Infected adults characteristically exhibit, in addition to fever, a concatenation of nonspecific host responses, termed the acute-phase reaction (APR). These include: neutrophilic leukocytosis, changes in the concentrations of certain plasma proteins and trace metals, and various other associated adjustments. It has long been known that the fever of infection is mediated by an endogenous factor from macrophages/monocytes, called Interleukin I (IL1). During the past decade, evidence has accumulated indicating that the nonthermal components of the APR also are mediated by IL1. It is well established that the primary site of the febrile action of IL1 is the preoptic are (PO) of the hypothalamus. Subsidiary IL1-sensitive sites that can drive fever have been localized in the lateral hypothalamus, pons, and medulla. Recent results from my laboratory indicate that the PO also is involved importantly in the regulation of certain nonthermal acute-phase responses to IL1, in particular the hepatic synthesis of glycoproteins. The data further suggest that the preoptic units that activate the febrile and nonfebrile responses to IL1 may be distinct. These proposed studies, therefore, are directed toward analyzing further the neural systems in the PO mediating the acute-phase reaction. Specifically, they are designed to determine whether the monoamines and the opioids, two classes of neurochemical substances with possible roles in fever production, might also be implicated in the control of the nonthermal acute-phase reaction. Subsequently, studies will be undertaken to determine whether identified extra-PO, IL1-sensitive febrigenic sites similarly can drive the nonfebrile APR, and whether they do so through the same transmitters as the PO. The results should permit differentiating among responses that might be activated by IL1 at different loci within the brain and provide information toward understanding the mode of action of IL1 in the induction of fever and other acute-phase host defense responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022716-03
Application #
3405544
Study Section
Neurology C Study Section (NEUC)
Project Start
1986-09-01
Project End
1990-09-27
Budget Start
1988-09-01
Budget End
1990-09-27
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Blatteis, C M; Sehic, E (1998) Cytokines and fever. Ann N Y Acad Sci 840:608-18
Blatteis, C M; Sehic, E; Li, S (1998) Afferent pathways of pyrogen signaling. Ann N Y Acad Sci 856:95-107
Sehic, E; Hunter, W S; Ungar, A L et al. (1997) Blockade of Kupffer cells prevents the febrile and preoptic prostaglandin E2 responses to intravenous lipopolysaccharide in guinea pigs. Ann N Y Acad Sci 813:448-52
Sehic, E; Gerstberger, R; Blatteis, C M (1997) The effect of intravenous lipopolysaccharide on NADPH-diaphorase staining (= nitric oxide synthase activity) in the organum vasculosum laminae terminalis of guinea pigs. Ann N Y Acad Sci 813:383-91
Blatteis, C M; Sehic, E (1997) Circulating pyrogen signaling of the brain. A new working hypothesis. Ann N Y Acad Sci 813:445-7
Sehic, E; Blatteis, C M (1996) Blockade of lipopolysaccharide-induced fever by subdiaphragmatic vagotomy in guinea pigs. Brain Res 726:160-6
Sehic, E; Szekely, M; Ungar, A L et al. (1996) Hypothalamic prostaglandin E2 during lipopolysaccharide-induced fever in guinea pigs. Brain Res Bull 39:391-9
Romanovsky, A A; Shido, O; Ungar, A L et al. (1994) Peripheral naloxone attenuates lipopolysaccharide fever in guinea pigs by an action outside the blood-brain barrier. Am J Physiol 266:R1824-31
Blatteis, C M; Xin, L; Quan, N (1994) Neuromodulation of fever. A possible role for substance P. Ann N Y Acad Sci 741:162-73
Romanovsky, A A; Shido, O; Ungar, A L et al. (1993) Genesis of biphasic thermal response to intrapreoptically microinjected clonidine. Brain Res Bull 31:509-13

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