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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↗

PubMed1980

Chloroquine pharmacokinetics in tissues of pyrogen treated rats and implications for chloroquine related pruritus.

The concentrations of chloroquine in the tissues and plasma of control and pyrogen treated Long Island rats were serially determined over 16 days. Significant alterations of pharmacokinetic parameters, a delayed completion of distribution with a biphasic pattern of uptake of chloroquine into peripheral organs (skin and skeletal musculature) and increased tissue uptake in visceral organs (heart, liver and kidneys) of pyrogen treated rats were found. It is suggested that the known hemodynamic changes in the febrile state produced these unusual pharmacokinetic changes in the peripheral tissues and may contribute significantly to the occurrence of pruritus and increased acute toxicity of chloroquine during a febrile illness. The uptake patterns of chloroquine into pyrogen treated rat skin and muscle strongly suggest the involvement of a blood flow-dependent process in the movement of the drug into the tissues.

Animals↗

PubMed1980

A pyrogen derived from human white cells which is active in mice.

An endogenous pyrogen smaller in molecular size than that previously obtained from human white cells has been found in supernatants of these cells after uptake of zymosan and incubation for 18 h. The new pyrogen after separation from other pyrogens which are produced at the same time has been found to produce fever in mice but not in rabbits. Because it is not formed if cycloheximide is present and is inactivated by leucine aminopeptidase, it is believed to be a peptide.

Animals↗

PubMed1977

Comparative pyrogen reactivity of rabbit and man to human albumin and immunoglobulin solutions.

According to the prescriptions of the Hungarian Pharmacopoeia regarding the pyrogenicity of human albumin and immunoglobulin solutions, the temperature increase should not exceed 0.5 degrees C in rabbits. If the average rise in temperature of rabbits is between 0.6 to 1.1 degrees C, the preparation--in other respects meeting the requirements--can be tested in man (generally 20 persons per preparation). Products causing an average rise in temperature less than 0.6 degrees C and provoking individual rises of temperature below 1 degrees C in man, can be issued. On the basis of these data going back for many years, no reliable correlation could be found between the pyrogen test in rabbits and temperature rise in man. The same preparation which failed to pass the rabbit pyrogen test proved to be apyrogenic in man.

Albumins↗

PubMed1976

Comparison of commercial pyrogen testing laboratories.

The pyrogen test results of four laboratories were compared to determine if any inconsistencies existed. Samples submitted for pyrogen testing were of two types: (1) radiopharmaceuticals which had been allowed to decay to negligible activity or mock radiopharmaceuticals prepared with saline instead of pertechnetate, and (2) positive controls of bacterial endotoxin. The drugs used in the eight-rabbit tests included 99mTc-macroaggregated albumin, 99mTc-human serum albumin, 99mTc-sulfur colloid, saline and iodinated fibrinogen. Laboratory A showed a 52% failure rate for the testing of 36 preparations. Samples identical to those not passed by laboratory A were passed by laboratories B, C and D. It is recommended that all users of pyrogen testing laboratories periodically submit samples of known apyrogenicity for testing.

Animals↗

PubMed1985

Interaction between the effects of centrally administered arecoline and leucocyte pyrogen on the activity of posterior hypothalamic neurons in the rabbit.

In experiments with urethane-anesthetized rabbits, the alteration in the activity of posterior hypothalamic neurons resulting from intracerebroventricular injection of leucocyte pyrogen was attenuated by subsequent administration of arecoline. Atropine failed to alter the neuronal response to leucocyte pyrogen but abolished the effect of arecoline. The neuronal response to arecoline was reversed in the absence of leucocyte pyrogen.

Animals↗

PubMed1995

Pyrogenic stimulation of vascular resistance in conscious sheep.

Increased arterial blood pressure following a pyrogenic reaction has been reported in previous studies, however the mechanism of this hypertension has not been examined in detail. The present study investigated the effects of both intravenous (IV) and intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) from E. coli on body temperature (Tb), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), calculated total peripheral resistance (CTPR), stroke volume (SV) and plasma levels of adrenocorticotropin (ACTH) and arginine vasopressin (AVP) in conscious, chronically instrumented sheep. IV injection of LPS (1 microgram) increased Tb in a biphasic manner from 38.7 +/- 0.1 to 39.5 +/- 0.2 degrees C after 50 min and to 39.9 +/- 0.2 degrees C after 130 min, and MAP increased biphasically from 64 +/- 1 to 70 +/- 4 mmHg after 40 min and to 78 +/- 3 mmHg after 130 min. CO initially decreased from 4.4 +/- 0.1 to 3.5 +/- 0.1 after 40 min followed by a secondary rise to 4.8 +/- 0.1 l/min after 100 min. This occurred together with a large, biphasic increase in CTPR from 14.5 +/- 1.0 to 22.0 +/- 2.0 mmHg/l/min at 40 min, and to 18.1 +/- 0.1 mmHg/l/min at 120 min. HR increased from 68 +/- 4 to 97 +/- 4 b/min and SV decreased from 65 +/- 2 to 41 +/- 4 ml/beat during the first phase of activation. Plasma ACTH increased from 22 +/- 9 to 1043 +/- 175 pg/ml after 80 min, and plasma AVP increased from 0.7 +/- 0.2 to 12 +/- 4.0 pg/ml after 60 min. ICV injection of LPS produced a long-lasting increase in Tb and MAP, but had no effect on HR or plasma AVP. Plasma ACTH increased from 30 +/- 12 to 427 +/- 110 pg/ml. These changes suggest that intravenous pyrogenic infection produces a potent vasoconstrictor action in sheep to increase blood pressure, possibly mediated by the actions of AVP within the CNS, or other pyrogenically released vasoconstrictor factors. Furthermore, the duration of activation of the cardiovascular system following peripheral and central LPS administration is different, which together with the contrasting effects on ACTH and AVP, indicate the involvement of several hypertensive mechanisms.

Adrenocorticotropic Hormone↗

PubMed1993

Inhibition of the thermogenic and pyrogenic responses to interleukin-1 beta in the rat by dietary N-3 fatty acid supplementation.

The thermogenic (increase in oxygen consumption, VO2) and pyrogenic (Tc) responses to the cytokine interleukin-1 beta (IL-1 beta) were studied in rats fed a n-3 fatty acid supplemented diet (8.75% n-3 fatty acids/kg diet). 4-6 weeks after commencing the diets, the n-3 supplemented rats exhibited reduced pyrogenic (0.5 +/- 0.1 degrees C versus 1.1 +/- 0.2 degrees C in control animals) and thermogenic (9 +/- 3% versus 22 +/- 6% in control animals) responses to intraperitoneal (i.p.) injection of IL-1 beta (1 micrograms/rat). However, responses to centrally administered IL-1 beta (5ng intracerebroventricular (i.c.v.)) were similar in both groups at this time. After 8-9 weeks of supplementation, n-3 supplemented animals exhibited attenuated responses to both ip IL-1 beta (VO2 responses reduced by 68% and Tc by 0.8 degrees C) and also i.c.v. IL-1 beta (VO2 responses reduced by 56% and Tc by 0.7 degrees C). N-3 supplementation did not, however, influence the thermogenic capacity of these animals since responses to noradrenaline were similar in control and n-3 fed animals (50% increase in VO2). These findings demonstrate that n-3 supplementation modifies the pyrogenic and thermogenic responses to IL-1 beta, probably via changes in eicosanoid metabolism. Modification of central responses to IL-1 are delayed compared to the effects of peripheral administration indicating separate mechanisms of IL-1 on fever and thermogenesis in the brain and the periphery.

Animals↗

PubMed1980

Purification and characterization of staphylococcal pyrogenic exotoxin type B.

Staphylococcal pyrogenic exotoxin (PE) type B was purified and characterized biochemically and biologically. The exotoxin was purified from cell-free culture supernatant fluids by using differential precipitation with ethanol and resolubilization in pyrogen-free distilled water followed by preparative thin-layer isoelectric focusing. A final purification of 153-fold was achieved on the basis of the capacity of the exotoxin to produce fever. The toxin migrated as a homogeneous protein with a molecular weight of approximately 18 000 when tested with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Hyperimmune antisera raised against the purified exotoxin reacted with partially purified toxin in an immuno-diffusion assay to form a single precipitin line. The isoelectric point of the PE was estimated to be 8.5. Alanine was identified as the N-terminal amino acid. The exotoxin contained significant amounts of lysine but few aromatic amino acids. The PE was pyrogenic and enhanced host susceptibility to lethal shock and myocardial damage by endotoxin. In addition, the exotoxin was a potent nonspecific lymphocyte mitogen and suppressed immunoglobulin M synthesis against sheep erythrocytes.

Animals↗

PubMed1970

A purified group A streptococcal pyrogenic exotoxin. Physiochemical and biological properties including the enhancement of susceptibility to endotoxin lethal shock.

