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04 fever
1. Dept. of PathologyDept. of Pathology
Medical CollegeMedical College
Hunan Normal UniversityHunan Normal University
(( 湖南 范大学医学院病理学教研室师湖南 范大学医学院病理学教研室师 )) 1
Chapter 4Chapter 4
FeverFever
( )发热( )发热
2. 22
FeverFever
a.a. IntroductionIntroduction
b.b. Causes and MechanismCauses and Mechanism
c.c. Stages and ManifestationsStages and Manifestations
d.d. Alterations of Metabolism andAlterations of Metabolism and
FunctionFunction
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment
3. Life Stages
0-2 years old 3-10 years old 11-65 years old Over 65
Circadian variation
of body temperature
2am 2pm 2am
37.5
36.5
Q: Why stable temperature?
Normal Temperature range: 36℃ ~ 37.5℃
Oral temperature: 37℃
5. Homeostasis (36℃ ~
37℃ )
Activates heat-loss center
in hypothalamus
Skin blood
vessels constrict
Skeletal muscles activated,
shivering begins
Skin blood
vessels dilate
Sweat glands
activated
Imbalance
Imbalance
Body
temperature
decreases
Activates heat-
promoting center in
hypothalamus
Hot stimulus
Blood warmer
than set point
Cold stimulus
Blood cooler
than set point
Body
temperature
increases
6. Definition of fever
Fever is a complicated pathological process characterized
by regulated elevation of body temperature following the
increased Set Point, which is caused by pyrogenic
substances.
Usually 0.5 higher℃ than normal body temperature.
There is no impairment in the thermoregulatory
mechanism during fever.
Q: Increase of body temperature = Fever?
8. 1616
FeverFever
a.a. IntroductionIntroduction
b.b. Causes and MechanismCauses and Mechanism
c.c. Stages and ManifestationsStages and Manifestations
d.d. Alterations of Metabolism andAlterations of Metabolism and
FunctionFunction
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment
11. Pyrogenic activators ( 发热激活物 ) are
substances which can activate the EP-producing
cells to produce and release endogenous
pyrogen (EP).
Concept
Pyrogenic Activators
14. Gram-negative Bacteria:
(E. coli)
Pathogenic substance:
LPS (lipopolysaccharide, also named
endotoxin, ET)
Major pyrogenic component is
Lipid A
High m.w. (1,000 kDa)
Heat resistant: inactivated by
160℃ dry heat, 2 h
High pyrogenic activity
1 ng/kg to rabbit → fever
Tolerability (resistance to
repeated injection)
17. Substances that areSubstances that are produced by EP-producingproduced by EP-producing
cellscells under the action of pyrogenic activatorsunder the action of pyrogenic activators andand
cause the increase in the thermoregulatory setcause the increase in the thermoregulatory set
pointpoint in the hypothalamus.in the hypothalamus.
Fever-inducing cytokines (large, hydrophilicFever-inducing cytokines (large, hydrophilic
peptides).peptides).
Endogenous Pyrogens (EPs)
20. •Interleukin 1 (IL-1)Interleukin 1 (IL-1)
Produced by monocytes/macrophages, epithelialProduced by monocytes/macrophages, epithelial
cells,cells, etc.etc.
IL-1a and IL-1b have the same effect.IL-1a and IL-1b have the same effect.
Pyrogenic activity can be inhibited by cyclooxygenasePyrogenic activity can be inhibited by cyclooxygenase
inhibitorinhibitor (Aspirin).(Aspirin).
Heat sensitive: Inactivated by heating (70 30 min).℃Heat sensitive: Inactivated by heating (70 30 min).℃
No tolerance by repeated injections.No tolerance by repeated injections.
21. •Tumor necrosis factor (TNF)Tumor necrosis factor (TNF)
Produced byProduced by macrophagesmacrophages,, lymphoid cells, mast cells,lymphoid cells, mast cells,
endothelial cellsendothelial cells,, etc.etc.
Pyrogenic activity can be inhibited by cyclooxygenasePyrogenic activity can be inhibited by cyclooxygenase
inhibitor (Aspirin).inhibitor (Aspirin).
TNF-TNF-αα, TNF-, TNF-ββ are pyrogenic.are pyrogenic.
Heat sensitive: Inactivated by heating (70 30 min).℃Heat sensitive: Inactivated by heating (70 30 min).℃
No tolerance by repeated injections.No tolerance by repeated injections.
22. Interferon (IFN)Interferon (IFN)
Produced by lymphocytes, NK cells, fibroblasts,Produced by lymphocytes, NK cells, fibroblasts, etc.etc.
IFN-IFN-αα and IFN-and IFN-γγ can cause fever.can cause fever.
Can be tolerated after long period of use.Can be tolerated after long period of use.
Heat sensitive.Heat sensitive.
23. Interleukin 6 (IL-6)Interleukin 6 (IL-6)
Produced by mononuclear cells, fibroblasts, endothelialProduced by mononuclear cells, fibroblasts, endothelial
cells,cells, etc.etc.
Can be induced by ET, IL-1, TNF.Can be induced by ET, IL-1, TNF.
IL-6 is the downstream mediator of fever from otherIL-6 is the downstream mediator of fever from other
EPs (IL-1 and TNF).EPs (IL-1 and TNF).
Pyrogenic activity can be inhibited by cyclooxygenasePyrogenic activity can be inhibited by cyclooxygenase
inhibitor (Aspirin).inhibitor (Aspirin).
25. POAH
Thermoregulatory Center
Positive regulatory center:Positive regulatory center:
Located at preoptic anteriorLocated at preoptic anterior
hypothalamus (POAH)hypothalamus (POAH)
Warm-sensitive neuronsWarm-sensitive neurons
Cold-sensitive neuronsCold-sensitive neurons
Negative regulatory center:Negative regulatory center:
Medial amydaloid nucleus (MANMedial amydaloid nucleus (MAN [[ 中杏仁核中杏仁核 ])])
Ventral septal area (VSAVentral septal area (VSA [[ 腹中膈腹中膈 ])])
Arcuate nucleus (ARCArcuate nucleus (ARC [[ 弓状核弓状核 ])])
26. Routes for Endogenous Pyrogens toRoutes for Endogenous Pyrogens to
Enter Thermoregulatory CenterEnter Thermoregulatory Center
a.a. Passive transport via organum vasculosumPassive transport via organum vasculosum
laminate terminal (OVLTlaminate terminal (OVLT [[ 小丘脑终板血管器小丘脑终板血管器 ], also called], also called
supraoptic crestsupraoptic crest))
Most importantMost important
a.a. Through stimulating vagus nerveThrough stimulating vagus nerve (( 迷走神经迷走神经 ))
b.b. Active transport across the blood brain barrierActive transport across the blood brain barrier
(BBB)(BBB)
Important in pathological conditionsImportant in pathological conditions
EPs can not directly act on thermoregulatory center
because of BBB.
28. Central Mediators of FeverCentral Mediators of Fever
- The positive regulatory mediators- The positive regulatory mediators
Prostaglandin E2 (PGE2)Prostaglandin E2 (PGE2)
Corticotrophin-releasing hormone (CRH)Corticotrophin-releasing hormone (CRH)
Cyclic adenosine monophosphate (cAMP)Cyclic adenosine monophosphate (cAMP)
Nitric oxide (NO)Nitric oxide (NO)
NaNa++
/Ca/Ca2+2+
ratioratio
29. Prostaglandin E2 (PGE2)
PGE2 can induce fever when injected into cerebralPGE2 can induce fever when injected into cerebral
ventricles.ventricles.
Bacterial endotoxin and EP can stimulate theBacterial endotoxin and EP can stimulate the
hypothalamus to produce PGE2.hypothalamus to produce PGE2.
Cyclooxygenase inhibitor can inhibit the production ofCyclooxygenase inhibitor can inhibit the production of
PGE2.PGE2.
PGE2PGE2 ↑↑ in cerebrospinal fluid during fever.in cerebrospinal fluid during fever.
31. Corticotrophin-releasing hormoneCorticotrophin-releasing hormone
(CRH)(CRH)
IL-1 and IL-6 can stimulate hypothalamus toIL-1 and IL-6 can stimulate hypothalamus to
secret CRH.secret CRH.
Intracerebroventricular injection of CRH causesIntracerebroventricular injection of CRH causes
body and rectum temperature ↑.body and rectum temperature ↑.
CRH receptor antagonist can inhibit theCRH receptor antagonist can inhibit the
fever caused by IL-1fever caused by IL-1ββ ,, IL-6.IL-6.
32. Cyclic AMP
(cAMP)cAMP levels in cerebrospinal fluid increase during fever induced
by endotoxin
cAMP initiates fever quickly if injected into cerebral ventricles
Adenylate cyclase (AC) inhibitor can decrease the effects
caused by cAMP.
PDE
Phosphodiesterase (PDE) inhibitor can increase the effects
caused by cAMP.
cAMPATP
Breakdown
AC PDE
33. NaNa++
/Ca/Ca2 +2 +
RatioRatio
NaNa++
/Ca/Ca2+2+
changes in the brain, the body temperaturechanges in the brain, the body temperature
also changes.also changes.
Intracerebroventricular perfusion of NaIntracerebroventricular perfusion of Na++
→ ↑→ ↑
body temperature.body temperature.
NaNa++
/Ca/Ca2+2+
ratioratio ↑↑ cAMPcAMP ↑↑ Set pointSet point ↑↑
Intracerebroventricular perfusion of CaIntracerebroventricular perfusion of Ca2+2+
→→↓↓body temperature.body temperature.
34. Nitric Oxide (NO)Nitric Oxide (NO)
Action on OVLT & POAHAction on OVLT & POAH
Stimulating metabolism of brown adipose tissueStimulating metabolism of brown adipose tissue
(in infants)(in infants)
Inhibit the synthesis and secretion of negativeInhibit the synthesis and secretion of negative
regulatory mediators.regulatory mediators.
36. Febrile CeilingFebrile Ceiling
(Fever Limit)(Fever Limit)
Upper limit of the febrile response.Upper limit of the febrile response.
Human core body temperature almost neverHuman core body temperature almost never
rises above 41 -42 during fever.℃ ℃rises above 41 -42 during fever.℃ ℃
- This phenomenon is called- This phenomenon is called febrile ceilingfebrile ceiling..
Regulated by negative fever mediators.Regulated by negative fever mediators.
39. αα-melanocyte-stimulating hormone-melanocyte-stimulating hormone
((αα-MSH-MSH ))
Injection ofInjection of αα-MSH-MSH
intracerebraventricularlyintracerebraventricularly
↓↓feverfever
αα-MSH receptor antagonist-MSH receptor antagonist
↑↑ fever causedfever caused
by IL-1by IL-1
EndogenousEndogenous αα-MSH restricts the amplitude and-MSH restricts the amplitude and
duration of fever.duration of fever.
40. Lipocortin-1 (LC-1)Lipocortin-1 (LC-1)
Biological function of glucocorticoid (relievingBiological function of glucocorticoid (relieving
fever) depends on LC-1fever) depends on LC-1
Central injection of LC-1 inhibits the feverCentral injection of LC-1 inhibits the fever
caused by IL-1, IL-6 and CRHcaused by IL-1, IL-6 and CRH
42. 5757
FeverFever
a.a. IntroductionIntroduction
b.b. Causes and MechanismCauses and Mechanism
c.c. Stages and ManifestationsStages and Manifestations
d.d. Alterations of Metabolism andAlterations of Metabolism and
FunctionFunction
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment
43. Three stages of feverThree stages of fever
I: Fervescence stageI: Fervescence stage
II: Persistent febrile stageII: Persistent febrile stage
III: Defervescence stageIII: Defervescence stage
Stages and Manifestations of Fever
I II III
45. Persistent Febrile Stage:Persistent Febrile Stage:
Thermal metabolism characteristicsThermal metabolism characteristics
T increases to the new level of set point
Balance of heat production and loss
- in a higher level
Clinical manifestationsClinical manifestations
Feeling hot
Dry skin
Flush (red)
High metabolic rate
46. Defervescence StageDefervescence Stage
Thermal metabolism characteristicsThermal metabolism characteristics
Core temperature > set point → heat loss↑Core temperature > set point → heat loss↑
Clinical manifestationsClinical manifestations
SweatingSweating
Skin is warm and flushedSkin is warm and flushed
47. 6262
FeverFever
a.a. IntroductionIntroduction
b.b. Causes and MechanismCauses and Mechanism
c.c. Stages and ManifestationsStages and Manifestations
d.d. Alterations of Metabolism andAlterations of Metabolism and
FunctionFunction
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment
48. Metabolic Changes During FeverMetabolic Changes During Fever
Basal metabolic rate increases by 13% with 1℃Basal metabolic rate increases by 13% with 1℃
elevation in body temperature.elevation in body temperature.
Glycolysis → Lactate ↑Glycolysis → Lactate ↑
Adipose tissue utilization → Ketone ↑, Weight lossAdipose tissue utilization → Ketone ↑, Weight loss
Glycogen degradation → Blood sugar ↑Glycogen degradation → Blood sugar ↑
Vitamin consumption ↑Vitamin consumption ↑
49. Systematic ChangesSystematic Changes
•Nervous systemNervous system
•Cardiovascular systemCardiovascular system
•Respiratory systemRespiratory system
•Digestive systemDigestive system
•Immune systemImmune system
51. Cardiovascular systemCardiovascular system
Increase of heart rate, 18 bpm/1℃Increase of heart rate, 18 bpm/1℃
Blood pressure changeBlood pressure change
Respiratory systemRespiratory system
Increase of respiratory rateIncrease of respiratory rate
HyperventilationHyperventilation
(may cause acid-base imbalance)(may cause acid-base imbalance)
52. Beneficial Effects of FeverBeneficial Effects of Fever
- Self defense- Self defense
Fever often increases the anti-infectionFever often increases the anti-infection
capacity of the body.capacity of the body.
The anti-tumor activity is also augmented duringThe anti-tumor activity is also augmented during
fever.fever.
EP can induce the acute phase response.EP can induce the acute phase response.
53. Biological Significance of FeverBiological Significance of Fever
Friend or Foe?Friend or Foe?
Answer:Answer: BothBoth
54. 6969
FeverFever
a.a. IntroductionIntroduction
b.b. Causes and MechanismCauses and Mechanism
c.c. Stages and ManifestationsStages and Manifestations
d.d. Alterations of Metabolism andAlterations of Metabolism and
FunctionFunction
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment
55. Principles of Fever Treatment
Fever does not necessarily need to be treated.
Basic principles for common fever:
Care
Suitable medication when necessary
56. Need to be Treated Immediately
T > 39℃T > 39℃
Heart disease patientsHeart disease patients
Cachexia patientsCachexia patients
Pregnant womenPregnant women
57. MedicationMedication
1. Chemical medication1. Chemical medication
SalicylateSalicylate (Aspirin)(Aspirin)
- Inhibit the synthesis of PGE2- Inhibit the synthesis of PGE2
2. Steroid antipyretic drugs2. Steroid antipyretic drugs (Dexamethasone)(Dexamethasone)
Inhibit the synthesis and secretion of the EPsInhibit the synthesis and secretion of the EPs
Inhibit the immune and inflammatory reactionInhibit the immune and inflammatory reaction
Inhibit the synthesis of PGE2Inhibit the synthesis of PGE2
58. 4. Other measures4. Other measures
physical coolingphysical cooling
3.Detoxificating Chinese herbs3.Detoxificating Chinese herbs
Four-Drug Juice [Four-Drug Juice [ 四磨汤四磨汤 ]]
Hinweis der Redaktion
http://v.qihuang99.com/player/1777.html?1777-0-2
Even moderate elevations of body temperature cause cell malfunction and irreversible protein denaturation.
