Elastase contributes to antigen-induced mucociliary dysfunction in ovine airways.
Antigen-induced bronchoconstriction is associated with impairment of mucociliary clearance with a time course that is consistent with the initial influx of neutrophils into the airway. In this study we tested the hypothesis that elastase released from activated neutrophils contributes to the acute (0 to 6-hr) antigen-induced mucociliary dysfunction. Tracheal mucous velocity CTMV), an index of mucociliary function, was measured with a roentgenographic technique before and serially after airway challenge with Ascaris suum antigen alone, or after pretreatment with aerosolized alpha1-protease inhibitor (alpha1-PI, 10 mg) or the specific neutrophil elastase inhibitor ICI 200,355 (10 mg). Antigen alone significantly decreased TMV. Treatment with either alpha1-PI or ICI 200,355, given either at 30 min before antigen challenge or 1 h after challenge, significantly attenuated the antigen-induced reduction in TMV at 6 h after challenge, whereas sheep treated with inactivated alpha1-PI were not protected from this antigen-induced event. Inhalation of ovine elastase (obtained from stimulated neutrophils) significantly decreased TMV, and this effect was also blocked by pretreatment with alpha1-PI. Both alpha1-PI and ICI 200,355 inhibited the activity of elastase obtained from stimulated ovine neutrophils. To verify that the neutrophil numbers and elastase activity increased in sheep airways after antigen challenge, nine animals underwent bronchoalveolar lavage (BAL) at 2 h and 4 h after instillation of A. summ antigen. Four hours after challenge, the number of neutrophils had increased by 50-fold, and free elastase activity in lavage fluid had increased. These data indicate that the antigen-induced impairment of mucociliary clearance is partly dependent on increased elastase activity, and that elastase inhibitors may be useful in protecting against mucociliary dysfunction.
O'Riordan
T G
TG
Pulmonary Division, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.
Otero
R
R
Mao
Y
Y
Lauredo
I
I
Abraham
W M
WM
D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D000947:Antigens, Helminth / Q000008:administration & dosage*; D017165:Ascaris suum; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D005260:Female; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000502:physiology*; D009079:Mucociliary Clearance / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils; D009842:Oligopeptides / Q000494:pharmacology; D012756:Sheep; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D000485:Allergens; D000947:Antigens, Helminth; D009842:Oligopeptides; D000515:alpha 1-Antitrypsin; C069366:ICI 200355; D019272:Leukocyte Elastase