Effect of heat stress on LPS-induced febrile response in D-galactosamine-sensitized rats.

We have previously reported that heat conditioning augments lipopolysaccharide (LPS)-induced fever in rats, which is accompanied by an accumulation of heat shock protein (HSP) in the liver and the reduction of the plasma level of tumor necrosis factor (TNF-alpha) (Kluger MJ, Rudolph K, Soszynski D, Conn CA, Leon LR, Kozak W, Wallen ES, and Moseley PL. Am J Physiol Regulatory Integrative Comp Physiol 273: R858-R863, 1997). In the present study we have tested whether inhibition of protein synthesis in the liver can reduce the effect of this heat conditioning on the LPS-induced febrile response in the rat. D-galactosamine (D-gal) was used to selectively inhibit liver protein synthesis. D-gal (500 mg/kg) or PBS as control was administered intraperitoneally 1 h before heat stress. LPS (50 microg/kg ip) was injected 24 h post-heat exposure. Treatment with D-gal blunted the febrile response to LPS. Moreover, heat-conditioned rats treated first with D-gal and subsequently with LPS demonstrated a profound fall in core temperature 10--18 h post-LPS. A significant increase of serum TNF-alpha accompanied this effect of D-gal on fever. Heat-conditioned animals receiving D-gal showed an inhibition in inducible HSP-70 in the liver. These data support the role of hepatic function in modulating the febrile response to LPS.

Response of F344 rats to inhalation of subclinical levels of sarin: exploring potential causes of Gulf War illness.

Subclinical, repeated exposures of F344 rats to sarin resulted in brain alterations in densities of chlonergic receptor subtypes that may be associated with memory loss and cognitive dysfunction. The exposures also depressed the immune system. The rat appears to be a good model for studying the effects of subclinical exposure to a nerve gas.

Role of cytochrome P-450 in endogenous antipyresis.

In previous reports, we (15, 18) and others (29) demonstrated data showing that various inhibitors of cytochrome P-450/epoxygenase augment fever in rats and mice, indicating that the enzyme may be involved in endogenous antipyresis. The aim of this study was to further test the hypothesis that the P-450-dependent epoxygenase pathway of arachidonic acid is part of the homeostatic system to control the height of fever. Sprague-Dawley rats were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide (LPS; 80 microg/kg). We demonstrate that intraperitoneal administration of P-450 inducers (bezafibrate and dehydroepiandrosterone, 10 and 100 mg/kg) before LPS reduced fever in rats in a dose-dependent manner. In complementary experiments, rats were implanted with brain cannulas in addition to the biotelemeters. Various isomers of epoxyeicosanoids were administered into the lateral ventricle at doses of 0.01 to 10 microg/rat to test their influence on LPS-induced fever in rats. Four of five isomers were antipyretic in a dose-dependent manner. The most potent antipyretic isomers were 11, 12-epoxyeicosatrienoic acid (EET) followed by 14,15-EET, 8,9-EET, and 12(R) hydroxyeicosatetraenoic acid. These data support the hypothesis that the cytochrome P-450/epoxygenase pathway of arachidonate metabolism is part of the endogenous antipyretic system.

Molecular mechanisms of fever and endogenous antipyresis.

This review summarizes recent studies on endogenous antipyretic mechanisms. Fever is the result of a balance between pyrogenic and cryogenic cytokines and hormones. Although there is considerable evidence that fever evolved as a host defense response, it is important that the rise in body temperature not be too high. Many endogenous cryogens or antipyretics that limit the rise in body temperature have been identified during the last 25 years. These include alpha-MSH, arginine vasopressin, glucocorticoids, TNF (under certain circumstances), and IL-10. Most recently, evidence has accumulated that cytochrome P-450 (P-450), part of the alternative pathway for arachidonic acid metabolism, plays an important role in reduction of fever and inflammation. Supporting a role for P-450 in endogenous antipyresis and antiinflammation includes evidence that (1) inducers of P-450 reduce fever, (2) inhibitors of P-450 cause a larger fever, (3) and P-450 arachidonic acid metabolites reduce fever.

Suprachiasmatic nuclei lesions do not eliminate homeostatic thermoregulatory responses in rats.

Electrolytic lesions aimed at the suprachiasmatic nuclei (SCN) were made in male Long-Evans rats. Body temperature (Tb), activity, and drinking were monitored continuously in a 12-h light:12-h dark (12:12 LD) cycle at an ambient temperature of 23 degrees C. Large SCN lesions eliminated activity and drinking rhythms and abolished or reduced the circadian rhythm of Tb. The Tb responses of the rats were measured in L after exposure to cold and injection of lipopolysaccharide (LPS), a fever-producing drug, and in both L and D during a 30-min exposure to a novel cage. Rats with SCN lesions (SCNX) maintained their Tb as well as did controls during 2-h exposure to 2 degrees C. They also showed the expected increases in Tb in response to novelty and LPS. Nevertheless, there were differences between SCNX rats and other rats. When measured 9 h after LPS injection, SCNX rats had lower Tb in D than did sham-lesioned or intact rats or rats with lesions that missed the SCN. This is not surprising; the Tb of SCNX rats does not go as high as that of intact rats in D. However, it was surprising that at night SCNX rats increased their Tb in response to novelty (lights on in the test situation), whereas normal rats did not. For some reason, light inhibits the Tb rise to novelty in normal rats but does not do so in rats with SCN lesions.

Individual differences in response to LPS and psychological stress in aged rats.

Old rats may show blunted fever or hypothermia after injection of lipopolysaccharide (LPS), a fever-producing agent, and have a reduced body temperature (Tb) rise in response to psychological stress. These results may partly be a consequence of aging per se, partly a sex difference, and partly an effect of differences in types and doses of pyrogen. Here we tested age and gender differences in Tb responses to 30-min exposure to a novel environment and to injection of several doses of LPS. There were age-related reductions in novelty-induced hyperthermia, and some old rats even became hypothermic. Sensitivity to the pyrogenic activity of LPS and to the toxic effects of endotoxin (manifested by hypothermia) both increased in aged female rats. A major finding was that there were no correlations between age-related changes in Tb in response to novelty and to LPS injection. Tb responses in aged rats were variable; in each situation, there were old rats whose Tb rose as high as did younger ones. We did not observe significant gender differences in response either to novelty or to LPS in young or old rats.

A moderate dose of cycloheximide does not prevent the febrile response to endotoxin but interfere with induction of pyrogenic tolerance in rabbit.

The purpose of the present study was to examine the effect of cycloheximide (Cx)--inhibitor of protein synthesis, on the development of pyrogenic tolerance to LPS. It has been observed that Cx at a dose of 1 mg/kg given intravenously 1 h prior to LPS did not prevent fever response, however it modified the induction of pyrogenic tolerance. It was manifested in existence of the second phase of fever after the following administrations of LPS into rabbits pretreated with Cx. In control group of rabbits the induction of pyrogenic tolerance was accompanied with decaying of the second peak of fever visible as early as the second dose of LPS.