title: Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis.
abstract: BACKGROUND
  Deregulated apoptosis and overshooting neutrophil functions contribute to immune and organ dysfunction in sepsis and multiple organ failure (MOF). In the present study, we determined the role of soluble Fas (sFas) in the regulation of posttraumatic neutrophil extrinsic apoptosis and the development of sepsis.
  
  
  METHODS
  Forty-seven major trauma patients, 18 with and 29 without sepsis development during the first 10 days after trauma, were enrolled in this prospective study. Seventeen healthy volunteers served as controls. Blood samples from severely injured patients were analyzed at day 1, day 5 and day 9 after major trauma. sFas levels, plasma levels of neutrophil elastase (PMNE) and levels of interleukin (IL)-6 were quantified by enzyme-linked immunosorbent assay and related to patients' Sequential Organ Failure Assessment (SOFA) score and Multiple Organ Dysfunction Score (MODS). Neutrophil apoptosis was determined by propidium iodide staining of fragmented DNA and flow cytometry. sFas-mediated effects on neutrophil apoptosis were investigated in cells cultured with agonistic anti-Fas antibodies in the presence of recombinant sFas, sFas-depleted serum or untreated serum from septic patients.
  
  
  RESULTS
  Serum levels of sFas in patients who later developed sepsis were significantly increased at day 5 (P < 0.01) and day 9 (P < 0.05) after trauma compared with patients with uneventful recovery. Apoptosis of patient neutrophils was significantly decreased during the observation period compared with control cells. Moreover, Fas-mediated apoptosis of control neutrophils was efficiently inhibited by recombinant sFas and serum from septic patients. Depletion of sFas from septic patient sera diminished the antiapoptotic effects. In septic patients, sFas levels were positively correlated with SOFA at day 1 (r = 0.7, P < 0.001), day 5 (r = 0.62, P < 0.01) and day 9 (r = 0.58, P < 0.01) and with PMNE and leukocyte counts (r = 0.49, P < 0.05 for both) as well as MODS at day 5 (r = 0.56, P < 0.01) after trauma.
  
  
  CONCLUSIONS
  Increased sFas in patients with sepsis development impairs neutrophil extrinsic apoptosis and shows a positive correlation with the organ dysfunction scores and PMNE. Therefore, sFas might be a therapeutic target to prevent posttrauma hyperinflammation and sepsis.
authors.affiliation: Department of Trauma and Hand Surgery, University Hospital Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Adnana
authors.initials: A
authors.lastname: Paunel-Görgülü
authors.forename: Sascha
authors.initials: S
authors.lastname: Flohé
authors.forename: Martin
authors.initials: M
authors.lastname: Scholz
authors.forename: Joachim
authors.initials: J
authors.lastname: Windolf
authors.forename: Tim
authors.initials: T
authors.lastname: Lögters
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D053222:Fas Ligand Protein / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000502:physiology*; D011379:Prognosis; D011446:Prospective Studies; D018805:Sepsis / Q000209:etiology*; D013997:Time Factors; D015599:Trauma Severity Indices; D014947:Wounds and Injuries / Q000097:blood* / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D053222:Fas Ligand Protein