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Sleep-promoting effects of endogenous pyrogen (interleukin-1).

When infused into the lateral cerebral ventricles of rabbits, human endogenous pyrogen (EP) preparations induced dose-dependent increases in slow-wave sleep concomitant with increasing body temperature. Heating EP to 70 degrees C destroyed its sleep-promoting and pyrogenic activity. Anisomycin (an antipyretic) prevented EP from increasing body temperature without affecting its sleep-promoting activity. Intravenous injection of EP induced fever and transient increases in slow-wave sleep but failed to induce prolonged increases in slow-wave sleep. We conclude that the somnogenic activity of EP is not secondary to its pyrogenic activity.

Animals↗

A cluster of bloodstream infections and pyrogenic reactions among hemodialysis patients traced to dialysis machine waste-handling option units.

From June 17 through November 15, 1995, ten episodes of Enterobacter cloacae bloodstream infection and three pyrogenic reactions occurred in patients at a hospital-based hemodialysis center. In a case-control study limited to events occurring during October 1-31, 1995, seven dialysis sessions resulting in E. cloacae bacteremia or pyrogenic reaction without bacteremia were compared with 241 randomly selected control sessions. Dialysis machines were examined, dialysis fluid and equipment were cultured, and E. cloacae isolates were genotyped by pulsed-field gel electrophoresis. Each dialysis machine had a waste-handling option (WHO) through which dialyzer-priming fluid was discarded before each dialysis session; in 7 of 11 machines, one-way check valves designed to prevent backflow from the WHO into patient bloodlines were dysfunctional. In the case-control study, case sessions were more frequent when machines with >/=1 dysfunctional check valves were used. E. cloacae with identical pulsed-field gel electrophoresis patterns were isolated from case patients, dialysis fluid, station drains, and WHO units. Our investigation shows that bloodstream infections and pyrogenic reactions were caused by backflow from contaminated dialysis machine WHO units into patient bloodlines. The outbreak was terminated when WHO use was discontinued, check valves were replaced, and dialysis machine disinfection was enhanced.

Adult↗

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.

Animals↗

Fever in young lambs: hypoxemia alters the febrile response to a small dose of bacterial pyrogen.

Experiments were done on eight young lambs to investigate the effects of hypoxemia on the body temperature, metabolic and cardiovascular responses to intravenous administration of a small dose of bacterial pyrogen (0.3 micrograms lipopolysaccharide extracted from Salmonella Abortus Equi; SAE). Each lamb was anaesthetized with halothane and prepared for sleep staging and measurements of cardiac output, arterial and mixed-venous haemoglobin oxygen saturations, body-core and ear-skin temperatures. Three experiments were done on each lamb, the first being done no sooner than three days after surgery. The first experiment consisted of establishing the thermal neutral environment during normoxemia (ie, environmental temperature at which total body oxygen consumption was minimal while body temperature was maintained) for each lamb. The second and third experiments were done at the lamb's thermoneutral environment as determined on day 1. One experiment was done during normoxemia (ie, control condition, SaO2 approximately 90%) and one experiment was done during hypoxemia (ie, experimental condition, SaO2 approximately 50%). Measurements were made during a control period and during one-minute experimental periods at 10 minute intervals for 120 minutes following administration of 0.3 micrograms of bacterial pyrogen in sterile saline. Administration of SAE produced a short-lived fever of about 0.8 degrees C in the normoxemic lambs, whereas no change in body-core temperature was observed in the hypoxemic lambs. During normoxemia, the increase in body-core temperature was preceded by peripheral vasoconstriction, the onset of shivering, and a surge in total body oxygen consumption. The increase in total body oxygen consumption was met primarily by an increase in total body oxygen extraction during the development of fever. Cardiac index, heart rate, and systemic oxygen transport increased during the peak body-core temperature response. Systemic arterial blood pressure did not change significantly during the febrile response; however, pulmonic arterial blood pressure increased. During hypoxemia, peripheral vasoconstriction and shivering occurred following administration of SAE, but there was no change in total body oxygen consumption or body-core temperature. Thus, our data provide evidence that hypoxemia alters the febrile response of young lambs to bacterial pyrogen. The precise mechanism remains to be determined.

Animals↗

Pyrogenic fever and blood plasma glucocorticoids after nonsteroid anti-inflammatory drugs.

Rabbits were injected with the lipopolysaccharide from E. coli (LPS) and received orally nonsteroid anti-inflammatory drugs (NSAIDs): acetylsalicylic acid, indomethacin, mefenamic acid, ibuprofen, aminophenazone, metamizole sodium, and phenylbutazone. These NSAIDs exerted antipyretic action without inhibiting the increase in the level of plasma glucocorticoids induced by LPS. This finding indicates the lack of correlation between the pyrogenic action of bacterial pyrogen and pyrogenic increase in the plasma glucocorticoid level. The investigated NSAIDs when given alone to normothermic rabbits differently affected the plasma glucocorticoid level: acetylsalicylic acid, indomethacin and ibuprofen depressed the plasma level of these hormones, mefenamic acid and phenylbutazone elevated it, and aminophenazone and metamizole sodium did not alter it significantly.

Animals↗

[Effect of drugs on the pyrogenic reactivity of sheep].

Investigated was the effect of coffeine, bromine, atropine, and pilocarpine on the course of experimentally induced (by means of an Alcaligenes falcalis lipopolysaccharide) pyrogenic response in sheep. It was noted that coffeine aggravated, and bromine and partly atropine made more feasible the manifestation of the pyrogenic response in these animals. Pilocarpine enhanced some of the functions of the body while this reaction tookplace. Some arguments are given to elucidate the mechanism of the pyrogenic response.

Alcaligenes↗

Differences of adrenal stress control mechanisms in subjects with glaucoma and normal subjects. Effect of vasopressin and pyrogen.

Various types of glaucomatous and normal subjects were tested for the adequacy of the stress response of their hypothalamic-pituitary-adrenal axis to pyrogen and vasopressin. With pyrogen, a significant response of elevation of plasma cortisol levels was positively correlated with ocular pressure and changes of the optic disc. Those subjects with increased ocular pressure and optic disc cupping and pallor had greater rises of plasma cortisol levels. With vasopressin, a decreased response of plasma cortisol levels was negatively correlated with the degree of elevated ocular pressure. Those subjects with increased ocular pressure and lower tonographic outflow facilities had smaller rises of plasma cortisol levels. Both tests indicated a disturbance of the hypothalamic-pituitary-adrenal axis in subjects with glaucoma.

Female↗

Detection of streptococcal pyrogenic exotoxin genes by a nested polymerase chain reaction.

Severe invasive disease associated with group A Streptococcus (GAS) has recently increased in frequency. Isolates of GAS from normally sterile sites were examined for the streptococcal pyrogenic exotoxin genes spe A, spe B and spe C to determine if they play a role in this disease. Four primers for each gene were used in a nested polymerase chain reaction (PCR) configuration. The first PCR generated fragments of 818, 1106, and 801 bp, respectively, for the extotoxin genes. The second PCR generated fragments of 500, 912 and 654 bp for the spe A, spe B and spe C genes using the fragments from the first PCR as template. Of 62 strains tested, 35 (56%) contained the spe A gene, and 17 (27%) contained the spe C gene. All GAS strains studied, regardless of disease association, contained the spe B gene. These data corroborate accumulating evidence that the genes encoding pyrogenic exotoxin types B and C are not associated with severe invasive streptococcal illness including streptococcal toxic shock-like syndrome. This PCR-based gene detection system has clinical and epidemiologic applications because of its ease of performance, non-isotope labelling, high specificity and sensitivity, and lack of requirement for purified DNA.

Bacterial Proteins↗

Pyrogenicity of polyadenylic.polyuridylic acid in rabbits.

Polyadenylic.polyuridylic acid injected intravenously into rabbits produced a rapid-onset, monophasic fever. Pyrogenic tolerance occurred in rabbits following daily injections of polyadenylic.polyuridylic acid. However, direct injection of the agent into the preoptic anterior hypothalamic region of rabbit's brain produced a markedly different fever. After an intrahypothalamic injection of polyadenylic.polyuridylic acid, fever was delayed in onset and persisted for a longer period. At room temperature, the fever was due to both increased metabolism and cutaneous vasoconstriction. In a colder atmosphere the fever was due solely to increased metabolism, whereas in the heat the fever was due to reduction in cutaneous blood flow and respiratory evaporative heat loss. In addition, the fever induced by intravenous polyadenylic.polyuridylic acid injection was reversed by a cyclooxygenase inhibitor, but not by a protein synthesis inhibitor. Polyadenylic.polyuridylic acid was shown to stimulate PGE2 production from rabbit's hypothalamus in vitro. The results reveal that this agent is a prostaglandin-dependent pyrogen.

