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PubMed1973

Pyrogenicity and immunogenicity of lipid A complexed with bovine serum albumin or human serum albumin.

The lipid A component of bacterial lipopolysaccharides (endotoxins), when complexed to bovine serum albumin (BSA) or human serum albumin (HSA), was shown to be a potent pyrogen. Furthermore, rabbits could be protected against endotoxin fever by immunization with both lipid A.BSA and lipid A.HSA complexes. The results presented in this paper show that lipid A is responsible for the pyrogenic activity of endotoxins and their ability to induce pyrogenic immunity.

Animals↗

PubMed1987

Responses of baboons to traditionally pyrogenic agents.

It is not clear whether baboons develop fever in response to endotoxin or other pyrogens. We injected various pyrogens intravenously in 12 unrestrained baboons (Papio ursinus) and measured their body temperature using intra-abdominal radiotelemeters. Serum iron concentration was also measured. The baboons developed fever after injection of killed Staphylococcus aureus (5 X 10(7) organisms/kg). No significant fever was measured after injection of lipopolysaccharide (Salmonella typhosa) (0.1, 8, 40, and 100 micrograms/kg), bovine serum albumin (4 mg/kg), killed Salmonella minnesota (5 X 10(7) organisms/kg), and killed Salmonella typhi (5 X 10(7) organisms/kg). A significant decrease in serum iron concentration was found only after injection of S. aureus and lipopolysaccharide, 100 micrograms/kg. The phagocytic synthesis of interleukin-1 following pyrogen stimulation in baboons and some other primates appears to differ from that in man and in nonprimates.

Animals↗

PubMed1976

Propranolol and pyrogen effects of shivering and nonshivering thermogenesis in rats.

Injection of bacterial endotoxin (Piromen) into unanesthetized rats elicited increases in shivering and nonshivering thermogenesis as well as in colonic temperature. In animals exposed to 24-25 degrees C, treatment with propranolol (a beta-adrenergic antagonist) markedly diminished the pyrogen-induced increases in oxygen consumption (heat production) and colonic temperature with little change occurring in shivering activity. In contrast, in rats exposed to mild cold (17-18 degrees C), propranolol did not significantly alter the magnitude of the pyrogen-evoked thermogenesis. Rather in these animals, shivering tended to increase when nonshivering thermogenesis was blocked. These data are interpreted as reflecting differential effects of pyrogen on the pathways controlling the two modes of heat production in the rat.

Animals↗

PubMed1981

Behavioral responses to pyrogen in cold-stressed and starved newborn rabbits.

Starvation for 2 days and a chronic mild cold stress prevented the rises in body temperature that normally occur in newborn rabbits that have been injected with pyrogen (Piromen, 5 mg/kg). Nevertheless, the stressed pups selected significantly warmer positions in a thermal gradient than did saline-injected littermates and thereby raised their body temperatures. Enhanced heat seeking and subsequent fever were also observed in normally fed pups that were incubated at 24 degrees C and had become hypothermic after pyrogen injection. The responses of the pups before they were allowed to thermoregulate behaviorally resemble the types of thermal responses to infection seen in human newborns. The temperature selection of these pups, and others, indicates that pyrogen elevates the set points of newborn rabbits when endothermic fever is attenuated or even absent.

Animals↗

PubMed1988

Further evidence implicating prostaglandin E2 in the genesis of pyrogen fever.

