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PubMed2000

RANTES: a new prostaglandin dependent endogenous pyrogen in the rat.

Fever, a hallmark of disease, is a highly complex process initiated by the action of a number of endogenous pyrogens on the thermosensitive cells of the brain. We describe the activity of RANTES, a chemotactic cytokine, as intrinsically pyrogenic in the rat, when it is delivered directly to the thermosensitive region of the rat's anterior hypothalamic, pre-optic area (AH/POA). RANTES, microinjected into the AH/POA in a dose of 1, 5, 10, 15, 25 or 50 pg, produces an immediate and intense dose-related fever following injection. Increasing the dose to 100 pg did not result in a further increase in the febrile response. No significant change in body temperature was produced by heat-inactivated RANTES. The intrahypothalamic injection of antibodies against RANTES (2.0 microg, 15 min prior to RANTES) significantly blocked the fever induced by this chemokine. Pretreatment with ibuprofen blocked the fever induced by RANTES. In order of potency, the magnitude of the febrile response induced by RANTES was greater than that produced with equipotent doses of either macrophage inflammatory protein-1beta or interleukin-6. The results thus demonstrate that RANTES is the most potent endopyrogen discovered thus far and exerts its action directly on pyrogen-sensitive cells of the AH/POA through a prostaglandin-dependent pathway.

Animals↗
PubMed1985

[Limulus test using a chromogenic method: application to the control of pyrogens in blood derivatives].

We report here the application of the LAL Test to a chromogenic substrate to detect endotoxins in Human Blood Products. In order to reduce the cost, we used a microplate procedure with the Multiskan Reader. Quantitative results in the range of 0,01 to 0,1 ng/ml allowed for a good correlation with the Rabbit Pyrogen test. For 20% albumins and 4% albumins, the mean endotoxins levels of non pyrogenic lots were 0,38 +/- 0,18 and 0,09 +/- 0,03 ng/ml. All the lots which passed the Rabbit Pyrogen test had endotoxins levels lower than 1 ng/ml and 0,2 ng/ml, respectively. We can use this test for other plasma derivatives; Gammaglobulines and PPSB are easily tested. Dried Concentrated Antihemophilic Factor and Dried plasma contain citrate which inhibits the reaction. Dilution and Addition of Calcium Chloride overcome this inhibition. For dried plasma, we should destroy plasma inhibitors by heating at 75 degrees C. This sensitive and reproductible in vitro assay improves the control of pyrogenecity in Human Blood Products.

Blood Transfusion↗
PubMed2002

Differential sensitivities of pyrogenic chemokine fevers to cyclooxygenase isozymes antibodies.

It has been proposed that prostaglandin (PG)E(2) production via a process catalyzed by the inducible isoform of cyclooxygenase (COX)-2 and activation of specific PGE(2) receptor subtypes within the preoptic/anterior hypothalamus (AH/POA) is the last step and unique pathway in the induction of a fever. However, many data support the existence of a PG-independent pathway. That is, other more rapid mechanisms, which involve the constitutive COX-1 isozyme, may be more critical for a PG-dependent fever. Thus, we examined the role of both COX isoforms in the AH/POA in fevers induced by macrophage inflammatory protein (MIP)-1beta, a PG-independent pyrogen, and RANTES (regulated on activation, normal T-cells expressed and secreted), a PG-dependent pyrogen. In freely moving rats, two independent polyclonal antibodies were used which neutralize COX-1 and COX-2. The microinjection of either MIP-1beta or RANTES into the pyrogen-sensitive region of the AH/POA induced an intense fever of rapid onset. Peripheral pretreatment with an antipyretic dose of dexamethasone which prevents COX-2 expression, or the microinjections into the AH/POA of either anti-COX-1 or anti-COX-2, blocked the febrile response induced by RANTES but not that induced by MIP-1beta. These results provide strong evidence for the existence of rapid mechanisms in the AH/POA which involve both COX isozymes during the fever induced by RANTES, and further support the existence of an alternative PG-independent pathway in the febrile response.

Animals↗
PubMed1999

A comparative study of Mono Mac 6 cells, isolated mononuclear cells and Limulus amoebocyte lysate assay in pyrogen testing.

Pyrogen induced secretion of interleukin 6 (IL-6) in Mono Mac 6 (MM6) cells was measured. The ability of the MM6 cell culture to detect pyrogens was compared to the Limulus amoebocyte lysate (LAL) test and isolated mononuclear cells (MNC). The detection limit of MM6 for lipopolysaccharide (LPS) and Staphylococcus aureus was comparable to that of MNC. Aspergillus niger and Candida albicans induced IL-6 in isolated MNC, but not in MM6. The detection limit for Salmonella typhimurium in the MM6 assay was comparable to that of the LAL assay. As expected, S. aureus and C. albicans did not show any LAL activity. A. niger and Influenza virus showed some activity in the LAL test, but could not be detected by MM6 cells. In conclusion, the MM6 assay is a good supplement to the current pyrogen assays for detection of LPS, S. aureus and S. typhimurium, but the MM6 assay could not detect A. niger, C. albicans and Influenza virus.

