Attenuated febrile response to lipopolysaccharide in rats with biliary obstruction

Patients with biliary tract obstruction have unexplained, inordinately high rates of perioperative morbidity and mortality, whereas cholestatic animals display abnormal hypothalamic responses to pyrogenic stimuli. We asked if obstructive cholestasis was associated with abnormal fever generation. Male Sprague-Dawley rats (250 g) underwent laparotomy for implantation of thermistors and either bile duct resection (BDR) or sham operation. After recovery, temperatures were recorded by telemetry and conscious, unrestrained rats in each group were injected intraperitoneally with either interleukin-1beta (IL-1beta;1 microg/kg) or Escherichia coli lipopolysaccharide (LPS; 50 microg/kg). Baseline temperatures in both groups were similar. Febrile responses after IL-1beta injection in BDR and sham groups were not significantly different. However, in response to LPS injection, BDR rats showed an initial hypothermia with a subsequently attenuated febrile response. Administration of anti-tumor necrosis factor-alpha (TNF-alpha) antibody 2 h before LPS injection blocked the LPS-induced hypothermia seen in BDR animals. However, serum levels of TNF-alpha were not significantly different between sham and BDR animals after LPS injection at any time point measured (0, 1.5, and 3 h).     

Site-specific modulation of LPS-induced fever and interleukin-1 beta expression in rats by interleukin-10

Bacterial lipopolysaccharide (LPS) induces fever that is mediated by pyrogenic cytokines such as interleukin (IL)-1 beta. We hypothesized that the anti-inflammatory cytokine IL-10 modulates the febrile response to LPS by suppressing the production of pyrogenic cytokines. In rats, intravenous but not intracerebroventricular infusion of IL-10 was found to attenuate fever induced by peripheral administration of LPS (10 microg/kg iv). IL-10 also suppressed LPS-induced IL-1 beta production in peripheral tissues and in the brain stem. In contrast, central administration of IL-10 attenuated the febrile response to central LPS (60 ng/rat icv) and decreased IL-1 beta production in the hypothalamus and brain stem but not in peripheral tissues and plasma. Furthermore, intravenous LPS upregulated expression of IL-10 receptor (IL-10R1) mRNA in the liver, whereas intracerebroventricular LPS enhanced IL-10R1 mRNA in the hypothalamus. We conclude that IL-10 modulates the febrile response by acting in the periphery or in the brain dependent on the primary site of inflammation and that its mechanism of action most likely involves inhibition of local IL-1 beta production.     

Putative antihyperpyretic factor induced by LPS in spleen of guinea pigs

We reported previously that the onset of LPS-induced fever, irrespective of its route of administration, is temporally correlated with the appearance of LPS in the liver and that splenectomy significantly increases both the febrile response to LPS and the uptake of LPS by Kupffer cells (KC). To further evaluate the role of the spleen in LPS fever production, we ligated the splenic vein and, 7 and 30 days later, monitored the core temperature changes over 6 h after intraperitoneal (ip) injection of LPS (2 microg/kg). Both the febrile response and the uptake of LPS by KC were significantly augmented. Like splenectomy, splenic vein ligation (SVL) increased the febrile response and LPS uptake by KC until the collateral circulation developed, suggesting that the spleen may normally contribute an inhibitory factor that limits KC uptake of LPS and thus affects the febrile response. Subsequently, to verify the presence of this factor, we prepared splenic extracts from guinea pigs pretreated with LPS (8 microg/kg ip) or pyrogen-free saline, homogenized and ultrafiltered them, and injected them intravenously into splenectomized (Splex) guinea pigs pretreated with LPS (8 microg/kg ip). The results confirmed our presumption that the splenic extract from LPS-treated guinea pigs inhibits the exaggerated febrile response and the LPS uptake by the liver of Splex guinea pigs, indicating the presence of a putative splenic inhibitory factor, confirming the participation of the spleen in LPS-induced fever, and suggesting the existence of a novel antihyperpyretic mechanism. Preliminary data indicate that this factor is a lipid.     

