title: Competition between elastase and related proteases from human neutrophil for binding to alpha1-protease inhibitor.
abstract: The protease-antiprotease imbalance that is characteristic of most inflammatory lung disorders depends on the spatial-temporal regulation of active inhibitor and protease concentrations in lung secretions. We have studied the competition between the three main serine proteases from human neutrophil primary granules in their binding to alpha1-Pi, the main serine proteases inhibitor in lung secretions. Elastase was the only target of alpha1-Pi when identical molar amounts of purified inhibitor and the three proteases were tested together. The other two proteases were only inhibited once elastase was saturated. Elastase remained the preferred target of inhibitors when bronchoalveolar lavage fluids from patients with lung pneumonia and acute respiratory distress syndrome were used as the source of inhibitors, in spite of the presence of additional inhibitors in lung secretions. Since neutrophil proteases are expressed at the neutrophil surface, we also measured residual activities of membrane-bound proteases after purified neutrophils were incubated with bronchoalveolar fluids. Again, elastase was the preferred target of the inhibitors. We conclude that protease 3 and cathepsin G are not controlled as efficiently as elastase in lung secretions, a feature that must be taken into account when developing inhibitor-based anti-inflammatory therapies.
authors.affiliation: INSERM U618 Protéases et Vectorisation pulmonaires, University François Rabelais, 10 Bd Tonnellé, 37032 Tours Cedex, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Korkmaz
authors.forename: Pierre
authors.initials: P
authors.lastname: Poutrain
authors.forename: Eric
authors.initials: E
authors.lastname: Hazouard
authors.forename: Michèle
authors.initials: M
authors.lastname: de Monte
authors.forename: Sylvie
authors.initials: S
authors.lastname: Attucci
authors.forename: Francis L
authors.initials: FL
authors.lastname: Gauthier
mesh_terms: D001667:Binding, Competitive / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology; D012697:Serine Endopeptidases / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000276:immunology / Q000378:metabolism*
chemical_list: D000515:alpha 1-Antitrypsin; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase