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PubMed1976

Intraventricular antipyretics and bacterial pyrogen fever.

In adult fowls with cannulae chronically implanted into the IIIrd cerebral ventricle or into the hypothalamus, the effects of various hydrosoluble antipyretics, given intraventricularly, on bacterial pyrogen fever were studied. It has been shown that fever evoked by intrahypothalamic or intraventricular infusion of O somatic antigen of Shigella Dysenteriae was reduced by intraventricular administration of acetylsalicylate-lysine, indomethacin-methylglucamine or ibuprofen-lysine given during the febrile plateau. However, a 3-day intraventricular pretreatment with acetylsalicylate or indomethacin, or a single administration 30 min before, did not prevent fever by subsequent intraventricular or intrahypothalamic injection of pyrogen. On the contrary, intraventricular infusion of indomethacin or acetylsalicylate substantially reduced pyrogen fever when given after pyrogen latency period, e.g. just at the beginning of the febrile response. A possible involvement of E prostaglandins as mediator to pyrogen fever is discussed.

Analgesics↗

PubMed1976

Comparison of the pyrogenicity, Limulus activity mitogenicity and complement reactivity of several bacterial endotoxins and related compounds.

The correlation of mitogenicity, complement activation, pyrogenicity and Limulus amebocyte lysate (LAL) gelation induced by 17 bacterial endotoxins (LPS), modified endotoxins, related compounds, and other B cell mitogens was examined. With the use of these compounds, a significant correlation was found between pyrogenicity and mitogenicity (r = 0.85, p is less than 0.0005), pyrogenicity and LAL reactivity (r = 0.84, p is less than 0.0005), and mitogenicity and LAL reactivity (r = 0.72, p is less than 0.0025). In contrast, complement activation by these compounds did not correlate with mitogenicity, pyrogenicity or LAL reactivity (r = 0.09, p is greater than 0.4; r = -0.17, p is greater than 0.3; r = 0.17, p is greater than 0.3, respectively). These results suggest that a specific chemical configuration may induce mitogenicity, pyrogenicity, and LAL reactivity which differs from that responsible for complement activation.

Animals↗

PubMed1985

Crystal-induced endogenous pyrogen production. A further look at gouty inflammation.

We found previously that crystals of sodium urate and silicon dioxide (silica) can stimulate the production of endogenous pyrogen (EP), now called interleukin-1 (IL-1), the polypeptide mediator of fever and other aspects of inflammation. We have confirmed and extended the work with urate crystals and have examined 2 other crystals associated with joint problems, hydroxyapatite (HA) and calcium pyrophosphate dihydrate (CPPD). The crystals were added to suspensions of human blood leukocytes (2.5 X 10(6) monocytes/dose, with 10% fresh autologous plasma); after 18 hours of incubation, the EP content of the supernatants was assayed in the rabbit pyrogen test. HA and CPPD crystals neither induced EP production nor reduced the amount of staphylococci-induced EP. Presized (10 - 40 micron) urate crystals were pyrogenic, but less so than the unsized and aggregated urate crystals investigated previously and reexamined here. On ultrasonication, the aggregated urate crystals became first more pyrogenic and then less so as the crystals were dispersed and broken down. Ultrasound did not impart pyrogenicity to HA or CPPD crystals: their failure to stimulate EP/IL-1 production from leukocytes in vitro indicates a difference in their phlogistic properties, compared with crystals of urate or silica. The results with urate crystals have pathogenetic implications in a number of areas of gouty inflammation: initiation of the acute attack, other aspects of the acute-phase response, polyarticular involvement, and the inflammatory consequences of chronic stimulation by tophaceous material.

Calcium Pyrophosphate↗

PubMed1992

Determination of cytokine release after in vivo and in vitro administration of Deodan (a preparation from Lactobacillus bulgaricus "LB51") by the rabbit pyrogen test.

We investigated the in vivo and in vitro cytokine inducing effects of Deodan, an oral preparation from Lactobacillus bulgaricus "LB-51", using the rabbit pyrogen test. In the first experimental approach we administered Deodan, or its chromatographically purified fraction, via the i.m. or i.v. routes. Low doses of Deodan i.m. caused the formation of a single temperature peak, whereas large doses produced a biphasic temperature curve. Intravenous injection of Deodan produced a monophasic fever in all tested doses. Chromatographically purified Deodan injected i.v. to rabbits caused a febrile response with a dose-dependent pattern, strikingly similar to that of lipopolysaccharide. LAL-testing of Deodan, however, showed that the preparation does not contain endotoxin. In in vivo neutralization studies we demonstrated that IL-1, TNF alpha, and IL-6 mediate the rabbit febrile response to Deodan. Interestingly, the effects of Deodan on the production of TNF alpha and IL-6 were more pronounced than its IL-1 inducing activity. In the second approach, we injected supernatants from mononuclear cells incubated with nonpyrogenic doses of Deodan, intravenously to rabbits ("monocyte type" of pyrogen test). Rapid-onset monophasic fevers were observed, typical for the rabbit pyrogen reaction to i.v. administration of exogenous IL-1 and TNF. Finally, we demonstrated the presence of pyrogenic cytokines in the supernatants from macrophages of Deodan-treated mice. Together, these results indicate that Deodan induces the production of cytokines with endogenous pyrogenic activity.