Conscious cats were used to study the effects of endotoxin and interleukin 1 (IL 1) on levels of prostaglandin (PG) E2 and thromboxane (TX) B2 (the stable TXA2 byproduct) in cerebrospinal fluid (CSF) from the third ventricle. Pyrogens were given intravenously or intraventricularly and prostanoids were measured by radioimmunoassay. PGE2 was normally less abundant than TXB2 (mean, 37 vs. 528 pg/ml), and its level increased severalfold during the sustained fever following intravenous endotoxin (bolus) or IL 1 (bolus plus infusion). PGE2 elevation preceded the fever and was maintained thereafter. Likewise, intraventricular pyrogens promoted PGE2 formation, and their effect was also manifest during the latent period of the fever. The PGE2 metabolite, 13,14-dihydro-15-keto-PGE2, was not measurable in CSF from either afebrile or febrile animals. Basal content of PGE2, on the other hand, was higher in animals pretreated with probenecid (30 mg/kg ip or iv; 50 or 100 micrograms ivt), confirming the importance of transport processes in removing prostanoids from brain. Unlike PGE2, TXB2 levels did not change during the fever to intravenous endotoxin. TXB2 rose instead in response to intraventricular endotoxin, although the elevation did not extend beyond fever uprise. Furthermore, a TXA2 analog (ONO-11113;2 or 4 micrograms ivt) had inconsistent effects on body temperature, while a TXA2 antagonist (ONO-11120;2 micrograms ivt) did not interfere with endotoxin fever. These findings strongly support a causative role for PGE2 in the onset and progression of pyrogen fever. No evidence of a similar role was obtained for TXA2.

Animals↗

PubMed1989

Age- and sex-related differences in febrile response to peripheral pyrogens in the rabbit.

A reduced febrile response with aging has been reported in mice, rats, rabbits, squirrel monkeys and man. Young adult male and female rats and rabbits respond differently to pyrogens, but little is known about relative febrile responses in old male and female animals. To further describe the effects of age and sex on fever, we gave intravenous injections of Salmonella typhosa endotoxin (0.05 micrograms/kg) and of endogenous pyrogen (EP) (40 microliters/kg) to old and young, male and female rabbits. Old females did not exhibit smaller fevers in response to endotoxin compared to young females, but both young and old females had smaller fevers than aged and young males. Old male rabbits did not have a decreased febrile response to endotoxin. Old females, but not old males, showed a reduced febrile response to EP, the presumed endogenous mediator of endotoxin fever, when compared to young rabbits. To determine if the reduced febrile responses were due to reduced capacity to generate heat, D-amphetamine sulfate (2 or 5 mg/kg i.v.) was administered, and the resulting hyperthermias indicated that all groups of rabbits, including the aged and young females, were capable of raising body temperature to high levels. Body weight and reduced capacity to produce and retain heat do not contribute to these differences in fever. We conclude that the febrile response is not uniform over age, and that it is also strongly influenced by sex and type of pyrogen.

Age Factors↗

PubMed1972

The influence of pyrogen-induced fever on salicylamide metabolism in man.

Salicylamide is metabolized in man by biotransformation to salicylamide glucuronide, salicylamide sulfate, and gentisamide glucuronide. The metabolites are quantitatively and rapidly excreted in urine. Study of the metabolism of this drug in volunteers during episodes of pyrogen-induced fever shows a significant reduction in the half-life (t(1/2)) of the excretion of the drug metabolites. The proportion of the drug transformed to its major metabolite, salicylamide glucuronide, is significantly reduced by fever, with concomitant increase in the proportion of one or both of the other metabolites. Thus, the pattern of urinary metabolites of salicylamide is altered. The shortened t(1/2) of the metabolite excretion is probably due to increased hepatic and renal blood flow known to accompany pyrogen-induced fever. This concept was supported by the observation that when two subjects were placed in a high-temperature environmental chamber, a condition in which hepatic and renal blood flows are known to diminish, the t(1/2) of salicylamide metabolite excretion actually increased. No simple explanation exists to explain the changed metabolite pattern noted during febrile periods. It is most likely to be due to complex interactions between the direct or indirect effects of the pyrogens and the factors affecting the hepatic biotransformation of drugs.

Adult↗

PubMed1979

Stimulation of neutrophil oxygen-dependent metabolism by human leukocytic pyrogen.

