Effect of platelet-activating factor on aerosol histamine responsiveness in awake sheep

Platelet-activating factor (PAF), a potent proinflammatory ether lipid, has been proposed as a potential mediator of airway hyperresponsiveness. We studied the effect of a single intravascular bolus of synthetic PAF (0.5 microgram/kg) on airway responsiveness to aerosolized histamine in 8 chronically instrumented awake sheep. Lung mechanics were assessed by whole-body plethysmography. Histamine dose-response curves were performed before and 4 h after PAF administration. PAF induced a 60% fall in dynamic compliance and a three-fold increase in resistance to air flow across the lung within 5 min. All animals tested became more responsive to aerosol histamine 4 h after PAF as evidenced by a fall in ED65Cdyn from 9.45 mg/ml before to 4.34 mg/ml. There was no correlation between the initial Cdyn or the Cdyn measured just prior to the second bronchial challenge and the calculated alteration in responsiveness. Animals displaying the greatest initial responsiveness to aerosol histamine also manifested the greatest alteration in lung mechanics after intravascular PAF (r = 0.92). We conclude that PAF consistently alters lung mechanics and increases airway responsiveness in awake sheep, and aerosol histamine responsiveness correlates with the maximal response to intravenous PAF.