Platelet-activating factor: a previously unrecognized mediator of fever.
Lipopolysaccharide (LPS)-induced systemic inflammation is accompanied by either hypothermia (prevails when the ambient temperature (Ta) is subneutral) or fever (prevails when Ta is neutral or higher). Because platelet-activating factor (PAF) is a proximal mediator of LPS inflammation, it should mediate both thermoregulatory responses to LPS. That PAF possesses hypothermic activity and mediates LPS-induced hypothermia is known. We asked whether PAF possesses pyrogenic activity (Expt 1) and mediates LPS fever (Expt 2). The study was conducted in Long-Evans rats implanted with jugular catheters. A complex with bovine serum albumin (BSA) was infused as a physiologically relevant form of PAF; free (aggregated) PAF was used as a control. In Expt 1, either form of PAF caused hypothermia when infused (83 pmol kg-1 min-1, 60 min, i.v.) at a subneutral Ta of 20 degrees C, but the response to the PAF-BSA complex (-4.5 +/- 0.5 degrees C, nadir) was ~4 times larger than that to free PAF. At a neutral Ta of 30 degrees C, both forms caused fever preceded by tail skin vasoconstriction, but the febrile response to PAF-BSA (1.0 +/- 0.1 degrees C, peak) was > 2 times higher than that to free PAF. Both the hypothermic (at 20 degrees C) and febrile (at 30 degrees C) responses to PAF-BSA started when the total amount of PAF infused was extremely small, < 830 pmol kg-1. In Expt 2 (conducted at 30 degrees C), the PAF receptor antagonist BN 52021 (29 micromol kg-1, i.v.) had no thermal effect of itself. However, it strongly (~2 times) attenuated the febrile response to PAF (5 nmol kg-1, i.v.), implying that this response involves the PAF receptor and is not due to a detergent-like effect of PAF on cell membranes. BN 52021 (but not its vehicle) was similarly effective in attenuating LPS (10 microg kg-1, i.v.) fever. It is concluded that PAF is a highly potent endogenous pyrogenic substance and a mediator of LPS fever.
Ivanov
Andrei I
AI
Systemic Inflammation Laboratory, Trauma Research, St Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Patel
Shreya
S
Kulchitsky
Vladimir A
VA
Romanovsky
Andrej A
AA
D000818:Animals; D004224:Diterpenes / Q000494:pharmacology; D004777:Environment; D005334:Fever / Q000503:physiopathology*; D046934:Ginkgolides; D007783:Lactones / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D010972:Platelet Activating Factor / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051381:Rats; D020318:Rats, Long-Evans; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013696:Temperature
D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D012710:Serum Albumin, Bovine; C045856:ginkgolide B