Myeloperoxidase-catalyzed inactivation of alpha 1-protease inhibitor by human neutrophils.
We have examined the effect of the myeloperoxidase-hydrogen peroxide-halide system and of activated human neutrophils on the ability of serum alpha 1-protease inhibitor (alpha 1-PI) to bind and inhibit porcine pancreatic elastase. Exposure to the isolated myeloperoxidase system resulted in nearly complete inactivation of alpha 1-PI. Inactivation was rapid (10 to 20 s); required active myeloperoxidase, micromolar concentrations of H2O2 (or glucose oxidase as a peroxide generator), and a halide cofactor (Cl- or I-); and was blocked by azide, cyanide, and catalase. Intact neutrophils similarly inactivated alpha 1-PI over the course of 5 to 10 min. Inactivation required the neutrophils, a halide (Cl-), and a phorbol ester to activate secretory and metabolic activity. It was inhibited by azide, cyanide, and catalase, but not by superoxide dismutase. Neutrophils with absent myeloperoxidase or impaired oxidative metabolism (chronic granulomatous disease) failed to inactivate alpha 1-PI, and these defects were specifically corrected by the addition of myeloperoxidase or H2O2, respectively. Thus, stimulated neutrophils secrete myeloperoxidase and H2O2 which combine with a halide to inactivate alpha 1-PI. We suggest that leukocyte-derived oxidants, especially the myeloperoxidase system, may contribute to proteolytic tissue injury, for example in elastase-induced pulmonary emphysema, by oxidative inactivation of protective antiproteases.
D000510:Alpha-Globulins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009504:Neutrophils / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000097:blood; D009195:Peroxidase / Q000378:metabolism*; D010544:Peroxidases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism*; D011485:Protein Binding; D000515:alpha 1-Antitrypsin
D000510:Alpha-Globulins; D002352:Carrier Proteins; D011480:Protease Inhibitors; D000515:alpha 1-Antitrypsin; D010544:Peroxidases; D009195:Peroxidase; D010196:Pancreatic Elastase