ABSTRACT Compromised alpha-1-protease inhibitor regulation of elevated neutrophil elastase levels may result in coagulation factor inactivation and contribute to coagulation disorders that accompany infections. The objective of this study was to determine whether inactivation of alpha-1-protease inhibitor was temporally associated with previously reported elevated neutrophil elastase levels and coagulation factor inactivation during inflammatory stress in baboons. The temporal changes of alpha-1-protease activity, antigen, and specific activity (activity/ antigen) were measured in three cyanocephalus baboons in response to low, medium, and lethal doses of intravenously infused Escherichia coli. With increasing doses of bacteria, alpha-1-protease inhibitor activity and antigen both increased by approx 1.2- to 2.2-fold and 1.5- to 4.0-fold, respectively, during 24-53h of severe sepsis. In contrast, the inhibitor was significantly inactivated during the final cell degeneration stage (24-53h) of severe sepsis as indicated by a 30-50% decrease in its specific activity (activity/antigen) over this time period. The observed inactivation of alpha-1-protease inhibitor during severe sepsis was reconstituted upon N-chlorosuccinimide oxidation and neutrophil elastase cleavage of purified alpha-1-protease inhibitor after native polyacrylamide gel electrophoresis. In conclusion, alpha-1-protease inhibitor inactivation during severe experimental sepsis is consistent with the inhibitor’s oxidation and neutrophil elastase cleavage and is temporally associated with elevated neutrophil elastase levels and decreased coagulation factor activity. Inactivation of alpha-1-protease inhibitor may enable elevated neutrophil elastase activity to inactivate coagulation factors during severe experimental sepsis.
Buy this Article
|