Critical Care, Jan 13, 2011, Vol.15, p.R20
Introduction 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 [less than] 0.01) and day 9 (P [less than] 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 [less than] 0.001), day 5 (r = 0.62, P [less than] 0.01) and day 9 (r = 0.58, P [less than] 0.01) and with PMNE and leukocyte counts (r = 0.49, P [less than] 0.05 for both) as well as MODS at day 5 (r = 0.56, P [less than] 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.
Apoptosis -- Physiological Aspects ; Apoptosis -- Genetic Aspects ; Apoptosis -- Research ; Injuries -- Complications And Side Effects ; Injuries -- Patient Outcomes ; Injuries -- Research ; Multiple Organ Failure -- Risk Factors ; Multiple Organ Failure -- Development And Progression ; Multiple Organ Failure -- Genetic Aspects ; Multiple Organ Failure -- Research ; Sepsis -- Risk Factors ; Sepsis -- Development And Progression ; Sepsis -- Genetic Aspects ; Sepsis -- Research
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