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

Abstract

Alpha-2-macroglobulin (ca2M) 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 ac2M 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 ac2M (ica2M) steadily increased, the changes being more pronounced in the animals that received the lethal dose. The rise in ica2M significantly correlated with the increase of thrombin-antithrombin IH, plasmin-ar2-antiplasmin, and, to a lesser extent, with that of elastase-adantitrypsin complexes, raising the question of involvement of fibrinolytic, clotting, and neutrophilic proteinases in the inactivation of a2M. Experiments with chromogenic substrates confirmed that thrombin, plasmin, elastase, and cathepsin G indeed had formed complexes with ar2M. Changes in ca2M similar to those observed in the animals that received E. coli occurred in baboons challenged with Staphylococcus aureus, indicating that ar2M formed complexes with the proteinases just mentioned in gram-positive sepsis as well. We conclude that a2M 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 av2M levels in clinical sepsis.

Tissue inhibitor of metalloproteinases 3-dependent microvascular endothelial cell barrier function is disrupted under septic conditions

“…Furthermore, other mechanisms to regulate metalloproteinase activity certainly exist within the circulatory system, such as ␣2-macroglobulin, a broad-spectrum proteinase inhibitor expressed primarily by the liver and found at very high levels in the serum (6). While ␣2-macroglobulin is known to have a role in regulation of inflammation during sepsis, it has a very broad proteinase inhibitory profile and much of the role for ␣2-macroglobulin in sepsis may be through inhibition of serine proteinases (12,18). Thus, while ␣2-macroglobulin may regulate metalloproteinase activity within circulation, our data identify TIMP3 as a key MVEC-derived metalloproteinase inhibitor regulating metalloproteinase function within the tissue and maintaining MVEC barrier function under homeostatic conditions.…”

Expression and oxidative modifications of plasma proteins in autism spectrum disorders: Interplay between inflammatory response and lipid peroxidation

“…These proteins include alpha‐2‐macroglobulin, alpha‐1‐antichymotrypsin, haptoglobin, and alpha‐1‐antitrypsin . Alpha‐2‐macroglobulin preferentially acts as inhibitor of coagulation proteinases, thus suggesting that it could play an important role in regulating hemostatic and inflammatory reactions . Alpha‐1‐antichymotrypsin and alpha‐1‐antitrypsin belong to the serpin family and possess tissue protective properties mainly observed during the inflammatory response .…”

Secreted protein profile from HepG2 cells incubated by S(−) and R(+) enantiomers of chiral drug warfarin – An analysis in cell‐based system and clinical samples

“…It plays an important role in blood coagulation. Although this protein is not a vitamin K‐dependent protein, it acts as an inhibitor of coagulation by inhibiting thrombin formation 24. Prothrombin, the precursor of thrombin, is a vitamin K‐dependent coagulating factor, whose expression is inhibited by warfarin.…”