Further evidence implicating prostaglandin E2 in the genesis of pyrogen fever.
Conscious cats were used to study the effects of endotoxin and interleukin 1 (IL 1) on levels of prostaglandin (PG) E2 and thromboxane (TX) B2 (the stable TXA2 byproduct) in cerebrospinal fluid (CSF) from the third ventricle. Pyrogens were given intravenously or intraventricularly and prostanoids were measured by radioimmunoassay. PGE2 was normally less abundant than TXB2 (mean, 37 vs. 528 pg/ml), and its level increased severalfold during the sustained fever following intravenous endotoxin (bolus) or IL 1 (bolus plus infusion). PGE2 elevation preceded the fever and was maintained thereafter. Likewise, intraventricular pyrogens promoted PGE2 formation, and their effect was also manifest during the latent period of the fever. The PGE2 metabolite, 13,14-dihydro-15-keto-PGE2, was not measurable in CSF from either afebrile or febrile animals. Basal content of PGE2, on the other hand, was higher in animals pretreated with probenecid (30 mg/kg ip or iv; 50 or 100 micrograms ivt), confirming the importance of transport processes in removing prostanoids from brain. Unlike PGE2, TXB2 levels did not change during the fever to intravenous endotoxin. TXB2 rose instead in response to intraventricular endotoxin, although the elevation did not extend beyond fever uprise. Furthermore, a TXA2 analog (ONO-11113;2 or 4 micrograms ivt) had inconsistent effects on body temperature, while a TXA2 antagonist (ONO-11120;2 micrograms ivt) did not interfere with endotoxin fever. These findings strongly support a causative role for PGE2 in the onset and progression of pyrogen fever. No evidence of a similar role was obtained for TXA2.
Coceani
F
F
Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Lees
J
J
Bishai
I
I
D000818:Animals; D001921:Brain / Q000502:physiology; D002415:Cats; D015232:Dinoprostone; D004731:Endotoxins / Q000494:pharmacology; D004926:Escherichia coli; D005260:Female; D005334:Fever / Q000134:cerebrospinal fluid / Q000139:chemically induced*; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D011458:Prostaglandins E / Q000134:cerebrospinal fluid / Q000502:physiology*; D011749:Pyrogens / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000502:physiology; D013929:Thromboxane B2 / Q000134:cerebrospinal fluid
D004731:Endotoxins; D007375:Interleukin-1; D011458:Prostaglandins E; D011749:Pyrogens; D013929:Thromboxane B2; D013928:Thromboxane A2; D015232:Dinoprostone