Temperature Regulation and the Pathogenesis of Fever

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temperature as regulated within a narrow range of temperatures by a composite setpoint of several thermosensitive areas and several different thermoregulatory responses. [77][78][79] A variety of endogenous substances and drugs appear to affect temperature regulation by altering the activity of hypothalamic neurons. Perhaps the best examples of such substances are the pyrogenic cytokines discussed later. These are released by mononuclear phagocytes in response to a wide array of stimuli and have the capacity to raise the thermoregulatory center’s thermal setpoint. Whether they cross the blood-brain barrier to do so [80][81] or act by evoking the release of other mediators (e.g., prostaglandin E2 [PGE2]) in circumventricular organs, such as the organum vasculosum laminae terminalis, [80] is uncertain. Whatever the precise endogenous mediators of fever, their primary effect appears to be to decrease the firing rate of preoptic warm-sensitive neurons, leading to the activation of responses designed to decrease heat loss and increase heat production. ENDOGENOUS PYROGENS Pyrogens have traditionally been divided into two general categories: those that originate outside the body (exogenous pyrogens) and those that are derived from host cells (endogenous pyrogens). Exogenous pyrogens are, for the most part, microorganisms and toxins or other products of microbial origin, whereas endogenous pyrogens are host cell–derived (pyrogenic) cytokines that are the principal central mediators of the febrile response. [82] According to traditional concepts, exogenous pyrogens, regardless of their physicochemical structure, initiate fever by inducing host cells (primarily macrophages) to produce endogenous pyrogens. Such concepts notwithstanding, certain endogenous molecules also have the capacity to induce endogenous pyrogens. These include, among others, antigen-antibody complexes in the presence of complement, [83][84] certain androgenic steroid metabolites, [85][86][87] inflammatory bile acids, [88] complement, [89] and various lymphocyte-derived molecules. [90][91] Likewise, data recently obtained in studies employing guinea pigs suggest that bacterial lipopolysaccharide (LPS) induces fever directly (rather than indirectly through the induction of pyrogenic cytokines) by interacting with Kupffer’s cells, thereby initiating pyrogenic signals that are transmitted to the preoptic area of the hypothalamus via the hepatic branch of the vagus nerve. [92] Thus, the distinction between endogenous and exogenous pyrogens is artificial at best. Complete understanding of the function of individual pyrogenic cytokines has been hampered by the fact that one cytokine often influences the expression of other cytokines or their receptors, or both, and may also induce more distal co-mediators of cytokine-related bioactivities (e.g., prostaglandins and platelet-activating factor). [93] In short, cytokines function within a complex regulatory network in which information is conveyed to cells by combinations, and perhaps by sequences, of a host of cytokines and other hormones. [94] Like the words of human communication, individual cytokines are basic units of information. On occasion, a single cytokine, like a single word, may communicate a complete message. More often, however, complete messages received by cells probably resemble sentences, in which combinations and sequences of cytokines convey information. Because of such interactions, it has been difficult to ascertain the direct in vivo bioactivities of particular cytokines. Nevertheless, several cytokines have in common the capacity
to induce fever. On the basis of this characteristic, they have been codified together as so-called pyrogenic cytokines. The list of currently recognized pyrogenic cytokines includes, among others, interleukin-1 (IL-1 [IL-1α and IL-β]), tumor necrosis factor-α (TNF-α), IL-6, ciliary neurotropic factor (CNF), and interferon (IFN). [95][96][97][98][99][100][101][102][103] Even among these few cytokines, complex relationships exist, with certain members upregulating the expression of other members or their receptors in certain situations and downregulating them in others. [93] The four major pyrogenic cytokines have monomeric molecular masses that range from 17 to 30 kDa. Undetectable under basal conditions in healthy subjects, they are produced by many different tissues in response to appropriate stimuli. Once released, pyrogenic cytokines have short intravascular half-lives. They are pleiotropic, in that they interact with receptors present on many different host cells. They are active in picomolar quantities, induce maximal cellular responses even at low receptor occupancy, and exert local (autocrine-paracrine) as well as systemic (endocrine) effects. [93] It has long been suspected that interactions between pyrogenic cytokines and their receptors in the preoptic region of the anterior hypothalamus activate phospholipase A2, liberating plasma membrane arachidonic acid as a substrate for the cyclooxygenase pathway. Some cytokines appear to do so by increasing cyclooxygenase expression directly, causing liberation of the arachidonate metabolite PGE2. Because this small lipid molecule easily diffuses across the blood-brain barrier, it is thought by some to be the local mediator that actually activates thermosensitive neurons. Although it is not yet widely accepted, additional studies indicate that the C5a component of the complement cascade is integral to LPS-induced fever [104] and that in some situations, thermal information involved in the febrile response is transmitted from the periphery to the thermoregulatory center via vagal pathways (see earlier). [105] Figure 47–4 depicts the modern, hypothetical model for the febrile response, [106] in which pyrogenic cytokines released by phagocytic leukocytes into the blood stream in response to exogenous pyrogens find their way to the organum vasculosum of the lamina terminalis (OVLT), where they induce synthesis of prostaglandins mediating the febrile response. The model has several shortcomings that have caused thermophysiologists to suspect that multiple pathways might be involved in the induction of fever (e.g., the vagal pathways referred to earlier, local production of pyrogenic cytokines in the hypothalamus itself, and participation of membrane-bound cytokines as mediators), with different pathways or combinations of pathways being responsible for fever in different situations. [105][107] All of the models proposed to date have been concerned with mechanisms responsible for the induction phase of fever. None have considered the plateau or ascending phases of fever or explained why a disorder such as endocarditis, in which exogenous pyrogens (i.e., bacteria) are present continuously in the blood, is associated with a remittent rather than a continuous fever pattern. As a consequence, our understanding of the febrile response remains incomplete and largely speculative. As indicated previously, it is not yet clear whether circulating cytokines cross the blood-brain barrier or have to be produced within the central nervous system in order to activate thermosensitive neurons; or if each of the pyrogenic cytokines is capable of raising the thermoregulatory setpoint independently or must exert this effect through some final, common pathway (see Fig. 47–4 ); or if PGE2 or other local mediators are a sine qua
Page 1 and 2: Temperature Regulation and the Path
Page 3 and 4: Likewise, proper positioning of the
Page 5 and 6: infrared TM thermometers, have made
Page 7 and 8: Thermoregulation has also been repo
Page 9 and 10: Figure 47-2 Mean oral temperatures
Page 11 and 12: young adults (six male and three fe
Page 13: Figure 47-3 Sagittal view of the br
Page 17 and 18: iochemical, and nutritional alterat
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Page 21 and 22: Nevertheless, the febrile response
Page 23 and 24: TNF-α acts to lower, rather than t
Page 25 and 26: in mortality. [167] Covert and Reyn
Page 27 and 28: Although clinicians have long had a
Page 29 and 30: induce shivering. [227] However, ca
Page 31 and 32: validity of this contention. Moreov

Temperature Regulation and the Pathogenesis of Fever

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