Platelet‐Activating Factor: A Previously Unrecognized Mediator of Fever

Open Access
Publisher Website
Google Scholar
Abstract
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.