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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↗
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↗
PubMed1979

Adherent cell function in murine T-lymphocyte antigen recognition. IV. Enhancement of murine T-cell antigen recognition by human leukocytic pyrogen.

A macrophage-dependent, antigen-specific murine T-cell proliferation assay was utilized to examine the role of soluble products of murine and human adherent cells in the activation of T lymphocytes. Highly purified human leukocytic pyrogen, and supernates from both murine and human mononuclear phagocytes-macrophages stimulated the immune T-cell proliferative response to the multideterminant antigens dinitrophenyl-ovalbumin and keyhole limpet hemocyanin. The implications of these studies and the relationship of leukocytic pyrogen to human lymphocyte-activating factor are discussed.

Animals↗
PubMed2000

Neural route of pyrogen signaling to the brain.

In the pathogenesis of systemic inflammation and fever, peripheral inflammatory and pyrogenic signals gain access to the brain via humoral and neural routes. One of the neural routes is represented by chemosensitive afferent fibers of the abdominal vagus. We summarize our recent studies of the role of the abdominal vagus in fever. We conclude that capsaicin-sensitive fibers traveling within the hepatic vagal branch constitute a necessary component of the afferent mechanism of the febrile response to low, but not high, doses of circulating pyrogens. We speculate that this mechanism is triggered by blood-borne prostaglandins of the E series.

Afferent Pathways↗
PubMed2000

Pyrogen sensing and signaling: old views and new concepts.

Fever is thought to be caused by endogenous pyrogenic cytokines, which are elaborated and released into the circulation by systemic mononuclear phagocytes that are activated by exogenous inflammatory agents and transported to the preoptic-anterior hypothalamic area (POA) of the brain, where they act. Prostaglandin (PG) E2 is thought to be an essential, proximal mediator in the POA, and induced by these cytokines. It seems unlikely, however, that these factors could directly account for early production of PGE2 following the intravenous administration of bacterial endotoxic lipopolysaccharides (LPS), because PGE2 is generated before the cytokines that induce it are detectable in the blood and the before cyclooxygenase-2, the synthase that they stimulate, is expressed. Hence other, more quickly evoked mediators are presumed to be involved in initiating the febrile response; moreover, their message may be conveyed to the brain by a neural rather than a humoral pathway. This article reviews current conceptions of pyrogen signalling from the periphery to the brain and presents new, developing hypotheses about the mechanism by which LPS initiates fever.

Brain↗
PubMed1991

Rapid preparation of pyrogen-free 2H2(18)O for human-nutrition studies.

We describe a compact ultrafiltration system for the removal of pyrogens and bacteria from water labeled with the stable isotopes of deuterium and oxygen-18. The ultrafiltration system is constructed from readily available commercial components and can achieve complete removal of pyrogens and bacteria from 1L contaminated water within 30 min. By use of our procedure, loss of the isotopically labeled water by retention in the filtration system was minimal. The purified water is suitable for both oral and intravenous administration to healthy human subjects participating in nutrition studies.

Deuterium↗
PubMed2000

Can sterile and pyrogen-free on-line substitution fluid be routinely delivered? A multicentric study on the microbiological safety of on-line haemodiafiltration.

