CV6209 inhibits airway wall thickening and airway hyperresponsiveness to histamine induced by intravenous administration of platelet-activating factor in guinea pigs.

We studied the effect of intravenous administration of platelet-activating factor (PAF) on airway responsiveness to histamine and airway wall thickening in guinea pigs. Guinea pigs were killed and the lungs were fixed in formalin. Slides from paraffin-embedded sections of the lungs were stained and the airways that were cut in transverse section were measured by tracing enlarged images using a digitizer. Moreover, airway resistance (Raw) was determined by a pulmonary mechanics analyzer and we calculated two indices, an index of airway wall thickening and one of airway hyperresponsiveness to histamine, from changes of baseline-Raw and peak-Raw following intravenous administration of histamine before and after PAF administration. The infusion of 600 ng/kg PAF for 1 h induced an increase in the thickness of the airway wall in main bronchi demonstrable by histological examination. In analysis of airway function, the infusion of 600 ng/kg PAF for 1 h induced airway hyperresponsiveness to histamine with airway wall thickening. The PAF antagonist CV6209, which was given intravenously 30 min prior to PAF administration, inhibited these effects of PAF in a dose-dependent manner, suggesting PAF may induce airway wall thickening and airway hyperresponsiveness through PAF receptors in the airways.