Platelet‐Activating Factor: A Previously Unrecognized Mediator of Fever

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.

Lipopolysaccharide fever is initiatedviaa capsaicin-sensitive mechanism independent of the subtype-1 vanilloid receptor

“…on LPS fever. In agreement with how ethanol-containing vehicles affect LPS fever (Ivanov et al, 2003b), the entire febrile response of the vehicle-pretreated rats was slightly suppressed, but it still had a distinct first phase (Figure 5a). Pretreatment with CPZ affected neither the febrile response to LPS nor the T c response to saline.…”

Central alpha-MSH, energy balance, thermal balance, and antipyresis

“…This is an unusual phenomenon, because slightly high environmental or initial core temperatures often contribute to a rise, whereas low ones rather contribute to a fall in core temperature in response to various transmitters (e.g. noradrenaline; Bligh, 1973;Bligh et al, 1971;Carlisle and Stock, 1995), platelet-activating factor (Ivanov et al, 2003), or pyrogens (Szé kely and Szelé nyi, 1979). In other studies elevation (not suppression) of T a augmented the hyperthermic responses to ecstasy (Brown and Kiyatkin, 2004).…”

Lipid Mediators and Lung Function

“…Surface expression of PAF on human endothelial cells leads to binding and activation of neutrophils in response to infection or injury (Zimmerman and McIntyre, 2004). Endogenously generated PAF causes fever and the cardinal signs of inflammation: pain, erythema, and edema (Ivanov et al, 2003). The concurrent generation of inflammatory cytokines by locally activated neutrophils and monocytes amplifies these responses.…”