1.Introduction1.Introduction2.Causes and mechanisms of fever 2.Causes and mechanisms of fever 3.Febrile phases and the characteristics of thermo-metabolism3.Febrile phases and the characteristics of thermo-metabolism4.Functional and metabolic changes induced by febrile response4.Functional and metabolic changes induced by febrile response5.Pathophysiological basis of prevention and treatment for fever5.Pathophysiological basis of prevention and treatment for feverthermometernJimin Shao (), Ph.D.nDirector and Professor, PathophysiologynTel: 88208209;nE-mail: 1.1.IntroductionIntroduction(1)Normal body temperature(1)Normal body temperature 37（98.6 F）with a variation 1CAxillary 36-37 .4 COral 36.7-37.7 CRectal 36.9-37.9 C（ 2 2） Regulation Regulation of of normal normal body body temperature temperature (h(homeostasis)omeostasis) Thermoregulatory center: Thermoregulatory center: mainly located in hypothalamus Set point of hypothalamic thermostat: Set point of hypothalamic thermostat: a a hypothetic model for regulation of body temperature, which use the mechanic principle of thermostat of incubator to explain the process of body thermoregulation.The neurons in “set point” can sense the deviation of body temperature from its thermostat point and issue pulses to control the heat production and heat dissipation correspondently. (3)Elevation of body temperature(3)Elevation of body temperature An elevation of body temperature above the normal amplitude of daily variation(0.5) Types of body temperature elevation Types of body temperature elevation Physiological elevation before menstruation severe exercise stressPathological elevationFever（发热）, e.g. Infection diseasesHyperthermia（过热）, e.g. heatstroke An elevation of body temperature is fever?36 40 Physiologic elevation of body temperatureA pathologic elevation of body temperature is fever?HeatstrokeHyperthyroidismCentral nervous system damagehyperthermiaFeverFever Fever is a complicated pathological process characterized by a regulated elevation of core body temperature that exceeds the normal daily variation (0.5), in which pyrogens cause a temporary upward resetting of the hypothalamic thermostatic setpoint, inducing a complex physiologic and pathophysiologic febrile response. Regulated increase of body temperature above 37.5Caused by pyrogens Body temperature =the changed setpointHyperthermiaHyperthermia An unregulated rise in body temperature beyond the unchanged hypothalamic thermostatic setpoint resulting from the dysfunction of body temperature center or impairment of heat production and/or heat loss mechanisms. Causes: overproduction of heatimpediment in heat lossdysfunction of body temperature centerFeatures:Passive increase of body temperature 0.5 C Body temperature beyond the unchanged setpointHyperthermiaHyperthermiaFeverFeverArising from changes within the body or by changes in environmentResulting from pyrogenSet-point remains unchanged or damaged, or effector organs failsAbility to regulate set-point remains intact, but is turned up at a high level functionallyBody temperature may rise to a very high levelRise of body temperature has an upper limitTreatment with water-alcohol bathingTreatment with antipyretics and measures and drugs to eliminate the causesComparison between hyperthermia and feverComparison between hyperthermia and fever2. Causes and mechanisms of fever2. Causes and mechanisms of fever(1)(1)PyrogenicPyrogenic activator activator（发热激活物）（发热激活物）(2)Endogenous (2)Endogenous pyrogenpyrogen (EP (EP，内生致热原，内生致热原) )(3)Mechanisms of set point elevation caused by EP(3)Mechanisms of set point elevation caused by EP(4)Pathogenesis of fever(4)Pathogenesis of fever(1) (1) Pyrogenic activator Pyrogenic activator ConceptConcept of pyrogenic activator of pyrogenic activator fever-inducing substances that can activate endogenous pyrogen-generating cells to generate and release EPs.Pyrogenic activator (exogenous pyrogen) stimulate the cells produce and release EPs.Category of Category of pyrogenic activatorpyrogenic activatorlInfectious factors: microbes and microbial productsInfectious factors: microbes and microbial productsG- bacteria: Lipopolysaccharide (LPS)/EndotoxinG+bacteria: Exotoxins;Peptidoglycans,Teichoic acid(LTA)VirusesOther microorganismslNon-infectious factors: Non-infectious factors: Antigen-Antibidy complexesComponents of the complement cascadeNon-infectious inflammation-genesis irritantsCertain steroids: etiocholanolone(本胆烷醇酮) Concept of Concept of EPEP EPs are fever-inducing cytokines, such as TNF, IL-1, IL-6 and IFN, via elevating the hypothalamic thermostatic setpoint, and derived from mononuclear cells, macrophages, Kupffer cell, endothelia cells and etc, under the action of pyrogenic activators.