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. 1980 Nov;66(5):987–995. doi: 10.1172/JCI109968

Potential Mediator of Inflammation

PHAGOCYTE-DERIVED OXIDANTS SUPPRESS THE ELASTASE-INHIBITORY CAPACITY OF ALPHA1-PROTEINASE INHIBITOR IN VITRO

Harvey Carp 1, Aaron Janoff 1
PMCID: PMC371535  PMID: 6253528

Abstract

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 α1-proteinase inhibitor (α1-Pi) and elastase showed that inactivation of α1-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 α1-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 H2O2 nor O2− alone, but a product of the two, may have oxidatively inactivated α1-Pi. In support of the foregoing, neutrophils or monocytes from a patient with chronic granulomatous disease failed to produce detectable levels of O2− 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 α1-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-H2O2-generating system, and Cl−, the EIC of human serum or purified α1-Pi could also be suppressed. Omission of any single reactant prevented this effect, as did NaN3 or catalase, suggesting that enzymatically active myeloperoxidase and H2O2 were necessary. Immunoelectrophoresis of myeloperoxidase-inactivated serum showed that, as before, inactivation of α1-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 α1-Pi had occurred. Oxidative inactivation of α1-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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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