Purified pyrogenic exotoxin from Group A streptococcal filtrates (Streptococcus pyogenes, type 10, strain NY-5) has been characterized primarily as a protein complexed with hyaluronic acid. Amino acid composition and analysis revealed a typical acidic protein with an average molecular weight of 29,000. The purified exotoxin was free of streptolysins O and S, nicotinamide adenine dinucleotidases (NADases), deoxyribonucleases (DNases), mucopeptide, and endotoxins. The biological activity was destroyed when the exotoxin was heated at 65 degrees C for 30 min or boiled for 2 min. The biological activities investigated were pyrogenicity in rabbits (minimal pyrogenic dose-3 hr, 0.07 microg/kg), lethality in rabbits (LD(50), 3500 microg/kg), skin test dose in human skin (> 10(9) skin test doses, per mg toxin), cytotoxicity of rabbit spleen macrophage (Cytotoxic Index 0.5-10 microg/ml), enhancement of susceptibility to endotoxin shock (in rabbits > 100,000-fold), and antigenic analysis (A-type toxin). The exotoxin was immunogenic and it was possible, therefore, to immunize animals against the various toxic activities. The immunity was specific for the A-type toxin. The clinical implications of the highly significant enhancement effect of these exotoxins are discussed. It is suggested that clinical or subclinical infection with Group A streptococci could prepare the host for fatal shock from Gram-negative infections or the inadvertent injection of small amounts of Gram-negative bacterial endotoxins.

Animals↗

PubMed1999

Pyrogenic toxins of Staphylococcus aureus in sudden unexpected nocturnal deaths in adults and older children: factors influencing the control of inflammatory responses to toxic shock syndrome toxins.

Sudden unexpected nocturnal deaths (SUND) occur in young immigrant workers, mainly from south-east Asia, who are employed in countries such as Singapore and Saudi Arabia. Pyrogenic toxins of Staphylococcus aureus have been identified in two cases of sudden unexpected death in adults in the UK and it has been suggested that these or other toxins with superantigen properties might induce strong inflammatory responses leading to sudden unexpected nocturnal deaths. The objectives of the present study were (1) to assess the levels of antibodies to pyrogenic staphylococcal toxins in the general population, (2) to assess the levels of IgG to the toxins needed to reduce the production of inflammatory mediators by 50% in a model system, (3) to assess in a model system the effects on inflammatory responses to toxic shock syndrome toxin-1 (TSST) of cortisol levels present at night, during the day and under conditions of physiological stress. Enzyme linked immunosorbent assays were used to assess levels of IgG to TSST, staphylococcal enterotoxin A (SEA) and staphylococcal enterotoxin C (SEC). Human buffy coats were used to examine the effect of IgG to the toxins for neutralising activity and the effect of cortisol on induction of inflammatory mediators. Tumour necrosis factor alpha (TNF-alpha) was detected by a bioassay with L929 cells, interleukin-6 (IL-6) and interleukin-10 (IL-10) were measured by an enzyme linked immunosorbent assay. IL-6 and TNF-alpha levels elicited by the toxins were not reduced by night time levels of cortisol (5-10 microg dl(-1)) levels. Day time levels of cortisol (10-20 microg dl(-1)) significantly inhibited IL-6 production but not TNF-alpha in responses. Stress levels of cortisol (40 80 microg dl(-1)) significantly reduced all three cytokines earlier than the normal day time levels. The majority of the population tested had sufficient antibodies to reduce TNF-alpha and IL-6 responses elicited by TSST and SEC in the model system. In the age range in which most sudden unexpected nocturnal death cases occur (20-39 years), males had significantly lower levels of IgG to TSST compared with females. If these toxins play a role in precipitating the series of events leading to sudden unexpected nocturnal death, the higher levels of IgG to the toxins observed in females might explain partly the much higher prevalence of these deaths among men in this age range. If inflammatory responses play a role in sudden unexpected nocturnal death, the inability of the night time levels of cortisol to control IL-6 and TNF-alpha in the model system might reflect these interactions in vivo. The methods developed for detection of the toxins in tissue samples and the quantitative IgG assays for anti-toxins can be applied to investigation of SUND victims to test the hypothesis that some of these deaths are precipitated by pyrogenic staphylococcal toxins.

Adult↗

PubMed1970

Mechanism of action of pyrogen.

1. In unanaesthetized rabbits the cerebral ventricles were perfused for 30-75 min from left lateral ventricle to cisterna magna with solutions of different composition, whilst rectal temperature was continuously recorded.2. Temperature did not rise during the perfusion when the perfusing fluid consisted of artificial c.s.f.; it did rise, however, when the perfusing fluid consisted merely of a 0.9% sodium chloride solution.3. Temperature fell, though not in all rabbits, during the perfusion when the calcium in the perfusing fluid was increased from 1.25 mM, the concentration in c.s.f. to 5 mM.4. Magnesium chloride had only a weak action, in comparison to calcium, in preventing the rise produced during perfusion with 0.9% sodium chloride solution. In a concentration of 1.25 mM it had no effect, but in a concentration of 5 mM it delayed and greatly reduced the rise.5. Temperature did not rise during perfusion with an isotonic sucrose solution.6. The rise in temperature produced by an intravenous injection of leucocyte pyrogen was not prevented when the injection was made during a perfusion with artificial c.s.f., but it was prevented when the calcium concentration in the perfusing fluid was raised to 5 mM or when the perfusing fluid consisted of isotonic sucrose solution. Again, magnesium had only a weak action in comparison to calcium.7. These results support the theory put forward recently (Feldberg, Myers & Veale, 1970) that the constancy of temperature depends upon the physiological balance of sodium and calcium ions in the anterior hypothalamus, that the calcium ions act as a kind of ;brake' preventing the sodium ions from exerting their temperature raising effect, and that pyrogen acts by removing the ;calcium brake', the pyrogen fever thus being a sodium fever.

