Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis

Adnana Paunel-Görgülü,Martin Scholz,Joachim Windolf,Tim Lögters,Sascha Flohé

doi:10.1186/cc9965

Abstract

IntroductionDeregulated 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.MethodsForty-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.ResultsSerum 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.ConclusionsIncreased 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.

Highlights

Deregulated apoptosis and overshooting neutrophil functions contribute to immune and organ dysfunction in sepsis and multiple organ failure (MOF)
In summary, the present study demonstrates for the first time a role of serum soluble Fas (sFas) in the inhibition of neutrophil extrinsic apoptosis associated with increased levels of plasma levels of neutrophil elastase (PMNE), a marker for systemic inflammation
Our results show a high correlation between sFas and patients’ Sequential Organ Failure Assessment (SOFA) and Multiple Organ Dysfunction (MOD) scores in sepsis and provide evidence for the clinical significance of the risk for the development of sepsis and MOF

Summary

Introduction

Deregulated apoptosis and overshooting neutrophil functions contribute to immune and organ dysfunction in sepsis and multiple organ failure (MOF). Neutrophils rapidly migrate from the blood into solid tissues to Apoptosis is tightly regulated and might be activated via membrane-bound “death” receptors, such as Fas (extrinsic pathway), or via the mitochondrion (intrinsic pathway). Fas/Fas ligand (FasL) signaling has emerged as an important cellular pathway regulating the induction of apoptosis in a wide variety of tissues as well as activated immune cells [10,11], playing a crucial role in the resolution of inflammatory responses [9]. The biologically active soluble form of FasL (sFasL) as well as agonistic anti-Fas antibodies are capable of inducing cytotoxicity, hepatocyte destruction and mortality in mice through the interaction with hepatocyte Fas [16,17] and might contribute to systemic tissue destruction during inflammation [18]

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