Role of alpha(2)-macroglobulin in fever and cytokine responses induced by lipopolysaccharide in mice

Alpha(2)-macroglobulin (alpha(2)M) is not only a proteinase inhibitor in mammals, but it is also a specific cytokine carrier that binds pro- and anti-inflammatory cytokines implicated in fever, including interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). To define the role of alpha(2)M in regulation of febrile and cytokine responses, wild-type mice and mice deficient in alpha(2)M (alpha(2)M -/-) were injected with lipopolysaccharide (LPS). Changes in body temperature as well as plasma levels of IL-1beta, IL-6, and TNF-alpha and hepatic TNF-alpha mRNA level during fever in alpha(2)M -/- mice were compared with those in wild-type control mice. The alpha(2)M -/- mice developed a short-term markedly attenuated (ANOVA, P < 0.05) fever in response to LPS (2.5 mg/kg ip) compared with the wild-type mice. At 1.5 h after injection of LPS, the plasma concentration of TNF-alpha, but not IL-1beta or IL-6, was significantly lower (by 58%) in the alpha(2)M -/- mice compared with their wild-type controls (ANOVA, P < 0.05). There was no difference in hepatic TNF-alpha mRNA levels between alpha(2)M -/- and wild-type mice 1.5 h after injection of LPS. These data support the hypotheses that 1) alpha(2)M is important for the normal development of LPS-induced fever and 2) a putative mechanism of alpha(2)M involvement in fever is through the inhibition of TNF-alpha clearance. These findings indicate a novel physiological role for alpha(2)M.     

Lipopolysaccharide-induced fever in Pekin ducks is mediated by prostaglandins and nitric oxide and modulated by adrenocortical hormones

Information on avian fever is limited, and, in particular, very little is known about the mediators and modulators of the febrile response in birds. Therefore, in this study, the possible mediatory roles of nitric oxide (NO) and prostaglandins (PGs), together with a potential modulatory role for adrenocortical hormones in the generation of fever was investigated in conscious Pekin ducks. Their body temperatures were continuously measured by abdominally implanted temperature-sensitive data loggers. The febrile response induced by intramuscular injection of LPS at a dose of 100 microg/kg was compared with and without inhibition of NO production by N-nitro-L-arginine methyl ester (L-NAME), inhibition of PG synthesis (by diclofenac), and elevation of circulating concentrations of dexamethasone and corticosterone (by exogenous administration). LPS administration induced a marked, monophasic fever with a rise in temperature of more than 1 degrees C after 3-4 h. In the presence of L-NAME, diclofenac, and adrenocorticoids at doses that had no effect upon normal body temperature in afebrile ducks, there was a significant inhibition of the LPS-induced fever. In addition, during the febrile response, the blood concentration of corticosterone was significantly elevated (from a basal level of 73.6 +/- 9.8 ng/ml to a peak level of 132.6 +/- 16.5 ng/ml). The results strongly suggest that the synthesis of both NO and PGs is a vital step in the generation of fever in birds and that the magnitude of the response is subject to modulation by adrenocorticoids.     

Kupffer cell-generated PGE2 triggers the febrile response of guinea pigs to intravenously injected LPS

Because the onset of fever induced by intravenously (i.v.) injected bacterial endotoxic lipopolysaccharides (LPS) precedes the appearance in the bloodstream of pyrogenic cytokines, the presumptive peripheral triggers of the febrile response, we have postulated previously that, in their stead, PGE2 could be the peripheral fever trigger because it appears in blood coincidentally with the initial body core temperature (Tc) rise. To test this hypothesis, we injected Salmonella enteritidis LPS (2 microg/kg body wt i.v.) into conscious guinea pigs and measured their plasma levels of LPS, PGE2, TNF-alpha, IL-1beta, and IL-6 before and 15, 30, 60, 90, and 120 min after LPS administration; Tc was monitored continuously. The animals were untreated or Kupffer cell (KC) depleted; the essential involvement of KCs in LPS fever was shown previously. LPS very promptly (<10 min) induced a rise of Tc that was temporally correlated with the elevation of plasma PGE2. KC depletion prevented the Tc and plasma PGE2 rises and slowed the clearance of LPS from the blood. TNF-alpha was not detectable in plasma until 30 min and in IL-1beta and IL-6 until 60 min after LPS injection. KC depletion did not alter the times of appearance or magnitudes of rises of these cytokines, except TNF-alpha, the maximal level of which was increased approximately twofold in the KC-depleted animals. In a follow-up experiment, PGE2 antiserum administered i.v. 10 min before LPS significantly attenuated the febrile response to LPS. Together, these results support the view that, in guinea pigs, PGE2 rather than pyrogenic cytokines is generated by KCs in immediate response to i.v. LPS and triggers the febrile response.     

Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats

Febrile responses to bacterial pathogens are attenuated near term of pregnancy in several mammalian species. It is unknown, however, whether this reflects a fundamental physiological adaptation of female rats or whether it is specific to pregnancy. The aims of this study therefore were 1) to determine whether febrile responses to the bacterial endotoxin lipopolysaccharide (LPS) are attenuated in female vs. male rats and, if so, to identify possible mechanisms involved in modulating this and 2) to assess whether plasma concentrations of the anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), an important regulator of fever, are dependent on the physiological state of the female and could therefore be involved in modulating febrile responses. We found febrile responses were attenuated in cycling female vs. male rats and also in near-term pregnant dams vs. cycling females after intraperitoneal injection of LPS (0.05 mg/kg). Plasma levels of IL-1ra were significantly greater in female rats after injection of LPS, particularly during pregnancy, than in males. This was accompanied by attenuated levels of hypothalamic IL-1beta and cyclooxygenase-2 mRNA, two key mediators of the febrile response, in female rats. Furthermore, increasing plasma levels of IL-1ra in male rats by intraperitoneal administration of the recombinant antagonist attenuated hypothalamic mRNA levels of these mediators after LPS. These data suggest that there is a fundamental difference in febrile response to LPS between the genders that is likely regulated by IL-1ra. This may be an important mechanism that protects the developing fetus from potentially deleterious consequences of maternal fever during pregnancy.     

Effect of palmitate on carbohydrate utilization and Na/K-ATPase activity in aortic vascular smooth muscle from diabetic rats

Immediately after bacterial endotoxin (LPS) enters the circulatory system there is increased production of free oxygen radicals by cells of the reticulo-endothelial system, followed by the release of cytokines considered as putative endogenous pyrogens. Fever originates by central nervous system activities, but neither exogenous nor endogenous pyrogens are able to cross the blood-brain barrier and the true signal which is transmitted to structures inside the blood-brain barrier is still unknown. To study the role of oxygen radicals in fever, we pretreated rats with methylene blue, an inhibitor of superoxide and hydroxyl radical production and investigated the febrile response to LPS in conscious rats by measuring malondialdehyde formation as an index of lipid peroxidation by oxygen radicals. Methylene blue lowered resting malondialdehyde levels to near detection level and significantly suppressed its rise which was regularly found following LPS in the untreated state. Pretreatment with methylene blue completely blocked the febrile response. Since fever is a central nervous system-mediated response these results indicate that the brain is able to sense oxidative stress and vicinal thiol groups of the redox-modulatory site of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor-channel complex could function as a possible receptive structure. To test this hypothesis we injected rabbits with the disulfide reducing agent dithiothreitol (DTT), known to penetrate the blood-brain barrier, and monitored its effect on normal and febrile body temperatures. DTT induced, independently of ambient temperature, within minutes and dose-dependently the full pattern of heat loss responses causing a fall of core temperature, indicative of a lowered thermoregulatory setpoint. Pretreatment with a bolus dose of 5 mg/kg DTT, followed by a continuous infusion of 5 mg/kg/h for 3 h completely prevented LPS-induced fever. A bolus dose of 20 mg/kg DTT, starting 30 min after LPS, immediately reversed the febrile cold defense pattern and lowered body temperature. We conclude that DTT reduces in the central nervous system oxidized vicinal thiol groups of NMDA receptors, thereby augmenting glutamate-induced nitric oxide synthase activation, and, thus, enhanced formation of NO, which, in turn, lowers the thermoregulatory setpoint. Reduction of other disulfide-containing molecules, especially oxidized glutathione and thiol-containing enzymes, by DTT by might additionally contribute to preventing fever.     

