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

doi:10.1016/j.pharmthera.2005.10.013

Pharmacology & Therapeutics

Volume 111, Issue 1, July 2006, Pages 194-223

https://doi.org/10.1016/j.pharmthera.2005.10.013 Get rights and content

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-α, 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 α1-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 α2 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.

Introduction

Fever is one among an array of host defense responses to the invasion of the body by microbial pathogens such as bacteria and viruses as well as by non-microbial, deleterious physical and chemical insults. Although disagreeable and debilitating, fever is thus a healing response. It arises as the result of a complex, phased sequence of interactions among soluble factors and cells that is initiated in the periphery by the presence of the pathogens or their products and then transmitted to the brain, which modulates the febrile response. The process is driven both in the periphery and in the brain by mediators that provide pro-pyretic and anti-pyretic signals at different points along the pathway and whose appearance is time-dependent and exquisitely regulated; the latter is an essential, autoregulatory feedback that serves to prevent an exaggerated fever from occurring during systemic infectious challenges.

In the last decade especially, there has occurred a remarkable expansion of our understanding of the mechanisms that underlie the regulation of the febrile response. The present article summarizes the pathophysiology of fever and its associated effects, and updates this knowledge regarding the functional organization and integration of the pathways that mediate the febrile response to, in particular, Gram-negative bacterial endotoxemia.

Section snippets

Fever: its status among the host responses to infection

When infectious microorganisms invade the body, a concatenation of nonspecific, local reactions promptly develops to protect the host and preserve normal function. The general term for these reactions is “inflammation”. Although it is generally taken to connote a destructive process, it is in fact a normal, physiological, homeostatic response that becomes pathological only when it escapes the host's regulatory control and/or becomes chronic. The local inflammatory response is initiated by the

Prevailing concept of fever induction

The generally held view of the genesis of infectious pathogen-induced fever is that it develops in sequential steps (Fig. 1), starting with the production by peripheral mononuclear phagocytes activated by the infectious noxa (Table 3) of pyrogenic cytokines, principally tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, but others as well (Table 4), the release of these cytokines into the bloodstream and their transport to the preoptic-anterior hypothalamic area (POA), the brain site

New data implicating a different triggering mechanism of endotoxic fever

Circulating LPS is cleared primarily by hepatic macrophages (Kupffer cells [Kc]) (Mathison & Ulevitch, 1979, Li & Blatteis, 2004); these cells constitute the single largest population of macrophages in the body and are its major source of pyrogenic cytokines (Dinarello et al., 1968, Michie et al., 1988, Cannon et al., 1990). If the levels of pyrogenic cytokines rose sufficiently to excite cognate receptors on sensory neurons in their vicinity before these mediators would be detectable in the

Synopsis of revised concept of endotoxic fever induction

In brief, the updated, general notion posits that pyrogenic doses of LPS (and likely also of live Gram-negative bacteria) activate on contact the alternative pathway of the C cascade, generating all components subsequent to C3. Among these, C5a induces virtually immediately the release by Kc of PGE2which, in turn, presumptively activates local vagal afferents to the POA. (It should be noted in this context that C5a also triggers the production by macrophages of cytokines (Okusawa et al., 1987,

Centrality of Kupffer cells

The role of the liver as the principal clearinghouse of circulating LPS was established long ago, as already noted. Its involvement in the pathogenesis of fever was first suggested in 1968 (Dinarello et al., 1968) and has been supported by many subsequent, but indirect findings (Fong et al., 1989, Szekely et al., 1998, Michie et al., 1988, Hesse et al., 1988, Cannon et al., 1990). Direct evidence that the Kc are specifically central to the production of LPS fever was provided by the

From the liver to the brain

There is no question that the microinjection of PGE2 icv or directly into the POA (intraPOA) causes almost immediately a dose-dependent rise in Tc and, furthermore, that this rise is prevented by pretreatment with appropriate receptor antagonists (Oka, 2004); these receptors (EP) are distributed on neurons in the POA/VMPO region (Ek et al., 2000, Oka et al., 2000, Oka, 2004). It is also clear that PGE2 rises and falls in the cerebrospinal fluid (CSF) and in the interstitial fluid of the POA in

From the NTS to the POA/VMPO

At least two routes are possible from the NTS to the POA/VMPO: (1) by way of intermediate relays in the brainstem reticular formation (Ramon-Moliner & Nauta, 1966) or (2) by way of noradrenergic projections originating in the A1 and A2 regions of the medulla (Fernandez-Galaz et al., 1994) and arriving in the POA via the ventral noradrenergic bundle (VNB) (Palkovits et al., 1980). Excitatory abdominal vagal inputs to A1 neurons have been described (Gieroba et al., 1995), and the ascending

Pathways to thermoeffectors

As described earlier (see Section 2.2), the major effector systems mediating pyrogen-induced fever are the skeletal muscle mass (shivering thermogenesis) in adult animals, brown adipose tissue (BAT) nonshivering thermogenesis (NST) in neonates and rodents, and the cardiovascular system (cutaneous vasoconstriction, for heat conservation). Although these thermoeffector mechanisms are well characterized, the central efferent pathways controlling them are not yet fully known. Recent advances in

