title: Endotoxic fever: new concepts of its regulation suggest new approaches to its management.
abstract: Endotoxic fever is regulated by endogenous factors that provide pro- and anti-pyretic signals at different points along the febrigenic pathway, from the periphery to the brain. Current evidence indicates that the febrile response to invading Gram-negative bacteria and their products is initiated upon their arrival in the liver via the circulation and their uptake by Kupffer cells (Kc). These pathogens activate the complement cascade on contact, hence generating complement component 5a. It, in turn, very rapidly stimulates Kc to release prostaglandin (PG)E2. Pyrogenic cytokines (TNF-alpha, etc.) are produced later and are no longer considered to be the immediate triggers of fever. The Kc-generated PGE2 either (1) may be transported by the bloodstream to the ventromedial preoptic-anterior hypothalamus (POA, the locus of the temperature-regulating center), presumptively diffusing into it and acting on thermoregulatory neurons; PGE2 is thus taken to be the final, central fever mediator. Or (2) it may activate hepatic vagal afferents projecting to the medulla oblongata, thence to the POA via the ventral noradrenergic bundle. Norepinephrine consequently secreted stimulates alpha1-adrenoceptors on thermoregulatory neurons, rapidly evoking an initial rise in core temperature (Tc) not associated with any change in POA PGE2; this neural, PGE2-independent signaling pathway is quicker than the blood-borne route. Elevated POA PGE2 and a secondary Tc rise occur later, consequent to alpha2 stimulation. Endogenous counter-regulatory factors are also elaborated peripherally and centrally at different points during the course of the febrile response; they are, therefore, anti-pyretic. These multiple interacting pathways are the subject of this review.
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, 38163, USA. blatteis@physio1.utmem.edu
authors.forename: Clark M
authors.initials: CM
authors.lastname: Blatteis
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000503:physiopathology; D004731:Endotoxins / Q000633:toxicity*; D005334:Fever / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D008099:Liver / Q000503:physiopathology; D015398:Signal Transduction
chemical_list: D018712:Analgesics, Non-Narcotic; D004731:Endotoxins