Hypothalamic neuronal histamine modulates febrile response but not anorexia induced by lipopolysaccharide

This study examined the contribution of hypothalamic neuronal histamine (HA) to the anorectic and febrile responses induced by lipopolysaccharide (LPS), an exogenous pyrogen, and the endogenous pyrogens interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Intraperitoneal (ip) injection of LPS, IL-1beta, or TNF-alpha suppressed 24-hr cumulative food intake and increased rectal temperature in rats.To analyze the histaminergic contribution, rats were pretreated with intracerebroventricular (icv) injection of 2.44 mmol/kg or ip injection of 244 mmol/kg of alpha-fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase (HDC), to deplete neural HA. The depletion of neural HA augmented the febrile response to ip injection of LPS and IL-1beta and alleviated the anorectic response to ip injection of IL-1beta. However, the depletion of neural HA did not modify the LPS-induced anorectic response or TNF-alpha-induced febrile and anorectic responses. Consistent with these results, the rate of hypothalamic HA turnover, assessed by the accumulation of tele-methylhistamine (t-MH), was elevated with ip injections of LPS and IL-1beta, but unaffected by TNF-alpha at equivalent doses. This suggests that (i) LPS and IL-1beta activate hypothalamic neural HA turnover; (ii) hypothalamic neural HA suppresses the LPS- and IL-1beta-induced febrile responses and accelerates the IL-1beta-induced anorectic response; and (iii) TNF-alpha modulates the febrile and anorectic responses via a neural HA-independent pathway. Therefore, hypothalamic neural HA is involved in the IL-1beta-dominant pathway, rather than the TNF-alpha-dominant pathway, preceding the systemic inflammatory response induced by exogenous pyrogens, such as LPS. Further research on this is needed.     

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.     

Blunted febrile response to intravenous endotoxin in starved rats

The effects of fasting on the febrile responses to intravenous injection of bacterial lipopolysaccharide (LPS; endotoxin) of Escherichia coli were investigated in rats. Ad libitum-fed rats (C) produced a biphasic fever with an increase in the temperature difference between brown adipose tissue and colon and shivering activity (SA). Measurement by a direct calorimeter showed no particular changes in heat loss. Rats starved for 4 days (F4) responded to intravenous LPS with a monophasic fever accompanied by an increase in SA only. However the maximal rise in colonic temperature (Tco) did not differ from C rats. Subsequent 2-day fasting reduced SA and the maximal fever height. Endogenous pyrogen (EP) injected intravenously produced a prompt rise in Tco followed by prolonged hyperthermia in C rats. In the F4 rats, there was no such sustained rise in Tco as a result of intravenous EP. The response in Tco to intravenous prostaglandin E2 (PGE2) was the same in fed and starved rats. The administration of LPS, EP, and PGE2 into the lateral ventricle evoked a similar extent of hyperthermia in C and F4 rats. Because the second phase of fever has been shown to occur after pyrogens are translated into a febrile stimulus within the blood-brain barrier, it is assumed that the functional changes of the blood-brain barrier such as in the permeability of pyrogens or in the sensitivity of pyrogen receptors resulted in the absence of the second phase of fever in starved rats.     

Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide

Over the last three decades, experiments in several mammalian species have shown that the febrile response to bacterial endotoxin is attenuated late in pregnancy. More recent evidence has established that the expression of nitric oxide synthase (NOS) enzymes is increased in the brain late in pregnancy. The current study investigated the possible role of brain nitric oxide in mediating the phenomenon of fever suppression. Core body temperature (Tb) of near-term pregnant rats (day 19 and 20) was measured following inhibition of brain NOS and intraperitoneal injection of LPS (50 microg/kg); they were compared with both day 15 pregnant and virgin animals. Intracerebroventricular injection with an inhibitor of NOS, NG-monomethyl-L-arginine citrate (L-NMMA; 280 microg), in near-term pregnant rats restored the febrile response to LPS. As expected, near-term dams that received intracerebroventricular vehicle + IP LPS did not increase Tb, in contrast to the 1.0 +/- 0.2 degrees C rise in Tb in dams treated with ICV L-NMMA + IP LPS (P < 0.01). In virgin females and day 15 pregnant controls receiving this treatment, the increases in Tb were 1.5 +/- 0.3 degrees C and 1.6 +/- 0.4 degrees C, respectively. Thus, blockade of brain NOS restored the febrile response to LPS in near-term dams; at 5 h postinjection, Tb was 60-70% of that observed in virgins and day 15 pregnant animals. Intracerebroventricular L-NMMA alone did not induce a significant change in Tb in any group. These results suggest that the mechanism underlying the suppression of the febrile response in near-term pregnancy is mediated by nitric oxide signaling in the brain.     

