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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 °C, but the response to the PAF‐BSA complex (−4.5 ± 0.5 °C, nadir) was ~4 times larger than that to free PAF. At a neutral Ta of 30 °C, both forms caused fever preceded by tail skin vasoconstriction, but the febrile response to PAF‐BSA (1.0 ± 0.1 °C, peak) was > 2 times higher than that to free PAF. Both the hypothermic (at 20 °C) and febrile (at 30 °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 °C), the PAF receptor antagonist BN 52021 (29 µmol 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 µg kg‐1, i.v.) fever. It is concluded that PAF is a highly potent endogenous pyrogenic substance and a mediator of LPS fever.