Hypothalamic prostaglandin E2 during lipopolysaccharide-induced fever in guinea pigs

Sehic, Elmir; Székely, Miklós; Ungar, A. L.; Oladehin, Akinniran; Blatteis, Clark M.

doi:10.1016/0361-9230(96)00037-8

Cited by 111 publications

(87 citation statements)

References 33 publications

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“…Pups in the indomethacin condition received a 10mg/kg dose of indomethacin (Sigma) in an equal volume of vehicle. This dose is in the range frequently found to reverse physiological and behavioral signs of sickness in laboratory rodents, including guinea pigs (Blatteis et al, 1990;Buller, Xu, & Day, 1998;Crestani, Seguy, & Dantzer, 1991;Dunn & Swiergiel, 2000;Sehic, Szekely, Ungar, Oladehin, & Blatteis, 1996;Wieczorek & Dunn, 2005). All injections were made subcutaneously in the nape of the neck 30 min prior to the behavioral test, which consisted of a 3-hr isolation in the standard novel test cage.…”

Section: Methodsmentioning

confidence: 99%

Anti-inflammatory agents attenuate the passive responses of guinea pig pups: Evidence for stress-induced sickness behavior during maternal separation

Hennessy

Schiml-Webb

Miller

et al. 2007

Psychoneuroendocrinology

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A previous study found that intracerebroventricular (ICV) infusion of 25 μg of α-MSH reduced the passive responses (crouched stance, eye-closing, piloerection) of guinea pig pups during a 3-hr isolation in a novel environment. Because α-MSH has broad anti-inflammatory properties, the results suggested that proinflammatory factors play a role in mediating the behavior of isolated infants. The present study further investigated this possibility. In Experiment 1, injection of lipopolysacchride (LPS) increased the number of 60-s intervals in which pups expressed the same three responses during a 1-hr test, and ICV infusion of α-MSH significantly reduced the effect of LPS on crouching and piloerection. In Experiment 2, the prostaglandin synthesis inhibitor indomethacin (10mg/kg) reduced the number of 60-s intervals in which pups exhibited both crouching and the full suite of passive responses during a 3-hr isolation in a novel environment. Together these results provide further support for the hypothesis that the passive behaviors exhibited during prolonged isolation are "stressinduced sickness behaviors" mediated by proinflammatory factors. Keywords sickness behaviors; acute phase response; inflammation; maternal separation; isolation; guinea pig Stimulation of the innate immune system results in a systemic physiological and behavioral reaction known as the acute phase response or sickness (Baumann & Gauldie, 1994). Components of the acute phase response include: fever, shifts in the synthesis of liver proteins, activation of the hypothalamic-pituitary-adrenal system, sleepiness, assumption of a curled or hunched posture, piloerection, shivering, and reductions in various activities. Though the behavioral components may appear to be simply the result of debilitation, they are adaptive responses that contribute to recuperation by, for instance, supporting the production of fever (e.g., hunched posture, piloerection, shivering), which in turn, can inhibit further proliferation of pathogens (Aubert, 1999;Hart, 1988). The acute phase response is triggered by the release of proinflammatory cytokines (e.g., IL-1, IL-6, TNF-α) in the periphery and CNS (Dantzer, 2004).Address correspondence to: Michael B. Hennessy, PhD, Department of Psychology, 335 Fawcett Hall, Wright State University, 3640 Col Glenn Hwy, Dayton, OH 45435, 937.775.2943 (voice), 937.775.3347 (FAX), michael.hennessy@wright.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In the last decade, it has become apparent that aspects of the acute phase response, including sickness behaviors, do not occur solely ...

