Septicemia and Shock: Pathogenesis and Novel Therapeutic Strategies
(2003, NS 124)
Anna Norrby-Teglund, Staffan Normark, Ragnar Norrby, Malak Kotb, Thierry Calandra, Terje Espevik
May 15 - 17
Nobel Forum, Karolinska Institutet, Stockholm, Sweden
Proceedings: Scandinavian Journal of Infectious Diseases, Vol. 35, No. 9, 2003, Stockholm.

 

Anti-Complement Strategies in Experimental Sepsis
Peter A. Ward*, Niels C. Riedemann*, Ren-Feng Guo*, Markus Huber-Lang#, J. Vidya Sarma*, Firas S. Zetoune*
*Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA and #Universitaetsklinik Ulm, Abteilung Unfallchirurgie, Steinhoevelstrasse, Germany

Using the cecal ligation/puncture (CLP) model of sepsis in rodents, we have obtained evidence for excessive activation of the complement system, which leads to nearly total loss of innate immune protective functions of blood neutrophils. These defects are associated with profound defects in chemotaxis, respiratory burst (H2O2 production) and phagocytosis. The molecular mechanisms of these defects are linked to the complement activation product, C5a. In CLP rats and mice, the C5a receptor (C5aR) is widely upregulated in organs, in part due to the production of IL-6. The upregulation of C5aR in the thymus is linked to C5a-dependent induction of apoptosis in thymocytes, as revealed by caspase activation, increased binding of C5a, and DNA laddering. Such events in thymocytes are prevented if rats first are treated with anti-C5a or with anti-C5aR at the time of CLP. Treatment of CLP rats and mice with anti-C5a, anti-IL-6 or anti-C5aR dramatically improves survival rates after CLP, indicating a linkage between C5a and C5aR in the harmful outcomes of sepsis in rodents. Studies are underway in humans with sepsis to determine if similar mechanisms are in play.