Adjuvants, Immunologic↗

PubMed1991

Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock-like syndrome.

Toxic shock-like syndrome (TSLS) is characterized by hypotension or shock, fever, multiorgan system involvement, and a concurrent group A streptococcal infection. We analyzed 34 streptococcal strains isolated from patients with clinically well-documented TSLS for their pyrogenic toxin profiles and M-protein types. Although strains of nine different M types were represented in the sample, 74% of the isolates were of either M type 1 or 3. It was determined that 53% produced streptococcal pyrogenic exotoxin type A under in vitro growth conditions and that 85% contained the gene encoding this toxin. These values are in contrast to the published value of 15% for the incidence of this gene in a sample of general group A streptococcal isolates. As has been found with all group A streptococci examined to date, regardless of disease association, 100% of TSLS-associated isolates contained the gene encoding pyrogenic exotoxin type B. This toxin was detectably produced by 59% of isolates. The gene encoding pyrogenic toxin type C was found in only 21% of isolates. We conclude that the pyrogenic exotoxin type A gene is associated with group A streptococcal strains isolated from patients with TSLS and may play a causative role in this illness. However, other factors are also likely to be important, since not all strains from patients with TSLS contained the A toxin gene.

Antigens, Bacterial↗

PubMed1987

A comparison of the febrile responses of the Brattleboro and Sprague-Dawley strains of rats to endotoxin and endogenous pyrogens.

The febrile responses of homozygous (di/di) Brattleboro rats, to both intravenous endogenous pyrogen and to a lipopolysaccharide endotoxin, were compared with those of normal Sprague-Dawley rats. There were no detectable differences between the fever curves of the two strains in response to endogenous pyrogen. Brattleboro rats, which are deficient in the neuropeptide arginine vasopressin (AVP), displayed fevers that were both qualitatively and quantitatively indistinguishable from those of normal Sprague-Dawley rats that do not suffer from congenital diabetes insipidus. It is concluded that the absence of AVP-containing cells in Brattleboro rats is not an important factor in determining the nature of their febrile responses to endogenous pyrogen. More remarkable, however, were the divergent febrile responses of the two strains to intravenously injected endotoxin. Normal rats displayed hypothermic responses, whereas the Brattleboro rats became febrile. By 2 h after the injection of endotoxin, body temperatures in both strains had returned to normal. Three hours after the rats had been exposed to endotoxin, both strains were found to be totally refractory to endogenous pyrogen. However, when both strains of rats were tested to endogenous pyrogen 3 days later, their febrile responses were more than double the magnitude of their initial control responses. These alterations in the febrile responsiveness of rats occurring at different times after the injection of endotoxin appear to be related to the effects that endotoxin has on the cells of the reticuloendothelial system, over the same time course.

Animals↗

PubMed1985

Observations on the development of the febrile response to pyrogen in newborn pigs.

The febrile response of newborn pigs to exogenous pyrogen injection was investigated. Lipopolysaccharides (LPS, E. coli) were injected intravenously into the superior vena cava of 1-30-day-old piglets. All the experiments were carried out in littermates half of which were injected with pyrogen and half with pyrogen-free saline. Newborn pigs did not develop a febrile response from 1 to 4 days of age; however, when the animals were 5 days old exogenous pyrogen determined a typical monophasic febrile response. A second intravenous injection of pyrogen into newborn pigs (1 day old) 24 h after the first did not raise body temperature. It is suggested that newborn pigs behave like the newborn of other mammalian species regarding endotoxin-induced thermogenesis.

Aging↗

PubMed1984

Interferon fever: absence of human leukocytic pyrogen response to recombinant alpha-interferon.

A sensitive in vitro assay for generation of human leukocytic pyrogen has been used to study the pathogenesis of fever accompanying administration of human alpha-interferon. Unlike other potent pyrogens, two recombinant interferon preparations tested over a wide concentration range did not stimulate release of leukocytic pyrogen. This result suggests that interferon may cause fever by a novel mechanism not dependent on leukocytic pyrogen.

Animals↗

PubMed1978

A new sensitive method for detecting human endogenous (leukocyte) pyrogen.