Animals↗

The effects of the protein synthesis inhibitor anisomycin on the febrile responses to intracerebroventricular injections of bacterial pyrogen, arachidonic acid and prostaglandin E2.

1. Anisomycin (15 mg/kg) was administered s.c. to cats at ambient temperatures of 5 degrees C, 20 degrees C and 38 degrees C. It produced biphasic effects on body temperature at 5 degrees C and 20 degrees C, an initial fall in temperature followed by a rise in body temperature, and a rise in body temperature of long latency at 38 degrees C. 2. Anisomycin (15 mg/kg) attenuated the hyperthermic responses to centrally injected PGE2 (1 microgram) at all ambient temperatures studied and also completely abolished the hyperthermic response to arachidonic acid (100 ng i.c.v.) at 20 degrees C. 3. Shigella dysenteriae (100 ng i.c.v.) raised the body temperature of cats by increasing heat production and reducing heat loss at 5 degrees C and 20 degrees C, and by increasing heat conservation at 38 degrees C. Anisomycin (15 mg/kg s.c.) pretreatment did not affect the temperature responses to the pyrogen at 20 degrees C and 38 degrees C, but did reduce the responses to Shigella dysenteriae (100 ng and 1 microgram i.c.v.) at 5 degrees C. 4. Anisomycin (15 mg/kg s.c.) was administered to cats, 90 min after the injection of Shigella dysenteriae (100 ng i.c.v.), at 20 degrees C at the onset of hyperthermia in control experiments. Under these conditions, no hyperthermia was observed over a 2 h period following anisomycin injection. 5. It is concluded that anisomycin interferes with pyrogen induced fever by acting at a site after PGE2 in the pathway to fever.

Animals↗

Response of body temperature and serum iron concentration to repeated pyrogen injection in rabbits.

We measured body temperature and serum iron concentration after five daily consecutive injections of febrile doses of Salmonella typhosa lipopolysaccharide (0.1 micrograms/kg) and two doses of Staphylococcus aureus cell walls (1 x 10(7) and 5 x 10(7) cells) in rabbits. Tolerance to endotoxin injection, as manifest by a significant attenuation in the body temperature elevation, developed after the first injection of endotoxin. The endotoxin-induced fall in serum iron concentration was attenuated significantly by the 5th day of endotoxin injection. In contrast, no tolerance developed in either the body temperature or serum iron response following repeated daily injections of S. aureus. Rabbits rendered tolerant to endotoxin showed normal febrile and serum iron responses to subsequent S. aureus injection. Rabbits given serial injections of S. aureus, although not tolerant to S. aureus itself, exhibited attenuated body temperature responses but not serum iron responses to endotoxin injection. We suggest that repeated injection of endotoxin diminishes the ability of endotoxin to stimulate endogenous pyrogen (EP) synthesis and/or release, a property not shared by the gram-positive pyrogen S. aureus. However, repeated injection of S. aureus weakens the central endotoxin-EP pathway.

Animals↗

The effect of an inhibitor of adenylate cyclase on the development of pyrogen, prostaglandin and cyclic AMP fevers in the rabbit.

An exotoxin of Bacillus thuringiensis known to inhibit adenylate cyclase in vitro has been used to investigate the role of cyclic AMP in the pathogenesis of fever in the rabbit. Intra-hypothalamic microinjections of the exotoxin are non-pyrogenic and significantly attenuate the hyperthermia caused by intrahypothalamic microinjections of both bacterial pyrogen (endotoxin) and prostaglandin E1. The hyperthermia produced by dibutyrl cyclic AMP is not affected by the exotoxin. These results support the idea that adenylate cyclase is activated during the development of fever in the rabbit.

Adenine Nucleotides↗

Influence of endogenous pyrogen on the cerebral prostaglandin-synthetase system.

The biotransformation of arachidonic acid to prostaglandins in vitro is specifically augmented by endogenous pyrogen to a degree depending on the concentration applied, providing that the microsomal fraction of the cerebral cortex is used as prostaglandin-synthetase system. This effect is inhibited by non-steroidal anti-inflammatory agents. These findings are compatible with the hypothesis that prostaglandins might act as mediators of the febrile reaction induced by endogenous pyrogen.

Animals↗

Interleukin-1 beta analogues with markedly reduced pyrogenic activity can stimulate secretion of adrenocorticotropic hormone in rats.

