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feverYu-HongJia,Ph.DDepartmentofpathophysiologyDalianmedicaluniversityFeverisacomplicatedpathologicalprocesscharacterizedbyaregulatedelevationofcorebodytemperature,inwhichthehypothalamicsetpointistemporarilyresetatanelevatedtemperatureinresponsetopyreticsubstances.ConceptoffeverT>37℃T<37℃thermostasisHeatloss（sweetgland,respiration,bloodvesselofskin）Heatproduction（skeletalmuscle,liver,thyroid,adrenalgland）ThermoregulatorycenterInhypothalamusSetpoint37℃thermoreceptorAfferentNEfferentNEfferentNNormalthermoregulationFeverand↑corebodytemperaturefever→↑corebodytemperature↑corebodytemperature→feverhyperthermia：minority(bodytemperature>setpoint)PhysiologicalbodytemperatureelevationPathologicalbodytemperatureelevationfever:majority(bodytemperature＝setpoint)↑corebodytemperature(>0.5℃)·PhysiologicalbodytemperatureelevationNormalbodytemperature:37oC(setpoint,SP)Thedifferenceamongdifferentpartofbody:rectum（36.9～37.9C）

>oral（36.7～37.7C）>armpit（36～37.4C）Differencebetweendayandnight<1C

：bodytemperatureinafternoon>inmorningDifferencebetweenindividual<1C

：young>old

PhysiologicalbodytemperatureelevationSevereexercise,dining,beforemenstruation,duringpregnancy→bodytemperatureincreaseslightlyhyperthermiaconcept：hyperthermiaisdescribedastheelevationofbodytemperaturethatoccurswithoutchangesofthesetpointinthehypothalamicthermoregulatorycenter.Seenin：DysfunctionofthermoregulatorycenterHeatstrokeduetoichthyosisofskinorenvironmentalhightemperaturehyperthyroidismcomparisionbetweenfeverandhyperthermiafeverhyperthermiaDuetoeffectofpyrogenSetpointuppershiftThermoregulatoryfunctionisnormalBodytemperatureisequaltothelevelofsetpointRegulatedelevationofbodytemperatureActiveelevationofbodytemperatureInfectionofmicroorganism,tumorNopyrogen’seffectSetpointnormalDysfunctionofthermoregulatorycenter,dysfunctionofheatproductionorganofheatlossorganBodytemperatureishigherthanthatofsetpointNon-regulatedelevationofbodytemperaturePassiveelevationofbodytemperature,degenerativediseaseofhypothalamus,ichthyosisofskin,heatstoke,hyperthyroidismClassification(accordingtoincreasingextentofbodytemperature)Low-gradefever:＜38℃Middle-gradefever:38-39℃High-gradefever:39-40℃Superhigh-gradefever:＞40℃Feverisaregulatedelevationofbodytemperaturecausedbyuppershiftofsetpointattheeffectofpyrogen.ExogenouspyrogensEndogenouspyrogens(cytokines)Endogenouspyrogens-producedcellproduce,releaseThermoregulatorycenterSetpointshiftsupward,bodytemperatureelevatesNon-microbialpyreticsubstancesPyrogenicactivatorsⅠetiologyⅡpathogenesismechanism？Ⅰetiology---PyrogenicActivator

Conceptofpyrogenicactivator：itisthesubstancethatcanactivateendogenouspyrogen-producedcelltoproduceandreleaseendogenouspyrogen,alsocalledendogenouspyrogeninducer.PyrogenicactivatorExogenouspyrogenNon-microbialpyreticsubstancesparasitefungusvirusspirochetebateriumsteroidsAgAb（Ⅰ）exogenouspyrogenPyrogenicsubstancecomingoutsidespeciesbacteriumvirusfungusspirocheteparasitebacteriumGram-positivebacteria:Staphylococcus,streptococcus,pneumococcus,diphtheriabacillus,haybacillus