The ability of highly purified human leukocytic pyrogen (LP) to stimulate neutrophil oxygen-dependent metabolism was studied. Human peripheral blood neutrophils exposed to leukocytic pyrogen in vitro demonstrated an increase in the percentage of neutrophils reducing nitroblue tetrazolium (NBT) dye and a marked stimulation of superoxide dismutase inhibitable reduction of ferricytochrome c. LP stimulation of neutrophil oxygen-dependent metabolism was dose and time dependent. Procedures that destroyed the pyrogenicity of LP also abolished the effects on neutrophil metabolism. Neutrophil hexose monophosphate shunt activity was also stimulated by LP. In a rabbit model, the effect of in vivo LP on neutrophil superoxide generation was also studied. There was a consistent increase in the percent and absolute number of NBT positive neutrophils. Peak stimulation of neutrophil metabolism occurred after defervescence suggesting several possible mechanisms. The observations reported here may, in part, explain the nonspecificity of the NBT test in febrile, noninfected patients and provide further understanding of neutrophil physiology during acute inflammation.

Adult↗

PubMed1998

Elevation of metabolic rate by pyrogen administration does not affect the gain of respiratory peripheral chemoreflexes in unanesthetized kittens.

We previously reported that reducing environmental temperature from 30 to 25 degrees C increases the gain of respiratory chemoreflexes. To investigate the role of increased metabolism in mediating the effect on the gain of the respiratory chemoreflex, we compared the respiratory responses, at ca. 26 degrees C to breath-by-breath alternations of inspired gas between air and 14% oxygen (hypoxia run) or air and 5% CO2 (CO2 run) with that to alteration of air between two inspired lines (control run) before and after the injection of a pyrogen (IL-1beta 400 ng/kg i.p.) in eight kittens at 27-35 d of postnatal age. The respiratory chemoreflex was quantified from the alternations in inspiratory and expiratory variables produced during test runs in terms of the direction and the amplitude of the alternation for each variable and compared with the results of control runs at the same temperature. Pyrogen administration produced a rise in rectal temperature and in oxygen consumption. However, there was no difference in the chemoreflex response to hypoxia or CO2 runs, in terms of either the pattern or of the amplitude of alternation, before and after the injection of the pyrogen. We conclude that the increase in the gain of chemoreflex observed during cooling in a previous study is not due to an increase in metabolism. Some change in input from thermoreceptors may bias the gain of chemoreflexes.

Animals↗

PubMed1981

Interactions between bacterial pyrogen and proteolipid extracted from the cerebrum (I).

As proteolipid of the myelin sheath and its parent glial membrane may possible interact with bacterial pyrogen (lipopolysaccharide, LPS) during penetration into the brain, we investigated the interaction of LPS with proteolipid derived from the cerebrum of rabbits, rats and chickens. Intravenous administration of LPS (1 microgram/kg) produced a febrile response in rabbits, but not in rats and chickens. Marked hyperthermia was observed in these three species after intracisternal administration of LPS (0.01-0.1 microgram/kg). Dinitrophenol (30 mg/kg s.c.) induced a high fever in these three species tested, particularly in the chickens. The pyrogenicity of LPS given intravenously to rabbits was inactivated by incubation of LPS with proteolipid in vitro. Inactivation effects of proteolipid extracted from the three species was in the order of: chickens, rats and rabbits. In rats, the inactivation effects of proteolipid from the adult animal were more potent than in the case of newborn animals. The febrile response induced by dinitrophenol and leucocytic pyrogen in rabbits, however, was not suppressed by incubation with proteolipid extracted from the rabbit brain. These results suggest that proteolipids do play an important role in the mechanism of penetration of LPS into the brain.

Animals↗

PubMed1983

[Studies on the Dutch rabbit for pyrogen test].

