Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1981 Oct 1;154(4):1212–1224. doi: 10.1084/jem.154.4.1212

Role of prostaglandin E in the biphasic fever response to endotoxin

RC Skarnes, SK Brown, SS Hull, JA McCracken
PMCID: PMC2186491  PMID: 7288365

Abstract

Biphasic fevers were induced in sheep with intravascular infusions or injections of 4-10 μg (80-200 ng/kg) of endotoxin, whereas monophasic fevers were obtained with doses of 1-2/μg (20-40 ng/kg). A marked increase in arterial blood pressure invariably accompanied the onset of fever; the latency of responses to the higher and lower doses of endotoxins averaged 26 min and 42 min, respectively. Prostaglandin (PG) assays of plasma from the carotid artery and jugular vein during fever episodes revealed a surge of PGE and PGF coincident with the pressor response and the first phase of fever, but PG were not detected in plasma samples taken throughout the second phase of fever. PG measurements of arterial and venous plasma collected at a distal site (hind limb) showed a similar surge of PGE and PGF in association with the early fever response, indicating that intravascular PG synthesis and release represents a generalized systemic response to circulating endotoxin. Carotid arterial infusions of PGE(2) produced immediate monophasic fevers and pressor responses, whereas PGD(2) infusions produced an immediate pressor effect but no fever. Infusions of PGF(2α) or prostacyclin, however, evoked neither fever nor pressor effects. Intracarotid infusions of leukocyte pyrogen (LP) caused monophasic fevers with latent periods of 15-20 min but pressor responses were not seen and neither PGE nor PGF were detected in plasma samples from the carotid artery or jugular vein before or during fever. Indomethacin, a potent inhibitor of arachidonic acid metabolism, blocked fever responses to endotoxin and to LP. These findings implicate PGE as the mediator of the early phase of endotoxin fever and imply a role for another pyrogenic metabolite ofarachidonic acid in the mediation of the second phase of fever, i.e., the phase associated with circulating LP. It is possible that both pyrogenic metabolites are generated within the vascular compartment, reaching thermoregulatory centers of the brain by transfer across the blood-brain interface.