Effects of nitric oxide synthase inhibitors on the febrile response to lipopolysaccharide and muramyl dipeptide in guinea pigs

We investigated the effect of N-nitro-L-arginine methyl ester (L-NAME), an unspecific nitric oxide synthase (NOS) inhibitor, and aminoguanidine, a relatively selective inhibitor of the inducible NOS enzyme, on both gram-negative lipopolysaccharide (LPS) and gram-positive muramyl dipeptide (MDP) fever in guinea pigs. Intraperitoneal injection of either 10 mg/kg L-NAME or 25 mg/kg aminoguanidine inhibited the febrile response to an intramuscular injection of 50 microg/kg MDP. However, LPS fever (20 microg/kg) was inhibited only by L-NAME. The development of LPS fever may therefore occur independently of the synthesis of nitric oxide by the inducible NOS enzyme, while MDP fever may involve synthesis of nitric oxide by both the inducible and the constitutively expressed NOS enzymes.     

Acute starvation alters lipopolysaccharide-induced fever in leptin-dependent and -independent mechanisms in rats

A decrease in leptin levels with the onset of starvation triggers a myriad of physiological responses including immunosuppression and hypometabolism/hypothermia, both of which can counteract the fever response to pathogens. Here we examined the role of leptin in LPS-induced fever in rats that were fasted for 48 h prior to inflammation with or without leptin replacement (12 μg/day). The preinflammation fasting alone caused a progressive hypothermia that was almost completely reversed by leptin replacement. The LPS (100 μg/kg)-induced elevation in core body temperature (T(core)) was attenuated in the fasted animals at 2-6 h after the injection, an effect that was not reversed by leptin replacement. Increasing the LPS dose to 1,000 μg/kg caused a long-lasting fever that remained unabated for up to 36 h after the injection in the fed rats. This sustained response was strongly attenuated in the fasted rats whose T(core) started to decrease by 18 h after the injection. Leptin replacement almost completely restored the prolonged fever. The attenuation of the prolonged fever in the fasted animals was accompanied by the diminution of proinflammatory PGE(2) in the cerebrospinal fluid and mRNA of proopiomelanocortin (POMC) in the hypothalamus. Leptin replacement prevented the fasting-induced reduction of POMC but not PGE(2). Moreover, the leptin-dependent fever maintenance correlated closely with hypothalamic POMC levels (r = 0.77, P < 0.001). These results suggest that reduced leptin levels during starvation attenuate the sustained fever response by lowering hypothalamic POMC tone but not PGE(2) synthesis.     