Biological Assay↗
PubMedDate not supplied

Activation of the complement system as an indicator of pyrogenic reaction to lipopolysaccharide (LPS).

The generation of biologically active complement split products through the direct reaction of microorganisms with complement proteins is one of the earliest events of the defence reaction in humans. Complement activation develops within minutes, which highly corresponds with the onset of a febrile reaction after exposure to pyrogens. The possibility of the use of complement activation in human plasma as an indicator of pyrogen contamination has been tested. Additionally, the co-stimulatory effect of complement activation on tumor necrosis factor-alpha (TNF-alpha) production by blood-separated macrophages exposed to lipopolysaccharide (LPS) has been demonstrated. As an indicator of complement activation in test samples, the concentration of the iC3b fragment was measured by using an ELISA system based on neoantigen formation. The 3-h exposure time has been identified as optimal for the test. The variability between iC3b concentrations in untreated control samples obtained from seven unrelated healthy donors was less than 10%, while after activation by 100 ng/ml LPS, it increased to 13%. The lower detection limit has been identified as 10 pg/ml LPS. As the complement test is not affected by drug-cell interactions or cell viability, the test can be used in situations where tested formulations contain active substances, which interfere with a cell-based test. We conclude that a test based on the detection of complement activation in human plasma should be considered as a valuable element of an in vitro pyrogenicity testing battery along with a cell-based assay.

Animal Testing Alternatives↗
PubMed2000

Pyrogenic signaling via vagal afferents: what stimulates their receptors?

Although there is good evidence that pyrogenic messages may be conveyed from the periphery to the brain via vagal afferents, the exact nature of the factors that activate their sensory terminals is unclear. Since IL-1beta and PGE2 have established roles in fever production and since their receptors have been identified on or near vagal nerves, they are potential candidate mediators. A difficulty, however, is that (1) IL-1beta is not expressed constitutively in mononuclear phagocytes, their presumed cell source upon stimulation by exogenous pyrogens, e.g. endotoxin, and (2) similarly, the isoform of the enzyme that selectively mediates the production and release of PGE2 by endotoxin-stimulated macrophages, COX-2, is also not constitutively expressed in these cells. Since the transcription and translation of these factors significantly lags the onset of fever induced by endotoxin administered intravenously, in particular, it is possible that a secondary, quickly-acting mediator evoked in almost immediate reaction to the presence of endotoxin excites, directly or indirectly, the sensory neurons. We have evidence that the complement component C5 contributes importantly to the initiation of the febrile response to endotoxin. This article briefly reviews the prevailing concepts of pyrogen sensing and signaling, examines their shortcomings particularly in terms of the temporal discrepancy between the very rapid onset of the febrile response to intravenously administered endotoxin and the significant delay in the elaboration of the putative mediators of fever, and presents newer data that may help to integrate the various preposed mechanisms.

Animals↗
PubMed1981

Measurement of hypozincaemia in mice: a sensitive test for detection of pyrogens.

1. The effect of bacterial pyrogens on plasma zinc concentration in mice was studied as a method of bioassay for these substances. 2. A dose-related depression of plasma zinc concentrations was observed 4 h after intravenous injection of doses of 0.05-500 ng of purified endotoxins of Salmonella abortus equi, Shigella dysenteriae and Escherichia coli. Responses were dose-dependent and reproducible for each endotoxin in five strains of mice. 3. Tolerance to endotoxin could be induced in mice by injection of doses of 500 ng but was not seen with doses of less than 5 ng, even after repeated treatment. 4. Dinitrophenol, a metabolic inhibitor, and amphetamine, a metabolic enhancer, did not affect plasma zinc levels, indicating that changes in basal metabolic rate do not affect the outcome of this assay. The effects of pyrogenic materials other than endotoxin on plasma zinc levels were also tested and the results suggest that measurement of hypozincaemia in mice provides the basis for a simple, practical and inexpensive test for endotoxins and other pyrogens.

Amphetamine↗
PubMed1958

Studies on the pathogenesis of fever. III. The leucocytic origin of endogenous pyrogen in acute inflammatory exudates.

The evolution of an acute inflammatory exudate produced in rabbits by the intraperitoneal injection of saline has been described. Evidence has been presented that polymorphonuclear leucocytes release endogenous pyrogen into the cell-free fluid of the exudate. Leucocytes from such exudates have also been shown to release pyrogen into the surrounding medium during incubation in vitro at 37 degrees C. The results of parallel cytological studies have provided evidence which suggests that the leucocytes give up their pyrogen while functionally intact. These observations add further support to the hypothesis that polymorphonuclear leucocytes play a significant role in the pathogenesis of fever.

Animals↗
PubMed1958

Studies on the pathogenesis of fever. IV. The site of action of leucocytic and circulating endogenous pyrogen.

By means of a method designed to compare the febrile responses produced by intracarotid and intravenous injections, the endogenous pyrogen, which is contained in leucocytic exudates and is present in the serum of rabbits 2 hours after intravenous injections of typhoid vaccine, has been shown to act directly upon the thermoregulatory centers of the brain. In contrast, the exogenous bacterial pyrogen present in serum obtained 5 minutes after vaccine injections was found to act by a different and less direct mechanism. These observations add strong support to the original hypothesis that endogenous pyrogen, presumably derived from polymorphonuclear leucocytes, is an essential factor in the pathogenesis of endotoxin fever.

Animals↗
PubMed1960

Studies on the pathogenesis of fever. VII. Preliminary chemical characterization of leucocytic pyrogen.

Study of the chemical properties of the pyrogenic component of rabbit polymorphonuclear leucocytes reveals it to contain an essential, non-dialyzable protein which: (a) is precipitated by perchloric acid, (b) is removed by extraction with phenol, (c) is soluble in 50 per cent methanol and 33 per cent saturated ammonium sulfate, and (d) is destroyed by the proteolytic action of both trypsin and pepsin. By combined chemical and chromatographic techniques the leucocytic pyrogen has been purified approximately 50-fold. The partially purified material contains less than 1 per cent carbohydrate, is resistant to periodate oxidation, is unaffected by extraction with butanol and contains at least two immunologically active components when tested by the Ouchterlony gel-diffusion technique. Its chemical properties distinguish it from other known pyrogenic substances which have been implicated in the pathogenesis of fever.

Animals↗
PubMed1961

Studies on tuberculin fever. II. Observations on the role of endogenous pyrogen in tolerance.

Certain characteristics of tolerance which develops to the pyrogenic effects of old tuberculin (OT) in BCG-vaccinated rabbits have been described. Rabbits made tolerant by several injections of OT lost their ability to produce detectable amounts of endogenous pyrogen (EP) in response to the specific agent (OT) but mobilized normal amounts of EP when given a small unrelated stimulus. On the other hand, when this stimulus followed shortly after an initial tuberculin fever of sufficient magnitude, release of additional EP was suppressed, presumably due to an inhibitory effect of the EP previously mobilized by tuberculin. Similarly, a single large dose of endotoxin almost completely suppressed the response of sensitized rabbits to OT given several hours later. Since several spaced injections of the same dosage were ineffective, this phenomenon does not appear to be attributable to the known mechanisms by which endotoxins promote non-specific resistance to toxicity and infection. Tolerance to tuberculin could not be definitely shown following an injection of Newcastle disease virus which also produces a circulating EP, and it has been inferred that endotoxin blocks the pyrogenic action of antigen on host tissues directly rather than through mobilizing EP. On the basis of these observations, the relationship of specific to non-specific tolerance to tuberculin fever has been compared in terms of the ability of such tolerant animals to mobilize EP to heterologous stimuli and it is concluded that the two forms of tolerance are different. Furthermore, the fact that a number of unrelated agents produce tolerance non-specifically supports the concept that there may be a common source of EP released by a number of stimuli, including endotoxins and myxoviruses, as well as antigen in specifically sensitized hosts.

Allergy and Immunology↗
PubMed1966

Studies on the pathogenesis of fever. XIV. Further observations on the chemistry of leukocytic pyrogen.

Leukocytic pyrogen previously reported to contain an essential protein moiety, appears to be a lipid-protein complex having a molecular weight in the range of 10,000 to 20,000. Evidence that it contains essential lipid includes its inactivation by Cu(++), its lability in alkaline solutions (pH 8.5 and above), and its loss of pyrogenicity when extracted with acid-isooctane. Its solubility in 66% methanol, and the enhancing action of ethanol in freeing it from sonicated cells, suggest the presence of exposed lipid groups at its surface. Once the complex is separated from other proteins, its biological activity is readily destroyed. Although the lipid component is presumed to contain unesterified fatty acid(s), its precise composition is unknown. The finding of lipid in the active complex is in keeping with the hypothesis that the pyrogen is derived from leukocytic membranes.

Fever↗
PubMed1967

Studies on the pathogenesis of fever. XV. The production of endogenous pyrogen by peritoneal macrophages.

Macrophages from oil-induced peritoneal exudates in rabbits produce endogenous pyrogen when first activated by incubation in 4 hr exudate fluid and then stimulated by incubation in potassium-free isotonic sodium chloride solution. The failure of earlier investigators to obtain pyrogen from macrophages is explained, and the relevance of macrophage pyrogen to fevers of agranulocytosis and other diseases, in which mononuclear rather than granulocytic exudates predominate, is discussed.

Animals↗
PubMed1970

Studies on the pathogenesis of fever. 18. Activation of leukocytes for pyrogen production.

Blood leukocytes, in contrast to exudate leukocytes, release little or no pyrogen when incubated in 0.15 M NaCl unless previously activated by exposure to endotoxin or to a protein activator that is present in acute exudate fluid. The activation process, which also occurs during phagocytosis, involves the synthesis of cellular protein, presumably related to the pyrogen molecule. Evidence is presented that generation of pyrogen in sterile inflammatory lesions depends on both the activator and the anaerobic conditions in the exudate fluid.

Animals↗
PubMed1970

Studies on the pathogenesis of fever. XX. Suppression and regeneration of pyrogen-producing capacity of exudate granulocytes.

Suppression of the pyrogen-producing capacity of exudate granulocytes results from incubation of the cells in plasma, serum, or Ringer's solution. When transferred in this state and incubated in isotonic NaCl, the cells release much less pyrogen than untreated exudate cells. The suppressive effect is reversible and appears to involve the cellular uptake of calcium ions. In contrast, regeneration of pyrogen-producing capacity in depleted exudate cells occurs only when the cells are incubated in serum. The process resembles activation and requires the cellular synthesis of protein.

Blood↗
PubMed2003

Improving water quality can reduce pyrogenic reactions associated with reuse of cardiac catheters.

OBJECTIVE: To report the results of our preintervention investigation and subsequent 19-month three-phase intervention study designed to reduce pyrogenic reactions among patients undergoing cardiac catheterization using reprocessed catheters. DESIGN: A case-control study for the preintervention period and a prospective cohort study for the intervention period. SETTING: A 400-bed hospital in Belo Horizonte, Brazil. PARTICIPANTS: Any patient undergoing cardiac catheterization in the hospital. INTERVENTIONS: Three intervention phases were implemented to improve the quality of the water supplied to the cardiac catheter reprocessing laboratory. Standard operating procedures for reprocessing cardiac catheters were established and reprocessing staff were trained and educated. RESULTS: The rate of pyrogenic reactions decreased significantly during the intervention phases, from 12.8% (159 of 1,239) in phase 1 to 5.3% (38 of 712) in phase 2 to 0.5% (4 of 769) in phase 3 (chi-square test for linear trend, 97.5; P < .001). CONCLUSION: Improving water quality and using standard operating procedures for reprocessing catheters can prevent pyrogenic reactions in hospitalized patients.

Adult↗
PubMed1999

Cytokines as endogenous pyrogens.

Cytokines are pleiotropic molecules mediating several pathologic processes. Long before the discovery of cytokines as immune system growth factors or as bone marrow stimulants, investigators learned a great deal about cytokines when they studied them as the endogenous mediators of fever. The terms "granulocytic" or "endogenous pyrogen" were used to describe substances with the biologic property of fever induction. Today, we recognize that pyrogenicity is a fundamental biologic property of several cytokines and hence the clinically recognizeable property of fever links host perturbations during disease with fundamental perturbations in cell biology. In this review, the discoveries made on endogenous pyrogens are revisited, with insights into the importance of the earlier work to the present-day understanding of cytokines in health and in disease.

Animals↗
PubMed1993

Group B streptococcal toxic shock-like syndrome: report of a case and purification of an associated pyrogenic toxin.

A patient with streptococcal toxic shock-like syndrome (TSLS) caused by Streptococcus agalactiae (group B Streptococcus) is described. The patient had all of the defining criteria for toxic shock syndrome (TSS), including fever, hypotension, erythematous rash, desquamation, and involvement of multiple organs. Neither Staphylococcus aureus nor group A streptococci were recovered, but vaginal and urine cultures yielded group B streptococci. The group B streptococcal isolate gave negative results in antibody tests for the production of TSS toxin 1, staphylococcal enterotoxins, and streptococcal scarlet fever toxins. However, the strain produced a novel pyrogenic toxin. This toxin, purified from culture fluids by ethanol precipitation, isoelectric focusing, and reverse-phase high-pressure liquid chromatography, had a molecular weight of 12,000 and an isoelectric point of approximately 7.0. The purified toxin was pyrogenic in rabbits, enhanced the susceptibility of the animals to lethal endotoxin shock, and caused the proliferation of rabbit splenocytes; these properties define pyrogenic toxins. When given to three rabbits via a subcutaneous miniosmotic pump, the toxin caused TSS-like symptoms ending in death. Three additional group B streptococcal strains from patients with TSLS were tested and were found to produce a toxin with similar properties.

Adult↗