Full Text

The Full Text of this article is available as a PDF (695.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ATKINS E. Pathogenesis of fever. Physiol Rev. 1960 Jul;40:580–646. doi: 10.1152/physrev.1960.40.3.580. [DOI] [PubMed] [Google Scholar]
  2. Blackwell G. J., Flower R. J., Herman A. G. Effect of endotoxin on 15-hydroxyprostaglandin dehydrogenase in the rabbit jejunum and lung. Arch Int Pharmacodyn Ther. 1976 Apr;220(2):325–326. [PubMed] [Google Scholar]
  3. Cranston W. I., Duff G. W., Hellon R. F., Mitchell D., Townsend Y. Evidence that brain prostaglandin synthesis is not essential in fever. J Physiol. 1976 Jul;259(1):239–249. doi: 10.1113/jphysiol.1976.sp011464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cranston W. I., Hellon R. F., Mitchell D. A dissociation between fever and prostaglandin concentration in cerebrospinal fluid. J Physiol. 1975 Dec;253(2):583–592. doi: 10.1113/jphysiol.1975.sp011208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Davidson E. M., Doig M. V., Ford-Hutchinson A. W., Smith M. J. Prostaglandin and thromboxane production by rabbit polymorphonuclear leukocytes and rat macrophages. Adv Prostaglandin Thromboxane Res. 1980;8:1661–1663. [PubMed] [Google Scholar]
  6. Davies P., Bonney R. J., Humes J. L., Kuehl F. A., Jr Synthesis and release of oxygenation products of arachidonic acid by mononuclear phagocytes in response to inflammatory stimuli. Inflammation. 1977 Dec;2(4):335–344. doi: 10.1007/BF00921012. [DOI] [PubMed] [Google Scholar]
  7. Ferreira S. H., Moncada S., Vane J. R. Indomethacin and aspirin abolish prostaglandin release from the spleen. Nat New Biol. 1971 Jun 23;231(25):237–239. doi: 10.1038/newbio231237a0. [DOI] [PubMed] [Google Scholar]
  8. Ferreira S. H., Vane J. R. Prostaglandins: their disappearance from and release into the circulation. Nature. 1967 Dec 2;216(5118):868–873. doi: 10.1038/216868a0. [DOI] [PubMed] [Google Scholar]
  9. Greisman S. E., Woodward C. L. Mechanisms of endotoxin tolerance. VII. The role of the liver. J Immunol. 1970 Dec;105(6):1468–1476. [PubMed] [Google Scholar]
  10. Hamberg M., Svensson J., Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci U S A. 1975 Aug;72(8):2994–2998. doi: 10.1073/pnas.72.8.2994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Harper M. J., Valenzuela G., Hodgson B. J. Accelerated ovum transport in rabbits induced by endotoxin. Changes in prostaglandin levels and reversal of endotoxin effect. Prostaglandins. 1978 Jan;15(1):43–63. doi: 10.1016/s0090-6980(78)80004-5. [DOI] [PubMed] [Google Scholar]
  12. Humes J. L., Bonney R. J., Pelus L., Dahlgren M. E., Sadowski S. J., Kuehl F. A., Jr, Davies P. Macrophages synthesis and release prostaglandins in response to inflammatory stimuli. Nature. 1977 Sep 8;269(5624):149–151. doi: 10.1038/269149a0. [DOI] [PubMed] [Google Scholar]
  13. Kessler E., Hughes R. C., Bennett E. N., Nadela S. M. Evidence for the presence of prostaglandin-like material in the plasma of dogs with endotoxin shock. J Lab Clin Med. 1973 Jan;81(1):85–94. [PubMed] [Google Scholar]
  14. Laburn H., Mitchell D., Rosendorff C. Effects of prostaglandin antagonism on sodium arachidonate fever in rabbits. J Physiol. 1977 May;267(2):559–570. doi: 10.1113/jphysiol.1977.sp011826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. McDONALD I. R., GODING J. R., WRIGHT R. D. Transplantation of the adrenal gland of the sheep to provide access to its blood supply. Aust J Exp Biol Med Sci. 1958 Feb;36(1):83–95. doi: 10.1038/icb.1958.10. [DOI] [PubMed] [Google Scholar]
  16. Milton A. S., Wendlandt S. Effects on body temperature of prostaglandins of the A, E and F series on injection into the third ventricle of unanaesthetized cats and rabbits. J Physiol. 1971 Oct;218(2):325–336. doi: 10.1113/jphysiol.1971.sp009620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Myers R. D., Rudy T. A., Yaksh T. L. Fever produced by endotoxin injected into the hypothalamus of the monkey and its antagonism by salicylate. J Physiol. 1974 Nov;243(1):167–193. doi: 10.1113/jphysiol.1974.sp010748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nakano J., Prancan A. V. Metabolic degradation of prostaglandin E1 in the lung and kidney of rats in endotoxin shock. Proc Soc Exp Biol Med. 1973 Nov;144(2):506–508. doi: 10.3181/00379727-144-37623. [DOI] [PubMed] [Google Scholar]
  19. Philipp-Dormston W. K., Siegert R. Identification of prostaglandin E by radioimmunoassay in cerebrospinal fluid during endotoxin fever. Naturwissenschaften. 1974 Mar;61(3):134–135. doi: 10.1007/BF00606298. [DOI] [PubMed] [Google Scholar]
  20. Piper P. J., Vane J. R., Wyllie J. H. Inactivation of prostaglandins by the lungs. Nature. 1970 Feb 14;225(5233):600–604. doi: 10.1038/225600a0. [DOI] [PubMed] [Google Scholar]
  21. Siegert R., Philipp-Dormston W. K., Radsak K., Menzel H. Mechanism of fever induction in rabbits. Infect Immun. 1976 Nov;14(5):1130–1137. doi: 10.1128/iai.14.5.1130-1137.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Skarnes R. C., Harper M. J. Relationship between endotoxin-induced abortion and the synthesis of prostaglandin F. Prostaglandins. 1972 Mar;1(3):191–203. doi: 10.1016/0090-6980(72)90004-4. [DOI] [PubMed] [Google Scholar]
  23. Stylos W., Howard L., Ritzi E., Skarnes R. The preparation and characterization of prostaglandin E1 antiserum. Prostaglandins. 1974 Apr 10;6(1):1–13. doi: 10.1016/s0090-6980(74)80035-3. [DOI] [PubMed] [Google Scholar]
  24. Wahl L. M., Olsen C. E., Sandberg A. L., Mergenhagen S. E. Prostaglandin regulation of macrophage collagenase production. Proc Natl Acad Sci U S A. 1977 Nov;74(11):4955–4958. doi: 10.1073/pnas.74.11.4955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Weidemann M. J., Peskar B. A., Wrogemann K., Rietschel E. T., Staudinger H., Fischer H. Prostaglandin and thromboxane synthesis in a pure macrophage population and the inhibition, by E-type prostaglandins, of chemiluminescence. FEBS Lett. 1978 May 1;89(1):136–140. doi: 10.1016/0014-5793(78)80539-0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES