoubtedlythisfactorcouldhavecontributedtoastressulcer.Aspractitioners,wetendtothinkofulcersasanadultdisease,butchildrenmaybeaffectedmorethanwethinkbysocialsituations.

(MaycockMA.Afive-year-oldboywithhematemesis.JournalofEmergencyNursing.22:454-456,1996).三、应激与心血管疾病(Stressandcardiovasculardiseases)原发性高血压

(essentialhypertension)冠心病

(coronaryarterydisease)心律失常

(arrhythmia)

InaFinnishstudy:812factoryworkers,foundrywork,heavyengineeringtoprecisionengineering,andclericalandadministrativework.Allfreefromcardiovasculardiseasesatbaseline,followedforameanof25.6years.Data

weregatheredbyquestionnaires,interviewsandclinicalexaminationstoexplorethedegreeofresponsibilityatwork,taskdifficultyandmentalload.Questionsonjobcontrolconcerneddecisionauthorityandskilldiscretion.Paceofwork,physicalandmentalload,satisfactionwithincome,fairnessofsupervision,jobsecurityandpromotionprospectswerealsoassessed.Afteradjustmentforageandsex,participantswithhighjobstrain(highdemandsatworkandlowjobcontrol)haddoublethecardiovascularmortalityrisk.Theriskwasmorethandoubledforemployeeswitheffort-rewardimbalance(lowsalary,lackofsocialapproval,andfewcareeropportunitiesrelativetoeffortsrequiredatwork).Highjobstrainandhigheffort-rewardimbalancewerealsoassociatedwithincreasedchole