Platelet-activating factor potentiates protamine-induced lung edema. Role of eicosanoids.
Platelet-activating factor (PAF) is a cell membrane-derived ether lipid that plays an important role in acute lung vascular injury. We recently reported that PAF potentiates protamine-induced lung edema by enhancing pulmonary venoconstriction. As PAF is known to stimulate lung eicosanoid synthesis, we investigated the role of peptidoleukotrienes and other eicosanoids in this priming effect of PAF. Addition of PAF (1.6 nM), followed 10 min later by protamine (50 micrograms/ml), to perfusate of salt solution-perfused rat lungs resulted in marked arterial and venous constrictions and severe lung edema. Lung tissue thromboxane B2, 6-ketoprostaglandin F1 alpha and leukotriene C4 (LTC4) were markedly elevated 20 min after PAF/protamine. Pretreatment of the lungs with AA-861, a specific 5-lipoxygenase inhibitor, blocked PAF/protamine-induced leukotriene synthesis, arterial and venous constrictions, and lung edema. In addition, injection of LTC4 (1 microgram) markedly potentiated protamine-induced arterial and venous constrictions and caused lung edema similar to PAF/protamine. Indomethacin, a specific cyclooxygenase inhibitor, also reduced the vasoconstrictive and edemagenic responses to PAF/protamine. However, the pulmonary edema after LTC4/protamine was not blocked by indomethacin. In separate experiments, infusion of this "priming" dose of PAF into isolated perfused lungs induced LTC4 synthesis and augmented lung thromboxane A2 synthesis after arachidonic acid infusion. We conclude that both cyclooxygenase and lipoxygenase products of arachidonic acid metabolism are involved in PAF-induced potentiation of protamine lung edema.
Chen
C R
CR
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver.
Voelkel
N F
NF
Chang
S W
SW
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000502:physiology; D016227:Benzoquinones / Q000494:pharmacology*; D003251:Constriction, Pathologic / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D004357:Drug Synergism; D007213:Indomethacin / Q000494:pharmacology*; D017997:Leukotriene C4 / Q000032:analysis / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010972:Platelet Activating Factor / Q000502:physiology*; D011292:Premedication; D011460:Prostaglandins F / Q000032:analysis / Q000502:physiology; D011479:Protamines; D011652:Pulmonary Circulation / Q000187:drug effects*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013929:Thromboxane B2 / Q000032:analysis / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects
D016227:Benzoquinones; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011460:Prostaglandins F; D011479:Protamines; D016718:Arachidonic Acid; D017997:Leukotriene C4; D013929:Thromboxane B2; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; C100006:prostaglandin F1; D007213:Indomethacin