Group leader: Sacha Zeerleder MD PhD
Clearance of dead cells is facilitated by a large number of plasma proteins. We study the role of Factor-VII-activating protein (FSAP) in the clearance of dead cells. FSAP circulates in plasma as an inactive single chain serine protease. FSAP binds to living as well as to dead cells. Interaction with dead cells leads to the activation of FSAP and to the release of nucleosomes. Although we do not know how FSAP is activated, exposure to nuclear proteins such as histones seems to be essential for this activation. Cell death is a central event in the pathogenesis of sepsis and is reflected by circulating nucleosomes. Circulating nucleosome levels correlate with severity and outcome in sepsis patients. Therefore we investigated FSAP activation in patients suffering from various inflammatory diseases of increasing severity. 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, 8 adult patients suffering from septic shock and 38 children suffering from meningococcal sepsis. FSAP activation occurred in post-surgery patients, patients suffering from severe sepsis, septic shock and meningococcal sepsis. Levels of FSAP-inhibitor complexes correlated with nucleosome levels and correlated with severity and mortality in these patients. These results suggest that FSAP is a sensor for cell death and that FSAP activation in sepsis might be involved in nucleosome release, thereby contributing to lethality.
C1-inhibitor (C1-inh) is a major Sanquin therapeutic product. We compare properties of recombinant C1-inh with plasma-derived C1-inh and investigate the effects of (glycosylated) C1-inh on neutrophil/endothelial cell interaction. In collaboration with Sanquin Plasma Products and Shire we are exploring possible new fields of clinical application for C1-Inh. In collaboration with Prof Hans Niessen (Department of Pathology, VUmc) we demonstrated in a rat burn wound model that systemic treatment with C1-inh improves the local healing of burn wounds and reduces inflammation in the heart. We will further explore the possibility of C1-inh as therapeutic intervention for burn wound patients. We also showed in an ex vivo model for acute vein graft injury that C1-inh protects against endothelial loss under arterial blood pressure.
- Stephan F, Aarden LA, Zeerleder S. FSAP, a new player in inflammation? Hamostaseologie 2012; 32:51-5.
- Stephan F, Hazelzet JA, Bulder I, Boermeester MA, van Till JO, van der Poll T, Wuillemin WA, Aarden LA, Zeerleder S. Activation of factor VII-activating protease in human inflammation: a sensor for cell death. Crit Care 2011; 15(2):R110.