EFFECT OF PLATELET-ACTIVATING FACTOR-RECEPTOR ANTAGONISM ON ENDOTOXIN-INDUCED LUNG DYSFUNCTION IN SHEEP

To further define the role of platelet-activating factor (PAF) in endo toxin-induced lung dysfunction, we examined the effect of ABT-299, a s pecific and potent PAF-receptor antagonist, on the response to endotox emia in six chronically instrumented awake sheep. We administered Esch erichia coli endotoxin (0.5 mu g/kg)intravenously with or without pret reatment with ABT-299 while monitoring mean pulmonary arterial pressur e (Ppa), mean systemic arterial pressure (Psa), dynamic compliance of the lungs (Cdyn), and functional residual capacity (FRC). Endotoxin ad ministration caused pulmonary hypertension, reduced Cdyn, leukopenia, and hypoxemia while having no significant effect on Psa or FRC. Admini stration of ABT-299 did not affect any of the measured variables at ba seline. Pretreatment with ABT-299 attenuated the peak Ppa seen after e ndotoxin administration but had minimal effects on endotoxin-induced c hanges in Cdyn, white blood cell count, or alveolar-to-arterial oxygen difference. ABT-299 was shown to completely block the pulmonary hyper tension and reduction in Cdyn seen after intravenous administration of exogenous PAF. We conclude that PAF does not play an essential role i n the sheep's response to endotoxin.