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

Abstract

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.

The inositol trisphosphate pathway mediates platelet-activating-factor-induced pulmonary oedema

“…Here, the mechanisms of PAF-induced changes in vascular permeability are investigated using the model of the isolated blood-free perfused rat lung. Compared to the in vivo situation, this model permits the exclusion of oedema formation due to increased hydrostatic pressure by the use of constant pressure perfusion; accordingly, under these conditions, PAF does not alter capillary pressure [3,5]. Conversely, PAF increases the capillary filtration coefficient and vascular permeability [5,29].…”

“…Compared to the in vivo situation, this model permits the exclusion of oedema formation due to increased hydrostatic pressure by the use of constant pressure perfusion; accordingly, under these conditions, PAF does not alter capillary pressure [3,5]. Conversely, PAF increases the capillary filtration coefficient and vascular permeability [5,29]. Thus, in the present model, PAF-induced pressor responses and oedema formation can be completely separated; the pressor responses but not oedema formation are prevented by thromboxane and leukotriene antagonists [7], whereas, conversely, treatment with ceramide antibodies attenuates oedema formation without affecting the pressor responses [6].…”

“…These data show that the response to PAF is highly reproducible over time. During studies on the mechanisms of PAF-induced oedema, various hypotheses were followed simultaneously; therefore, the data from the control groups have also been used in previous studies performed at the same time [5,6].…”

“…PAF induces oedema by activation of two lipidmodifying enzymes, cyclooxygenase (COX) and sphingomyelinase, which give rise to the formation of prostaglandin E 2 and ceramide [5,6]. The signalling pathways through which these lipid mediators alter vascular permeability are largely unknown.…”

“…The signalling pathways through which these lipid mediators alter vascular permeability are largely unknown. The actions of prostaglandin E 2 depend on voltage-gated potassium channels in a poorly understood manner [5], whereas the non-COX-dependent pathway is blocked by quinolines such as quinine, quinidine and chloroquine [7]. Among the known molecular targets of quinolines are the inositol 1,4,5-trisphosphate (IP 3 ) receptors [8], phospholipase A 2 and phospholipase C (PLC) isoenzymes [9][10][11].…”