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[Effect of drugs on the pyrogenic reactivity of sheep].

Investigated was the effect of coffeine, bromine, atropine, and pilocarpine on the course of experimentally induced (by means of an Alcaligenes falcalis lipopolysaccharide) pyrogenic response in sheep. It was noted that coffeine aggravated, and bromine and partly atropine made more feasible the manifestation of the pyrogenic response in these animals. Pilocarpine enhanced some of the functions of the body while this reaction tookplace. Some arguments are given to elucidate the mechanism of the pyrogenic response.

Alcaligenes

Differences of adrenal stress control mechanisms in subjects with glaucoma and normal subjects. Effect of vasopressin and pyrogen.

Various types of glaucomatous and normal subjects were tested for the adequacy of the stress response of their hypothalamic-pituitary-adrenal axis to pyrogen and vasopressin. With pyrogen, a significant response of elevation of plasma cortisol levels was positively correlated with ocular pressure and changes of the optic disc. Those subjects with increased ocular pressure and optic disc cupping and pallor had greater rises of plasma cortisol levels. With vasopressin, a decreased response of plasma cortisol levels was negatively correlated with the degree of elevated ocular pressure. Those subjects with increased ocular pressure and lower tonographic outflow facilities had smaller rises of plasma cortisol levels. Both tests indicated a disturbance of the hypothalamic-pituitary-adrenal axis in subjects with glaucoma.

Female

Detection of streptococcal pyrogenic exotoxin genes by a nested polymerase chain reaction.

Severe invasive disease associated with group A Streptococcus (GAS) has recently increased in frequency. Isolates of GAS from normally sterile sites were examined for the streptococcal pyrogenic exotoxin genes spe A, spe B and spe C to determine if they play a role in this disease. Four primers for each gene were used in a nested polymerase chain reaction (PCR) configuration. The first PCR generated fragments of 818, 1106, and 801 bp, respectively, for the extotoxin genes. The second PCR generated fragments of 500, 912 and 654 bp for the spe A, spe B and spe C genes using the fragments from the first PCR as template. Of 62 strains tested, 35 (56%) contained the spe A gene, and 17 (27%) contained the spe C gene. All GAS strains studied, regardless of disease association, contained the spe B gene. These data corroborate accumulating evidence that the genes encoding pyrogenic exotoxin types B and C are not associated with severe invasive streptococcal illness including streptococcal toxic shock-like syndrome. This PCR-based gene detection system has clinical and epidemiologic applications because of its ease of performance, non-isotope labelling, high specificity and sensitivity, and lack of requirement for purified DNA.

Bacterial Proteins

Pyrogenicity of polyadenylic.polyuridylic acid in rabbits.

Polyadenylic.polyuridylic acid injected intravenously into rabbits produced a rapid-onset, monophasic fever. Pyrogenic tolerance occurred in rabbits following daily injections of polyadenylic.polyuridylic acid. However, direct injection of the agent into the preoptic anterior hypothalamic region of rabbit's brain produced a markedly different fever. After an intrahypothalamic injection of polyadenylic.polyuridylic acid, fever was delayed in onset and persisted for a longer period. At room temperature, the fever was due to both increased metabolism and cutaneous vasoconstriction. In a colder atmosphere the fever was due solely to increased metabolism, whereas in the heat the fever was due to reduction in cutaneous blood flow and respiratory evaporative heat loss. In addition, the fever induced by intravenous polyadenylic.polyuridylic acid injection was reversed by a cyclooxygenase inhibitor, but not by a protein synthesis inhibitor. Polyadenylic.polyuridylic acid was shown to stimulate PGE2 production from rabbit's hypothalamus in vitro. The results reveal that this agent is a prostaglandin-dependent pyrogen.

Animals

The effects of the protein synthesis inhibitor anisomycin on the febrile responses to intracerebroventricular injections of bacterial pyrogen, arachidonic acid and prostaglandin E2.

1. Anisomycin (15 mg/kg) was administered s.c. to cats at ambient temperatures of 5 degrees C, 20 degrees C and 38 degrees C. It produced biphasic effects on body temperature at 5 degrees C and 20 degrees C, an initial fall in temperature followed by a rise in body temperature, and a rise in body temperature of long latency at 38 degrees C. 2. Anisomycin (15 mg/kg) attenuated the hyperthermic responses to centrally injected PGE2 (1 microgram) at all ambient temperatures studied and also completely abolished the hyperthermic response to arachidonic acid (100 ng i.c.v.) at 20 degrees C. 3. Shigella dysenteriae (100 ng i.c.v.) raised the body temperature of cats by increasing heat production and reducing heat loss at 5 degrees C and 20 degrees C, and by increasing heat conservation at 38 degrees C. Anisomycin (15 mg/kg s.c.) pretreatment did not affect the temperature responses to the pyrogen at 20 degrees C and 38 degrees C, but did reduce the responses to Shigella dysenteriae (100 ng and 1 microgram i.c.v.) at 5 degrees C. 4. Anisomycin (15 mg/kg s.c.) was administered to cats, 90 min after the injection of Shigella dysenteriae (100 ng i.c.v.), at 20 degrees C at the onset of hyperthermia in control experiments. Under these conditions, no hyperthermia was observed over a 2 h period following anisomycin injection. 5. It is concluded that anisomycin interferes with pyrogen induced fever by acting at a site after PGE2 in the pathway to fever.