Overview of propyresis

The updated concept that thus emerges from the sum of these data is that fever induced by the peripheral administration of bacterial LPS is triggered when it arrives in the liver and there stimulates virtually immediately the generation of PGE2 by C5a-activated Kc, the signal of which is then transmitted to the brain either neurally or humorally. Because of the short onset latency of the febrile response to iv LPS particularly and on the basis of this author's extensive data, this signal is

Endogenous counter-regulatory mechanisms

It is apparent from the preceding that fever develops in sequential steps controlled by a series of endogenous mediators that provide “go” signals (e.g., C5a, PGE2, NE) at different points along the pathway, from the periphery to the brain, and whose sequence is time-dependent. Fever height, however, is self-limiting, only rarely rising to very high levels (see earlier); the term “hyperthermic ceiling” was coined long ago to describe this characteristic (Bornstein et al., 1963). Moreover, under

Concluding remarks

When an organism becomes infected, a series of host defense responses are initiated. These are largely mediated by the CNS and are collectively termed the APR. Prominent and characteristic among these reactions is fever, a regulated rise in Tc that is a beneficial, homeostatic response. It is a phylogenetically old response, but subject to a variety of extraneous factors that can alter it in one way or another, e.g., age, gender, diet, early life immune challenge, etc. (Kluger, 1979, Ellis et

Acknowledgments

I wish hereby to express my grateful appreciation to all my co-workers over the years without whose dedicated and untiring assistance my own contributions to fever research would not have advanced. In particular, I thank Drs. Elmir Sehic, Shuxin Li, Carlos Feleder, Vit Perlik and Zhonghua Li, whose work has been so material to the development of my admittedly biased view of the mechanism of afferent pyrogenic signaling.

This research was supported by the National Institute of Health grants Nos.

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Associate editor: R. BallouEndotoxic fever: New concepts of its regulation suggest new approaches to its management

Abstract

Introduction

Section snippets

Fever: its status among the host responses to infection

Prevailing concept of fever induction

New data implicating a different triggering mechanism of endotoxic fever

Synopsis of revised concept of endotoxic fever induction

Centrality of Kupffer cells

From the liver to the brain

From the NTS to the POA/VMPO

Pathways to thermoeffectors

Overview of propyresis

Endogenous counter-regulatory mechanisms

Concluding remarks

Acknowledgments

Physiol Behav

Am J Med

Eur J Pharmacol

J Thermal Biol

J Thermal Biol

Auton Neurosci

J Thermal Biol

J Thermal Biol

Prostaglandins Other Lipid Mediat

Prostaglandins, Leukotrienes Essent Fatty Acids

Brain Res

Brain Res

Brain Res Mol Brain Res

Brain Res Mol Brain Res

Neuroscience

Neurosci Lett

Brain Res

Int Rev Neurobiol

J Hepatol

Brain Res

Phagocytic activity of Kupffer cells in splenectomized rats

Virchows Arch A Pathol Anat Histopathol

Prostaglandin E2 enters the brain following stimulation of the acute phase immune response

Ann N Y Acad Sci

The cell biology of macrophage activation

Annu Rev Immunol

Distribution of rat C5a anaphylatoxin receptor

Microbiol Immunol

Molecular characterization of an arachidonic acid epoxygenase in rat brain astrocytes

Stroke

Targeting C5a: recent advances in drug discovery

Curr Med Chem

Splenectomy and sepsis: the role of the spleen in the immune-mediated bacterial clearance

Immunopharmacol Immunotoxicol

Role of cytosolic phospholipase A2 in arachidonic acid release of rat-liver macrophages: regulation by Ca2+ and phosphorylation

Biochem J

Clinical fever: its history, manifestations and pathogenesis

Fed Proc

Fever in mammals: is it beneficial?

Yale J Biol Med

Factors regulating isoprostane formation in vivo

Antioxid Redox Signal

Experimental study of the effects of splenectomy and partial splenectomy on bacterial translocation

J Trauma

Endotoxin and the hypothalamus–pituitary–adrenal (HPA) axis

J Endotoxin Res

Toll-like receptors: how they work and what they do

Curr Opin Hematol

Splenectomy alters Kupffer cell response to endotoxin

Arch Surg

Inhibition of in vitro concentrative prostaglandin accumulation by prostaglandins, prostaglandin analogues and by some inhibitors of organic anion transport

J Physiol (Lond)

Fever; exchange of shivering by nonshivering pyrogenesis in cold-acclimated guinea pigs

J Appl Physiol

Fever: is it beneficial?

Yale J Biol Med

Prostaglandin E2: a putative fever mediator

Circulating pyrogen signaling of the brain. A new working hypothesis

Ann N Y Acad Sci

Fever: how may circulating pyrogens signal the brain?

News Physiol Sci

Cytokines and fever

Ann N Y Acad Sci

Kupffer cells and complement mediate the febrile response of guinea pigs to endotoxin

Associate editor: R. Ballou
Endotoxic fever: New concepts of its regulation suggest new approaches to its management

Role of cytosolic phospholipase A2 in arachidonic acid release of rat-liver macrophages: regulation by Ca²⁺ and phosphorylation