Blood-borne, albumin-bound prostaglandin E2 may be involved in fever.
Although the involvement of blood-borne PGE2 in fever has been hypothesized by several authors and has substantial experimental support, the current literature often rejects this hypothesis because several attempts to induce fever by a peripheral PGE2 failed. However, it is usually ignored that the amphipathic molecules of PGE2 are readily self-associating and that such an aggregation could have prevented the peripherally administered PGE2 (free form) from expressing its pyrogenic activity, thus leading to false negative results. To ensure disaggregation of PGE2, we prepared its complex within a carrier protein, human serum albumin (HSA). HSA was purified with activated charcoal and polymixin B-polyacrylamide gel and incubated with PGE2 for 1 h at 37 degrees C. Adult Chinchilla rabbits were injected intravenously with PGE2-HSA complex in either the higher (75 micrograms/kg PGE2:30 mg/kg HSA) or the lower (15 micrograms/kg:6 mg/kg) dose, and the rectal temperature (Tr) was measured. In the controls, either the ligand alone or the carrier alone was administered. At the higher dose, neither free PGE2 nor albumin alone was pyrogenic, whereas the PGE2-HSA complex produced a fever characterized by a short latency (<10 min) and a maximal Tr rise of 0.7 +/- 0.2 degrees C. At the lower dose, none of the substances affected the Tr. This study demonstrates a marked pyrogenic activity of the intravenous PGE2-HSA, but not of the free PGE2. Administration of a preformed complex may be more physiologically relevant than administration of the free ligand because of the ligand's disaggregation, protection from enzymatic degradation, and facilitated delivery to targets. Our study supports the hypothesis that peripheral PGE2 is involved in fever genesis.
Romanovsky
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Thermoregulation Laboratory, Legacy Holladay Park Medical Center, Portland, Oregon 97208, USA. aromanov@lhs.org
Ivanov
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Karman
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EK
D000818:Animals; D002682:Chinchilla; D003672:Defecation / Q000502:physiology; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology*; D007275:Injections, Intravenous; D008297:Male; D012709:Serum Albumin / Q000378:metabolism*; D013997:Time Factors; D014554:Urination / Q000502:physiology
D012709:Serum Albumin; D015232:Dinoprostone