Platelet-activating factor-induced pulmonary edema is partly mediated by prostaglandin E(2), E-prostanoid 3-receptors, and potassium channels.
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.
Division of Pulmonary Pharmacology, Research Center Borstel, Borstel, Germany.
Rolf
R
Göggel
Sven
S
Hoffman
Rolf
R
Nüsing
Suh
S
Narumiya
Stefan
S
Uhlig
D000818:Animals; D046508:Culture Techniques; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D010972:Platelet Activating Factor; D015221:Potassium Channels / Q000032:analysis / Q000378:metabolism*; D011336:Probability; D011654:Pulmonary Edema / Q000378:metabolism* / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000032:analysis / Q000378:metabolism*; D012016:Reference Values; D012680:Sensitivity and Specificity
D010972:Platelet Activating Factor; D015221:Potassium Channels; D018078:Receptors, Prostaglandin E; D015232:Dinoprostone