ELASTASE CONTRIBUTES TO ANTIGEN-INDUCED MUCOCILIARY DYSFUNCTION IN-OVINE AIRWAYS

Antigen-induced bronchoconstriction is associated with impairment of m ucociliary clearance with a time course that is consistent with the in itial influx of neutrophils into the airway. In this study we tested t he hypothesis that elastase released from activated neutrophils contri butes to the acute (0 to 6-hr) antigen-induced mucociliary dysfunction . Tracheal mucous velocity (TMV), an index of mucociliary function, wa s measured with a roentgenographic technique before and serially after airway challenge with Ascaris suum antigen alone, or after pretreatme nt with aerosolized alpha(1)-protease inhibitor (alpha(1)-Pl, 10 mg) o r the specific neutrophil elastase inhibitor ICI 200,355 (10 mg). Anti gen alone significantly decreased TMV. Treatment with either alpha(1)- PI or ICI 200,355, given either at 30 min before antigen challenge or 1 h after challenge, significantly attenuated the antigen-induced redu ction in TMV at 6 h after challenge, whereas sheep treated with inacti vated alpha(1)-PI were not protected from this antigen-induced event. Inhalation of ovine elastase (obtained from stimulated neutrophils) si gnificantly decreased TMV, and this effect was also blocked by pretrea tment with alpha(1)-PI. Both alpha(1)-PI and ICI 200,355 inhibited the activity of elastase obtained from stimulated ovine neutrophils. To v erify that the neutrophil numbers and elastase activity increased in s heep airways after antigen challenge, nine animals underwent bronchoal veolar lavage (BAL) at 2 h and 4 h after instillation of A. summ antig en. Four hours after challenge, the number of neutrophils had increase d by 50-fold, and free elastase activity in lavage fluid had increased . These data indicate that the antigen-induced impairment of mucocilia ry clearance is partly dependent on increased elastase activity, and t hat elastase inhibitors may be useful in protecting against mucociliar y dysfunction.