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

Inter-alpha-inhibitor (\alpha\) is a human plasma serine proteinase inhibit or. It contains one light peptide chain called bikunin that exerts antiprot einase activity and other antiinflammatory functions. Bikunin is covalently linked to two heavy chains that, after tissular diffusion, stabilize the e xtracellular matrix. Owing to its negative acute-phase reactant character a nd its susceptibility to proteolysis, \alpha\ has been implicated in the pa thophysiology of sepsis, Moreover, \alpha\ has been shown to exert a protec tive 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 pr esent study. \alpha\ and antithrombin III (ATIII) levels were measured on a dmission. Sequential measurements of \alpha\ could be done in 4 patients. W e demonstrate that \alpha\ levels are significantly decreased in plasma sam ples collected on admission from patients with sepsis (59 +/- 32 mg/L vs 24 1 +/- 70 mg/L; P <.0001). This decrease was greater in severe sepsis and se ptic shock than in sepsis. Death was not predictable from initial \alpha\ l evels. In 2 patients with a favorable course, \alpha\ values regularly incr eased during the ICU stay. By sodium dodecyl sulfate-polyacrylamide gel ele ctrophoresis followed by immunoblot analysis and microsequencing, we charac terized \alpha\-related components in plasma from several patients; they ob viously arise from \alpha\ through proteolytic cleavage. Thus, systemic pro teolysis and decreased biosynthesis both contribute to the fall in the plas ma level of \alpha\. Because \alpha\ is very sensitive to proteolysis by po lymorphonuclear granulocytes (PMNs) that are stimulated during sepsis, we s uggest that \alpha\ plasma level would be a useful marker for neutrophil pr oteinase activity. ATIII, as well as \alpha\, is considered a negative acut e phase protein. Because in vitro ATIII is less susceptible than \alpha\ to proteolysis by PMNs and because their relative levels weakly correlated, w e suggest that an unspecific systemic proteolysis is not significantly invo lved in the ATIII deficiency occurring in sepsis.