FeverFeverFeverFever

Regulation mode of normal body temperature Regulation mode of normal body temperature

Preoptic anteriorPreoptic anterior hypothalamus, hypothalamus, POAHPOAH

Set-pointSet-point ，， 37℃37℃

Thermal receptorThermal receptor

Heat production

Heat dissipation

Elevation of body temperatureElevation of body temperature

•physiological elevationphysiological elevation

•Pathophysiological elevationPathophysiological elevation feverfever hyperthermiahyperthermia

An elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point----fever

Fever and Fever and hyperthermiahyperthermia

Fever due to a disturbance of thermal regulatory control----hyperthermiaFor example:

●● excessive heat production (vigorous exercise, reaction to some anesthetics)

● ● decreased dissipation (dehydration)● loss of regulation (hypothalmic injury)

●● excessive heat production (vigorous exercise, reaction to some anesthetics)

● ● decreased dissipation (dehydration)● loss of regulation (hypothalmic injury)

Etiology and Mechanism of FeverEtiology and Mechanism of FeverEtiology and Mechanism of FeverEtiology and Mechanism of Fever

Development of Development of feverfever

Macrophage, monocyte, lymphocyte, Macrophage, monocyte, lymphocyte, etc.etc.

Endogenous pyrogenEndogenous pyrogen

Thermoregulatory CentreThermoregulatory Centre

feverfever

Mediators in regulation Mediators in regulation of body temperatureof body temperature

Rise in set pointRise in set point

Pyrogenic activatorPyrogenic activator

Pyrogenic activatorPyrogenic activator

11 ．． Exogenous pyrogenExogenous pyrogen

bacteriabacteria virusvirus

other microorganismother microorganism

2. internal metabolic product 2. internal metabolic product

antigen-antibody complex antigen-antibody complex

steroid steroid

inflammatory substanceinflammatory substance

A substance that can manufacture and release endogeneous pyrogen which produces a fever.

Exogenous pyrogenExogenous pyrogen

1. 1. Gram-negative bacteriumGram-negative bacterium

Lipoplysaccharide,LPSLipoplysaccharide,LPS

Endotoxin,ETEndotoxin,ET

structure of ETstructure of ET pyrogenic and toxic substance----lipid Apyrogenic and toxic substance----lipid A

。 。 LPS---strong heat resistance which allows bacteria to endure LPS---strong heat resistance which allows bacteria to endure 160 ℃ dry 160 ℃ dry

heat for about 2 hoursheat for about 2 hours

。。

2. g2. gram-positive bacteriumram-positive bacterium

engulfed by macrophagesengulfed by macrophages ；；

exogenous toxin exogenous toxin （（ enterotoxin enterotoxin 、、 erythogenic toxin, diphthera toxinerythogenic toxin, diphthera toxin ））

peptide polysaccharidepeptide polysaccharide

Exogenous pyrogenExogenous pyrogen

3. Virus and other microorganism3. Virus and other microorganism

1. pyrogen of virus related with lipoprotein, hemagglutinin 1. pyrogen of virus related with lipoprotein, hemagglutinin

within the envelopewithin the envelope ；； 2. pyrogens of 2. pyrogens of

fungusfungus 、、 Spirochaeta Spirochaeta 、、 Chlamydia Chlamydia 、、 plasmodium may plasmodium may

be considered to be LPS be considered to be LPS

Pyrogenic activator—Pyrogenic activator—internal metabolic productinternal metabolic product

1. Ag-Ab1. Ag-Ab complexcomplex

activation of pyrogenic cellsactivation of pyrogenic cells 。。

2. Steroid and inflammatory 2. Steroid and inflammatory

Testosterone’s metabolic intermediateTestosterone’s metabolic intermediate （（ etiocholanoloneetiocholanolone

）） Uric Acid CrystalsUric Acid Crystals

Development of Development of feverfever

endogenous pyrogenic endogenous pyrogenic cellscells

Endogenous pyrogenEndogenous pyrogen

Nerve centerNerve center

feverfever

Mediators in Mediators in regulation of body regulation of body

temperaturetemperatureRise in set pointRise in set point

Pyrogenic activatorPyrogenic activator

Endogenous PyrogenEndogenous Pyrogen

Source of EPSource of EP

monocytes and macrophages monocytes and macrophages ：： blood blood

mononuclear cell mononuclear cell 、、 hepatic stellate hepatic stellate

cells cells 、、 pulmonary alveolar pulmonary alveolar

macrophage macrophage 、、 peritoneal macrophageperitoneal macrophage

Cancer cellCancer cell ：： hodgkin cancer hodgkin cancer

cellcell 、、 leukemia cell leukemia cell 、、 renal carcinoma cellrenal carcinoma cell

other cellsother cells ：：lymphocytes lymphocytes 、、 fibroblast fibroblast 、、 endothelial endothelial

cellscells

Endogenous pyrogenic cellsEndogenous pyrogenic cells

A fever-inducing substance (protein) produced by cells of the A fever-inducing substance (protein) produced by cells of the

host body, such as leukocytes and macrophageshost body, such as leukocytes and macrophages

