Am. J. Respir. Crit. Care Med., Vol 149, No. 1, Jan 1994, 34-40.
Platelet-activating factor potentiates protamine-induced lung edema. Role of eicosanoids
CR Chen, NF Voelkel and SW Chang
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver.
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.
