Open Access Research

Activation of factor VII-activating protease in human inflammation: a sensor for cell death

Femke Stephan1, Jan A Hazelzet2, Ingrid Bulder1, Marja A Boermeester3, JW Olivier van Till3, Tom van der Poll4, Walter A Wuillemin5, Lucien A Aarden1 and Sacha Zeerleder16*

Author Affiliations

1 Department of Immunopathology, Sanquin Research at CLB and Landsteiner Laboratory of the AMC, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands

2 Department of Pediatrics, Division of Pediatric Intensive Care, Erasmus MC - Sophia Children's Hospital, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands

3 Department of Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

4 Center for Infection and Immunity Amsterdam (CINIMA) and Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

5 Division of Hematology and Central Laboratory of Hematology, Luzerner Kantonsspital Luzern, CH-6000 Lucerne 16, Switzerland

6 Department of Hematology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

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Critical Care 2011, 15:R110  doi:10.1186/cc10131

Published: 5 April 2011

Abstract

Introduction

Cell death is a central event in the pathogenesis of sepsis and is reflected by circulating nucleosomes. Circulating nucleosomes were suggested to play an important role in inflammation and were demonstrated to correlate with severity and outcome in sepsis patients. We recently showed that plasma can release nucleosomes from late apoptotic cells. Factor VII-activating protease (FSAP) was identified to be the plasma serine protease responsible for nucleosome release. The aim of this study was to investigate FSAP activation in patients suffering from various inflammatory diseases of increasing severity.

Methods

We developed ELISAs to measure FSAP-C1-inhibitor and FSAP-α2-antiplasmin complexes in plasma. FSAP-inhibitor complexes were measured in the plasma of 20 adult patients undergoing transhiatal esophagectomy, 32 adult patients suffering from severe sepsis and 8 from septic shock and 38 children suffering from meningococcal sepsis.

Results

We demonstrate plasma FSAP to be activated upon contact with apoptotic and necrotic cells by an assay detecting complexes between FSAP and its target serpins α2-antiplasmin and C1-inhibitor, respectively. By means of that assay we demonstrate FSAP activation in post-surgery patients, patients suffering from severe sepsis, septic shock and meningococcal sepsis. Levels of FSAP-inhibitor complexes correlate with nucleosome levels and correlate with severity and mortality in these patients.

Conclusions

These results suggest FSAP activation to be a sensor for cell death in the circulation and that FSAP activation in sepsis might be involved in nucleosome release, thereby contributing to lethality.