title: Recombinant secretory leukoprotease inhibitor augments glutathione levels in lung epithelial lining fluid.
abstract: Secretory leukoprotease inhibitor (SLPI), a 12-kDa serine antiprotease, serves as the major inhibitor of neutrophil elastase (NE) on the epithelial surface of the upper airways. As a control for studies to evaluate the aerosol administration of recombinant SLPI (rSLPI) to augment the anti-NE defenses of the lung, the status of antioxidants in respiratory epithelial lining fluid (ELF) was evaluated. Unexpectedly, aerosol administration of rSLPI caused an elevation in ELF glutathione, a major component of the epithelial antioxidant screen; i.e., rSLPI may provide not only augmentation of anti-NE defenses but also antioxidant defenses. To evaluate this concept, rSLPI (100 mg) was aerosolized to sheep, and SLPI, glutathione, anti-NE capacity, and anti-H2O2 capacity were evaluated in respiratory ELF over a 30-h period. As expected, aerosolization of rSLPI increased ELF SLPI levels and anti-NE capacity. Strikingly, postaerosol levels of glutathione in ELF were also increased (5-fold 24 h after aerosol), with a concomitant increase in ELF anti-H2O2 capacity; i.e., the rSLPI augmented the antioxidant screen of ELF. This suggests that rSLPI may be particularly well suited for therapy in lung diseases characterized by excess of both serine proteases and oxidants on the respiratory epithelial surface.
authors.affiliation: Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: A
authors.initials: A
authors.lastname: Gillissen
authors.forename: P
authors.initials: P
authors.lastname: Birrer
authors.forename: N G
authors.initials: NG
authors.lastname: McElvaney
authors.forename: R
authors.initials: R
authors.lastname: Buhl
authors.forename: C
authors.initials: C
authors.lastname: Vogelmeier
authors.forename: R F
authors.initials: RF
authors.lastname: Hoyt
authors.forename: R C
authors.initials: RC
authors.lastname: Hubbard
authors.forename: R G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000336:Aerosols; D000818:Animals; D003545:Cysteine / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology; D010084:Oxidation-Reduction; D010196:Pancreatic Elastase / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012756:Sheep
chemical_list: D000336:Aerosols; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D010196:Pancreatic Elastase; D005978:Glutathione; D003545:Cysteine