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Platelet-Activating Factor–induced Pulmonary Edema Is Partly Mediated by Prostaglandin E₂, E-Prostanoid 3-Receptors, and Potassium Channels

Division of Pulmonary Pharmacology, Research Center Borstel, Borstel; Department of Pediatrics, Philipps-University of Marburg, Marburg, Germany; and Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, Japan

Correspondence and requests for reprints should be addressed to Stefan Uhlig, Ph.D., Division of Pulmonary Pharmacology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany. E-mail: suhlig{at}fz-borstel.de

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 E₂ (PGE₂). In isolated rat lungs, PAF administration stimulated release of PGE₂ into the venous effluate and increased lung weight as a measure of edema formation. Perfusion with a neutralizing PGE₂ 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 PGE₂ caused pulmonary edema, which was largely prevented by inhibition of voltage-gated potassium channels (25 nM ß-dendrotoxin), but not by blocking calcium-dependent potassium currents (100 µM paxilline). In line with its effects on PGE₂-induced edema formation, ß-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 PGE₂, activation of EP3 receptors, and activation of voltage-gated potassium channels.

Key Words: adult respiratory distress syndrome • platelet-activating factor • prostaglandin E₂ • pulmonary edema

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