Pyrogenicfactor:wholecell,exotoxin,fragmentofcellwall(Peptidoglycan)Gram-negativebacteria:colonbacillus,typhoidbacillus,gonococcus,meningococcus,Shigella

dysenteriae,etal.Pyrogenicfactor:wholecellandpeptidoglycanincellwall,endotoxin(ET)incellwallmycobacteria:tuberclebacillusPyrogenicfactor:wholecell,peptidoglycanandpolysaccharidesandproteincontainedincellwallvirusInfluenzavirus,SARSvirus,measlesvirus,coxsackievirusPyrogenicfactor:virion,haemagglutininandtoxin-likesubstancecontainedinvirusInfluenzavirusSARSvirusmeaslesvirusfungusCandidaalbicans,histoplasmosis,Coccidioides

immitis,Paracoccidioides,Cryptococcusneoformans

Pyrogenicfactor:wholefungusandcapsularpolysaccharideandproteininitCandidaalbicansoralcandidaalbicansinfectionspirocheteLeptospira,Spirochaeta

recurrentis,Microspironema

pallidumPyrogenicfactor:hemolysin,cytotoxicfactor,metaboliclysate,andexotocininspirocheteParasitePlasmodium,leishmaniaPyrogenicfactor:merozoiteandmetaboliteLeptospiraMicrospironemapallidumendotoxinO-sidechainCorepolysaccharidesLipidAProtein/lipidsEndotoxincomplexPeptidoglycanlayerCellmembraneComponentofcellwallofallgram-negativebacteriaLocatedattheoutermostlayerofcellwall,attachdtopeptidoglycanMaincomponent:

lipopolysaccharide(LPS)Consistsofthreeparts:O-sidechain,corepolysaccharides,lipidACharacteristic:thermostability(160Chotair,2h),havingtolerance,bigmolecularweight,unabletopassthroughblood-brain-barrierPotentpyrogenicactivatorEndotoxinincellwallofG-bacteria(Ⅱ)non-microbialpyreticsubstancesAntigen-antibodycomplexesComponentsofthecomplementcascadeCertainSteroidsEtiocholanoloneLithocholicacidTheinjuredorabnormalcellsCertainanticancerdrugs(BSA)(BSA)(BSA)(anti-BSAantibody)A:InjectionofserumforsensitizingrabbitB:normalrabbitC:normalrabbitbovinserumalbuminSerumtransferfeverNofeverⅡpathogenesis(Ⅰ)EndogenousPyrogens(EP)

concept：EParefever-inducingsubstances(cytokines)producedandreleasedbyEP-producedcellsinthebody,suchasmacrophages,attheeffectofpyrogenicactivator.EP-producedcells:indicateallcellsthatcanproduceandreleaseEP,includingmononuclearcells,macrophages,epithelialcells,astrocytes,keratinocytesandtumorcells1.typesofEP(1)Interleukin-1(IL-1)

Producedbymononuclearcells,macrophages,epithelialcells,astrocytes,keratinocytesandtumorcells.Twosubtype:IL-1α(17KD)andIL-1β(17.5KD)IL-1receptorsarewidelydistributedinbrain,withthegreatestdensityintheouterhypothalamusnearthethermoregulatorycenter.IntravascularinjectionofIL-1orInjectionofIL-1toPOAHcanevokefeverNotresistheat(70C30mindeactivation)Havingnotolerance(2)TumorNecrosisFactor(TNF)Secretedbymacrophages,lymphocyteTwosubtye:TNFαandTNFβIntravascularorintracerebroventricularinjectionofTNFcanleadtofeverHeatlabile(70C30mindeactivation)(3)Interferon(IFN)HavingantivirusandantitumoreffectMainlyproducedbyleukocyteSeveralsubtypes:thesubtypesrelatedwithfeverareIFNαandIFN

γHavingpyrogenicreactionHavingtoleranceHeatlabile(60C40mindeactivation)(4)interleukin-6(IL-6)Secretedbymononuclearcells,fibroblasts,endothelialcellsandothercellsBraintissuealsocanproduceIL-6InjectionofIL-6toanimalcanmakefeverSeveralothercytokinesareprobableEPinvolvinginfeverIL-2Macrophageinflammatoryprotein(MIP)-1Ciliaryneurotrophicfactor(CNTF)IL-8EndothelinLPSLBPCD14Toll-likereceptorSignaltransductionGeneexpressionEP:LI-1、TNF、LI-6、IFNEP-producedcell

