Studies on the Pathogenesis of Fever

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Rabbit blood leukocytes ~ contain no detectable preformed pyrogen (4) and produce much less pyrogen than exudate leukocytes (about 1/50) when incubated in 0.15 ~ NaC1 (4). 3 After phagocytosis (5) or exposure to endotoxin (6), 3 on the other hand, they produce about the same or even greater amounts of pyrogen than exudate leukocytes. These findings suggest that blood leukocytes must be "activated" to release pyrogen in 0.15 ~ NaC1, and that activation of blood leukocytes automatically takes place after phagocytosis or exposure to endotoxin. The following experiments deal with the process of activation and the presence of an activating factor in acute peritoneal exudates. Materials and MethodsThe procedures used to exclude exogenous pyrogens (7), to prepare suspensions of leukocytes from both rabbit blood (4) and acute peritoneal exudates (7), to generate pyrogen from the cells (7), to assay the amount of pyrogen released (7,8), and to measure the cellular contents and fluid concentrations of Na and K (5, 9) and the fuid concentration of Ca (5, 9) and of protein (7) have all been previously described. Endotoxin (lipopolysaccharide B from Escherichia coli 011 l:B4) was purchased from Difco Laboratories, Detroit, Mich., and cycloheximide (Acti-dione), puromycin dihydrochloride, and acfinomycin D were obtained from Nutritional Biochemicals Corp., Cleveland, Ohio.

Section: Methodsmentioning

confidence: 99%

Section: Evidence That Activation Involves Synthesis Of Protein--thementioning

confidence: 99%

Section: Evolution Of Acute Peritonealmentioning

confidence: 99%

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Studies on the Pathogenesis of Fever

Moore

Cheuk

Morton

et al. 1970

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“…Chemical characterization of LP has shown it to be a protein molecule (6)(7)(8) and since the original discovery of its production by rabbit peritoneal exudate cells (9), many attempts have been made to determine the mechanism of its synthesis by leukocytes. With one exception (10), preformed pyrogen has not been obtained from disrupted rabbit cells (11,12).…”

mentioning

confidence: 99%

Studies on the Origin of Human Leukocytic Pyrogen

Nordlund

Root

Wolff

1970

Granulocytes and monocytes derived from inflammatory exudates or the peripheral circulation of several mammalian species (1-5) can be stimulated to release a pyrogen, leukocytic pyrogen (LP) 1, which induces a characteristic febrile response in rabbits. Chemical characterization of LP has shown it to be a protein molecule (6-8) and since the original discovery of its production by rabbit peritoneal exudate cells (9), many attempts have been made to determine the mechanism of its synthesis by leukocytes. With one exception (10), preformed pyrogen has not been obtained from disrupted rabbit cells (11,12). Its release in vitro has been shown to take place over a several hour period (4, 11, 12), to be dependent upon the temperature of incubation (11), and inhibited by agents which bind sulfhydryl groups in enzymes (13). These findings suggest that LP is either synthesized de novo or activated from a precursor substance after contact with an appropriate stimulating agent.In the present studies, the role of RNA and protein synthesis and the energy requirements for pyrogen release by human peripheral leukocytes activated by the ingestion of heat-killed bacteria have been investigated. The results reported here indicate that both transcription of messenger RNA and its translation by ribosomes into

“…It does, however, provide a simple method of obtaining granulocytic pyrogen for experimental use (5), and detailed studies of its kinetics and cationic control have revealed additional information about the cellular physiology of pyrogen production (11).…”

Section: Discussionmentioning

confidence: 99%

Studies on the Pathogenesis of Fever

Hahn

Cheuk

Moore

et al. 1970

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Previous studies on the release of endogenous pyrogen from rabbit exudate granulocytes in vitro (1) have revealed: (a) that large amounts of pyrogen are released when the cells are incubated (37°C) in 0.15 M NaC1; (b) that the release is blocked if physiological concentrations of K + are added to the medium; and (c) that inhibition by ouabain of K + transport into the cells nullifies the blocking effect of K + on the release process. These results indicate that deprivation of K ions causes exudate granulocytes to release endogenous pyrogen. Other cellular proteins (e.g., aldolase) are also released with the pyrogen (1). Furthermore, it has been found that sulfhydryl reagents, such as iodoacetate, p-chloromercuribenzoate, and N-ethylmaleimide, which inhibit the energyrequiring N a -K transport system of the cells (2), also inhibit the release process (3). The present studies were undertaken to investigate further the mechanism whereby K + deprivation stimulates exudate granulocytes to release pyrogen. Material and MethodsThe methods used to exclude extraneous pyrogens, to obtain exudate granulocytes from rabbits, and to assay granulocytic pyrogen, have been described elsewhere (4, 5).Plasma was separated from rabbit blood after the addition of heparin (10 IU per ml of Liquaemin, Organon, Inc., West Orange, N. J.). Endotoxin from Escherlchla coli 0111:B4 was purchased from Difco Laboratories, Detroit, Mich.; inulin from Mann Research Laboratories, Inc., New York, N.Y.; and puromycin dihydrochloride from Nutritional Biochemicals Corp,, Cleveland, Ohio; modified Hanks' solution (MH) was prepared as described in reference (6).