Endotoxic fever: New concepts of its regulation suggest new approaches to its management

Blatteis, Clark M.

doi:10.1016/j.pharmthera.2005.10.013

Cited by 152 publications

(140 citation statements)

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“…Yet the traditional mechanism of the PGE 2 -dependent febrile response has been reevaluated because of time course discrepancies. The appearance of these circulating cytokines lags the onset of the febrile response when LPS is intravenously injected, and the synthesis of cyclooxygenase-2 (COX-2), responsible for PGE 2 production, only appears well after the onset of fever (Blatteis, 2006). New evidence suggests this peripheral febrile message is relayed to the hypothalamus via a much faster neural route, through the hepatic vagus to the nucleus tractus solitarius (NST; Blatteis, 2007).…”

Section: Introductionmentioning

confidence: 99%

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

et al. 2008

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Peripheral exposure to LPS induces a biphasic fever thought to be initiated via vagal afferents to the preoptic area of the anterior hypothalamus (POAH), an important thermoregulatory control center in the brain. Previous studies have shown norepinephrine synaptically mediates this Prostaglandin E 2 (PGE 2 )-dependent change in temperature through the selective activation of alpha-2 adrenoreceptors (AR). However, there is clear evidence that alpha-1 AR activation of thermoregulatory hypothalamic neurons will result in a rapid hyperthermia that is not dependent on PGE 2 . This direct action of norepinephrine in the POAH was tested in the present study by recording the single-unit activity of POAH neurons in a tissue slice preparation from the adult male rat, in response to temperature and the selective alpha-1 AR agonist Cirazoline (1−100 μM). Neurons were classified as either warm sensitive or temperature insensitive. Warm sensitive neurons responded to Cirazoline with a decrease in firing rate, while temperature insensitive neurons showed a firing rate increase. These responses are similar to those reported for PGE 2 and suggest that both warm sensitive and temperature insensitive neurons in the POAH are important in mediating this alpha-1 AR dependent hyperthermic shift in body temperature.

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Section: Introductionmentioning

confidence: 99%

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

et al. 2008

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“…Our studies show that LPS-induced fever and hypothermia are both physiological responses brought about by brain-driven changes in thermoeffector activity (3,4,70). Whereas the biological value of fever is thought to be related to its immunostimulant and antibacterial effects (43), the biological value of hypothermia may be related to energy conservation when inflammation is severe enough to compromise tissue perfusion or threaten energy reserves (72, 82).There is no doubt that cyclooxygenase (COX) plays a critical role in the genesis of fever by catalyzing the conversion of arachidonic acid to prostaglandin (PG) H 2 , the immediate precursor of febrigenic PGE 2 (10,35,55,66). Clinical fevers (5) and all phases of experimental, LPS-induced fever (13,49,81,83,90) are thought to be mediated by COX-2, the inducible isoform, and not by COX-1, the predominantly constitutive isoform.…”