Endogenous opioids: role in prostaglandin-dependent and -independent fever

This study evaluated the participation of mu-opioid-receptor activation in body temperature (T(b)) during normal and febrile conditions (including activation of heat conservation mechanisms) and in different pathways of LPS-induced fever. The intracerebroventricular treatment of male Wistar rats with the selective opioid mu-receptor-antagonist cyclic d-Phe-Cys-Try-d-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP; 0.1-1.0 microg) reduced fever induced by LPS (5.0 microg/kg) but did not change T(b) at ambient temperatures of either 20 degrees C or 28 degrees C. The subcutaneous, intracerebroventricular, and intrahypothalamic injection of morphine (1.0-10.0 mg/kg, 3.0-30.0 microg, and 1-100 ng, respectively) produced a dose-dependent increase in T(b). Intracerebroventricular morphine also produced a peripheral vasoconstriction. Both effects were abolished by CTAP. CTAP (1.0 microg icv) reduced the fever induced by intracerebroventricular administration of TNF-alpha (250 ng), IL-6 (300 ng), CRF (2.5 microg), endothelin-1 (1.0 pmol), and macrophage inflammatory protein (500 pg) and the first phase of the fever induced by PGF(2alpha) (500.0 ng) but not the fever induced by IL-1beta (3.12 ng) or PGE(2) (125.0 ng) or the second phase of the fever induced by PGF(2alpha). Morphine-induced fever was not modified by the cyclooxygenase (COX) inhibitor indomethacin (2.0 mg/kg). In addition, morphine injection did not induce the expression of COX-2 in the hypothalamus, and CTAP did not modify PGE(2) levels in cerebrospinal fluid or COX-2 expression in the hypothalamus after LPS injection. In conclusion, our results suggest that LPS and endogenous pyrogens (except IL-1beta and prostaglandins) recruit the opioid system to cause a mu-receptor-mediated fever.     

Intracerebroventricular injection of neuronal and inducible nitric oxide synthase inhibitors attenuates fever due to LPS in rats.

Nitric oxide (NO) has been shown to be an important mediator of febrile response to lipopolisaccharide (LPS). To clarify the role of different isoforms of NO synthase (NOS) in febrile response to immune challenge, effects of selective iNOS and nNOS inhibitors on fever to LPS were examined in freely moving biotelemetered rats. Vinyl-L-NIO (N(5) - (1-Imino-3-butenyl) - ornithine (vL-NIO), a neuronal nitric oxide synthase (nNOS) inhibitor, and aminoguanidine hydrochloride, an inducible nitric oxide synthase (iNOS) inhibitor, were injected intracerebroventricularly at a dose of 10 microg/rat just before intraperitoneal injection of LPS at a dose of 50 microg/kg. Both inhibitors injected at a selected doses had no effect on normal day-time body temperature (T(b)) and normal night-time T(b). vinyl-L-NIO and aminoguanidine injected intracerebroventricularly at a dose of 10 microg/animal suppressed the LPS-induced fever in rats. The fever index calculated for rats pretreated with v-LNIO or with aminoguanidine and injected with LPS was reduced by 43% and 72%, respectively, compared to that calculated for water-pretreated and LPS-injected rats. Whereas vL-NIO partly attenuated both phases of febrile rise in T(b), administration of aminoguanidine into the brain completely prevented fever induced by LPS. These data indicate that activation of iNOS inside the brain is not only responsible for triggering but also for maintaining of LPS-induced fever in rats. It is, therefore, reasonable to hypothesize that, activation of iNOS inside the brain is more important in fever development than activation of nNOS.     

High hemoglobin affinity to oxygen and its relationships with lipid peroxidation during fever

The effects of high hemoglobin-oxygen affinity (HOA) on rectal temperature and lipid free radical oxidation were investigated in red blood cells, heart, liver and kidneys of male rats during fever. Fever was induced by intraperitoneal injection of Salmonella typhi lipopolysaccharide (LPS; 5.0 mg kg(-1)). HOA was increased by addition of 0.5% sodium cyanate to drinking water for eight weeks. HOA modification (actual half-saturation oxygen pressure, P50act, decreased to 23.3+/-0.7 vs. 31.6+/-0.7 Torr in control; p < 0.001) weakened a febrile response: rise of temperature after 4 hours was 0.79+/-0.2 degrees C vs. 1.38+/-0.1 degrees C in rats with normal HOA (p < 0.05). In red cells and tissues of rats with normal HOA, concentrations of conjugated dienes and Schiff bases increased during fever, and alpha-tocopherol level and catalase activity decreased. Rats with increased HOA had an inverse pattern of such changes. Changes in rectal temperature and markers of free radical oxidation correlated with a shift of oxyhemoglobin dissociation curve leftwards. The present results indicate that the intentional increment of HOA may substantially diminish lipid peroxidation activity, increase the body antioxidant content during fever and decrease the febrile response on LPS.