LBP:LPSbindingproteinCD14：SolubleCD14(epitheliums,endothelialcells)membraneboundCD14(mononuclearcells,macrophages)Tolllikereceptor:(transmembraneprotein)ExtracellulardomaincandiscernLPSintracellulardomainhashomologicdomainwithIL-1receptor2.theproductionandreleaseofEP---theactivatioofEP-producedcells,theproductionandreleaseofEP(Ⅱ)EPandthethermoregulatorycenter1.thermoregulatorycenterPositiveregulatorycenter:

preopticanteriorhypothalamus(POAH)Negativeregulatorycenter:

medialamygdaloidnucleus(MAN)ventralseptalarea(VSA)

arcuatenucleusAmplitudeanddurationThermoregulatorycenter？EP-producedcellsPyrogenicactivatorsEPSetpointshiftsupwardPositiveregulationnegativeregulation(2).EPactonthermoregulatorycenterthroughorganumvasculosumlaminateterminal(OVLT)

(4).EPtransmitthepyrogenicmessagetothePOAHviaperipheral(largelyvagal)afferentnerves(1).EPtransportintobrainthroughblood-brain-barrier(BBB)2.therouteforEPenteringthermoregulatorycenter(3).EPinducegenerationofBBB-permeableprostaglandinE2(PGE2)

BBBEndothelialcellcapillaryastrocyteblood－CSFbarrierCerebralspinalfluidcirculationChoroidplexusLateralventricles3rdventricle4thventricleFetalventricleLateralventricleChoroidplexus3rdventricleBlood-brainbarrier(BBB)Blood-CSFbarrierCSF-brainbarrierChoroidplexusepitheliumIL-1,IL-6，TNFsaturabletransportSchemeofcerebralspinalfluidcirculation3rdventricleorganumvasculosumlaminaeterminalis,(OVLT)EPdirectlyenterintobrainfenestratedcapilaries,highpermeabilityEPindirectlyenterintobrainStimulatemacrophage,gliacelltoproducedregulatorymediators(3).EPinducegenerationofBBB-permeablePGE2PGE2isinducedtogeneratedbyendothelialcellsofthecerebralmicrovasculatureorperivascularmicrogliaandmeningealmacrophages.PGE2isthemostproximal,putativemediatoroffever

(4).

EPtransmitthepyrogenicmessagetothePOAHviavagalnerves

intraperitonealorintravenousinjectionofLPSafterexcisionofsubdiaphragmaticvagusganglion(orcutofhepaticbranchesofvagusnerve)willnomoreinducefever(Ⅲ)centralmediatorsoffeverEPthermoregulatorycenter（positveornegativeregulatorycenter）releaseofcentralmediatorsoffever(positiveornegativeregulatorymediators)Set-pointchange(1)prostaglandinE，(PGE)(2)Na+/Ca2+ratio(3)cAMP(4)corticotropinreleasinghormone(CRH)(5)nitricoxide(NO)1thepositiveregulatorymediators(1)prostaglandinE(PGE)InjectPGEintocerebralventriclesofanimalsObviousfeverThelatencyforbodytemperaturerisingisshorterthanthatcausedbyEPThesensitivesiteforpyrogeniceffectofPGEisatPOAHDuringEP-inducedfeverPGElevelsinCSFincreasesignificantlyThelevelsofPGEinbloodandCSFcorrelatewiththechangesinbodytemperatureInhibitorsofPGEsynthesis(nonsteriodalanti-inflammatorydrugs,e.g.aspirin,brufen）AttenuatefeverDecreasePGElevelsinCSFBothETandEPcanstimulatethehypothalamictissuetoproducePGE(2)Na+/Ca2+ratioTestsofintraventricularperfusionshowperfusionofNa+→Na+/Ca2+ratio↑→bodytemperatureelevatesquicklyperfusionofCa2+→Na+/Ca2+ratio↓→bodytemperaturereducesquicklyPerfusionofcalciumreducingreagent(e.g.EGTA)→Na+/Ca2+ratio↑→bodytemperatureelevatesNa+/Ca2+ratio↑→cAMP↑→setpointshiftsupwardsIntraventricularperfusionofEGTAcanmakefever,simultaneouslycAMPinCSFincreasesPreinfusionofCaCl2→canpreventthepyrogeniceffectofEGTAandinhibittheincreaseofcAMPinCSFCaCl2caninhibitthefeverinducedbyendotoxin，andtheelevationofcAMPcontentinCSFisalsosuppressed.Thedegreeofbothsuppressionarepositivelycorrelative.(3)cAMPIntraventricularinjectionofexogenouscAMP（dibutyrylcAMP，Db-cAMP）Initiatesfeverquickly,andthelatencyismuchshorterthanthatoffeverinducedbyEPPyrogeniceffectofcAMPisincreasedbyphosphodiesteraseinhibitor(reducingcAMPdecomposition)