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Section: Methodsmentioning

confidence: 99%

Anti-inflammatory agents attenuate the passive responses of guinea pig pups: Evidence for stress-induced sickness behavior during maternal separation

Hennessy

Schiml-Webb

Miller

et al. 2007

Psychoneuroendocrinology

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“…Tumor necrosis factor-␣ (TNF-␣), IL-1␤, and IL-6 are the major cytokines implicated in this response (9). There is, however, a temporal disconnect between the first appearance of these cytokines and the onset of the febrile response to intravenous LPS; that is, fever appears within 10 -15 min (13,51) whereas TNF-␣, the first cytokine to appear, is not detectable until 30 min after LPS treatment (18,23,24,39). This temporal discrepancy is less evident after the intraperitoneal administration of low to moderate doses of LPS, when the latency of fever onset is ϳ60 min but becomes evident also when higher doses are administered, when the onset latency approaches that after intravenous LPS (7).…”

mentioning

confidence: 99%

LPS-activated complement, not LPS per se, triggers the early release of PGE₂by Kupffer cells

Perlik¹,

Li²,

Goorha³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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The intravenous injection of LPS rapidly evokes fever. We have hypothesized that its onset is mediated by prostaglandin (PG)E2 quickly released by Kupffer cells (Kc). LPS, however, does not stimulate PGE2 production by Kc as rapidly as it induces fever; but complement (C) activated by LPS could be the exciting agent. To test this hypothesis, we injected LPS (2 or 8 g/kg) or cobra venom factor (CVF, an immediate activator of the C cascade that depletes its substrate, ultimately causing hypocomplementemia; 25 U/animal) into the portal vein of anesthetized guinea pigs and measured the appearance of PGE2, TNF-␣, IL-1␤, and IL-6 in the inferior vena cava (IVC) over the following 60 min. LPS (at both doses) and CVF induced similar rises in PGE2 within the first 5 min after treatment; the rises in PGE2 due to CVF returned to control in 15 min, whereas PGE2 rises due to LPS increased further, then stabilized. LPS given 3 h after CVF to the same animals also elevated PGE2, but after a 30-to 45-min delay. CVF per se did not alter basal PGE2 and cytokine levels and their responses to LPS. These in vivo effects were substantiated by the in vitro responses of primary Kc from guinea pigs to C (0.116 U/ml) and LPS (200 ng/ml). These results indicate that LPS-activated C rather than LPS itself triggers the early release of PGE2 by Kc. liver; fever; portal vein cannulation; cobra venom factor; pyrogenic cytokines FEVER DEVELOPS QUICKLY AFTER the intravenous bolus administration of a pyrogenic dose of LPS to conscious guinea pigs, rats, and other species, but the afferent mechanism that induces this response is controversial. It is generally thought that it is mediated by pyrogenic cytokines produced secondarily in response to the LPS challenge, rather than by its direct action. Tumor necrosis factor-␣ (TNF-␣), IL-1␤, and IL-6 are the major cytokines implicated in this response (9). There is, however, a temporal disconnect between the first appearance of these cytokines and the onset of the febrile response to intravenous LPS; that is, fever appears within 10 -15 min (13, 51) whereas TNF-␣, the first cytokine to appear, is not detectable until 30 min after LPS treatment (18,23,24,39). This temporal discrepancy is less evident after the intraperitoneal administration of low to moderate doses of LPS, when the latency of fever onset is ϳ60 min but becomes evident also when higher doses are administered, when the onset latency approaches that after intravenous LPS (7).We have shown previously that the onsets of the febrile responses to intravenous and intraperitoneal LPS are correlated with the appearance of LPS in the liver's Kupffer cells (Kc) (31), the body's principal clearinghouse of LPS (16,34,45) and source of pyrogenic cytokines (10). As cytokines are not constitutively expressed by Kc and their de novo production occurs after some delay (32), we and others have proposed, to account for the promptness of the febrile response to intravenous LPS, that the peripheral pyrogenic signal could be transmitted to the preoptic-anterior...

