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PubMedDate not supplied

Serum thyroxin levels during hyperthermia evoked in the monkey by intrahypothalamic injection of PGE1, 5-HT or pyrogen.

Serotonin (5-HT), prostaglandin E1 (PGE1) or a bacterial pyrogen (E. coli or S. typhosa) was microinjected in a volume of 1.0--1.5 microliter into the hypothalamus of the unanesthetized monkey to evoke a long-term hyperthermia. Samples of venous blood collected every 15 min, before, during and after each fever were analyzed by radioimmunoassay for plasma thyroxin levels. There was no statistically significant correlation between plasma thyroxin values and a given phase of the hyperthermic episode induced by the microinjections of 5--HT, PGE1 or bacteria. The possibility that an enhanced release of the thyroid hormone serves to sustain a long-term elevation in temperature evoked by a centrally acting pyrogenic substance is not supported.

Animals↗
PubMedDate not supplied

Central thermosensitivity during fever produced by intra-PO/AH and intravenous injections of pyrogen.

Squirrel monkeys with thermodes implanted in the preoptic/anterior hypothalamic (PO/AH) region and the medulla oblongata were used to examine three questions about central thermoresponsiveness in fever: Does thermoresponsiveness of the PO/AH region and medulla change during fevers caused by injection of bacterial endotoxin IV or directly into the PO/AH region? Does thermosensitivity of these brain regions determine the upper fever limit? Is thermoresponsiveness of the PO/AH region affected by local injections of salicylate? Changes in rectal temperature and oxygen consumption in response to heating and cooling the PO/AH region were reduced during fever caused by intra-PO/AH injections of bacterial endotoxin compared with changes produced during afebrile periods. PO/AH thermosensitivity was also reduced during fever caused by IV administration of bacterial pyrogen. Prolonged cooling of the PO/AH region or the medulla oblongata during fever produced by peripheral and central pyrogen injections did not cause rectal temperature (Tre) to rise above 41.1 degrees C although local heating reduced Tre or limited the fever maximum. From the latter result it is concluded that both pools of central thermoreceptors can limit maximal fever by reacting to local high temperature but that lowered temperature in neither region can raise Tre above a level determined by antagonistic input from thermoreceptors in other parts of the body. Injections of sodium salicylate into the PO/AH region had no effect on thermoresponsiveness of the region. This finding reinforces the idea that salicylates do not produce antipyresis by acting directly on thermosensitive cells of the central temperature control system.

Animals↗
PubMedDate not supplied

The role of protein synthesis in the hypothalamic mechanism mediating pyrogen fever.

The effects of inhibition of protein synthesis by anisomycin on the pathogenesis of fever and normal thermoregulatory processes were investigated in the conscious and unrestrained cat. Subcutaneous administration of 5.0-25.0 mg/kg of anisomycin prevented the fever normally evoked by an intravenous infusion of either 1.0 ml (10(8) organisms) of a 1:10 dilution of S. typhosa or 1.0-5.0 ml (3.5 x 10(5)-2.1 X 10(7) cells/ml) of endogenous pyrogen. In addition, systemic pre-treatment with anisomycin delayed and/or blocked the fever typically elicited by a direct micro-injection into the anterior hypothalamic, preoptic area (AH/POA) at AP 12.5-16.0 of 1.0 microliters of the endotoxin. Anisomycin did not alter the hyperthermic response to an anterior hypothalamic injection of either 1.0-7.0 micrograms/1.0 microliters of serotonin (5-HT) or 100.0 ng/1.0 microliters of prostaglandin (PGE). Inhibition of protein synthesis, furthermore, did not prevent the fall in body temperature usually produced by an intrahypothalamic micro-injection of 2.33-14.0 micrograms/1.0 microliters of either norepinephrine (NE) or dopamine (DA). The thermoregulatory capacity of the cat was unaffected by the administration of comparable doses of anisomycin, i.e., the animal was able to maintain normal body temperature (+/- 0.5 degrees C) when exposed to an ambient temperature of either 10 degrees C or 34 degrees C. These results strongly suggest that the synthesis of new protein within the region of the AH/POA is a functional requisite for the development of a pyrogen-induced fever.

Animals↗
PubMed2004

Cryopreservation of human whole blood for pyrogenicity testing.