BACKGROUND: Microbial contamination is characterized not only by the presence of bacteria, but also by high concentrations of biologically active by-products. They are potentially able to cross ultrafiltration and dialysis membranes and stimulate immunocompetent blood cells to synthesize cytokines. In turn, cytokine induction causes acute symptoms and has been incriminated in the long-term complications of haemodialysis patients. Infusion of large volumes of substitution fluids following ultrafiltration of microbially contaminated dialysis fluids may place patients on on-line therapies at particular risk. METHODS: In this study we evaluated 30 machines with a two-stage ultrafiltration system in routine clinical haemodiafiltration settings in six centres for 6 months. Microbiological safety was assessed monthly and at the last use of the filters by determining microbial counts, endotoxin concentration and cytokine-inducing activity. RESULTS: No pyrogenic episodes were observed during the study period. Double-filtration of standard dialysis fluid (range, <1-895 cfu/ml, 0.0028-4.6822 IU/ml) resulted in sterile substitution fluids with endotoxin concentrations well below the Ph.Eur. standard for haemofiltration solutions (range, 0.0014-0.0281 vs 0.25 IU/ml). Moreover, they did not differ from commercial haemofiltration solutions and depyrogenated saline. Likewise, there was no difference in the cytokine-inducing activity between the solutions tested. The high microbiological quality of the ultrafiltered dialysis fluid, which was in the same range as substitution fluid, translates into both the absence of cytokine induction by dialyser back-transport and a redundant safety mode of the on-line system by a second filtration step. CONCLUSION: On-line HDF treatment can routinely be provided with ultra-pure dialysis fluids and sterile substitution fluids at pyrogen-free levels. The online preparation of substitution fluids thus can be considered microbiologically safe.

Bacteria↗
PubMedDate not supplied

Catheter related bacterial infections mimic reactions to exogenous pyrogens during hemodialysis.

Pyrogenic reactions are characterized by fever, chills, hypotension, or a combination of these developing during or shortly after hemodialysis in a previously asymptomatic patient. The temporal association with treatment implicates exposure of the patient's blood to bacterial pyrogens from contaminated dialysate or a reused dialyzer. Routine body temperature monitoring is recommended to detect these exposures. The current study was prompted by the appearance of several symptomatic febrile episodes in patients who were asymptomatic and afebrile before treatment with high-flux hemodialysis. During a 6 month period, temperatures were measured with a digital oral thermometer before and after 9,605 high-flux hemodialyses in 163 patients. Elevations above 100 degrees F (37.8 degrees C) were observed during or after 33 dialyses in 15 patients. In 18 of these dialyses, the temperature was also elevated before treatment began. Four patients who had no symptoms or fever before dialysis accounted for febrile reactions during 11 of the remaining 15 dialysis treatments. Fever was accompanied by rigors during most of the episodes. Subsequent blood cultures grew Enterococcus faecalis (two), Enterobacter cloacae (two), and Pseudomonas aeruginosa and cepacia (one). All four patients had indwelling silastic double lumen venous catheters (PermCaths), all responded to intravenous antibiotics, and all required eventual removal of the catheter. The apparent precipitation of sepsis by dialysis indicates that shear forces caused by high pulsatile blood flow through the catheter may dislodge organisms that have colonized the lumen. Intraluminal instillation of antibiotics is suggested as a preventative measure.

Adult↗
PubMed1986

Severity of fever in influenza: differential pyrogenicity in ferrets exhibited by H1N1 and H3N2 strains of differing virulence.

Intracardial inoculation of large quantities (200 micrograms viral protein/kg body weight) of infectious or u.v.-inactivated purified influenza viruses into ferrets resulted in a rapid febrile response which was significantly lower for two recently isolated H1N1 viruses, A/USSR/90/77 and A/Fiji/15899/83, than for two virulent clones, 7a and 64c, of the A/Puerto Rico/8/34-A/England/939/69 (H3N2) reassortant virus system. These results, which are in accord with the severity of fever produced by these strains in intranasally infected ferrets, show that influenza virus strains can differ in their capacity to induce fever (probably reflecting a differential capacity to induce endogenous pyrogen from phagocytes) and indicate, since u.v.-inactivated strains are pyrogenic, that this may be due to differences between strains in the nature or amount of certain virion components.

Animals↗
PubMed1990

Comparison of cultured human mononuclear cells, Limulus amebocyte lysate and rabbits in the detection of pyrogens.

