Fever is the hallmark of infection. It is generally believed that it is caused not by exogenous, but by endogenous pyrogens, members of an array of peptide mediators called cytokines. These are elaborated and released into the circulation largely by systemic mononuclear phagocytes activated by the exogenous agents, and transported to the preoptic anterior hypothalamic area (POA) of the brain, where they act. Prostaglandin E2 (PGE2) is thought to be a fever mediator in the POA, induced by these cytokines. Although the intrapreoptic level of PGE2 rises rapidly following the intravenous (iv) administration of exogenous (e.g., lipopolysaccharides, LPS) or endogenous pyrogens, recent data indicate that these substances cannot account directly for the rapid production of PGE2 because it is initiated well before the synthase that they stimulate (cyclooxygenase-2, COX-2) becomes active. Moreover, cytokines also are not detectable in blood following iv LPS until after the febrile response is already underway, and there is no evidence that they can readily penetrate the brain. Hence, other, more quickly evoked mediators may be presumed to be involved in initiating the febrile response. Based on well-recognized mechanisms of LPS action and on new data regarding the induction of PGE2 synthesis, we have hypothesized that 1) iv LPS virtually immediately activates the complement cascade, generating the anaphylatoxins C3a, C4a, and C5a, which 2) function to rapidly induce various mediators, e.g., platelet-activating factor (PAF), bradykinin (BK), that 3) have the capacity to stimulate the formation of nitric oxide (NO) which, in turn, 4) induces PGE2 and, consequently, fever. We have preliminary evidence supporting the involvement of systemic complement and of nitric oxide in the organum vasculosum laminae terminalis (OVLT, the interface between the brain and circulating pyrogens) in the febrile response to iv LPS. The purpose of this proposed research is to substantiate the putative roles of complement and NO in the pyrogenic response to iv LPS, and to determine whether PAF and/or BK are factors that may link the two. If confirmed, this hypothesis would allow formulating a novel, specific concept of the pathophysiology of LPS-mediated fever, particularly regarding the onset of this response. The results will be relevant to the still essentially unknown central nervous mechanisms underlying the multivariate host defense reactions to infectious pathogens.
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| Blatteis, Clark M (2007) The onset of fever: new insights into its mechanism. Prog Brain Res 162:3-14 |
| Feleder, Carlos; Perlik, Vit; Blatteis, Clark M (2007) Preoptic nitric oxide attenuates endotoxic fever in guinea pigs by inhibiting the POA release of norepinephrine. Am J Physiol Regul Integr Comp Physiol 293:R1144-51 |
| Feleder, Carlos; Perlik, Vit; Blatteis, Clark M (2007) Preoptic norepinephrine mediates the febrile response of guinea pigs to lipopolysaccharide. Am J Physiol Regul Integr Comp Physiol 293:R1135-43 |
| Li, Zhonghua; Perlik, Vit; Feleder, Carlos et al. (2006) Kupffer cell-generated PGE2 triggers the febrile response of guinea pigs to intravenously injected LPS. Am J Physiol Regul Integr Comp Physiol 290:R1262-70 |
| Blatteis, Clark M (2006) Endotoxic fever: new concepts of its regulation suggest new approaches to its management. Pharmacol Ther 111:194-223 |
| Perlik, Vit; Li, Zhongua; Goorha, Sarita et al. (2005) LPS-activated complement, not LPS per se, triggers the early release of PGE2 by Kupffer cells. Am J Physiol Regul Integr Comp Physiol 289:R332-R339 |
| Blatteis, Clark M; Li, Shuxin; Li, Zhonghua et al. (2005) Cytokines, PGE2 and endotoxic fever: a re-assessment. Prostaglandins Other Lipid Mediat 76:1-18 |
| Li, S; Boackle, S A; Holers, V M et al. (2005) Complement component c5a is integral to the febrile response of mice to lipopolysaccharide. Neuroimmunomodulation 12:67-80 |
| Feleder, Carlos; Perlik, Vit; Tang, Ying et al. (2005) Putative antihyperpyretic factor induced by LPS in spleen of guinea pigs. Am J Physiol Regul Integr Comp Physiol 289:R680-7 |
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