Human whole blood assays are increasingly employed to test immune function or detect pyrogenic contamination, since they offer advantages, such as ease of performance, few preparation artifacts and a physiological cell environment. However, the approach is often limited by the availability of freshly drawn blood, putative safety concerns in the case of infected donors and interindividual donor differences. To overcome these limitations, a method was developed and optimized to produce batches of cryopreserved blood that can be used directly after thawing without any washing steps. Mononuclear cells remained intact as shown by FACS analysis. Cytokine release could be induced by a variety of immunological stimuli. The cell preparation released higher amounts of interleukin-1beta (IL-1beta) and IL-6 compared to fresh blood, but no TNF. These differences could be attributed to the presence of the cryoprotectant dimethylsulfoxide (DMSO) alone by addition of DMSO to fresh blood. Large batches of cryopreserved blood could be produced by mixing blood donations of up to 10 donors, independent of differing blood groups. The detection limit for the World Health Organization (WHO) lipopolysaccharides (endotoxin, LPS) reference preparation (EC-6) with regard to the induction of IL-1beta release was at least 0.5 endotoxin equivalent units (EU)/ml. Endotoxin spikes at the limit concentrations prescribed in the European Pharmacopoeia could be detected in a series of drugs, showing that the In vitro Pyrogen Test (IPT) can also be run with cryopreserved blood. Further possible applications include high-throughput screening for immunomodulators or toxins as well as preservation of patient samples for later analysis of cell functions.

Blood↗
PubMed1995

Congenital streptococcal toxic shock syndrome with absence of antibodies against streptococcal pyrogenic exotoxins.

Congenital infection with group A beta-hemolytic streptococcus was complicated by toxic shock syndrome in a neonate. We hypothesize that the severity of the clinical syndrome was related to the streptococcal pyrogenic exotoxin in the absence of corresponding antibodies. The outcome may have been favorably influenced by the antibodies to streptococcal pyrogenic exotoxin present in the immunoglobulins given as treatment.

Antibodies, Bacterial↗
PubMed2001

Involvement of brain glutamate release in pyrogenic fever.

Whether the glutamate release in the organum vasculosum laminae terminalis (OVLT) is attributable to genesis of a pyrogenic fever is unclear. The lack of information led us to evaluate the changes in glutamate concentrations of OVLT during the fever induced by staphylococcal enterotoxin A (SEA) in unanesthetized rabbits. Both the OVLT concentrations of glutamate and the colonic temperatures were simultaneously monitored during systemic injection of SEA, MK801 (an N-methyl-D-aspartate (NMDA) receptor channel blocker), ketamine (an NMDA receptor channel blocker), or normal saline. The extracellular dialysates in the brain were collected using a microdialysis probe previously placed in the OVLT region. The concentrations of glutamate in the microdialysates were measured by a high-pressure liquid chromatography in combination with a fluorescence detector. Systemic administration of SEA (30 ng x kg(-1) I.V.) increased both the concentrations of glutamate in the OVLT and the colonic temperatures. Glutamate appeared to rise slightly earlier than body temperature. Pretreatment or posttreatment with MK801 or ketamine significantly attenuated the SEA-induced augmenting glutamate release in the OVLT and fever in rabbits. The suppression of glutamate release appeared to start slightly earlier than temperature decline. In addition, the SEA-induced fever could be mimicked by direct injection of glutamate or SEA into the OVLT area. The fever induced by intra-OVLT injection of SEA or glutamate was significantly attenuated by pretreatment with an intra-OVLT dose of MK801 (5 microg) or ketamine (10 microg). The results suggest that glutamatergic pathways in the OVLT region are in pyrogenic fever genesis.

Animals↗
PubMed1992

Role of the OVLT in the febrile response to circulating pyrogens.

The available data suggest that circulating endogenous pyrogens (EPs) probably do not penetrate the brain, but interact with sensory elements in the organum vasculosum laminae terminalis (OVLT) which may involve 5HT and SP as neurotransmitters. It is proposed that substance P (SP) may affect thermo-regulatory neurons in the preoptic area (POA) directly or induce the local synthesis of cytokines that secondarily act on these neurons. Recent evidence indicates that endothelial cells in the OVLT bind circulating cytokines to receptors on their luminal surface. This may result in the release of putative neuroregulators which then process the original signals inwardly to the POA, where they then affect neuronal functions leading to fever production. Thus, trans-BBB passage of cytokines is prevented, but the brain site mediating their pyrogenic effect is informed and the appropriate responses are activated. It is emphasized, however, that this suggested mechanism is still speculative.

Animals↗
PubMed1983

The preparation of pyrogen-free foetal calf serum for use in cell and tissue cultured.

A method is described for the preparation of foetal calf serum from blood drawn by heart puncture from calf foetuses obtained from a local municipal abattoir. This method differs from that previously described in that the Seitz Supra EK filter pads used in preliminary purification steps have been abandoned. These pads contain significant amounts of pyrogenic bacterial lipopolysaccharides and attempts to depyrogenate them with sodium hypochlorite, hydrogen peroxide and 1% foetal calf serum were unsuccessful. The modified method uses pyrogen-free glass fibre and cellulose fibre filters and provides an entirely satisfactory serum as proved by negative Limulus amoebocyte lysate tests and the excellent growth of cells.

