Alpha-2-macroglobulin functions as an inhibitor of fibrinolytic, clotting, and neutrophilic proteinases in sepsis: Studies using a baboon model

Abstract

Alpha-2-macroglobulin (α2M) may function as a proteinase inhibitor in vivo. Levels of this protein are decreased in sepsis, but the reason these levels are low is unknown. Therefore, we analyzed the behavior of α2M in a baboon model for sepsis. Upon challenge with a lethal (4 baboons) or a sublethal (10 baboons) dose of Escherichia coli, levels of inactivated α2M (iα2M) steadily increased, the changes being more pronounced in the animals that received the lethal dose. The rise in iα2M significantly correlated with the increase of thrombin-antithrombin III, plasmin-α2-antiplasmin, and, to a lesser extent, with that of elastase-α1-antitrypsin complexes, raising the question of involvement of fibrinolytic, clotting, and neutrophilic proteinases in the inactivation of α2M. Experiments with chromogenic substrates confirmed that thrombin, plasmin, elastase, and cathepsin G indeed had formed complexes with α2M. Changes in α2M similar to those observed in the animals that received E. coli occurred in baboons challenged with Staphylococcus aureus, indicating that α2M formed complexes with the proteinases just mentioned in gram-positive sepsis as well. We conclude that α2M in this baboon model for sepsis is inactivated by formation of complexes with proteinases, derived from activated neutrophils and from fibrinolytic and coagulation cascades. We suggest that similar mechanisms may account for the decreased α2M levels in clinical sepsis.