We examined the adrenocorticotropic hormone-releasing activities of several human interleukin-1 beta analogues that have markedly reduced pyrogenic activities in rats. Among the analogues tested, [Gly4]-, [Leu93]- and [1-148]-interleukin-1 beta increased the plasma adrenocorticotropic hormone level to almost that induced by authentic human interleukin-1 beta. Modifications of the N-terminus of the authentic molecule, i.e., [7-153]- and [Des-Ala1, Asp4]-interleukin-1 beta, significantly reduced the hormone-releasing activity. These data suggest that the adrenocorticotropic hormone-releasing activity of human interleukin-1 beta resides in the N-terminal structure of the authentic peptide and can be separated from its pyrogenic activity.

Adrenocorticotropic Hormone↗

Effects of methylxanthine drugs on pyrogen-induced hyperthermia.

The hyperthermic response to pyrogen was not potentiated by caffeine or theophylline administered i.p. into cats or rabbit. Injection of these drugs into the anterior hypothalamus or into the third cerebral ventricle in cats was also without effect on pyrexia. These results support the hypothesis that cyclic AMP in the anterior hypothalamus does not mediate pyrogen-induced hyperthermia in cats.

Animals↗

Dexamethasone inhibits the pyrogenic activity of prostaglandin F2 alpha, but not prostaglandin E2.

The effect of dexamethasone on prostaglandin (PG) E2- and PGF2 alpha-induced fever was studied in rats. Intracerebroventricular injection of PGE2 and PGF2 alpha (500 ng) induced increases in body temperature (maximal temperature rises of 0.97 +/- 0.13 degrees C and 0.78 +/- 0.18 degrees C, respectively, vs. vehicle 0.12 +/- 0.09 degrees C) of unrestrained rats maintained within the thermoneutral zone. PGE2-induced fever peaked earlier and the defervescence was faster when compared to the response induced by PGF2 alpha. Subcutaneous pre-administration of dexamethasone (0.5 mg/kg) did not affect PGE2-induced fever (maximal temperature rise of 1.00 +/- 0.08 degrees C), but completely prevented the pyrogenic activity of PGF2 alpha (maximal temperature rise of 0.16 +/- 0.16 degrees C). Neither PGE2- nor PGF2 alpha-induced fever was significantly altered (maximal temperature rises of 0.90 +/- 0.11 degrees C and 0.64 +/- 0.14 degrees C, respectively) by intraperitoneal administration of indomethacin (2 mg/kg). These results demonstrate for the first time that glucocorticoids, in addition to inhibiting endotoxin- and cytokine-induced fever, can also modulate the pyrogenic activity of some prostaglandins, possibly via suppression of the synthesis of corticotropin-releasing factor, indicating that multiple mechanisms may be involved in the antipyretic activity of these steroids.

Animals↗

Fever and changes in plasma zinc and iron concentrations in the goat: the role of leukocytic pyrogen.

In goats with trypanosomiasis (T. vivax or T. congolense) no marked fall in plasma zinc concentration was seen despite high temperature peaks, whereas plasma concentrations of iron tended to undergo some decline. In goats infected with Ehrlichia phagocytophila, there was a marked decline in plasma zinc and iron to low values on the 3rd and 4th day, respectively. Circulating endogenous pyrogen (EP) or leukocytic endogenous mediator (LEM) could not be detected in plasma from febrile goats with tick-borne fever. The intravenous injection of leukocytic pyrogen (LP) in kids caused characteristic monophasic febrile reactions, whereas no significant changes in plasma trace metals were found. So, previous evidence purporting to show that LP is similar to or may be identical with LEM is demonstrably inconclusive. Intravenous injection of E. coli lipopolysaccharide (LPS) or staphylococcal enterotoxin B (SEB) induced fever and lowering of plasma zinc and iron concentrations. The decrease in those trace metal values was more persistent in goats given SEB than in those given E. coli LPS. After intramammary infusion of SEB or E. coli LPS, fever and significant decreases in plasma zinc and iron concentrations were observed but no clear relationship was found between the temperature responses and the alterations in plasma trace metal concentrations. Furthermore, the decrease in plasma iron concentration developed more rapidly in goats given SEB than in those given E. coli LPS, whereas the decrease in plasma zinc concentrations in the former was more delayed. These data support the theory that the concentrations of zinc and iron in plasma are regulated by different mechanisms, whereas febrile reactions are mediated by another type of endogenous protein.

Animals↗