Isolated human mononuclear cells exposed to either lipopolysaccharide or Staphylococcus aureus secreted interleukin-1 like material. The secretion was concentration dependent. The minimal detectable level in the test solution of lipopolysaccharide and Staphylococcus aureus was 200 pg/ml and 10(5) cells/ml respectively. The sensitivity and specificity of the Limulus Amebocyte Lysate test, the rabbit pyrogen test and the monocyte test are compared. The monocyte test is proposed as an alternative in-vitro test to the rabbit pyrogen test.

Animals↗
PubMed1983

Interferon-inducing, pyrogenic and proclotting enzyme of horseshoe crab activation activities of chemically synthesized lipid A analogues.

Interferon-inducing, pyrogenic and proclotting enzyme of horseshoe crab activation activities of chemically synthesized lipid A analogues were investigated and compared with the same activities of a natural lipid A. These analogues are nonphosphorylated, C-1 or C-4' monophosphorylated and C-1,4' bisphosphorylated derivatives of beta-1,6-linked D-glucosamine disaccharide possessing both ester-bound and amide-bound fatty acid substituents. Fatty acid substituents of the analogues are tetradecanoyl (C14), (R)-3-hydroxytetradecanoyl (C14-OH) or (R)-3-tetradecanoyloxytetradecanoyl [C14-O-(C14)] groups. The biological activities of the samples were assayed after solubilization with triethylamine and complexing with bovine serum albumin. Interferon-inducing activity was exhibited by both the C-1 monophosphorylated compounds examined. Ester-bound and amide-bound fatty acid substituents of these compounds are both C14 or C14 and C14-OH, respectively. Nonphosphorylated, C-4' monophosphorylated and C-1,4' bisphosphorylated compounds possessing the same fatty acid substituents as those of the C-1 monophosphorylated compounds showed no detectable interferon-inducing activity. C-4' monophosphorylated compounds possessing C14-OH as ester-bound and C14-OH or C14-O-(C14) as amide-bound fatty acid substituents exhibited interferon-inducing activity, but nonphosphorylated compounds possessing the same fatty acid substituents did not. None of the analogues exhibited significant pyrogenicity nor proclotting enzyme of horseshoe crab activation activity under the conditions employed in this study.

Animals↗
PubMed1990

A study of the pyrogenic actions of interleukin-1 alpha and interleukin-1 beta: interactions with a steroidal and a non-steroidal anti-inflammatory agent.

1. The pyrogenic effects of intravenously administered human recombinant interleukin-1 alpha (IL-1 alpha) and IL-1 beta were studied in the rabbit. 2. Both cytokines produced dose-related increases in body temperature. At all doses studied (100-5000 u kg-1) both cytokines elicited a monophasic increase in body temperature, beginning 15 min and reaching a maximum 45 min after administration. 3. A comparison of thermal response index (TRI2, the magnitude of febrile responses over 2 h obtained by integrating the change in temperature in degrees C against time in hours) values indicated that IL-1 beta (500 u kg-1, TRI2 = 0.69 +/- 0.04, n = 4) was approximately 5 fold more potent than IL-1 alpha (2500 u kg-1, TRI2 = 0.73 +/- 0.07, n = 4, all values are means +/- s.e.means) in elevating body temperature. delta Tmax values for the above doses of IL-1 beta and IL-1 alpha were 0.60 +/- 0.06 and 0.61 +/- 0.03 respectively. When IL-1 alpha and IL-1 beta were heated for 30 min at 60 degrees C prior to administration no biological activity was observed. 4. A cyclo-oxygenase inhibitor, ketoprofen (3 mg kg-1) administered 15 min before either cytokine completely abolished the fever induced by both IL-1 alpha (2500 u kg-1) and IL-1 beta (500 u kg-1). 5. Intravenous administration of the steroidal anti-inflammatory agent dexamethasone (3 mg kg-1) 1 h before either cytokine attenuated the fever induced by IL-1 alpha (2500 u kg-1) and IL-1 beta (500 u kg-1). 6. The effects of ketoprofen and dexamethasone on IL-I pyrogenicity indicate that prostanoids are almost certainly involved in the responses. The different potencies of IL-l alpha and IL-1 beta may be related to their relative ability to stimulate prostanoid biosynthesis.