A study was conducted on Dutch rabbits to examine their applicability for the pyrogen test in comparison with the Japanese white rabbit which, conventionally, has been mainly used for the test in Japan. The following results were obtained. Adult Dutch rabbits, so small as to weight only about 60% of average adult weight of the Japanese white, showed a food consumption as low as 40% of that in the latter. None in the Dutch rabbit group suffered dislocation of the hip-joint during restraint on a neck stock while it was frequently encountered among Japanese white rabbits. The body temperature during restraint was unstable in infantile Dutch rabbits (7-8 weeks old)(, but stable in the young (14 weeks old) and in the adult (20-47 weeks old). Adult Dutch rabbits exhibited greater febrile responses to intravenously injected bacterial pyrogen (LPS) than infantile and young Dutch rabbits and adult Japanese white rabbits. A good linear regression was observed between the dose of LPS (0.01-0.1 microgram/kg, iv) and the febrile response in adult Dutch rabbits as well as in adult Japanese white rabbits. From these data, it is concluded that the Dutch rabbit has an advantage over the Japanese white for the pyrogen test in respect of febrile responsiveness and cost of rearing.

Age Factors↗

PubMed1979

Thirst and renal excretion of water and electrolytes during pyrogen fever in dogs.

Body temperature, water intake, urine output, sodium and potassium excretion, osmolal and free water clearance, plasma osmolality, sodium and potassium concentrations and osmotic thirst were examined in conscious dogs during pyrogen fever and compared to those found under control conditions. Arterial blood pressure and central venous pressure were also measured in some experiments. Administration of pyrogen produced transient but significant decreases in urine output and striking increases in the spontaneous water intake in some of the experiments in the phase of increasing fever. Arterial blood pressure decreased, whetreas central venous pressure increased at this stage of fever. No significant changes in renal excretion of solutes and free water as well as sodium and potassium were found. Plasma osmolality and sodium concentration increased and potassium concentration decreased unsignificantly both in control and pyrogen experiments. The main finding was that the thirst threshold to osmotic stimuli increased markedly during the phase of stabilized fever may be caused by significant increase in internal body temperature.

Animals↗

PubMed1975

Effect of metabolic inhibitors on pyrogen production by rabbit leukocytes.

The metabolic inhibitors, actinomycin D, cycloheximide, puromycin dihydrochloride, puromycin aminonucleoside, and p-fluorophenylalanine did not inhibit the release of leukocytic pyrogen whether endotoxin was preincubated with cells for 20 min at 37 degrees C before addition of inhibitor or inhibitor was preincubated with cells for 1 hr before addition of endotoxin. On the other hand, cortison inhibited release of pyrogen under both experimental conditions. Poly(I): poly(C) was not effective in inducing rabbit leukocytes to produce an endogenous pyrogen.

Animals↗

PubMed1983

Circadian variation in circulating pyrogen: possible role in resistance to infection.

In the rat, body temperature (bt) is highest, and plasma iron (Fe) and zinc (Zn) concentrations are lowest at night while the rat is most active; the inverse is true during the day. Based on data implicating endogenous pyrogen (EP) as a mediator of the rise in body temperature and fall in plasma trace metal levels during infection we hypothesized that the circadian rise in body temperature and fall in plasma Fe and Zn levels may be attributed to a cyclic release of EP. To test this hypothesis: (1) Rats were injected ip with an antipyretic dose of sodium salicylate (300 mg/kg). The result was a reduction (P less than 0.05) in bt at night. (2) Rats were injected during the day with 1 ml each of plasma collected from rats during the night. As a control, rat plasma collected during the day was injected at this same time point. A rise (P less than 0.05) in bt was observed only in animals who had received plasma collected at night. These results support the hypothesis that a pyrogen, perhaps EP, is present in the plasma of rats at night. The release of EP during periods of greatest activity may have an adaptive role since rats are more likely to come into contact with pathogens during these times. If EP were released during periods of activity, the likelihood of severe infection occurring would be diminished. To test this hypothesis, two groups of rats were injected with Salmonella typhimurium, one group at midnight (A) and one group at noon (B). The mortality rate was 25% in group A and 60% in group B (P less than 0.025). These data support the hypothesis that the immune/host defense of rats to S. typhimurium is more effective at night, possibly due to an increased level of circulating pyrogen.