Endogenous, or leukocyte pyrogen (EP), the mediator of fever, is currently detected by injection of pyrogen-containing supernatants into rabbits. This assay has been of little value in the study of human fever because it required injection of relatively large amounts of pyrogen. We now report that injection of medium containing human EP produces fever in mice. Supernatant from 1 c 10(5) granulocytes, stimulated by phagocytosis of staphylococci and incubated overnight, or 1 x 10(4) monocytes similarly treated, produce clear pyrogenic responses. This method for detecting EP is about 100-fold more sensitive than the rabbit assay, and it appears to be specific for EP. Preliminary studies of EP released by small samples of needle liver biopsies from febrile and afebrile patients suggests that this sensitive assay may be useful for investigations into the mechanisms of clinical fever.

Animals↗

PubMed1977

Partial purification of human leukocytic pyrogen.

Human leukocytes stimulated in vitro release leukocytic pyrogen (LP), a protein which is the mediator of fever. In order to study human leukocytic pyrogen, we attempted to purify this molecule from the large quantity and variety of proteins which are present in leukocyte supernates. Human peripheral leukocytes were stimulated in vitro by phagocytosis of killed staphylococci, and several methods were used to isolate the pyrogen protein. First, using isoelectric focusing, it was found that crude leukocyte supernates contained two molecular species of LP which were separable by precipitation in cold alcohol. Isoelectric focusing, although used for confirmation of the molecular homogeneity of LP, could not be employed as a preparative purification technique. Following alcohol precipitation, human LP was chromatographed on ion-exchange materials at various pH with modest recovery of initial activity but marked increase in specific activity. Gel-filtration was also employed and yielded partially purified LP. When alcohol precipitation was combined with ion exchange at alkaline pH and followed by gel-filtration, resulting LP preparations contained 5 or 6 contaminating proteins. These results demonstrate that human LP can be partially purified from the large quantity and variety of proteins present in crude leukocyte supernates and during purification procedures, the pyrogen did not change in either molecular weight or isoelectric point. This work provides reliable techniques for initial purification of human LP.

Chemical Precipitation↗

PubMed1978

Naloxone does not antagonize leukocytic pyrogen.

In a crossover experiment, cats were given third cerebral ventricular injections of 500 microgram naloxone hydrochloride or saline vehicle followed in 15 min by i.v. injections of saline solution or leukocytic pyrogen. The pyrogen produced comparable fevers after both saline and naloxone pretreatment. Intravenous administration of naloxone hydrochloride (5 mg/kg) likewise did not prevent febrile responses to leukocytic pyrogen. These results indicate that endogenous opioid peptides are not likely central mediators of pyrogen-induced fevers.

Animals↗

PubMed1988

Pyrogenic immunomodulators increase the level of prostaglandin E2 in the blood simultaneously with the onset of fever.

Blood prostaglandin E2 (PGE2) levels, estimated by radioimmunoassay, and body temperatures of conscious rabbits were measured simultaneously during fever in response to polyinosinic: polycytidylic acid, lipopolysaccharide and interleukin 1/endogenous pyrogen. The effects of the antipyretic agent ketoprofen on both parameters was also studied. Significant rises (in the order of 6- to 8-fold) in the PGE2 level were observed after injection of either of the three pyrogens and occurred simultaneously with the rise in temperature. Ketoprofen given after the onset of fever in response to the pyrogens produced an immediate defervescence and a simultaneous decrease in plasma PGE2. Ketoprofen given before the pyrogens prevented any rise in either body temperature or plasma PGE2 level. When animals were subjected to an environmental temperature of 34 degrees C a hyperthermia was observed without any change in the blood PGE2 level. These results suggest that an increase in the blood PGE2 level may contribute to the pathogenesis of fever.

Animals↗

PubMed1987

Single-unit responses of serotonergic dorsal raphe nucleus neurons to environmental heating and pyrogen administration in freely moving cats.

Single-unit activity of serotonergic neurons in the dorsal raphe nucleus was examined in response to environmental heating and pyrogen-induced fever in freely moving cats. In the heating study, ambient temperature was rapidly raised from a baseline of 25 degrees to 43 +/- 1 degrees C and maintained at this level for 2 h. Cats displayed hyperthermia, intense panting, and signs of heat stress, however, the discharge rate of serotonergic neurons of the dorsal raphe nucleus was not significantly different from baseline at any time during heat exposure. Similarly, the activity of these neurons was not significantly altered at any time during an approximately 6-h long febrile response induced by the synthetic pyrogen muramyl dipeptide (50 micrograms/kg, i.v.). These results indicate that serotonergic unit activity in the dorsal raphe nucleus is not related to either the activation of behavioral or physiological mechanisms underlying heat defense, or to alterations in thermoregulatory mechanisms during the febrile response to exogenous pyrogen. Furthermore, because these neurons do not respond to an elevation in body temperature induced by either ambient heating or pyrogen, they do not appear to be directly temperature-sensitive. These results do not support a specific role for serotonergic neurons of the dorsal raphe nucleus in thermoregulation.