Types of EPTypes of EP

（（ 11 ）） IL-1 (Interleukin-1)IL-1 (Interleukin-1)

mainly from monocytes and macrophagesmainly from monocytes and macrophages

（（ 22 ）） IL-6 (Interleukin-6)IL-6 (Interleukin-6)

mainly from monocytes fibroblasts and TB mainly from monocytes fibroblasts and TB lymphocytes lymphocytes

（（ 33 ）） TNF (Tumor necrosis factor)TNF (Tumor necrosis factor) TNF-TNF- 、、 TNF-TNF-

rTNFrTNF used for treatment during the stage I of tumor, used for treatment during the stage I of tumor,

however with side effect “ fever ”however with side effect “ fever ” to the patientsto the patients

（（ 44 ）） IFN (Interferon)IFN (Interferon) IFN-IFN- with strong pathogenicitywith strong pathogenicity

（（ 55 ）） Macrophage inflammatory proteinMacrophage inflammatory protein -1-1 （（ MIP-MIP-11 ））

Site affected by EPSite affected by EP ：：

Advanced thermoregulator Advanced thermoregulator centre-centre-

Preoptic anterior Preoptic anterior hypothalamushypothalamus （（ POAHPOAH ））

Lower thermoregulator Lower thermoregulator centre-centre-

Medulla oblongataMedulla oblongata 、、 ponspons 、、mesencephalonmesencephalon 、、 spinal spinal cordcord

Pyrogenic activatorPyrogenic activator

Macrophage, monocyte, Macrophage, monocyte, lymphocyte, etc.lymphocyte, etc.

Endogenous pyrogenEndogenous pyrogen

Thermoregulatory CentreThermoregulatory Centre

feverfever

Mediators in regulation of body Mediators in regulation of body temperaturetemperature

Rise in set pointRise in set point

EP’s ways of affecting EP’s ways of affecting nervous system nervous system

（（ 11 ）） blood-brain barrierblood-brain barrier

IL-1, IL-6, TNF through saturable transport system IL-1, IL-6, TNF through saturable transport system

infilterating to the brain from choroid plexus infilterating to the brain from choroid plexus

（（ 22 ）） organum vasculosum laminae terminalis organum vasculosum laminae terminalis (OVLT)(OVLT)

OVLT: the blood-brain barrier’s weakest site comprising OVLT: the blood-brain barrier’s weakest site comprising

fenestrated capillary with high permeabilityfenestrated capillary with high permeability

（（ 33 ）） indirect regulation through vagus nerveindirect regulation through vagus nerve

EP conduct impulse to the brain by stimulating vagus EP conduct impulse to the brain by stimulating vagus nerve.nerve.

Mediators of positive regulationMediators of positive regulation

3. CRH3. CRH （（ Corticotrophin releasing hormoneCorticotrophin releasing hormone ））

2. cAMP2. cAMP （（ Cyclin adenosine monophosphateCyclin adenosine monophosphate ）） cAMP, second messager cellscAMP, second messager cells ，， regultion of cellular regultion of cellular function and synaptic transmission in POAH function and synaptic transmission in POAH

neuronsneurons ，， positive regulation of body temperaturepositive regulation of body temperature 。。

1. PGE1. PGE

4. Na4. Na++/Ca/Ca2+2+ ratioratio

＊ ＊ NaNa++/Ca/Ca2+2+ratio↑ elevated thermoregulationratio↑ elevated thermoregulation

＊＊ ventricle[Caventricle[Ca2+2+] ↑ limit EP and cAMP in cerebrospinal ] ↑ limit EP and cAMP in cerebrospinal fluid ↑ fluid ↑

