Inflammation
Project leaders: Diana Wouters PhD, Sacha Zeerleder MD PhD and Prof Lucien A Aarden PhD
Complement activation
Complement is a major effector system in inflammation. We are interested in genetic variation and therapeutic application of proteins that regulate complement. In cooperation with prof Taco Kuijpers (Academic Medical Center) we study the molecular organization of the lectin pathway and investigate why complement activation is attenuated in pediatric oncology patients. We also developed diagnostic assays to analyze variations in complement regulatory protein factor H. C1-inhibitor (C1-inh) is a major therapeutic product of Sanquin. 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. Moreover, we investigate potential anti-inflammatory activity of C1-inh in LPS stimulated whole blood and mononuclear cells.
Factor VII activating protein
Factor VII activating protein (FSAP) is a plasma serine protease. FSAP binds to dead cells and becomes activated. FSAP activity is further regulated by the serine protease inhibitors C1-inh and alpha2-anti-plasmin which form covalent complexes with FSAP. We used these complex ELISAs to monitor in vitro as well as in vivo FSAP activation. Surprisingly coagulation does not activate FSAP. FSAP activation can be observed in sepsis patients and in patients undergoing major surgery. Our data suggest that FSAP acts as a plasma sensor for cell death.
Key publications
- Ter Weeme M, Vonk AB, Kupreishvili K, van Ham M, Zeerleder S, Wouters D, Stooker W, Eijsman L, van Hinsbergh VW, Krijnen PA, Niessen HW. Activated complement is more extensively present in diseased aortic valves than naturally occurring complement inhibitors: a sign of ongoing inflammation. Eur J Clin Invest 2010; 40:4-10.
- 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):R100.