Animals

Response of body temperature and serum iron concentration to repeated pyrogen injection in rabbits.

We measured body temperature and serum iron concentration after five daily consecutive injections of febrile doses of Salmonella typhosa lipopolysaccharide (0.1 micrograms/kg) and two doses of Staphylococcus aureus cell walls (1 x 10(7) and 5 x 10(7) cells) in rabbits. Tolerance to endotoxin injection, as manifest by a significant attenuation in the body temperature elevation, developed after the first injection of endotoxin. The endotoxin-induced fall in serum iron concentration was attenuated significantly by the 5th day of endotoxin injection. In contrast, no tolerance developed in either the body temperature or serum iron response following repeated daily injections of S. aureus. Rabbits rendered tolerant to endotoxin showed normal febrile and serum iron responses to subsequent S. aureus injection. Rabbits given serial injections of S. aureus, although not tolerant to S. aureus itself, exhibited attenuated body temperature responses but not serum iron responses to endotoxin injection. We suggest that repeated injection of endotoxin diminishes the ability of endotoxin to stimulate endogenous pyrogen (EP) synthesis and/or release, a property not shared by the gram-positive pyrogen S. aureus. However, repeated injection of S. aureus weakens the central endotoxin-EP pathway.

Animals

The effect of an inhibitor of adenylate cyclase on the development of pyrogen, prostaglandin and cyclic AMP fevers in the rabbit.

An exotoxin of Bacillus thuringiensis known to inhibit adenylate cyclase in vitro has been used to investigate the role of cyclic AMP in the pathogenesis of fever in the rabbit. Intra-hypothalamic microinjections of the exotoxin are non-pyrogenic and significantly attenuate the hyperthermia caused by intrahypothalamic microinjections of both bacterial pyrogen (endotoxin) and prostaglandin E1. The hyperthermia produced by dibutyrl cyclic AMP is not affected by the exotoxin. These results support the idea that adenylate cyclase is activated during the development of fever in the rabbit.

Adenine Nucleotides

Influence of endogenous pyrogen on the cerebral prostaglandin-synthetase system.

The biotransformation of arachidonic acid to prostaglandins in vitro is specifically augmented by endogenous pyrogen to a degree depending on the concentration applied, providing that the microsomal fraction of the cerebral cortex is used as prostaglandin-synthetase system. This effect is inhibited by non-steroidal anti-inflammatory agents. These findings are compatible with the hypothesis that prostaglandins might act as mediators of the febrile reaction induced by endogenous pyrogen.

Animals

Interleukin-1 beta analogues with markedly reduced pyrogenic activity can stimulate secretion of adrenocorticotropic hormone in rats.

We examined the adrenocorticotropic hormone-releasing activities of several human interleukin-1 beta analogues that have markedly reduced pyrogenic activities in rats. Among the analogues tested, [Gly4]-, [Leu93]- and [1-148]-interleukin-1 beta increased the plasma adrenocorticotropic hormone level to almost that induced by authentic human interleukin-1 beta. Modifications of the N-terminus of the authentic molecule, i.e., [7-153]- and [Des-Ala1, Asp4]-interleukin-1 beta, significantly reduced the hormone-releasing activity. These data suggest that the adrenocorticotropic hormone-releasing activity of human interleukin-1 beta resides in the N-terminal structure of the authentic peptide and can be separated from its pyrogenic activity.

Adrenocorticotropic Hormone

Effects of methylxanthine drugs on pyrogen-induced hyperthermia.

The hyperthermic response to pyrogen was not potentiated by caffeine or theophylline administered i.p. into cats or rabbit. Injection of these drugs into the anterior hypothalamus or into the third cerebral ventricle in cats was also without effect on pyrexia. These results support the hypothesis that cyclic AMP in the anterior hypothalamus does not mediate pyrogen-induced hyperthermia in cats.

Animals

Dexamethasone inhibits the pyrogenic activity of prostaglandin F2 alpha, but not prostaglandin E2.

The effect of dexamethasone on prostaglandin (PG) E2- and PGF2 alpha-induced fever was studied in rats. Intracerebroventricular injection of PGE2 and PGF2 alpha (500 ng) induced increases in body temperature (maximal temperature rises of 0.97 +/- 0.13 degrees C and 0.78 +/- 0.18 degrees C, respectively, vs. vehicle 0.12 +/- 0.09 degrees C) of unrestrained rats maintained within the thermoneutral zone. PGE2-induced fever peaked earlier and the defervescence was faster when compared to the response induced by PGF2 alpha. Subcutaneous pre-administration of dexamethasone (0.5 mg/kg) did not affect PGE2-induced fever (maximal temperature rise of 1.00 +/- 0.08 degrees C), but completely prevented the pyrogenic activity of PGF2 alpha (maximal temperature rise of 0.16 +/- 0.16 degrees C). Neither PGE2- nor PGF2 alpha-induced fever was significantly altered (maximal temperature rises of 0.90 +/- 0.11 degrees C and 0.64 +/- 0.14 degrees C, respectively) by intraperitoneal administration of indomethacin (2 mg/kg). These results demonstrate for the first time that glucocorticoids, in addition to inhibiting endotoxin- and cytokine-induced fever, can also modulate the pyrogenic activity of some prostaglandins, possibly via suppression of the synthesis of corticotropin-releasing factor, indicating that multiple mechanisms may be involved in the antipyretic activity of these steroids.

