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Chapter 2 Fever

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. Introduction

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Chapter 2 Fever

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  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. Introduction • (1)Normal body temperature ~37℃（~98.6。F） • Axillary 36~37 .4 C • Oral 36.7~37.7 C • Rectal36.9~37.9 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. Comparison between hyperthermia and fever

  7. 2. Causes and mechanisms of fever(发热的原因和机制) • 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. (2)Endogenous pyrogen 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.

  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. 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 stimulation of vagus nerve • Direct entry through blood-brain barrier

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

  20. Mechanisms of Setpoint Elevation by EP Central mediators of fever • The positive regulation mediators •  Prostaglandins,PGE2 •  Corticotropin releasing hormone,CRH •  The ratio of centralNa+/Ca2+ • cAMP • Nitric oxide, NO

  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 FEVER Heat conservation, heat production Monocytes/macrophages, endothelial cells, others Elevated thermoregulatory set point Endogenous pyrogens/Pyrogenic cytokines IL-1,6, TNF, IFN,MIP-1 Hypothalamus Central mediators of fever Circulation, etc

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

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

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

  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 fevertreatment Antipyretic therapy

  31. Case study

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