PyrogeniceffectofcAMPisloweredbyphosphodiesteraseactivator(increasingcAMPdecomposition)ThefevercausedbyexogenouscAMPisnotinfluencedbyadenylatecyclaseinhibitor(whichcaninhibittheproductionofcAMP);butadenylatecyclaseinhibitorcanreducethefevercausedbypyrogenandPGE.cAMPlevelsinCSFsignificantlyincreaseduringfever,andthedegreeofelevationispositivelycorrelativewithfevereffect.Butduringhyperthermia,cAMPlevelinCSFhasnomarkedchange.cAMPlevelsinCSFandhypothalamusshowsynchronousvariationwithbodytemperature(4)corticotropinreleasinghormone(CRH)TheevidencesupportingCRHtobepositiveregulatorymediatorsIL-1andIL-6canstimulatehypothalamustissuetosecreteCRHbothinvitroandinvivo.IntraventricularinjectionofCRH→bodytemperatureincreasesAnti-CRHmonoclonalantibodyorCRHreceptorantagonistcancompletelyinhibitthefeverinducedbyIL-1βandIL-6OpposingevidenceThefeverinducedbyTNFαandIL-1αisindependentofCRHInanimalswithfever,intraventricularinjectionofCRHcanmaketheincreasedbodytemperaturedecreaseInpresent,CRHisbelievedasbidirectionalregulatorymediators.(5)nitricoxide(NO)NOinsynthesizedfromargininebyacomplexreaction,whichiscatalyzedbynitricoxidesynthase(NOS)NOandNOSarewidelyexpressedinCNSNOismultifunctional,includingbeacentralmediatorinfevergenerationThemechanismsofNOinvolvinginfevergeneration:NOincreasesbodytemperaturethroughtheactionsonOVLTandPOAHNOincreasesheatproductionthroughstimulatingthemetabolismofbrownadiposetissueNOinhibitsthesynthesisandsecretionofthenegativeregulatorymediatorsrelatedtofever

Argininevasopressin(AVP)-melanocyte-stimulatinghormone(-MSH)

lipocortin-12thenegativeregulatorymediatorsFebrileceiling:thephenomenonthathumancorebodytemperatureisalmostneverpermittedtoriseabove41℃-42℃duringfeveriscalledfebrileceiling(1)Argininevasopressin(AVP)AVPisaneuropeptidehormonesecretedbyposteriorpituitaryandsynthesizedbyhypothalamus.EvidenceforAVP’santipyreticeffect:intraventricularinjectionofAVPorinjectionofAVPthroughotherpathwaysallshowantipyreticeffectIndifferentenvironmentaltemperature,AVPshowsitsantipyreticactionthroughdifferenteffectormechanism.At4℃throughinhibitingheatproduction;at25℃throughincreasingheatloss.AVPantagonistorAVPreceptorantagonistcanabolishtheantipyreticactionofAVPorpotentiatethepyreticactionofpyrogens.(2)-melanocyte-stimulatinghormone(-MSH)

