Inflammation-induced systemic proteolysis of inter-α-inhibitor in plasma from patients with sepsis

Inter-alpha-inhibitor (\alpha\) is a human plasma serine proteinase inhibitor. It contains one light peptide chain called bikunin that exerts antiproteinase activity and other antiinflammatory functions. Bikunin is covalently linked to two heavy chains that, after tissular diffusion, stabilize the extracellular matrix. Owing to its negative acute-phase reactant character and its susceptibility to proteolysis, \alpha\ has been implicated in the pathophysiology of sepsis, Moreover, \alpha\ has been shown to exert a protective effect on a pig model of endotoxic shock. Twenty patients admitted to the intensive care unit (ICU) for a septic syndrome were included in the present study. \alpha\ and antithrombin III (ATIII) levels were measured on admission. Sequential measurements of \alpha\ could be done in 4 patients. We demonstrate that \alpha\ levels are significantly decreased in plasma samples collected on admission from patients with sepsis (59 +/- 32 mg/L vs 241 +/- 70 mg/L; P <.0001). This decrease was greater in severe sepsis and septic shock than in sepsis. Death was not predictable from initial \alpha\ levels. In 2 patients with a favorable course, \alpha\ values regularly increased during the ICU stay. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by immunoblot analysis and microsequencing, we characterized \alpha\-related components in plasma from several patients; they obviously arise from \alpha\ through proteolytic cleavage. Thus, systemic proteolysis and decreased biosynthesis both contribute to the fall in the plasma level of \alpha\. Because \alpha\ is very sensitive to proteolysis by polymorphonuclear granulocytes (PMNs) that are stimulated during sepsis, we suggest that \alpha\ plasma level would be a useful marker for neutrophil proteinase activity. ATIII, as well as \alpha\, is considered a negative acute phase protein. Because in vitro ATIII is less susceptible than \alpha\ to proteolysis by PMNs and because their relative levels weakly correlated, we suggest that an unspecific systemic proteolysis is not significantly involved in the ATIII deficiency occurring in sepsis.