(2)Endogenous pyrogen (EP)(2)Endogenous pyrogen (EP)EP generating cellsEP generating cellsvMonocyte vMacrophagevT lymphocytevKupffer cellsvEndothelia cellsvSome tumor cellsCategory of Category of EPsEPsvInterleukin-1 (IL-1) vTumor necrosis factor (TNF) vInterferon (IFN) vMacrophage inflammatory protein-1 (MIP-1)vInterleukin-6 (IL-6) vOthersEPsPrinciple sourceInducersIL-1aIL-1bMacrophages and other cell typesLPS,TNF, Other microbial productsTNF-aTNF-bMacrophagesLymphocytes(T&B)LPS, Other microbial productsantigen, mitogen stmulationIFN- aIFN- bIFN-gLeukocytesFibloblastsT-lymphocytesLPS, viral infectionIL-6Many cell typesLPS, TNFMIP-1aMIP-1bMacrophagesLPSIL-8Many cell typesLPS, TNF, IL-1Endogenous Pyrogenic cytokinesProduction and release of EPProduction and release of EP LPS + LBP (LPS binding protein, serum)- + sCD14 -TLR (Toll-like receptors, EP-producing cells)- NF-B-Target genes - EP expression and release Thermoregulation centerThermoregulation centervPositive regulation center Preoptic region of anterior hypothalamus(POAH，视前区-下丘脑前部）: Temperature-sensitive neurons Cold sensitive neuron Warm sensitive neuronvNegative regulation center Medial amygdaloid nucleus (MAN，中杏仁核) Ventral septal area (VSA，下丘脑腹隔区) (3)Mechanisms of setpoint elevation by EP(3)Mechanisms of setpoint elevation by EPThe routes for EP signals The routes for EP signals into the thermoregulatory center of hypothalamusinto the thermoregulatory center of hypothalamusvOrganum vasculosum laminae terminalis (OVLT，下丘脑终板血管器) specialized neural regions along the margins of the cerebral ventricular system that have fenestrated capillaries (almost no blood-brain-barrier)vBlood-brain barriervVagal afferent nerve fibersEPMacrophageOVLT neuronPOAH neuronSupraoptic recessThird ventricle of brainChiasma of optic nervesCapillaryOVLT areaMacrophagePOAH neuronPGE2PGE2Cells of ventricle tubal membrane The Role of OVLT in pathogenesis of feverHypertension: high blood pressure opens the BBB Development: the BBB is not fully formed at birth. Radiation: exposure to radiation can open the BBB. Infection: exposure to infectious agents can open the BBB. The BBB can be broken down by:Central mediators of feverCentral mediators of fevervThe positive regulatory mediatorsThe positive regulatory mediators Prostaglandins (PGE2) Corticotropin releasing hormone (CRH) The ratio of central Na+/Ca2+ cAMP Nitric oxide (NO)vThe negative regulatory mediatorsThe negative regulatory mediators Febrile ceiling（热限）: The febrile response is controlled within a strict limit, the upper limit almost never exceeds 41.0. Endogenous cryogen: the endogenous antipyretic substances that antagonize the effects of pyrogens on thermosensitive neurons, including: Arginine vasopressin (AVP，精氨酸加压素) -melanocyte-stimulating hormone (-MSH，黑素细胞刺激素) Lipocortin-1/Annexin A1（脂皮质蛋白-1/膜联蛋白A1）Pyrogenic activators: microorganisms, non-microbial pyretic substancesEP-producing cells: Monocytes/macrophages, endothelial cells, etcEndogenous pyrogens (EP)/ pyrogenic cytokines: IL-1,6, TNF, IFN,MIP-1,etcHypothalamus thermoregulatory center： Central mediators of fever(Positive：PGE2,CRH,cAMP,Na+/Ca2+,NO;Negative:AVP, -MSH, Lipocortin-1)Elevated thermoregulatory set pointOVLT , BBB, Vagus nerveHeat conservation; heat productionFEVER(4) Pathogenesis of fever(4) Pathogenesis of fever3. Febrile phases and the 3. Febrile phases and the characteristics of thermo-metabolismcharacteristics of thermo-metabolismEffervescence periodEffervescence periodHeat productionHeat production heat loss heat loss 体温上升期体温上升期Three stages of fever (typical) 3737 C C42 42 C CPersistent febrile periodPersistent febrile periodHeat equipoise at a Heat equipoise at a higher levelhigher level体温持续期体温持续期Defervescence period Defervescence period Heat loss Heat loss heat productionheat production体温下降期体温下降期The setpoint is raised to a higher levelThe setpoint is restored to the normal level4.Functional and metabolic changes 4.Functional and metabolic changes induced by febrile responseinduced by febrile response In addition to changes of the primary disease eliciting fever, a series of functional and metabolic alterations occur during fever because of the elevated body temperature.( (2)Changes of metabolism2)Changes of metabolismGenerally, the basal metabolic rate increases 13% while 1 oC elevation in body temperature.Consumption and catabolism of nutrients increase during fever: Carbohydrates, Lipid, Protein, Walter, Salts, Vitamines(1)Functional changes(1)Functional changes Central nervous system: excitabilityCardiovascular system: beat rate,cardiac output Respiratory system: hyperventilation/respiratory rate Digestive system: suppressedImmune system: anti-infection and anti-tumor activities 5. Pathophysiological basis of 5. Pathophysiological basis of prevention and treatment for fever prevention and treatment for fever Basic principles for fever treatmentBasic principles for fever treatmentDetermine and eliminate the cause of a fever；Antipyretic therapy: High fever, children, pregnant wommen, patients with severe cardiopathySupport measures:fluid and nutrientsPhysical measuresCase study