ALPHA-2-MACROGLOBULIN FUNCTIONS AS AN INHIBITOR OF FIBRINOLYTIC, CLOTTING, AND NEUTROPHILIC PROTEINASES IN SEPSIS - STUDIES USING A BABOON MODEL

Alpha-2-macroglobulin (alpha 2M) may function as a proteinase inhibito r in vivo. Levels of this protein are decreased in sepsis, but the rea son these levels are low is unknown. Therefore, we analyzed the behavi or of alpha 2M in a baboon model for sepsis. Upon challenge with a let hal (4 baboons) or a sublethal (10 baboons) desk of Escherichia coli, levels of inactivated alpha 2M (i alpha 2M) steadily increased, the ch anges being more pronounced in the animals that received the lethal do se. The rise in i alpha 2M significantly correlated with the increase of thrombin-antithrombin III, plasmin-alpha 2-antiplasmin, and, to a l esser extent, with that of elastase-alpha 1-antitrypsin complexes, rai sing the question of involvement of fibrinolytic, clotting, and neutro philic proteinases in the inactivation of alpha 2M. Experiments with c hromogenic substrates confirmed that thrombin, plasmin, elastase, and cathepsin G indeed had formed complexes with alpha 2M. Changes in alph a 2M similar to those observed in the animals that received E. coli oc curred in baboons challenged with Staphylococcus aureus, indicating th at alpha 2M formed complexes with the proteinases just mentioned in gr am-positive sepsis as well. We conclude that alpha 2M in this baboon m odel for sepsis is inactivated by formation of complexes with proteina ses, derived from activated neutrophils and from fibrinolytic and coag ulation cascades. We suggest that similar mechanisms may account for t he decreased alpha 2M levels in clinical sepsis.