-MSHisa13-amino-acidpeptidehormonesecretedbytheanteriorpituitary-MSHhasantipyreticeffect-MSH,giveneitherintraventricularlyorintravenously,canreducefeverinducedbyEP.DuringEP-inducedfever,-MSHlevelincreasesinventralseptalarea(VSA).WhendirectlyinjectedintoVSA,-MSHattenuatesfeverinducedbyEP.AbovephenomenonssuggestVSAisprobablythetargetsiteof-MSHTheantipyreticeffectof-MSHisrelatedwithincreasingheatloss.Endogenous-MSHcanlimitthealtitudeanddurationoffever.(3)lipocortin-1(LC-1)AlsodesignatedasannexinA1isaphospholipid-bindingproteinIswidelycontributedinthebody,mainlylocatedinbrainandlungAntipyreticeffectofglucocorticoidreliesonthereleaseofLC-1inbrainIntraventricularinjectionofLC-1canmarkedlyinhibitthefeverinducedbyIL-1ß,IL-6,IL-8,andCRH.PyrogenicactivatorsEP-producedcellsEPs(IL-1,TNF,IL-6)Setpoint↑ThermoregulatorycenterPGENa+/Ca2+cAMPCRHNOAVPα-MSHLC-1（positiveregulation:POAHNegativeregulation:VSA,MAN）Vasoconstrictionofskinmetabolism↑SkeletalmuscleshiverHeatloss↓Heatproduction↑feverSympatheticNVagalNPathogenesisoffeverBBB;OVLT;VagalnerveNormalvalueis37℃ⅢStagesandmanifestationsoffeverThefervescencestageThepersistentfebrilestageThedefervescencestage1.Thefervescencestage上升期Thesetpointiselevatedtoahigherlevel,corebodytemperature<setpointCharacteristicsofheatmetabolism:heatlossdecrease,heatproductionincrease,heatproductionismorethanheatloss,bodytemperatureiselevated.Manifestations:shiveringFeelcoldPaleskingoosefleshShiveringshivering：theinvoluntaryrhythmiccontractionofskeletalmuscle,itcanrapidlyincreaseheatproductionmechanism:causedbyexcitationofshiveringcenternormallyshivercenterisinhibitedbytheimpulsecomingfromheat-sensitiveneuronsofPOAH.WhenPOAHreceivescoldstimulus,aboveinhibitionisremovedandshiveringishappened.decreaseofskintemperaturealsocanexciteshivercenterthroughafferentpathwayafterstimulatingthecoldreceptor持续期2.ThepersistentfebrilestageThecorebodytemperatureisadaptedtotheelevatedsetpointCharacteristicsofheatmetabolism:

theheatproductionbalancestheheatlossattheelevatedlevelManifestations:ShiveringstopSkintemperatureelevates,skinmayfeelwarm,goosefleshisdisappearedSkinandoralliparedryPersistenttimeofthisstageisdependentoncauses,fromseveralhours,daystoover1week3.thedefervenscencestageSetpointisrestoredtonormal,corebodytemperature>setpointCharacteristicsofheatmetabolism:heatlossincreases,heatproductiondecreases,heatproductionislessthanheatloss,bodytemperaturedropsManifestation:heavysweatSkiniswarmandflushedPersistenttimeBodytemperaturedropsuddently(severalhours~oneday)Bodytemperaturedropslowly(severaldays)Ⅳalterationsofmetabolismandfunction(Ⅰ)alterationofmetabolismCharacteristicsofmetabolism:catabolismofthreemajornutrientsincrease.Glucosecatabolism↑，glycogenreserve↓，duringshiveringglycolysis↑↑→lacticacid↑Fatcatabolism↑Catabolismofprotein↑，negativenitrogenbalanceEach1℃increaseinbodytemperature,thebasalmetabolicrateincreases13%WaterandelectrolytedisturbancemayoccurSuggestion:supplyenoughnutrientduringfever,ifnotthepatientwillcatabolizehisbodytissueandlosehisbodyweight(Ⅱ)alterationoffunctionAlterationofCNSFever→excitabilityofCNSincrease.Irritability,delirium,hallucinationmayoccurwhenthetemperaturereaches40-41℃HeadacheFebrileconvulsionsdepressionofCNSinsomepatientwithhighfever2.AlterationofcardiovascularsystemHeartrate（HR）increasesevery1℃riseintemperatureleadsto18-bpm(beatsperminute)increaseinheartbeatMechanismofHRincreasing：theelevationofbloodtemperaturestimulatingthesinoatrialnode;activationofsympathetic-adrenalmedullaaxisandtheelevationofcatecholaminescanalsoincreasetheheartrateConsequenceofHRincreaseIncreaseofHR(HR≤150次/min)→cardiacoutput↑IncreaseofHR(HR＞150次/min)→cardiacoutput↓Diastolicstageisshorten→perfusionofcoronaryarterydecreases,leadingtomyocardialischemiaandhypoxia;ventricularfillingdecreasesMyocardialcontractilityincreasesMechanism:excitingofsympatheticnerveAlterationoftheBPduringthefervescencestagetheBPmayslightlyincreasebecauseofperipheralvasoconstrictionandthehighcardiacoutput