Fever and Mediators of the Febrile Response

febrile response is in most cases a part of a physiologic defense reaction and caused by cytokine-in-

Figure 2.36 Effects of aspirin on pain rating, pain-related somatosensory evoked potentials (SEPs) and power density (PD) in response to pain-inducing stimuli in healthy volunteers. Encephalographic measurements (EEG) were taken before (pre) and 90min after (post) oral aspirin (1 g) intake. Note the aspirin-induced alterations, suggesting reduced signal transmission. No changes were seen with a matching placebo (PLA) in a double-blind crossover design (modified after [32]).

Figure 2.36 Effects of aspirin on pain rating, pain-related somatosensory evoked potentials (SEPs) and power density (PD) in response to pain-inducing stimuli in healthy volunteers. Encephalographic measurements (EEG) were taken before (pre) and 90min after (post) oral aspirin (1 g) intake. Note the aspirin-induced alterations, suggesting reduced signal transmission. No changes were seen with a matching placebo (PLA) in a double-blind crossover design (modified after [32]).

duced rise in core temperature, generation of active phase reactants, and subsequent upregulation of peripheral defense systems [379, 380]. The febrile response starts with exposition of the organism to exogenous pyrogens, such as viruses, bacterial toxins, or other products of microbial origin. These enter the body and stimulate white cells to phagocytosis and generation of pyrogenic cyto-kines. These endogenous pyrogens IL-1, TNFa, interferon-g and IL-6 have the capacity to raise the thermoregulatory center set point in the hypothalamus. They do so either by acting directly on thermosensitive neurons after crossing the blood-brain barrier and/or by release of other mediators, such as PGE2, in circumventricular organs. This involves induction of COX-2 and results in subsequent increase of PGE2 in the preoptic region ofthe hypothalamus. This is an area with high expression levels of prostaglandin EP3 receptors [381], the putative sites of PGE action [382] (Figure 2.37).

Questions about risk-benefit ratio of fever have generated considerable controversies in recent years and are still not finally answered. Substantial data indicate both potentiating and inhibitory effects of the fever response to inflammatory reactions. The induction of heat-shock proteins by salicylates rather indicates stimulation of a protective system. The potential of the febrile response for harm is reflected in reports showing

Figure 2.37 Hypothetical model for the febrile response and possible sites of action of aspirin and salicylates (modified after [380]).

that IL-1, TNFa, interferon-g, and IL-6 mediate the physiological abnormalities of certain infections. Thus, treatment with antipyretic, anti-inflammatory analgesics, such as salicylates, will normalize the body temperature by fighting the generation and action of inflammatory pyrogenic cytokines [380].

Mechanisms of Antipyretic Actions of Aspirin Aspirin does not reduce normal body temperature, nor does it modify an elevated body temperature subsequent to physical exercise [384] or increased temperature in the environment [385]. Aspirin selectively reduces pyrogen-induced fever [386] by an interaction with the pyrogenic cytokines IL-1, TNFa, interferon-g, and IL-6 (Figure 2.37). The antipyretic response to aspirin is probably salicylate mediated. It can be obtained after i.v. administration ofsodium salicylate at antipyretic salicylate-plasma levels of about 1 mM (210-230 mg/ml). The antipyretic action of aspirin is typically associated with sweating, indicating extra "heat" production and "export" through the skin as a result of uncoupling of oxidative phosphorylation (Section 2.2.3) [383] (Figure 2.38). This might also explain the paradoxi cal "hyperpyrexia" seen in children with salicylate poisoning (Section 3.1.1). Thus, aspirin affects both sides of pyrogen-induced upregulation of temperature control: heat production and heat loss.

In addition to salicylate-mediated inhibition of endogenous pyrogens, salicylates also antagonize the actions of endogenous pyrogens on COX-2 expression and inhibit prostaglandin biosynthesis. This involves at least two mechanisms: inhibition of cytokine-induced expression of COX-2 protein [387] by salicylates and inhibition of enzymatic activity of COX-1 and COX-2. COX-2 appears to be the target cyclooxygenase since selective COX-2 inhibition in man reduces fever to the same extent as nonselective COX-1/COX-2 inhibitors [388]. Application of PGE2 into the hypothalamus or the ventricles ofthe brain causes fever that, in contrast to that induced by IL-1 or TNFa, cannot be blocked by aspirin or salicylates. Thus, PGE2 - generated via COX-2 - determines the severity of the febrile response and possibly acts via EP3 receptors [382]. Aspirin inhibits the febrile response partly via inhibition of PGE2 formation.

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