mentioning

confidence: 99%

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

Steiner

Hunter²,

Phipps³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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DL, Romanovsky AA. Cyclooxygenase-1 or -2-which one mediates lipopolysaccharide-induced hypothermia? Am J Physiol Regul Integr Comp Physiol 297: R485-R494, 2009. First published June 10, 2009 doi:10.1152/ajpregu.91026.2008.-Systemic inflammation is associated with either fever or hypothermia. Fever, a response to mild systemic inflammation, is mediated by cyclooxygenase (COX)-2 and not by COX-1. However, it is still disputed whether COX-2, COX-1, neither, or both mediate(s) responses to severe systemic inflammation, and, in particular, the hypothermic response. We compared the effects of SC-236 (COX-2 inhibitor) and SC-560 (COX-1 inhibitor) on the deep body temperature (Tb) of rats injected with a lower (10 g/kg iv) or higher (1,000 g/kg iv) dose of LPS at different ambient temperatures (Tas). At a neutral Ta (30°C), the rats responded to LPS with a polyphasic fever (lower dose) or a brief hypothermia followed by fever (higher dose). SC-236 (2.5 mg/kg iv) blocked the fever induced by either LPS dose, whereas SC-560 (5 mg/kg iv) altered neither the febrile response to the lower LPS dose nor the fever component of the response to the higher dose. However, SC-560 blocked the initial hypothermia caused by the higher LPS dose. At a subneutral T a (22°C), the rats responded to LPS with early (70 -90 min, nadir) dose-dependent hypothermia. The hypothermic response to either dose was enhanced by SC-236 but blocked by SC-560. The hypothermic response to the higher LPS dose was associated with a fall in arterial blood pressure. This hypotensive response was attenuated by either SC-236 or SC-560. At the onset of LPS-induced hypothermia and hypotension, the functional activity of the COX-1 pathway (COX-1-mediated PGE2 synthesis ex vivo) increased in the spleen but not liver, lung, kidney, or brain. The expression of splenic COX-1 was unaffected by LPS. We conclude that COX-1, but not COX-2, mediates LPS hypothermia, and that both COX isoforms are required for LPS hypotension. body temperature; thermoregulation; fever; inflammation SO STRONGLY IS SYSTEMIC INFLAMMATION associated with changes in deep body temperature (T b ) that every clinical definition of the systemic inflammatory response syndrome includes a change in T b (11,48). Whereas the majority (ϳ90%) of patients with systemic inflammation have an increased T b , a number of them (ϳ10%) have a lowered T b (6, 17). Thermoregulatory manifestations are also present in animal models of systemic inflammation. In a rat model of systemic inflammation induced by bacterial LPS, the pattern of T b change depends on the ambient temperature (T a ) and the LPS dose. At a neutral or supraneutral T a (warm environment), fever is the prevailing response; the fever is monophasic when the dose of LPS is low (just suprathreshold), but it turns polyphasic as the dose increases (66, 68, 69, 71, 79); a mild hypothermia may precede the polyphasic fever when the dose of LPS is high (68). At a subneutral T a (cool environment), hypothermia followed by fever is the predominant response; th...

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“…As peripheral organs like liver and lungs displayed an earlier up-regulation of the enzyme transcripts (Ivanov et al, 2002) than the brain, it was suggested that peripheral PGE2 was responsible for the first phase of fever (Ivanov and Romanovsky, 2004). This idea was further supported by a study from the same group showing that the fever response was suppressed after administration of blocking antibodies against PGE2 (Blatteis, 2006;Steiner et al, 2006b). In mice, however, we found that non-hematopoietic (i.e.…”

Section: Brain Pge2 As a Mediator Of Fever At The Preoptic Regionmentioning

confidence: 85%

“…Still, in an endothelial-specific IL-1R1 KO mouse model impairing the immune signal transmission at the BBB, the discrepancy seen between iv and ip IL-1β treatments (no fever if iv, fever if ip) can best be explained by activation of the afferent somatic and/or autonomic neurons (Ching et al, 2007). Through their fast impulse signaling to the CNS the afferent neurons were also proposed to be responsible for the early phase of the sickness syndrome (Blatteis, 2006;Dantzer et al, 2008;Konsman et al, 2002;Quan, 2008;Romanovsky, 2004). Nevertheless, as NSAIDs are effective also in local inflammation, the neural pathway is still prostaglandin-dependent and thus dependent on de novo cytokine and prostaglandin enzyme production, i.e.…”

Section: Afferent Neuronal Pathwaysmentioning

confidence: 99%

“…In unstressed animals, for example animals injected through an indwelling iv catheter, the first fever response could be measured between 16 to 70 minutes after LPS injection (Romanovsky et al, 1998). This response is believed to be governed by mechanisms other than phase 2 and phase 3 fevers (Blatteis, 2006;Ivanov and Romanovsky, 2004). The second phase from 1.5 to 3 h, peaking at approximately 2 h, and the third phase are believed to depend on the same mechanisms but with the third phase being highly dependent on the LPS dose (Romanovsky, 2004).…”

Section: Induction Stimuli For Inflammation and Stress Hyperthermiamentioning

confidence: 99%

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Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

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Endotoxic fever: New concepts of its regulation suggest new approaches to its management

Cited by 152 publications

References 274 publications

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

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