Studies on the Pathogenesis of Fever

A substance with pyrogenic properties appears in the blood streams of rabbits made febrile by the intravenous inoculation of the PR8 strain of influenza A and Newcastle disease viruses (NDV). By means of a technique involving passive transfer of sera from animals given virus to recipient rabbits, the titer of circulating pyrogen was found to be closely correlated with the course of fever produced by virus. Certain properties of the pyrogen are described which differentiate it from the originally injected virus and suggest that the induced pyrogen is of endogenous origin. These properties resemble those of endogenous pyrogens occurring in other forms of experimental fever. The source of virus-induced pyrogen is unknown. In vitro incubation of virus with various constituents of the circulation did not result in the appearance of endogenous pyrogen. Granulocytopenia induced by HN2 failed to influence either fever or the production of endogenous pyrogen in rabbits injected with NDV. Similarly, the intraperitoneal inoculation of NDV into prepared exudates did not modify the febrile response. These findings do not lend support to the possibility that the polymorphonuclear leukocyte is a significant source of endogenous pyrogen in virus-induced fever. It is concluded that the liberation of an endogenous pyrogen from some as yet undefined source is an essential step in the pathogenesis of fever caused by the influenza group of viruses.

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Studies on the Pathogenesis of Fever With Influenzal Viruses

Atkins

Huang

1958

“…In addition, when bacterial endotoxin is incubated with polymorphonuclear leucocytes in vitro, the endotoxin is inactivated, and the endogenous pyrogen is released from the leucocytes (17). Finally, there is indirect evidence that leucocytic and endogenous pyrogens act upon the thermoregulatory centers of the brain (14). Despite the foregoing evidence, the observations of Bennett, Petersdorf, and Keene (5) are frequently cited as contradicting the endogenous pyrogen hypothesis (5-13).…”

Section: Comparative Concentrations Of Transferable Pyrogen In Sera Omentioning

confidence: 63%

Studies on the Pathogenesis of Fever

Gillman

Bornstein

Wood

1961

Self Cite

During the febrile response to intravenous endotoxin, there appears in the circulation an endogenous pyrogen, the properties of which are indistinguishable from those of the fever-producing substance contained in polymorphonuclear leucocytes (1, 2). Whereas most of the injected endotoxin is cleared from the blood stream during the latent period, the endogenous factor becomes demonstrable with the onset of fever and is present in a concentration which parallels the degree of pyrexia (2). The establishment of these facts has led to the concept that the hypothalamic stimulus which causes endotoxin fever is provided, not by the injected endotoxin itself, but rather by the endogenous pyrogen released from toxin-injured leucocytes (2, 3).Despite the numerous experimental observations which support it (3, 4), the endogenous pyrogen hypothesis has been challenged (5, 6) on the grounds that during endotoxin fever endogenous pyrogen was not demonstrable in the sera of animals previously made leucopenic with nitrogen mustard. The apparent absence of the circulating endogenous factor under these circumstances has been interpreted as evidence against the thesis that it plays a central role in endotoxin fever (5-13).Because of the importance which has been placed upon this evidence (5-13), it has been reexamined in the present study. MethodsElimination of Extraneous Pyrogens.--All glassware and needles were rendered pyrogenfree by exposure to 180°C for 2 hours. Normal saline was autoclaved and was demonstrated to be non-pyrogenic.

“…The presence of an endogenous pyrogen in the blood of normal animals given endotoxin intravenously (13)(14)(15), differing in properties and action from the exogenous pyrogen (9,16,35), is well established. The recognition of the polymorphonuclear leucocyte as the source of serum pyrogen is equally well established: leucocytic pyrogen (18,(20)(21)(22) appears to be identical with the circulating endogenous pyrogen, and animals made severely leucopenic by treatment with a nitrogen mustard prior to injection of endotoxin lack endogenous pyrogen (24,25).…”

Section: Tolerance To Pyrogenicit¥mentioning

confidence: 99%

“…Following the demonstration by Grant and Whalen (13) of an endogenous pyrogen in the blood of rabbits injected with typhoid vaccine, an impressive series of experiments by Wood and coworkers (14)(15)(16)(17) has led to the hypothesis that endotoxininduced fever is a consequence of the action of the exogenous pyrogen upon the leucocytes, or other cells, causing release of endogenous pyrogen which then acts upon the thermoregulatory centers of the brain (4). From an equally impressive series of researches, Bennett and associates (9,(18)(19)(20)(21)(22)(23)(24)(25) have shown that the fever seen after administration of endotoxin requires neither significant numbers of circulating leucocytes nor the presence of endogenous serum pyrogen, and have postulated a dual mechanism, involving a direct action of endotoxin, possibly accounting for the biphasic nature of the febrile response (3).…”

mentioning

confidence: 99%

Further Studies on Passive Transfer of Tolerance to Pyrogenicity of Bacterial Endotoxin

Freedman

1960

In a previous report (1) we have described the passive transfer of tolerance to pyrogenicity of bacterial endotoxin. Such transfer was shown to depend upon the manner in which tolerance was induced in the donor animal, and this parameter has been further investigated. Both prolonged administration of the bacterial lipopolysaccharide, through 5 weeks, and daily injections of a large constant dose of endotoxin for a few days, permit demonstration of passive transfer, depending upon the magnitude of the test dose of the pyrogen in the recipient.Intravenously injected doses of endotoxin which cause a fever also elicit an almost immediate peripheral granulocytopenia. It has been thought that development of tolerance to the fever-producing effect of the toxin, which is accompanied by refractoriness to various other responses, extends to the acute leucopenia (2-5). If tolerance to leucopenia regularly paralleled tolerance to pyrogenicity the hypothesis suggesting endogenous leucocytic pyrogen as the mediator of endotoxin-induced fever (4) would be strengthened. Not finding refractoriness to the drop in peripheral white cell count in our rabbits passively tolerant to the pyrogenicity of endotoxin, we have studied the changes in numbers of circulating leucocytes in endotoxin-treated animals. We have not found tolerance to the leucopenia under conditions yielding substantial tolerance to pyrogenicity. A search of the literature largely supports this finding that tolerance to the pyrogenic effect becomes manifest without change in the acute leucopenic response (6)(7)(8)(9)(10)(11)(12).Following the demonstration by Grant and Whalen (13) of an endogenous pyrogen in the blood of rabbits injected with typhoid vaccine, an impressive series of experiments by Wood and coworkers (14-17) has led to the hypothesis that endotoxininduced fever is a consequence of the action of the exogenous pyrogen upon the leucocytes, or other cells, causing release of endogenous pyrogen which then acts upon the thermoregulatory centers of the brain (4). From an equally impressive series of researches, Bennett and associates (9,(18)(19)(20)(21)(22)(23)(24)(25) have shown that the fever seen after administration of endotoxin requires neither significant numbers of circulating leucocytes nor the presence of endogenous serum pyrogen, and have postulated a dual mechanism, involving a direct action of endotoxin, possibly accounting for the biphasic nature of the febrile response (3). 619on May 7, 2018 jem.rupress.org Downloaded from