Animals↗

PubMedDate not supplied

The effect of low ambient temperature on the febrile responses of rats to semi-purified human endogenous pyrogen.

The febrile responses of Sprague-Dawley rats to semi-purified human endogenous pyrogen were studied at a thermoneutral ambient temperature (26 degrees C) and in the cold (3 degrees C). It was found that while rats developed typical monophasic febrile responses at thermoneutrality, febrile responses were absent in the cold-exposed rats. Experiments were conducted to determine whether this lack of febrile responses in cold-exposed rats was due to an inability of these animals to generate or retain heat in the cold. Thermogenesis and vasoconstriction were stimulated in cold-exposed rats by selectively cooling the hypothalamus, using chronically implanted thermodes. It was shown that, using this stimulus, metabolic rate could be increased by more than 50 percent and body temperature could be driven up at a rate of 5 degrees C/hour in rats exposed to the cold. Therefore, it was concluded that the lack of febrile responses of cold-exposed rats to pyrogen is in no way due to a physical or physiological inability to retain heat. Instead, it appears that in some manner cold exposure suppresses the sensitivity or responsiveness of the rat to pyrogenic stimuli.

Animals↗

PubMed1978

[Endogenous pyrogen formation by bone marrow cells].

The cells of the rabbit bone marrow produced endogenous pyrogen in response to stimulation with bacterial lipopolysaccharide. Incubation of the cells in medium No 199 containing a 15% homologous serum is optimal for the release of pyrogen. It is supposed that the cells of the bone marrow take part in the formation of endgenous pyrogen and in the mechanism of pyrexia in the organism.

Animals↗

PubMed1978

[Mechanisms of leukocyte activation during formation of leukocyte pyrogen].

The inhibotors of protein synthesis--actinomycin D and cycloheximide--inhibit endogenous pyrogen production by blood granulocytes in response to stimulation by the bacterial lipopolysaccharide and specific antigranulocytic serum and have no effect on the pyrogen release by exudate leukocytes. These results indicate that the mentioned inhibitors suppress the activation phase, but not the pyrogen labilization process.

Animals↗

PubMed1980

Endogenous pyrogens made by rabbit peritoneal exudate cells are identical with lymphocyte-activating factors made by rabbit alveolar macrophages.

Purified endogenous pyrogen (EP), isolated in one laboratory from stimulated rabbit peritoneal exudate cells (PEC), was compared with purified lymphocyte activating factor (LAF), isolated in another laboratory from stimulated rabbit alveolar macrophages (AM). Both EP and LAF occurred in two forms, one with an isoelectric point (pI) of 7.3 to 7.4, the other with a pI of 4.6 to 4.7. Both forms of EP and LAF had m.w. of 13,000 to 16,000 daltons as judged by gel filtration. Both forms of EP had LAF activity, and both forms of LAF were pyrogenic. The pI 7.3 EP, which is known to have an -SH group essential for its biologic activity, bound to Thiol Sepharose columns and could be eluted with mercaptoethanol. The pI 7.3 LAF behaved in exactly the same way. Furthermore, antisera from three different goats were available that completely blocked the pyrogenicity of pI 7.3 EP in vivo; these sera also blocked the pI 7.3 LAF activity in vitro. The pI 4.6 EP and LAF did not bind to Thiol Sepharose columns, nor were they inhibited by any of the antisera that blocked the pI 7.3 EP and LAF. Moreover, isoelectric focusing of pI 4.6 EP in very shallow gradients revealed microheterogeneity with sharp peaks of EP activity observed at pH 4.6 and 4.7. Analysis for LAF activity showed an identical microheterogeneity. These results are consistent with the idea that EP and LAF are identical.

Animals↗