Cystic fibrosis sputum induces a secretory response from airway gland serous cells that can be prevented by neutrophil protease inhibitors.
High activities of the neutrophil proteases, elastase and cathepsin G, are found in the sputum of patients with cystic fibrosis (CF). Because both proteases have been shown to be potent secretagogues for airway submucosal glands, and because hypersecretion is a characteristic feature of CF, the objective of the present study was to examine whether there is secretagogue activity in CF sputum, and to determine the contribution of neutrophil proteases to the secretagogue activity. Confluent monolayers of cultured bovine tracheal serous cells were pulse-labelled with Na2(35)SO4, incubated with diluted CF sputum supernatants in the presence or absence of different protease inhibitors, and the subsequent release of the radio-labelled macromolecules was measured. CF sputum potently induced secretion concentration-dependently. Addition of the selective neutrophil elastase inhibitor ICI 200,355 inhibited the secretory response to CF sputum supernatant by 89%. Addition of a cathepsin G-inhibitor resulted in further inhibition of the secretory response. Addition of phosphoramidon, a drug known to inhibit Pseudomonas aeruginosa elastase, had no effect. We conclude that CF sputum potently stimulates airway submucosal gland cell secretion. These studies with protease inhibitors suggest that neutrophil proteases account substantially for the secretagogue activity present in CF sputum.
Schuster
A
A
Cardiovascular Research Institute, University of California, San Francisco, USA.
Fahy
J V
JV
Ueki
I
I
Nadel
J A
JA
D000328:Adult; D000818:Animals; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000503:physiopathology*; D005088:Exocrine Glands / Q000378:metabolism; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase; D009842:Oligopeptides / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D012697:Serine Endopeptidases; D013183:Sputum / Q000201:enzymology*; D014132:Trachea / Q000378:metabolism*
D006020:Glycopeptides; D009842:Oligopeptides; D011480:Protease Inhibitors; C069366:ICI 200355; C002101:chymostatin; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; C008890:phosphoramidon