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fever

fever - the febrile response to infections

why have a febrile response?

  • it is thought that the high body temperature in the febrile response helps fight off infections
    • the febrile mechanism is found in 5 of the 7 classes of vertebrates and it appears to be increasing in complexity with evolution so it is probably helpful to survival
      • earlier evolutionary species such as sharks and bony fish did not mount a fever physiologically but behaviourally moved into warmer environments to increase body temperature
      • reptiles evolved 350 mya and appear to be amongst the first to have developed a physiologic fever response based upon cytokines in the blood acting on the hypothalamus
      • it appears rats and humans evolved a 2nd pyrogenic pathway to the hypothalamus - via the vagus nerve which activates local cytokines allowing for a much more rapid febrile response
    • optimal growth rates of Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli occur at a temperature range of 35-37degC, their growth rates drop dramatically at higher temperatures1))
    • higher temperatures have been shown to denature pathogenic proteins and inactivate their toxins
    • as part of the inflammatory response, temperature elevation stimulates the release of histamines from mast cells and basophils that cause vessels to vasodilate allowing increased blood flow and transport of components of the nonspecific immune response - phagocytic macrophages, neutrophils, monocytes, and immunological NK cells
    • a temperature increase of 1degC increases the body's metabolism by 10-20% in what is called the Q10 Effect and increases rates of immunologic reactions
    • fever stimulates the release of leukocyte-endogenous mediator proteins into the bloodstream and digestive tract reducing free iron which retards bacterial growth as iron is needed for the cytochrome and electron-shuffling components of bacterial metabolism 2)
    • fever increases melatonin release which increases sleepiness and diverts energy to fighting the infection 3)
  • despite the above, there is actually little evidence that fever does improve survival

physiology

  • infections may cause a febrile response or a hypothermic response (cold sepsis) - presumably by similar pathways
  • experimental fevers are generally polyphasic, and different mechanisms underlie different febrile phases:4)
    • Phase 1:
      • involves transcriptional up-regulation of the couple COX-2 –>mPGES-1 in the liver and lungs
      • transcriptional down-regulation of PGE2 transporters and dehydrogenases: 15-PGDH in the lungs
    • Phase 2:
      • entails robust up-regulation of the major inflammatory triad sPLA2-IIA –>COX-2 –>mPGES-1 throughout the body
      • transcriptional down-regulation of PGE2 transporters and dehydrogenases: 15-PGDH and CR in the lungs
    • Phase 3:
      • involves induction of cPLA2-alpha in the hypothalamus and further up-regulation of sPLA2-IIA and mPGES throughout the body.
      • transcriptional down-regulation of PGE2 transporters and dehydrogenases: PGT, MOAT, 15-PGDH, and CR in the liver and lungs
      • Importantly, Phase 3 occurs despite a drastic decrease in the expression of COX-1 and -2 in both the brain and periphery, thus suggesting that transcriptional up-regulation of COX-2 is not an obligatory mechanism of PGE2-dependent inflammatory responses at later stages

current concepts

  1. the febrile response is initiated by the presence of a pyrogen which is typically an infectious organism or toxin by-product (eg. bacterial lipopolysaccharide (LPS)) from the infection, but can also be tissue trauma, blood products and certain medications
  2. Toll-like receptor 4 appears to be involved in certain pyrogens such as LPS
  3. the body produces a wide array of pyrogenic cytokines such as interleukins (IL-1beta, IL-6), interferon, and tumour necrosis factor alpha and perhaps complement factor 5a and platelet-activating factor, are carried to the blood-brain-barrier (BBB) in the blood
    • Suppressors of Cytokine Signalling (SOCS) molecules control the flow of chemical messages inside cells and suppress the activity of the cytokines to prevent unwanted inflammation and tissue damage.
      • the protein SOCS4 plays a crucial role in the immune system's response to influenza
  4. the endothelial and perivascular cells of the BBB, detects the circulating pyrogenic cytokines and starts prostaglandin synthesis, especially prostaglandin E2 5)
    • the “physiological,” low-scale production of PGE2 and the accelerated synthesis of PGE2 in inflammation are catalyzed by different sets of these enzymes which include:
      • numerous phospholipases (PL) A2
      • cyclooxygenases (COX)-1 and 2
      • several newly discovered terminal PGE synthases (PGES)
      • The “inflammatory” set includes several isoforms of PLA2 and inducible isoforms of COX (COX-2) and microsomal (m) PGES (mPGES-1)
    • antipyretics generally act by blocking this prostaglandin synthesis
  5. effector pathways of fever start from PGE2-EP3 receptor-bearing preoptic neurons
    • these neurons have been found to project to the raphe pallidus, where premotor sympathetic neurons driving thermogenesis in the brown fat and skin vasoconstriction are located and temperature is then based upon a balance of active and passive processes rather than the previous notion of a hypothalamic “setpoint”
    • inflammatory signaling and thermoeffector pathways involved in fever and hypothermia are modulated by neuropeptides and peptide hormones
      • ?roles of leptin, orexins, arginine vasopressin, angiotensin II, and cholecystokinin
  6. various autonomic, endocrine, and behavioural processes are then activated to raise the body temperature such as:
    1. thermogenesis using brown fat
    2. skin vasoconstriction
    3. shivering
    4. increased secretion of thyroxine
    5. perception of being cold ⇒ increased clothing, heaters, blankets

the vagal pathway hypothesis

  • an alternative vagal pathway has been proposed, although discarded by some
    • immediate activation by LPS of the complement (C) cascade, the stimulation by the anaphylatoxic C component C5a of Kupffer cells, their consequent, virtually instantaneous release of PGE(2), its excitation of hepatic vagal afferents, their transmission of the induced signals to the POA via the ventral noradrenergic bundle, and the activation by the thus, locally released norepinephrine (NE) of neural alpha(1)- and glial alpha(2)-adrenoceptors.
    • The activation of the first causes an immediate, PGE(2)-independent rise in core temperature (Tc) [the early phase of fever; an antioxidant-sensitive PGE(2) rise, however, accompanies this first phase], and of the second a delayed, PGE(2)-dependent Tc rise [the late phase of fever].
    • Meanwhile-generated pyrogenic cytokines and their consequent upregulation of blood-brain barrier cells COX-2 also contribute to the latter rise.6)
    • a recent rat study suggests activation of kinin B1 receptor evokes hyperthermia through a vagal sensory mechanism which is mediated via prostaglandins (via COX-2) and nitric oxide 7)

adverse consequences of fever

  • however, the fever itself may have adverse consequences such as:
  • part of the febrile response to infections involves release of thyroxine
    • it appears half of the Western Australian aboriginal population have inherited genes which have turned OFF this thyroxine response which then reduces the febrile response to infections and helps survival on hot, arid desert conditions8)
fever.txt · Last modified: 2014/05/11 18:49 (external edit)