The onset and recovery from airway hyperresponsiveness: relationship with inflammatory cell infiltrates and release of cytotoxic granule proteins

Abstract

Previous studies from our laboratory have demonstrated a temporal relationship between eosinophil influx into the airways and the onset of airway hyperresponsiveness to inhaled methacholine. The purpose of the present study was to extend this observation by evaluating changes in airway cellular composition and measuring the levels of granulocyte-derived mediators recovered in BAL fluid during the onset and recovery from antigen-induced airway hyperresponsiveness. Airway cellular composition, airway responsiveness to inhaled methacholine and the levels of BAL fluid EPO and MPO were monitored over a 32 day study in eight adult male Ascaris suum sensitive cynomolgus monkeys. Repeated Ascaris suum inhalation (nine challenges during days 0-21) resulted in a selective, sustained airway eosinophilia that was temporally related with the onset and maintenance of airway hyperresponsiveness (r = 0.67, P less than 0.001). The level of BAL eosinophil-derived EPO was increased and remained elevated concurrent with the increase in airway eosinophils and airway responsiveness. During the recovery phase (days 22-32) the actual number of eosinophils remained elevated, while BAL EPO levels were significantly decreased. The recovery phase was also associated with a transient increase in the number of BAL neutrophils and MPO concentration. We conclude that the number and state of activation of airway eosinophils directly correlate with the onset and maintenance of airway hyperresponsiveness. Recovery from airway hyperresponsiveness is associated with a decrease in eosinophil activation and a transient increase in the number of activated neutrophils.