Mechanism of Airway Narrowing Caused by Inhaled Platelet-activating Factor: Role of Airway Microvascular Leakage

Abstract In order to study the mechanism of airway narrowing after inhaled platelet-activating factor (PAF) we measured concomitant changes in lung resistance (Rl) and in airway microvascular leakage in anesthetized guinea pigs. Rl and its recovery after hyperinflation at 5 min were measured until 6 min after PAF aerosol (0.1, 0.3, 1, and 3 mM), and in the case of 3 mM PAF also until 10 min. Microvascular leakage in trachea, main bronchi, and proximal and distal intrapulmonary airways was determined by measurement of extravasated Evans blue dye content. For comparison, the responses to inhaled histamine (3 mM) and 5-hydroxytryptamine (5HT) (3 mM), which act directly on airway smooth muscle, were also examined. Inhaled PAF increased Rl dose-dependently, with a maximal response (peak Rl) at 4 min after the inhalation, whereas the response to histamine or 5HT was maximal within a few seconds after the inhalation. Peak Rl (cm H2O/ml/s) was significantly less after PAF (1.03 ± 0.09) than after histamine (8.39 ± 1.07) or 5HT (18.3 ± 6.48), although there was no significant difference in Rl after hyperinflation (recovery Rl). No additional increase in Rl was seen between 5 and 10 min after exposure. PAF caused a dose-dependent increase in Evans blue dye extravasation; 3 mM PAF induced significantly higher leakage than did histamine or 5HT at all airway levels at 6 min. PAF did not cause any additional extravasation of Evans blue dye at 10 min compared with that at 6 min after exposure. After PAF, recovery Rl, as well as peak Rl, correlated significantly with the degree of Evans blue dye extravasation at all airway levels. PAF was comparably more potent than histamine and 5HT in inducing airway microvascular leakage than in causing increase in Rl. These data suggest that airway edema resulting from airway microvascular leakage is an important component of airway narrowing induced by inhalation of PAF.