Platelet-activating factor mediates ischemia-induced leukocyte-endothelial adherence in newborn pig brain

The authors examined the involvement of platelet-activating factor (PAF) in mediating leukocyte adherence to brain postcapillary pial venules and altering blood-brain barrier (BBB) permeability during basal conditions and during reoxygenation after asphyxia in newborn piglets. Intravital epifluorescence videomicroscopy, closed cranial windows, and labeling of leukocytes with rhodamine 6G allowed us to obtain serial measurements of adherent leukocytes within postcapillary venules. Blood-brain barrier breakdown was determined by optical measures of cortical extravascular fluorescence intensity after intravenous sodium fluorescein. Superfusion of PAF over the cortex induced a dose-dependent increase in leukocyte adherence to cerebral venules and leakage of fluorescein; with 1 micromol/L PAF, the magnitude of adherence and BBB breakdown was similar to that seen during reoxygenation after 9 minutes of asphyxia. Both adherence and loss of BBB integrity resulting from either exogenous PAF or asphyxia-reoxygenation could be significantly attenuated by intravenous administration of WEB 2086, a PAF receptor antagonist. Window superfusion of superoxide dismutase with PAF attenuated PAF-induced increases in adherence and associated fluorescein leakage. These findings indicate that PAF exhibits proinflammatory effects in piglet brain and that PAF contributes to leukocyte adherence and BBB breakdown after cerebral ischemia. These PAF effects are mediated by increases in superoxide radical generation.