病理生理學(xué)系課件

病理生理學(xué)系

DepartmentofPathophysiology

高遠(yuǎn)生應(yīng)激Stress

對(duì)各種刺激的非特異性全身性反應(yīng)稱為應(yīng)激(stress)或應(yīng)激反應(yīng)(stressresponse)

第一節(jié)概念(Concept)二、應(yīng)激原(Stressor)

外環(huán)境因素(externalfactors)

高溫，嚴(yán)寒，低氧，創(chuàng)傷等

內(nèi)環(huán)境因素(internalfactors)

器官功能紊亂，心率失常，低血糖等

心理社會(huì)環(huán)境因素(psychosocialfactors)

職業(yè)競(jìng)爭(zhēng)，沮傷，恐懼，激怒，驚喜等

良性應(yīng)激(eustress);

劣性應(yīng)激(distress)問題：應(yīng)激?應(yīng)激原?第二節(jié)應(yīng)激反應(yīng)的基本表現(xiàn)(Manifestationsofstressresponse)

神經(jīng)-內(nèi)分泌反應(yīng)細(xì)胞體液反應(yīng)神經(jīng)-內(nèi)分泌反應(yīng)蘭斑-去甲腎上腺素/交感-腎上腺髓質(zhì)軸(Locusceruleus-norepinephrine/sympathetic-adrenalmedullaaxis,LC/NE)下丘腦-垂體-腎上腺皮質(zhì)系統(tǒng)(Hypothalamus-pituitary-adrenalcortexsystem,HPA)其他內(nèi)分泌反應(yīng)(Neuroendocrineresponsesinstress)蘭斑-去甲腎上腺素/交感-腎上腺髓質(zhì)軸(Locusceruleus-norepinephrine/sympathetic-adrenalmedullaaxis,LC/NE)蘭斑：位于橋腦與中腦交界處后側(cè)的核團(tuán)，含約20，000去甲腎上腺素能神經(jīng)元應(yīng)激原蘭斑興奮交感神經(jīng)系統(tǒng)興奮腎上腺素去甲腎上腺素Fight-or-FlightResponse急性應(yīng)激反應(yīng)生理意義：

促進(jìn)多種激素的分泌

支氣管擴(kuò)張→供氧量

血液重分布→保證心、腦、骨骼肌的供血心功能增強(qiáng)→組織供血

糖元、脂肪分解

→能量供應(yīng)持續(xù)時(shí)間過長(zhǎng)對(duì)機(jī)體的不利影響:心肌耗氧量應(yīng)激性心功能異常外周血管持續(xù)收縮應(yīng)激性高血壓,組織缺血血小板數(shù)目

粘附聚集誘發(fā)DIC分解代謝能量過度消耗下丘腦-垂體-腎上腺皮質(zhì)系統(tǒng)(Hypothalamus-pituitary-adrenalcortexsystem,HPA)AdrenalglandPain,fearInfectionhemorragehypoglycemiaCentralnervoussystemCRH(ng)HypothalamusAnteriorpituitaryACTH(mg)Cortisol(mg)CRH:corticotropin-releasinghormone

（促腎上腺皮質(zhì)激素釋放激素）ACTH:adrenocorticotropichormone

（促腎上腺皮質(zhì)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生理意義：提高抵抗力

允許作用(permissiveeffects)

兒茶酚胺兒茶酚胺胰高血糖素代謝反應(yīng)心血管反應(yīng)糖皮質(zhì)激素Oncatecholamineaction:Inducingphenylalanine-N-methyltransferase，therate-limitingenzymeinepinephrinesynthesis.Inhibitingcatecholaminereuptake,decreasingperipherallevelsofcatechol-O-methyltransferaseandmonoamineoxidaseIncreasingthebindingcapacityandaffinityofb-adrenergicreceptors,receptor-Gproteincoupling,andcatecholamine-inducedcAMPsynthesis.Onmetabolicaction:Increasinginthecapacityoftheliverforgluconeogenesis,primarilybyenhancingtheactivityofphosphoenolpyruvatecarboxykinaseandglucose6-phosphatase.Increasingsubstratesforgluconeogenesis,primarilyaminoacidsreleasedfrommuscleandotherperipheraltissues,andglycerolreleasedfromadiposetissueMechanismsofthepermissiveeffects

穩(wěn)定溶酶體膜

抑制炎性介質(zhì)與細(xì)胞因子的生成與釋放

促進(jìn)蛋白質(zhì)的糖異生糖皮質(zhì)激素:有利作用糖皮質(zhì)激素增多的不利影響:

負(fù)氮平衡

免疫功能過低

應(yīng)激性胃粘膜病變其他內(nèi)分泌反應(yīng)(Otherendocrineresponses)

胰高血糖素和胰島素胰高血糖素，胰島素

→血糖調(diào)節(jié)水鹽代謝的激素

腎素,血管緊張素Ⅱ,醛固酮及ADH

→維持血容量及BP問題：蘭斑-去甲腎上腺素/交感-腎上腺髓質(zhì)軸?下丘腦-垂體-腎上腺皮質(zhì)系統(tǒng)?二、應(yīng)激的細(xì)胞體液反應(yīng)(Cellularandhumoralresponsesinstress)熱休克蛋白

(Heatshockprotein,Hsp)急性期反應(yīng)蛋白

(Acutephaseprotein,AP)(一)熱休克蛋白(Heatshockprotein,Hsp)應(yīng)激反應(yīng)時(shí)細(xì)胞新合成或合成增加的一類高度保守的蛋白質(zhì)，在細(xì)胞內(nèi)發(fā)揮作用，屬非分泌型蛋白

Hsp的概念：HSP的基本組成：結(jié)構(gòu)性Hsp

正常時(shí)即存在于細(xì)胞內(nèi)誘生的Hsp

由各種應(yīng)激原誘導(dǎo)生成HSP的基本功能：結(jié)構(gòu)性Hsp

分子伴娘。HSP控制新生蛋白質(zhì)正確的三維結(jié)構(gòu)和定位誘生的Hsp

與應(yīng)激時(shí)受損蛋白質(zhì)的修復(fù)或移除有關(guān)，在蛋白質(zhì)水平起防御、保護(hù)作用

(二)急性期反應(yīng)蛋白(Acutephaseprotein,AP)應(yīng)激時(shí)由于感染、炎癥或組織損傷等原因使血漿中某些蛋白質(zhì)濃度迅速升高，這些蛋白質(zhì)被稱為急性期反應(yīng)蛋白，屬于分泌型蛋白AP的概念：AP的主要構(gòu)成及來源：

構(gòu)成50%：銅藍(lán)蛋白，補(bǔ)體C3，補(bǔ)體C4<5倍：纖維蛋白原，纖溶酶原激活物抑制物-1

1-蛋白酶抑制劑，1-抗糜蛋白酶結(jié)合珠蛋白5-100倍：甘露糖結(jié)合蛋白，脂多糖結(jié)合蛋白>1000倍：C反應(yīng)蛋白，血清淀粉樣A蛋白

來源

主要由肝細(xì)胞合成AP的生物學(xué)功能：抗感染（調(diào)理素作用,促進(jìn)吞噬細(xì)胞功能:C反應(yīng)蛋白;補(bǔ)體作用:C反應(yīng)蛋白,補(bǔ)體C3)

抗炎癥（C反應(yīng)蛋白：抑制中性新粒細(xì)胞激活)

促凝血作用（纖維蛋白原，纖溶酶原激活物抑制物-1；C反應(yīng)蛋白：促進(jìn)單核細(xì)胞組織因子表達(dá))

抗損傷(1-蛋白酶抑制劑，1-抗糜蛋白酶）

結(jié)合與運(yùn)輸功能（銅藍(lán)蛋白，結(jié)合珠蛋白）問題：Hsp與AP的基本功能?

