title: Alpha 1-proteinase inhibitor abrogates proteolytic and secretagogue activity of cystic fibrosis sputum.
abstract: Airway disease in cystic fibrosis (CF) is characterized by neutrophil-dominated chronic inflammation with an excess of uninhibited neutrophil elastase (NE), which is regarded as an important factor in progressive lung destruction. Therefore, inhalation of alpha 1-proteinase inhibitor (alpha 1-PI) seems to be a reasonable therapeutic approach. To estimate its therapeutic potential, we quantitatively investigated the in vitro interactions of exogenous alpha 1-PI with CF sputum samples (n = 28). High NE and alpha 1-PI concentrations were detected in CF sputum (6.03 +/- 0.78 and 2.56 +/- 0.16 mumol/l, respectively). There was significant NE activity (2.6 +/- 0.4 U/l) due to both the surplus of NE and proteolytic degradation of alpha 1-PI. Addition of exogenous alpha 1-PI resulted in a dose-dependent inhibition of NE activity in CF sputum; > 90% inhibition was achieved at 10 micrograms/ml alpha 1-PI. Purified NE as well as CF sputum potently induced secretion from porcine tracheal glands. Corresponding to inhibition of NE activity, CF sputum-induced secretion was also inhibited by exogenous alpha 1-PI; > 90% inhibition was also achieved at 10 micrograms/ml alpha 1-PI. Incubation of exogenous alpha 1-PI with CF sputum for 24 h did not reduce the inhibitory effects. From our in vitro results we conclude that inhalation of alpha 1-PI might effectively inhibit both NE activity and airway gland hypersecretion in CF airways.
authors.affiliation: Universitäts-Kinderklinik, Heinrich-Heine-Universität, Düsseldorf, Deutschland.
authors.forename: G
authors.initials: G
authors.lastname: Hansen
authors.forename: A
authors.initials: A
authors.lastname: Schuster
authors.forename: C
authors.initials: C
authors.lastname: Zubrod
authors.forename: V
authors.initials: V
authors.lastname: Wahn
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002648:Child; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019272:Leukocyte Elastase; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D013183:Sputum / Q000737:chemistry* / Q000276:immunology; D013552:Swine; D014132:Trachea / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000515:alpha 1-Antitrypsin; D007770:L-Lactate Dehydrogenase; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase