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

Femke Stephan,Tom Van Der Poll,Sacha Zeerleder,Jan A Hazelzet,Jw Van Till,Lucien A Aarden,Walter A Wuillemin,Marja A Boermeester,Ingrid Bulder

doi:10.1186/cc10131

Abstract

IntroductionCell 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.

Highlights

Cell death is a central event in the pathogenesis of sepsis and is reflected by circulating nucleosomes
By means of that assay we demonstrate factor VIIactivating protease (FSAP) activation in post-surgery patients, patients suffering from severe sepsis, septic shock and meningococcal sepsis
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

Summary

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. Sepsis is characterized by an extensive inflammatory response including cytokine generation, activation of plasmatic cascade systems and inflammatory cells leading to organ dysfunction and in many cases to death [1]. As a result of extensive cell death circulating nucleosomes could be measured in sepsis patients [6]. Levels of circulating nucleosomes and pulmonary nucleosome levels were demonstrated to correlate with severity and outcome in sepsis patients [6,7]. Recent findings suggest that these circulating nucleosomes play a crucial role in inflammation. We recently showed that Factor VII-activating protease (FSAP) in plasma can remove nucleosomes from late apoptotic cells [9,10]

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