Animals↗

PubMed1988

The effects of peptidoglycan, a pyrogenic constituent of gram-positive microorganisms, on the pharmacokinetics of rifampicin.

Pharmacokinetics of rifampicin (20 mg/kg orally or i.v.) was determined in calves and rabbits. Seven days later a model pyrogen was administered i.v. to the same animals and 1 hr later the rifampicin administration was repeated. The pharmacokinetic analysis of oral rifampicin was performed using a one-compartment open model with absorption. Intravenously administered rifampicin was analysed by a two-compartment intravascular model. Injection of peptidoglycan in pyrogenic doses led to a significant increase of orally applied rifampicin serum levels in both animal species. The i.v. administration of rifampicin had the same parameters in the control and peptidoglycan experiments. Daily pretreatment of rabbits with small doses of peptidoglycan induced tolerance to the pyrogenic effect. In tolerant animals we did not observe any changes of rifampicin serum levels. Elevated temperature alone was not responsible for observed pharmacokinetic changes leading to the increase of bioavailability of oral rifampicin since another pyrogenic substance (endotoxin) had an opposite effect on pharmacokinetics of previously tested drugs.

Administration, Oral↗

PubMed1988

Characteristics of pyrogen fevers are altered in the aged rabbit.

The febrile response to both intravenous and intracerebral administration of pyrogens was investigated in young and old male New Zealand White rabbits. Intravenous bacterial pyrogen evoked biphasic fevers in both groups of animals. However, the fevers in the group of older rabbits were significantly less than in younger animals. In contrast, intravenous injection of endogenous pyrogen produced identical fevers in the two groups. Bacterial and endogenous pyrogens injected into a lateral cerebral ventricle evoked marked febrile responses of long duration in both young and old rabbits. The responses of the old rabbits were significantly less than those of the younger ones. Finally, direct microinjection of prostaglandin E1 into tissue sites within the anterior hypothalamic preoptic area elicited short latency hyperthermic responses which were significantly less in the older rabbits. Analysis of ear skin temperatures during fever demonstrated that some of the differences may, in part, be due to altered vasoconstrictor responses in the peripheral vasculature. Thus, these data indicate that the febrile response is altered with increasing age in the rabbit.

Aging↗

PubMed1983

Characteristics of immobilized histamine for pyrogen adsorption.

The characteristics of immobilized histamine for pyrogen adsorption were investigated. The adsorbent showed a high affinity for pyrogen at low ionic strength, at around neutral pH, at high temperature and at low flow-rates of a solution containing pyrogen. The adsorption capacity per millilitre of the adsorbent was 0.9 mg pyrogen. Immobilized histamine could be completely regenerated by washing with 0.2 M sodium hydroxide solution containing 10--30% ethanol followed by 1.5 M sodium chloride solution, or 0.2 M sodium hydroxide solution followed by 0.5% sodium deoxycholate solution, 0.2 M sodium hydroxide solution and 1.5 M sodium chloride solution.

Chromatography, Agarose↗

PubMed1979

Sites of clearance of leucocyte pyrogen in the rabbit.

1. The dose-response curve for sustained infusions of leucocyte pyrogen has been demonstrated, and an optimum dose indicated for leucocyte pyrogen clearance experiments. 2. The lungs, liver and small bowel are not significantly involved in removal of leucocyte pyrogen from the circulation in conscious rabbits. 3. A single circulation through one kidney removes up to half of the infused dose of leucocyte pyrogen.

Animals↗

PubMed1981

Demonstration of a human pyrogen-inducing factor during mixed leukocyte reactions.

The role of lymphocytes in the pathogenesis of fever was investigated by stimulating human blood mononuclear cells in a two-way mixed leukocyte reaction (MLR). After 2-7 d of incubation, MLR supernates contained a factor that was not pyrogenic itself when injected into rabbits; however, these supernates, when incubated with human blood monocytes from a third donor, induced the synthesis of LP. The pyrogen-inducing activity was stable at 56 degrees C, destroyed at 70 degrees C, and was neither dialyzable nor removable by adsorption by anti-human leukocytic pyrogen (LP) attached to Sepharose 4B. Production of this factor was not always correlated with increased thymidine incorporation in the MLR. Its production was absent when peripheral lymphocytes were purified over nylon wool. The concentration of mononuclear cells in the MLR varied from 5 X 10(5) to 5 X 10(6)/ml in round-bottomed tubes. Under the latter conditions, some donor cells produced this factor without stimulation in the MLR culture, but when these cells were cultured on flat-bottomed containers at low cell concentration, autologous production was not observed. These experiments demonstrate the production of a human lymphocyte factor (lymphokine) that induces LP synthesis. This pyrogen-inducing lymphokine may be important in the pathogenesis of fever in certain immunologically mediated diseases.

DNA↗