Potential mediator of inflammation. Phagocyte-derived oxidants suppress the elastase-inhibitory capacity of alpha 1-proteinase inhibitor in vitro.
Human polymorphonuclear leukocytes, monocytes, or pulmonary alveolar macrophages, stimulated in vitro by phorbol myristate acetate (PMA), released reactive oxygen species able to suppress the elastase inhibitory capacity (EIC) of human serum. Immunoelectrophoresis using antibodies against alpha(1)-proteinase inhibitor (alpha(1)-Pi) and elastase showed that inactivation of alpha(1)-Pi was responsible for the decreased serum EIC. Treatment of phagocyte-inactivated serum with a reducing agent (dithiothreitol) resulted in significant recovery of EIC, suggesting that alpha(1)-Pi had been oxidatively inactivated. Serum EIC was partially protected by superoxide dismutase or catalase. Hydrogen peroxide alone had no effect on serum EIC. Thus, neither H(2)O(2) nor O(2) (-) alone, but a product of the two, may have oxidatively inactivated alpha(1)-Pi. In support of the foregoing, neutrophils or monocytes from a patient with chronic granulomatous disease failed to produce detectable levels of O(2) (-) after incubation with PMA. These cells also failed to suppress serum EIC. In the case of PMA-stimulated polymorphonuclear leukocytes or monocytes, extracellular myeloperoxidase may have also played a role in alpha(1)-Pi inactivation since serum EIC was partly protected by azide, cyanide, or the depletion of extracellular chloride. Indeed, in a cell-free system consisting of purified myeloperoxidase, a glucose oxidase-H(2)O(2)-generating system, and Cl(-), the EIC of human serum or purified alpha(1)-Pi could also be suppressed. Omission of any single reactant prevented this effect, as did NaN(3) or catalase, suggesting that enzymatically active myeloperoxidase and H(2)O(2) were necessary. Immunoelectrophoresis of myeloperoxidase-inactivated serum showed that, as before, inactivation of alpha(1)-Pi was responsible for the decreased EIC. Treating myeloperoxidase-inactivated serum with dithiothreitol led to significant recovery of EIC, again suggesting that oxidative inactivation of alpha(1)-Pi had occurred. Oxidative inactivation of alpha(1)-Pi in the microenvironment of inflammatory cells, at sites of acute or chronic inflammation, may allow proteases released from these cells to damage adjacent connective tissue components more readily.
D005949:Glucose Oxidase / Q000494:pharmacology; D006105:Granulomatous Disease, Chronic / Q000097:blood; D006801:Humans; D007122:Immunoelectrophoresis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D009195:Peroxidase / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
D000515:alpha 1-Antitrypsin; D005949:Glucose Oxidase; D009195:Peroxidase; D010196:Pancreatic Elastase; D013755:Tetradecanoylphorbol Acetate