1. Chapter 2 Fever 1.Introduction 2.Causes and mechanisms of fever 3.Febrile phases and the characteristics of thermo-metabolism 4.Functional and metabolic changes induced by febrile response 5.Pathophysiological basis of prevention and treatment for fever

2. 1.Introduction (1)Normal body temperature ~37 ℃（ ~98.6 。 F ） Axillary 36~37.4  C Oral 36.7~37.7  C Rectal 36.9~37.9  C Normal body temperature homeostasis (2) Elevation of body temperature An elevation of body temperature above the normal amplitude of daily variation(>0.5 ℃ )

3. Types of the elevation of body temperature Physiological elevation the setpoint of hypothalamic thermostat before menstruation severe exercise stress Pathological elevation Fever Hyperthermia

4. Fever 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.

5. Hyperthermia ( 过热 ) An unregulated rise in body temperature beyond the unchanged hypothalamic thermostatic setpoint resulting from the dysfunction of body temperature center or impairment of thermogenesis and heat loss mechanisms. 体温调节机制失调或调节障碍，使得机体不能将体温控制在与 调定点相适应的水平而引起的非调节性的体温升高。 Causes: overproduction of heat ( 过度产热 ) impediment in heat loss ( 散热障碍 ) dysfunction of body temperature center ( 体温调节中枢功能障碍 ) Passive increase of body temperature >0.5  C ( 被动性体温升 高 ) Body temperature beyond the setpoint ( 体温 > 调定点水平 )

6. HyperthermiaFever Arising from changes within the body or by changes in environment Resulting from pyrogen Set-point remains unchanged or damaged, or effector organs fails Ability to regulate set-point remains intact, but is turned up at a high level functionally Body temperature may rise to a very high level Rise of body temperature has an upper limit Treatment with water-alcohol bathingTreatment with antipyretics and measures and drugs to eliminate the causes Comparison between hyperthermia and fever

7. 2. Causes and mechanisms of fever ( 发热的原因和机制 ) (1)Pyrogenic activator ( 发热激活物 ) (2)Endogenous pyrogen ( 内生致热原 ) (3)Mechanisms of set point elevation caused by EP (EP 升高体温中枢 “ 调定点 ” 的机制 ) (4)Pathogenesis of fever ( 发热时体温上升的基本环节和机制 )

8. (1) Pyrogenic activator Pyrogenic activator A fever-inducing substances that can activate endogenous pyrogen-generating cells to generate and release endogenous pyrogens. Category of pyrogenic activator Infectious factors: microbes and microbial products Non-infectious factors: non-microbe pyrogenic activators

9. Infectious factors: microbes and microbial products  G - bacteria, Lipopolysaccharide (LPS)/endotoxin  G+bacteria, Exotoxins, Cell wall peptidoglycans  Viruses  Other microorganisms

10. Non-infectious factors: non-microbe pyrogenic activators  Ag-Ab complexes  Non-infectious inflammation-genesis irritants  Steroids: etiocholanolone

11. Concept of endogenous pyrogen (EP) EPs are fever-inducing cytokines 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

12. EP generating cells Monocyte Macrophage T lymphocyte Kupffer cells endothelia cells Some tumor cells

13. Category of endogenous pyrogen  Interleukin-1 (IL-1)  Tumor necrosis factor (TNF)  Interferon (IFN)  Macrophage inflammatory protein-1 (MIP-1)  Interleukin-6 (IL-6)  Others

14. Endogenou s pyrogen Principle sourceInducers IL-1  IL-1  Macrophages and other cell types LPS,TNF, Other microbial products TNF-  TNF-  Macrophages Lymphocytes(T&B) LPS, Other microbial products antigen, mitogen stmulation IFN-  IFN-  IFN-  Leukocytes Fibloblasts T-lymphocytes LPS, viral infection IL-6Many cell typesLPS, TNF MIP-1  MIP-1  MacrophagesLPS IL-8Many cell typesLPS, TNF, IL-1 Endogenous Pyrogenic cytokines

15. Production and release of EP LPS + LBP --- LPS + sCD14 --- TLR (EP-producing cells)--- NF-κB--- Target genes --- EP expression and release (Textbook P143:figure 9-1)

16. (3)Mechanisms of setpoint elevation by EP

17. Thermoregulation center  Positive regulation center Preoptic anterior hypothalamus, POAH  Cold sensitive neuron  Warm sensitive neuron  Negative regulation center : Medial amygdaloid nucleus,MAN Ventral septal area,VSA

18. Three pathways for EP signal transduction to the thermoregulation center  Via organum vasculosum laminae terminalis, OVLT Via organum vasculosum laminae terminalis, OVLT  Via stimulation of vagus nerve Via stimulation of vagus nerve  Direct entry through blood-brain barrier Direct entry through blood-brain barrier

19. EP Macrophage OVLT neuron POAH neuron Supraoptic recess Third ventricle of brain Chiasma of optic nerves Capillary OVLT area Macrophage POAH neuron PGE2 Cells of ventricle tubal membrane The Role of OVLT in pathogenesis of fever

20. Central mediators of fever  The positive regulation mediators  Prostaglandins,PGE2  Corticotropin releasing hormone,CRH  The ratio of central Na + /Ca 2+  cAMP  Nitric oxide, NO Mechanisms of Setpoint Elevation by EP

21.  The negative regulation mediators Febrile ceiling, Endogenous cryogen  Arginine vasopressin, AVP  α-melanocyte-stimulating hormone,α-MSH  Lipocortin-1/Annexin A1

22. (4) Pathogenesis of fever

23. Pyrogenic activators: infection, microbial toxins, mediators of inflammation, immune reactions Monocytes/macrophages, endothelial cells, others Endogenous pyrogens/ Pyrogenic cytokines IL-1,6, TNF, IFN,MIP-1 Hypothalamus Central mediators of fever Elevated thermoregulatory set point Circulation, etc Heat conservation, heat production FEVER

24. 3. Febrile phases and the characteristics of thermo- metabolism

25. 典型的发热过程分为 3 个阶段 37  C 42  C 体温正常 体温上升期 高热 持续期 体温下降期

26.  Effervescence period Heat production > heat loss  Persistent febrile period Heat equipoise at a higher level  Defervescence period Heat loss> heat production Phases of fever

27. 4.Functional and metabolic changes induced by febrile response

28. (1)Functional changes Central nervous system Cardiovascular system Respiratory system Digestive system Immune system

29. (2) Changes of metabolism Sugar Lipid Protein Walter, salts, vitamines

30. 5. Pathophysiological basis of prevention and treatment for fever Basic principles for fever treatment Antipyretic therapy

31. Case study