Animals

Fever and changes in plasma zinc and iron concentrations in the goat: the role of leukocytic pyrogen.

In goats with trypanosomiasis (T. vivax or T. congolense) no marked fall in plasma zinc concentration was seen despite high temperature peaks, whereas plasma concentrations of iron tended to undergo some decline. In goats infected with Ehrlichia phagocytophila, there was a marked decline in plasma zinc and iron to low values on the 3rd and 4th day, respectively. Circulating endogenous pyrogen (EP) or leukocytic endogenous mediator (LEM) could not be detected in plasma from febrile goats with tick-borne fever. The intravenous injection of leukocytic pyrogen (LP) in kids caused characteristic monophasic febrile reactions, whereas no significant changes in plasma trace metals were found. So, previous evidence purporting to show that LP is similar to or may be identical with LEM is demonstrably inconclusive. Intravenous injection of E. coli lipopolysaccharide (LPS) or staphylococcal enterotoxin B (SEB) induced fever and lowering of plasma zinc and iron concentrations. The decrease in those trace metal values was more persistent in goats given SEB than in those given E. coli LPS. After intramammary infusion of SEB or E. coli LPS, fever and significant decreases in plasma zinc and iron concentrations were observed but no clear relationship was found between the temperature responses and the alterations in plasma trace metal concentrations. Furthermore, the decrease in plasma iron concentration developed more rapidly in goats given SEB than in those given E. coli LPS, whereas the decrease in plasma zinc concentrations in the former was more delayed. These data support the theory that the concentrations of zinc and iron in plasma are regulated by different mechanisms, whereas febrile reactions are mediated by another type of endogenous protein.

Animals

Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens.

In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.

Animals

Effects of prostaglandin antagonist SC-19220 on body temperature and on hyperthermic responses to prostaglandin E-1 and leukocytic pyrogen in the cat.

Intravenous injection of SC-19220 (3-9 mg/kg) caused dose-related hypothermic responses in cats. Repeated administration of SC-19220 resulted in tolerance to its hypothermic action. During SC-19220-induced hypothermia, the hyperthermic activity of both prostaglandin E-1 and leukocytic pyrogen was reduced or abolished. Neither prostaglandin E-1 nor leukocytic pyrogen was antagonized when given shortly after recovery from SC-19220-induced hypothermia or by doses of SC-19220 which did not cause hypothermia. Although these results may indicate a role of prostaglandins in normal physiological thermoregulation, it is also possible that production of hypothermia by SC-19220 is unrelated to prostaglandin antagonism.

Animals

Pyrogens fail to produce fever in the snakes Psammophis phillipsii and Lamprophis fuliginosus.

1. Preferred body temperature of five diurnal, Psammophis philipsii and three nocturnal, Lamprophis fuliginosus, snakes was measured in a thermal gradient chamber by indwelling colonic thermocouples, before and after injection of a variety of pyrogens. 2. The snakes achieved their preferred body temperature by moving up and down in the gradient chamber; it was about 33 degrees C for P. phillipsii and 25 degrees C for L. fuliginosus. 3. The snakes did not develop fever in response to any of the pyrogens, whether gram-negative or gram-positive in origin, either on the day of injection or on the subsequent day. 4. We believe that fever is rare amongst reptiles.

Animals

Pyrogens fail to produce fever in the leopard tortoise Geochelone pardalis.

1. The body temperature of seven tortoises, Geochelone pardalis, was measured in a thermal gradient chamber, by indwelling thermocouples, after injection of various pyrogens. 2. The tortoises regulated their body temperature by moving in the chamber. 3. The tortoises did not develop fever in response to any of the pyrogens we tested. 4. The results support the contention that fever in reptiles is not ubiquitous.

Animals

Changes in pre- or postsynaptic adrenergic mechanisms modify the thermoregulatory responses produced by pyrogen in rabbits.

1. Thermoregulatory responses to BHT 920, prazosin (PRA) and 6-hydroxydopamine (6-OHDA) were investigated in pyrogen (lipopolysaccharide Escherichia coli, LPS) treated rabbits. 2. All the compounds in question, despite their different selectivity for pre- or postsynaptic adrenergic structures, significantly reduced pyrogen fever. Antipyresis was associated with inhibition of the metabolic rate. 3. The role of adrenergic mechanisms in fever, with particular respect to those of postsynaptic alpha-2, is discussed.

Adrenergic alpha-Agonists