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

Abstract

Inter-α-inhibitor (IαI) is a human plasma serine proteinase inhibitor. It contains one light peptide chain called bikunin that exerts antiproteinase activity and other anti-inflammatory 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, IαI has been implicated in the pathophysiology of sepsis. Moreover, IαI 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. IαI and antithrombin III (ATIII) levels were measured on admission. Sequential measurements of IαI could be done in 4 patients. We demonstrate that IαI 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 IαI levels. In 2 patients with a favorable course, IαI values regularly increased during the ICU stay. By sodium dodecyl sulfate–polyacrylamide gel electrophoresis followed by immunoblot analysis and microsequencing, we characterized IαI-related components in plasma from several patients; they obviously arise from IαI through proteolytic cleavage. Thus, systemic proteolysis and decreased biosynthesis both contribute to the fall in the plasma level of IαI. Because IαI is very sensitive to proteolysis by polymorphonuclear granulocytes (PMNs) that are stimulated during sepsis, we suggest that IαI plasma level would be a useful marker for neutrophil proteinase activity. ATIII, as well as IαI, is considered a negative acute phase protein. Because in vitro ATIII is less susceptible than IαI 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. (J Lab Clin Med 2000;135:188-98)