Animals↗

PubMed1986

Adjuvant activity of 6-O-acyl-muramyldipeptides to enhance primary cellular and humoral immune responses in guinea pigs: adaptability to various vehicles and pyrogenicity.

Thirteen 6-O-acyl-N-acetylmuramyl-L-alanyl-D-isoglutamines (6-O-acyl-MDPs), including four inactive D-isoasparagine and L-isoglutamine analogs, were tested for their pyrogenicity and immunopotentiating activity to stimulate primary humoral and cellular immune responses in guinea pigs to a model protein antigen, ovalbumin, when administered in various vehicles. Among them, derivatives whose muramic acid residue was substituted by alpha-branched (and beta-hydroxylated) higher fatty acids at the carbon-6 position, especially 6-O-(2-tetradecylhexadecanoyl)-MDP (B3O-MDP) and, to a lesser extent, 6-O-(3-hydroxy-2-docosylhexacosanoyl)-MDP (BH48-MDP) and its L-serine analog [BH48-MDP(L-Ser)], were found to exert strong adjuvant activity in both the induction of delayed-type hypersensitivity and the stimulation of circulating precipitating antibody levels when combined with nonirritating vehicles (liposomes, squalene-in-water emulsion, and phosphate-buffered saline). These vehicles did not efficiently support the adjuvant activity of MDP, the parent molecule of the above lipophilic derivatives. Pyrogenicity tests showed that introduction of alpha-branched higher fatty acid groups but not of straight, long-chain fatty acids at the 6-position of the muramic acid residue resulted in marked decrease of the pyrogenicity inherent to MDP via intravenous administration.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1968

Host-parasite relationships among group A streptococci. IV. Suppression of antibody response by streptococcal pyrogenic exotoxin.

In rabbits, purified streptococcal pyrogenic exotoxin, at 0.002 of the ld(50) dose, suppressed the antibody response to injected sheep erythrocytes. The antibody suppressed was determined by density gradient ultracentrifugal analysis to be of the 19S class. Background serum antibody (50% hemolytic units), as determined photometrically, correlated well with background antibody-forming spleen cells, as determined by the hemolytic-plaque technique. The exotoxin induced neither positive nor negative changes in background antibody levels, but suppressed the early secondary response to injected antigen. A comparison and control experiment showed that purified gram-negative bacterial endotoxin at identical protocol did not induce antibody suppression, but did induce the well-known adjuvant effect. Because streptococcal pyrogenic exotoxin is known to inhibit the phagocytic function of the reticuloendothelial system (RES), these data strongly support the concept that antigen is processed by cells of the RES before it evokes a secondary immune response. The results also demonstrated that streptococcal pyrogenic exotoxin may play a unique role in lowering the acquired defense of the host against infection. If the anamnestic immune response of the host is temporarily suppressed, then the host-parasite balance would be upset in favor of the parasite.

Animals↗

PubMed1976

Changes in body temperature produced by prostaglandins and pyrogens in the chicken.

Bacterial pyrogen from S. abortus equi (SAE) was injected into the wing veins of chickens. Following injection of 0.05-0.5 mug SAE, body temperatures did not change significantly, whereas 2.0 or 10 mug of pyrogen caused falls in body temperature of 0.56 +/- 0.10degrees C and 1.1 +/- 0.21degrees C (mean +/- SE, n=5). The temperature falls were accompanied by a flushing of the comb and an increase in respiratory rate and were not antagonized by 1.0 g of acetylsalicylic acid (ASA) given orally. The injection of SAE (0.1 mug in 1 mul) into the anterior hypothalamus produced fevers averaging 1.24 +/- 0.07 degrees C (n=9) which were antagonized by oral ASA. Injections of SAE at other brainstem loci produced no temperatur changes. Seven chickens were also injected with 0.1 mug PGE in 1.0 mul into the anterior hypothalamus, and they developed fevers averaging 0.90 +/- 0.16 degrees C. The results support the concept that prostaglandins may be involved in fever in chickens but suggest that the action of pyrogen injected intravenously may be different from that following its injection directly into the hypothalamus.

Animals↗

PubMed1984

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↗

PubMed1998

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↗