三、應(yīng)激時(shí)機(jī)體的功能代謝變化

(Functionalandmetabolicresponsesinstress)

(一)中樞神經(jīng)系統(tǒng)(Centralnervoussystem,CNS)去甲腎上腺素↑適度緊張，專注程度升高過度焦慮、害怕、憤怒HPA興奮適度維持良好的認(rèn)知學(xué)習(xí)能力和良好的情緒過度或不足抑郁、厭食、自殺傾向(二)免疫系統(tǒng)(Immunity)急性應(yīng)激外周吞噬細(xì)胞，補(bǔ)體，C反應(yīng)蛋白過強(qiáng)過久或慢性應(yīng)激GC和兒茶酚胺抑制免疫功能，誘發(fā)自身免疫病(三)心血管系統(tǒng)(Thecardiovascularsystem)

基本變化

HR,心肌收縮力,心輸出量,BP

機(jī)制

交感-腎上腺髓質(zhì)系統(tǒng)興奮，兒茶酚胺釋放

代償意義

維持循環(huán)血量和BP,保證心,腦等重要器官的血液供應(yīng)(四)消化系統(tǒng)(Thedigestivesystem)應(yīng)激時(shí)交感-腎上腺髓質(zhì)興奮，導(dǎo)致：

胃腸血管收縮、血流量胃腸粘膜糜爛,潰瘍,出血(應(yīng)激性潰瘍)

(五)血液系統(tǒng)(Theblood)急性應(yīng)激白細(xì)胞、血小板數(shù)目及粘附力，凝血因子等→抗感染、抗損傷及抗出血

慢性應(yīng)激單核吞噬細(xì)胞對(duì)紅細(xì)胞破壞

→貧血、低色素血癥、紅細(xì)胞壽命縮短等(六)泌尿生殖系統(tǒng)(Theurinarysystem)

交感-腎上腺髓質(zhì)興奮腎素-血管緊張素-醛固酮系統(tǒng)激活腎血管收縮腎小球?yàn)V過率↓ADH↑重吸收水↑少尿促性腺激素釋放激素分泌↓

(七)生殖系統(tǒng)(Thereproductivesystem)

問題：應(yīng)激時(shí)心血管系統(tǒng)的變化?

(Stressrelatedinjuriesanddiseases)第三節(jié)應(yīng)激損傷與應(yīng)激相關(guān)疾病應(yīng)激性疾病應(yīng)激起主要致病作用應(yīng)激性潰瘍應(yīng)激相關(guān)疾病應(yīng)激是疾病發(fā)生的重要原因和誘因原發(fā)性高血壓、動(dòng)脈粥樣硬化、冠心病、潰瘍性結(jié)腸炎、支氣管哮喘

一、全身適應(yīng)綜合征(Generaladaptationsyndrome，GAS)

Selye于1946年提出

定義應(yīng)激原持續(xù)作用于機(jī)體，產(chǎn)生一個(gè)動(dòng)態(tài)的連續(xù)過程并最終導(dǎo)致內(nèi)環(huán)境紊亂和疾病，稱為全身適應(yīng)綜合征

分期警覺期

(thealarmstage)

抵抗期

(theresistancestage)

衰竭期

(theexhaustionstage)

(一)警覺期

(Thealarmstage)

保護(hù)防御機(jī)制的快速動(dòng)員期交感-腎上腺髓質(zhì)系統(tǒng)興奮、腎上腺皮質(zhì)激素↑有利于機(jī)體增強(qiáng)抵抗或回避損傷的能力(二)抵抗期

(Theresistancestage)警覺反應(yīng)逐步消退出現(xiàn)以腎上腺皮質(zhì)激素分泌增多為主的適應(yīng)反應(yīng)適應(yīng)、抵抗能力增強(qiáng)

(三)衰竭期

(Theexhaustionstage)抵抗能力耗竭腎上腺皮質(zhì)激素持續(xù)↑，但受體的數(shù)量和親和力↓內(nèi)環(huán)境明顯失衡出現(xiàn)應(yīng)激相關(guān)的疾病問題：全身適應(yīng)綜合征？分期？病人在遭受各類重傷、重病和其他應(yīng)激情況下，出現(xiàn)胃、十二指腸粘膜的急性病變，主要表現(xiàn)為胃、十二指腸粘膜的糜爛、淺潰瘍、滲血等，少數(shù)潰瘍可較深或穿孔。二、應(yīng)激性潰瘍(Stressulcer)Multiplestressulcersofthestomach,highlightedbythedarkdigestedbloodintheirbases.發(fā)生機(jī)制

(Mechanisms)

胃、十二指腸粘膜缺血

胃腔內(nèi)H+向粘膜內(nèi)的反向彌散

酸中毒，膽汁逆流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、應(yīng)激與心血管疾病(Stressandcardiovasculardiseases)原發(fā)性高血壓

(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