title: Activation of factor VII-activating protease in human inflammation: a sensor for cell death.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Immunopathology, Sanquin Research at CLB and Landsteiner Laboratory of AMC, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Stephan
authors.forename: Jan A
authors.initials: JA
authors.lastname: Hazelzet
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bulder
authors.forename: Marja A
authors.initials: MA
authors.lastname: Boermeester
authors.forename: Jw Olivier
authors.initials: JO
authors.lastname: van Till
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Walter A
authors.initials: WA
authors.lastname: Wuillemin
authors.forename: Lucien A
authors.initials: LA
authors.lastname: Aarden
authors.forename: Sacha
authors.initials: S
authors.lastname: Zeerleder
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation; D016629:Esophagectomy; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000097:blood / Q000201:enzymology; D012697:Serine Endopeptidases / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; C433550:HABP2 protein, human; D012697:Serine Endopeptidases