Animals↗
PubMed1994

Separation of mitogenic and pyrogenic activities from so-called erythrogenic toxin type B (Streptococcal proteinase).

It is well-established that three types of erythrogenic toxins (ETA, ETB, ETC) are produced by Streptococcus pyogenes (group A streptococci) strains. Culture filtrate concentrates from Streptococcus pyogenes strains T19P (T19, ETA+, ETB+, ETC-), 27337 (T12, B3264, ETA-, ETB+, ETC+), 27252 (T4, ETA-, ETB+, ETC+) and 27195 (T8, ETA-, ETB+, ETC-) were analyzed by preparative isoelectric focusing. These concentrates and the purified erythrogenic toxin type B (ETB) isolated by ion exchange chromatography had mitogenic and pyrogenic activity. Now, it has been found that the mitogenic activity and the pyrogenic activity of this ETB can be separated by preparative isoelectric focusing in Sephadex gels. This means that ETB is not a superantigen as described in literature. The mitogenic and biological activity is caused by traces of ETA (strain T19P), ETC (strains 27252 and 27337) and/or by unknown mitogen(s) (MX, strain 27195) which preferentially stimulate V beta 8+ T cells. The differentiation between ETA (stimulating V beta 12+ but not V beta 8+ or V beta 2+), ETC (stimulating V beta 2+ but not V beta 8+), and MX (stimulating V beta 8+) was done using established leukemic cell lines.

Animals↗
PubMed2002

Characterization of a novel staphylococcal enterotoxin-like superantigen, a member of the group V subfamily of pyrogenic toxins.

Staphylococcus aureus is an important human pathogen, causing a variety of diseases. Major virulence factors of this organism include staphylococcal enterotoxins (SEs) that cause food poisoning and toxic shock syndrome. Our study identified a novel enterotoxin-like protein that is a member of the new subfamily (group V) of pyrogenic toxin superantigens (PTSAgs) and examined its biochemical and immunobiological properties. The gene encoding the SE-like protein is directly 5' of another recently identified PTSAg, SEK. The SE-like protein had a molecular weight of 26000 and an experimentally determined isoelectric point between 7.5 and 8.0. We demonstrated that the PTSAg had many of the biological activities associated with SEs, including superantigenicity, pyrogenicity, and ability to enhance endotoxin shock, but lacked both lethality in rabbits when administered in subcutaneous miniosmotic pumps and emetic activity in monkeys. Recombinant protein stimulated human CD4 and CD8 T cells in a T cell receptor variable region, beta chain (TCRVbeta) specific manner. T cells bearing TCRVbeta 2, 5.1, and 21.3 were significantly stimulated.

Amino Acid Sequence↗
PubMed1999

Sudden infant death syndrome: hypothalamic failure to sense elevated blood pyrogens.

Sudden infant death syndrome (SIDS) is frequently associated with a mild infection, the incidence peaking during the third month of life. We hypothesize that the neonatal immaturity of both the acute febrile response and hypothalamus promote neonatal protection from SIDS. Vagal afferents modify the febrile response. Vagotomized rodents displayed a loss of febrile responsiveness in a 'non-sensing' brain. The failure of a 'non-sensing' brain to react to elevated blood pyrogens leads to failure of the febrile response and to a shock-like state. SIDS infants may appear well yet, within hours of this observation, may be found dead. There is a mismatch between the acute febrile response and hypothalamic hypoactivation. The discrepancy increases with development. There is an elevated cytokine response in endothelial cells which induces nitric oxide (NO) production and retarded development of the hypothalamus. Cigarette smoke also induces NO production and retards hypothalamic development by augmented apoptosis. Zinc inhibits this effect in mouse thymocytes. Fetal haemoglobin (HbF) induces hypoxia, which is a stimulator of the immune response while vasodilator gases (carbon monoxide (CO), NO) reduce hypothalamic function. The hypothalamic failure to sense elevated blood pyrogens induces toxic shock - a feature of SIDS.

Animals↗
PubMed2000

Sudden infant death syndrome: hypothalamic failure to sense elevated blood pyrogens.

