Platelet-activating factor (PAF) is an important endogenous mediator of
pulmonary edema in many models of
acute lung injury. PAF triggers
edema formation by simultaneous activation of two independent pathways; one is mediated by a
cyclooxygenase metabolite, and the other is blocked by
quinine. We examined the hypothesis that the
cyclooxygenase-dependent part of PAF-induced
edema is mediated by
prostaglandin E(2) (
PGE(2)). In isolated rat lungs, PAF administration stimulated release of
PGE(2) into the venous effluate and increased lung weight as a measure of
edema formation. Perfusion with a neutralizing
PGE(2) antibody attenuated the PAF-induced
edema formation. In vivo, E-
prostanoid 3-receptor-deficient mice showed less pulmonary
Evans blue extravasation in response to PAF injection than did mice deficient in EP1, EP2, or EP4 receptors. Perfusion of rat lungs with
PGE(2) caused
pulmonary edema, which was largely prevented by inhibition of
voltage-gated potassium channels (25 nM
beta-dendrotoxin), but not by blocking
calcium-dependent
potassium currents (100 micro M
paxilline). In line with its effects on PGE(2)-induced
edema formation,
beta-dendrotoxin attenuated PAF-induced
edema partly if given alone, and completely in combination with
quinine. Our findings suggest that PAF-triggered
edema is partly mediated by the release of
PGE(2), activation of EP3 receptors, and activation of
voltage-gated potassium channels.