Animals↗
PubMed1990

Macrophage hyperreactivity to endotoxin induced by streptococcal pyrogenic exotoxin in rabbits.

Pretreatment of rabbits with streptococcal pyrogenic exotoxin (SPE) resulted in an enhancement of their febrile response to subsequent endotoxin challenge. This suggested that SPE may enhance the macrophage capacity to respond to endotoxin in vivo to produce an endogenous pyrogen. It was also demonstrated that peritoneal macrophages derived from SPE-treated rabbits exhibited hyperreactivity to endotoxin in vitro as assessed by endotoxin-induced increase in glucose consumption. These data indicate that SPE has the ability to enhance macrophage reactivity to endotoxin.

Animals↗
PubMed1978

Antidiuretic action of intravenous and intracerebral pyrogen in conscious rabbits.

1. In conscious rabbits an i.v. infusion of 30 or 60 microgram E. coli pyrogen/kg body wt. decreased urine flow from control of 1.13 +/- 0.11 (S.E. of mean) ml./min to 0.43 +/- 0.09 ml./min while urine osmolality increased from 212 +/- 16 to 679 +/- 82 m-osmole/kg H2O. Clearances of exogenous creatine and p-aminohippurate did not change significantly. 2. Plasma antidiuretic activity (rat bio-assay) increased from control of 15.5 +/- 4.2 to 56.8 +/- 5.5 muu./ml. at the top of antidiuresis. 3. Comparable urine flow and osmolality changes were evoked by a pyrogen dose of only 0.2 microgram per animal injected into the lateral cerebral ventricle. 4. The results suggest that in the rabbit pyrogen stimulates ADH release by an unknown central mechanism.

Animals↗
PubMed1979

Effects of central administation of probenecid on fevers produced by leukocytic pyrogen and PGE2 in the rabbit.

1. Single intracerebroventricular (I.C.V.) injections of probenecid (PBCD, 0.125--0.5 mg) enhanced and prolonged fever caused by I.V. administration of leukocytic pyrogen (LP) in rabbits resting in neutral (23 degrees C), cold (10 degrees C) and hot (30 degrees C) environments. Similar effects were produced by single I.C.V. injections of PBCD given before PGE2 (0.5 microgram) was injected I.C.V. in the three ambient temperatures. 2. Fever produced by IV. LP was also prolonged by infusion and by multiple injections of PBCD. 3. PBCD given I.P. (100 mg/kg) enhanced and prolonged fever caused by I.V. injection of Salmonella typhosa endotoxin. 4. Hyperthermia produced by I.C.V. PGE2 was not augmented by subsequent PBCD infusion. However, pre-treatment with PBCD followed by PGE2 injection and PBCD infusion caused hyperthermia that was very high and prolonged, and, in some cases, lethal. 5. Acetaminophen (2 mg, I.C.V.) and indomethacin (10 mg/kg, I.V.) lowered body temperature when given during fever induced by LP and prolonged by PBCD infusion. 6. The concentration of PGE in cerebrospinal fluid (c.s.f.) samples taken from the third or lateral ventricles rose or stabilized during PBCD infusions made during LP fever. However, similar changes in PGE concentration also occurred during control infusions when body temperature was low. 7. We conclude that termination of the actions of both central endogenous pyrogen and centrally administered PGE2, and the subsequent reduction of fevers produced by them, require a PBCD-sensitive facilitated transport system. The reduction of PBCD-prolonged PL fevers by antipyretics which block PGE synthesis suggests that prolongation by PBCD of LP fever is not due to blockade of PGE transport in a subsequent step in fever mediation per se, but is due to inhibition of transport of LP itself, or of other mediators associated with it.

Animals↗