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“…Clinically, it is not clear how much and by which route endotoxins enter the fetal circulation, but it is likely that the fetus is usually exposed to quite small amounts of endotoxin. In fetal sheep, doses of LPS Ͼ1 g/kg can be fatal (27), whereas doses of 1-100 g/kg are often used in studies of the adult laboratory animal (16,28). In this study, using a low dose of LPS (0.1 g/kg) that produced only transient effects on fetal pH and blood gas parameters, we found that LPS caused changes of cerebral COX-2 expression and penetration of endogenous albumin and peripheral macrophages into the brain.…”

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confidence: 99%

Cerebrovascular Responses in the Fetal Sheep Brain to Low-Dose Endotoxin

et al. 2004

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Clinical and experimental evidence indicate that infection in pregnancy is associated with fetal brain damage. However, the inflammatory processes that compromise the fetal brain are not fully understood. In this study, we used a single, low dose of lipopolysaccharide (LPS, 0.1 g/kg i.v.) to provoke an acutephase response in unanesthetized fetal sheep in utero. COX-2 mRNA was increased in the cortex and cerebellum at 24 and 48 h after LPS, and immunoreactive COX-2 protein was increased in perivascular cells throughout gray and white matter at 24 h after LPS administration. Plasma albumin was observed in the parenchyma of the brain in cortex, thalamus, hypothalamus, corpus callosum, fornix, hippocampus, midbrain, subcallosal bundle, and cerebellar Purkinje cells. Large, rounded, lectin-positive cells with the appearance of macrophages were observed around blood vessels in subventricular white matter. These results indicate that blood-brain barrier permeability is increased in the fetal brain after exposure to endotoxin and suggests that cytotoxic and pro-inflammatory substances could pass from the circulation into the brain after peripheral inflammatory stimulation. There is a strong association between perinatal brain damage and intrauterine infection in human pregnancy (1). Infection is associated with histologic evidence of vascular inflammation of the umbilical cord (2), raised cytokine levels in amniotic fluid (3, 4), and increased incidence of white matter damage in the brain of the neonate (5). Nonetheless, the inflammatory responses provoked by infection in the fetus, and the events that lead to compromise of the fetal and neonatal brain, are poorly understood.Stimulation of the immune system by the bacterial endotoxin LPS leads to a series of host responses known as the acutephase reaction. The acute-phase reaction is mediated in large part by inflammatory cytokines (6). Cytokines in the circulation cross the BBB slowly and in amounts too small to stimulate inflammatory responses in the brain itself (7). However, cytokine receptors present on the luminal surface of the endothelial cells of cerebral blood vessels (8) may lead to stimulation of PG production on the basal side of the endothelial cell (9). This suggests that endothelial-derived PG could act on signal transduction pathways within the CNS, leading to the febrile response (10), changes of the sleep-wake cycle, and activation of the autonomic nervous system and hypothalamopituitary-adrenal axis (11).COX-1 and COX-2 are the rate-limiting enzymes for PG production from arachidonic acid. COX-1 is constitutively expressed in many cell types and is relatively unaffected by immune stimulation (12). In the adult brain, the constitutive synthesis of PG may be important for maintaining neuronal metabolism and synaptic function. COX-1 is localized to specific regions in fetal sheep brain, including some regions of cortex, hypothalamus, hippocampus, midbrain, pons, and medulla (13). In contrast to the COX-1 isoform, COX-2 expression is usually minimal unde...

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Hypothalamic prostaglandin E2 during lipopolysaccharide-induced fever in guinea pigs

Cited by 111 publications

References 33 publications

Anti-inflammatory agents attenuate the passive responses of guinea pig pups: Evidence for stress-induced sickness behavior during maternal separation

Anti-inflammatory agents attenuate the passive responses of guinea pig pups: Evidence for stress-induced sickness behavior during maternal separation

LPS-activated complement, not LPS per se, triggers the early release of PGE₂by Kupffer cells

Cerebrovascular Responses in the Fetal Sheep Brain to Low-Dose Endotoxin

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Hypothalamic prostaglandin E2 during lipopolysaccharide-induced fever in guinea pigs

Cited by 111 publications

References 33 publications

Anti-inflammatory agents attenuate the passive responses of guinea pig pups: Evidence for stress-induced sickness behavior during maternal separation

Anti-inflammatory agents attenuate the passive responses of guinea pig pups: Evidence for stress-induced sickness behavior during maternal separation

LPS-activated complement, not LPS per se, triggers the early release of PGE2by Kupffer cells

Cerebrovascular Responses in the Fetal Sheep Brain to Low-Dose Endotoxin

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LPS-activated complement, not LPS per se, triggers the early release of PGE₂by Kupffer cells