Neutrophil elastase stimulates tracheal submucosal gland secretion that is inhibited by ICI 200,355.
To investigate whether human neutrophil elastase (HNE) stimulates airway submucosal gland secretion, we studied the effect of purified HNE on secretion of 35S-labeled macromolecules from isolated tracheal tissues from ferrets, dogs, and humans. HNE stimulated secretion in a concentration-dependent fashion, the secretory response being most pronounced in ferret tissues with a maximal response of 1,498 +/- 384% above baseline at 10(-5) M. In dog tissues, maximal secretory responses (509 +/- 169%) to HNE were much greater than to bethanechol (80 +/- 26%). Human tissues obtained several hours postmortem still responded to HNE (179 +/- 48% at 10(-5) M) significantly more than to the combination of isoproterenol, phenylephrine, and bethanechol (23 +/- 10%). Morphometric analysis of canine tracheal tissues showed degranulation of submucosal gland cells after HNE. A specific inhibitor of HNE (ICI 200,355) potently inhibited secretory responses in a concentration-dependent fashion. We suggest that HNE in airways of patients may cause hypersecretion and that treatment with ICI 200,355 may provide a strategy for therapeutic intervention.
Schuster
A
A
Cardiovascular Research Institute, University of California, San Francisco 94143.
Ueki
I
I
Nadel
J A
JA
D000818:Animals; D004285:Dogs; D005289:Ferrets; D006801:Humans; D046911:Macromolecular Substances; D009092:Mucous Membrane / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013194:Staining and Labeling; D014132:Trachea / Q000166:cytology / Q000378:metabolism*
D046911:Macromolecular Substances; D009842:Oligopeptides; C069366:ICI 200355; D010196:Pancreatic Elastase