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Expression and Role of Myeloid-related Protein-14 in Clinical and Experimental Sepsis

¹ Center for Infection and Immunity Amsterdam and ² Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; ³ Institute of Immunology, University of Muenster, Muenster, Germany; ⁴ Sanquin, Amsterdam, The Netherlands; ⁵ Department of Surgery, ⁶ Department of Pathology, and ⁷ Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and ⁸ Department of Critical Care Medicine, St. Luc University, Université Catholique de Louvain, Brussels, Belgium

Correspondence and requests for reprints should be addressed to Marieke A. D. van Zoelen, M.D., Academic Medical Center, Room G2-130, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. E-mail: M.A.D.vanZoelen{at}umcutrecht.nl

Rationale: Myeloid-related protein-8 (MRP8) and MRP14 can form heterodimers that elicit a variety of inflammatory responses. We showed that MRP8/14 is a ligand for Toll-like receptor-4, and that mice deficient in MRP8/14 are protected against endotoxic shock–induced lethality.

Objectives: To determine (1) the extent of MRP8/14 release in patients with sepsis and/or peritonitis and in healthy humans exposed to LPS and (2) the contribution of MRP8/14 to the host response in murine abdominal sepsis.

Methods: MRP8/14 was measured in 51 patients with severe sepsis, 8 subjects after intravenous injection of LPS, and 17 patients with peritonitis. Host responses to sepsis were compared in mrp14 gene–deficient (and thereby MRP8/14-deficient) and wild-type mice intraperitoneally injected with Escherichia coli.

Measurements and Main Results: Patients with sepsis displayed elevated circulating MRP8/14 concentrations on both Days 0 and 3, and LPS injection resulted in systemic MRP8/14 release in healthy humans. In patients with peritonitis, MRP8/14 levels in abdominal fluid were more than 15-fold higher than in plasma. MRP14-deficient mice displayed improved defense against E. coli abdominal sepsis in an early phase, as indicated by diminished dissemination of the bacteria at 6 hours. In addition, MRP14-deficient mice demonstrated decreased systemic inflammation, as reflected by lower cytokine plasma concentrations, and less severe liver damage.

Conclusions: Human sepsis and endotoxemia are associated with enhanced release of MRP8/14. In abdominal sepsis, MRP8/14 likely occurs primarily at the site of the infection, facilitating bacterial dissemination at an early phase and liver injury.

Key Words: myeloid-related protein-8/14 • S100A8/S100A9 • calgranulin • sepsis • Toll-like receptor-4

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Myeloid-related protein 8 (MRP8) and MRP14 are members of the S100 protein family; the MRP8/14 complex is a ligand for Toll-like receptor-4. Mice deficient in MRP14 are protected against endotoxic shock–induced lethality. What This Study Adds to the Field MRP8/14 plasma levels are elevated in patients with sepsis and in healthy humans injected with LPS; patients with peritonitis show highest MRP8/14 levels at the site of infection. In murine Escherichia coli sepsis, MRP14 contributes to early bacterial dissemination and liver injury.