Deep thermosensors are in the blood.
POAH: preoptic anterior hypothalamus (视前区-下丘脑前部)
Typhoid (伤寒)
Undulant:
56556
resembling waves in form or outline or motion
Strenuous: vigorous
Hyperthermia: Non-regulatory/Passive elevation of Temp
Hyperthermia differs from fever in that the body's temperature set point remains unchanged.
(Ichthyosis [鱼鳞癣]: fish skin disease.)
There are many types of Ichthyosis and an exact diagnosis may be difficult. Types of Ichthyosis are classified by their appearance and their genetic cause. Ichthyosis caused by the same gene can vary considerably in severity and symptoms. Some Ichthyoses don't appear to fit exactly into any one type. Also different genes can produce Ichthyoses with similar symptoms. ses) is a heterogeneous family of at least 28,1 generalized, mostly genetic skin disorders. All types of ichthyosis have dry, thickened, scaly or flaky skin.
Other microorganisms include fungus, Spirochetes, parasites.
Pyretic (similar to pyrogenic)
Be very careful about aseptic operation.
LPS m.w.: 5 – 9000 kDa, can’t pass through BBB.
1 ng/kg (rabbit) is 1/10,000 of toxic dose.
葡萄球菌
Originally called granulocytic/leukocytic pyrogens.
Initially people thought neutrophils are EP-producing cells (actually they are, but they are much weaker than monocytes.)
These are almost all immune cells.
Essence: small molecule proteins.
There are many sub-types of ILs, the receptor of ILs were located throughout the brain, with the highest density located in the outer hypothalamas near the thermoregulatory center.
TNF shares many biological activity with IL-1, while the amino sequence of them shares no discernable region of significant homology. TNF-alpha is able to induce IL-1beta in vitro and in vivo, while the vise versa is allright as well.
IFN: Anti-viral ,anti-tumor function
The weakest among the major Eps.
The critical role played by IL-6 in the induction of fever was recently demonstrated in IL-6 gene knockout mice, which were un-responsive to the pyrogenic effectors of LPS and TNF.
Active transport by cytokine-specific carriers across the blood brain barrier (BBB)
The organum vasculosum of the lamina terminalis (OVLT) (or supraoptic crest) is one of the circumventricular organs of the brain. OVLT as a circumventricular organ has special atypical blood-brain barrier.
Cerebellum 英 [ˌserə'beləm] 美 [ˌserə'beləm]
n.【医】小脑
Capillary in OVLT serving as atypical BBB, allowing transport of some molecules.
#3 is through local neurons.
Supraoptic recess (视上隐窝)
Arachidonic acid other than PGE2 may be involved as central mediators.
Generation of arachidonic acid metabolites and their roles in inflammation
Robbins and Cotran Pathologic Basis of Disease 7th edition
CRH: 促皮质激素释放素
CA inhibitor: cholera toxin
PDE inhibitor: thyroid hormone, Viagra
LC-1 (脂皮质蛋白-1) is also called annexin A1, it is a phospholipid-binding protein found in 1980s.
LC-1 functions by inhibiting phospholipase A2 (PLA2).
Glucocorticoids (GCs) are a class of steroid hormones that bind to the glucocorticoid receptor (GR),[1] which is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) derives from its role in the regulation of the metabolism of glucose, its synthesis in the adrenal cortex, and its steroidal structure (see structure to the right). Cortisol (or hydrocortisone) is the most important human glucocorticoid. Others include: Prednisone, Dexamethasone, etc.