Functional inactivation and structural disruption of human alpha 2-macroglobulin by neutrophils and eosinophils.
Human alpha 2-macroglobulin (alpha 2M) rapidly lost functional and structural integrity in the course of a short-term incubation with either triggered neutrophils or eosinophils. In contrast to native alpha 2M, the modified antiproteinase was unable to bind neutrophil elastase or pancreatic elastase in a manner that restricted the enzymes' access to high molecular weight substrates. In addition to the complete loss of its antiproteolytic potential, the conformation of the dysfunctional inhibitor was radically altered and susceptible to further modification by exogenous proteinases as assessed by polyacrylamide gel electrophoresis. Analysis of the mechanism by which alpha 2M was inactivated by neutrophils revealed that the process was dependent on the generation of hypochlorous acid, an oxidant generated by the hydrogen peroxide-myeloperoxidase-chloride system. In contrast to the neutrophil, maximal eosinophil-dependent inactivation required the presence of physiologic concentrations of bromide and appeared to involve the generation of hypobromous acid. The ability of either hypochlorous acid or hypobromous acid to directly disrupt alpha 2M function and structure was confirmed under cell-free conditions. These results demonstrate that alpha 2M, an antiproteinase heretofore considered to be resistant to physiologic inactivation, could be destroyed by two populations of human phagocytes via oxidative modifications mediated by hypophalous acids.
Reddy
V Y
VY
Department of Internal Medicine, Simpson Memorial Research Institute, University of Michigan, Ann Arbor 48109.
Pizzo
S V
SV
Weiss
S J
SJ
D002474:Cell-Free System; D004804:Eosinophils / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009504:Neutrophils / Q000378:metabolism*; D010084:Oxidation-Reduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000511:alpha-Macroglobulins; D013755:Tetradecanoylphorbol Acetate