Sudden infant death syndrome (SIDS) is frequently associated with a mild infection, the incidence peaking during the third month of life. We hypothesize that the neonatal immaturity of both the acute febrile response and hypothalamus promote neonatal protection from SIDS. Vagal afferents modify the febrile response. Vagotomized rodents displayed a loss of febrile responsiveness in a 'non-sensing' brain. The failure of a 'non- sensing' brain to react to elevated blood pyrogens leads to failure of the febrile response and to a shock-like state. SIDS infants may appear well yet, within hours of this observation, may be found dead. There is a mismatch between the acute febrile response and hypothalamic hypoactivation. The discrepancy increase wtih development. There is an elevated cytokine response in endothelial cells which induces nitric oxide (NO) production and retarded development of the hypothalamus. Cigarette smoke also induces NO production and retards hypothalamic development by augmented apoptosis. Zinc inhibits this effect in mouse thymocytes. Fetal haemoglobin (HbF) induces hypoxia which is a stimulator of the immune response, while vasodilator gases (carbon monoxide (CO), NO) reduce hypothalamic function. The hypothalamic failure to sense elevated blood pyrogens induces toxic shock--a feature of SIDS.

Animals↗
PubMed1984

Specific absorption with monoclonal antibodies to muramyl dipeptide of the pyrogenic and somnogenic activities of rabbit monokine.

It is well established that muramyl dipeptide (MDP) can induce fever and enhance slow-wave sleep. Recently, crude or purified supernatants of activated macrophages containing endogenous pyrogen (EP) were also shown to enhance slow-wave sleep. These similarities and the recent finding that a mammalian factor that enhances slow-wave sleep is a muramyl peptide triggered us to study the possibility of the presence of this bacterial structure in the EP molecule. In the present study, EP was produced by stimulation of rabbit peritoneal cells with a nonpyrogenic, nonsomnogenic analog of MDP. The EP-containing supernatant lost its pyrogenicity and somnogenicity after passage over an immunoadsorbent column of monoclonal anti-MDP but not of another monoclonal antibody of different specificity. High percentage of the EP was recovered by elution of the anti-MDP columns with HCl/glycine buffer. Results suggest that bacterial muramyl peptides may be incorporated by mammalian cells into substances that act in picomole quantities to mediate immunological and physiological processes. In addition, the technique may be useful to extract interleukin 1 for structural studies.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1960

Pathogenesis of fever: effects of various endogenous pyrogens upon the level of circulating granulocytes in normal rabbits.

The endogenous pyrogen in the serum or plasma of rabbits 2 hours after the intravenous injection of typhoid vaccine had a marked effect on the circulating leucocytes of normal rabbits. Immediately following intravenous injection there was a brief, but marked, granulocytopenia which was quickly followed by a granulocytosis. Under the same circumstances pooled heterologous serum or plasma from normal rabbits produced no fever or significant change in the level of circulating leucocytes. The cell-free fluid of sterile peritoneal exudates produced a marked leucocytosis without a preceding leucopenia when injected intravenously into normal rabbits. When comparably pyrogenic doses of typhoid vaccine were injected in the same manner no significant change in the level of circulating leucocytes occurred. The relevance of these findings to the pathogenesis of fever is discussed.

Agranulocytosis↗
PubMed1968

Studies on the pathogenesis of fever. XVI. Purification and further chemical characterization of granulocytic pyrogen.

Small quantities of highly purified granulocytic pyrogen have been separated from contaminating proteins by disc electrophoresis in polyacrylamide gel. The biologically active material thus isolated was shown to be electrophoretically homogeneous at pH 9 and pH 3.8. Earlier work on the chemical properties of the pyrogen molecule has been extended to include: (a) estimation of its molecular weight by gel filtration; (b) demonstration of free sulfhydryl groups essential for its biological activity; and (c) evidence that it is not inactivated by exhaustive extraction with ethanolether or n-heptane.

Animals↗
PubMed1970

Studies on the pathogenesis of fever. XVII. The cationic control of pyrogen release from exudate granulocytes in vitro.

Evidence has been presented that the release of active endogenous pyrogen from rabbit exudate granulocytes incubated in isotonic NaCl is a relatively prompt energy-dependent process that is preceded by a rise in intracellular pyrogen, and involves a rise in total intracellular cations and an increased permeability of the cell membranes, but does not require the synthesis of new proteins.

Animals↗
PubMed1977

Differences in pyrogen production by mononuclear phagocytes and by fibroblasts or HeLa cells.

Phagocytosis of bacteria stimulates "professional" phagocytes to produce and release endogenous pyrogen (EP), the protein that mediates fever. To determine whether "nonprofessional" phagocytes also have this capacity, mouse and human fibroblasts and HeLa cells were cultured after ingestion of latex or chicken erythrocytes (CE), and EP release into culture supernate measured by mouse assay. No detectable pyrogen was released by these cell types after phagocytosis, whereas both latex and CE stimulated EP production by cultured mouse macrophages. These studies support the hypothesis that only professional phagocytes of bone marrow origin synthesize EP and induce fever.

Animals↗