EP PGEEP PGE22↑↑ NaNa++/Ca/Ca2+2+ratio↑ cAMP↑ elevated ratio↑ cAMP↑ elevated

thermoregulationthermoregulation ↑↑ 5. NO5. NO

＊ ＊ new type of neurotransmitternew type of neurotransmitter

＊＊ mechanism ①act on POAHmechanism ①act on POAH 、、 OVLTOVLT

② ②stimulate metabolism of brown fat to produce heatstimulate metabolism of brown fat to produce heat

③ ③inhibit negative regulationinhibit negative regulation

Mediators of positive regulationMediators of positive regulation

3. A1(annexin A1)3. A1(annexin A1)

the working together of positive and negative the working together of positive and negative regulation to produce heat rise in the course of feverregulation to produce heat rise in the course of fever

2. α-melanocyte stimulating hormone,α-MSH2. α-melanocyte stimulating hormone,α-MSH

decomposition product of adrenocorticotropic hormonedecomposition product of adrenocorticotropic hormone ，， highly highly effective in reducing temperatureeffective in reducing temperature

Mediators of negative regulationMediators of negative regulation

1. Arginine vasopressin, AVP1. Arginine vasopressin, AVP

AVP ↑ VSAAVP ↑ VSA 、、 MAN MAN

EPEP↓ ↓ PO/AH temperature↓ PO/AH temperature↓

OVLT capOVLT cap permeability ↓permeability ↓

Action mode of EPAction mode of EP

EPEP

Positive regulation Positive regulation center center POAHPOAH

Negative regulation Negative regulation center center VSA,MANVSA,MAN

Elevated set Elevated set pointpoint

CRH↑CRH↑

cAMP↑cAMP↑

PGEPGE22↑↑

CaCa2+2+↓↓

↑↑AVPAVP

↑ ↑α-MSHα-MSH

↑↑CaCa2+2+

VVentral entral SSeptaleptal A Arearea

Medical Amygdaloid Medical Amygdaloid NeuleusNeuleus

The phase of feverThe phase of fever

Ⅰ .feverscence period

Ⅱ .fastigium

Ⅲ.defeverscene

period

ⅠⅠ ⅡⅡ ⅢⅢ

phasephase characteristicscharacteristics Clinical Clinical manifestationsmanifestations

Onset of fever Set point core temperature Set point core temperature lower than the set point lower than the set point

Dissipation < productionDissipation < production

Pale Pale skinskin ，， chillychilly ，， shivshiverer

Persistent of fever

Core temeprature meets set Core temeprature meets set pointpoint

Dissipation = productionDissipation = production

rubefactionrubefaction ，， dry dry skinskin ，， hot hot

Subsidence of fever

Set pointSet point normal set pointnormal set pointDissipation > productionDissipation > production

Heavy perspirationHeavy perspiration

1.Metabolic features and clinical 1.Metabolic features and clinical manifestationsmanifestations

■■ cardiovascularcardiovascular ：： heartbeat, blood heartbeat, blood

pressurepressure

■■ respiratory: respiratory: fever, blood temperature, fever, blood temperature,

metabolism, acid metabolism, acid

production, production,

respiration frequencyrespiration frequency

■■ digestivedigestive ：： appetiteappetite ，， digestiondigestion

■■CNS: CNS: headache, illusion, febrile headache, illusion, febrile

convulsion convulsion

2.Changes in physiological 2.Changes in physiological functionsfunctions

Anti-infectionAnti-infection 　　 inactivation of some heat-sensitive pathogenic

microorganism like streptococcus , enhancement of the ability of some immune cells like human lymphocytes, while reduced function of some immune cells like NK cells

Cancer cellsCancer cells

to some extent, EP could inhibit cancer cells growth..

Acute phase responseAcute phase response

definition ： a series of reactions against injury caused

by bacteria infection and tissue damages, including

increased acute phase proteins and changes in microelements

of blood plasma and white cells

3.Changes in immune systems3.Changes in immune systems

Prevention and treatment Prevention and treatment

1. Primary affection1. Primary affection

2. Basic treatment of fever2. Basic treatment of fever

3. Cases in need of treatment in time3. Cases in need of treatment in time

11. high fever (> 40℃). high fever (> 40℃)

22. patients with heart disease . patients with heart disease

33. pregnant women. pregnant women

4. headache, disturbance of 4. headache, disturbance of consciousness, infantile convulsionconsciousness, infantile convulsion

Cases Cases need need emergencemergency y treatmenttreatment

drugs

Chemicals like

salicylic acid

TreamentTreament

Physical measures

Herbal drugsSteroids like

glucocorticoids