Anti-complement strategies in experimental sepsis.
Using the cecal ligation/puncture (CLP) model of sepsis in rodents, evidence was obtained 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 up-regulated in organs, in part owing to the production of interleukin-6 (IL-6). The up-regulation 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 whether similar mechanisms are in play.
Ward
Peter A
PA
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA. pward@umich.edu
Riedemann
Niels C
NC
Guo
Ren-Feng
RF
Huber-Lang
Markus
M
Sarma
J Vidya
JV
Zetoune
Firas S
FS
D000818:Animals; D002633:Chemotaxis; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D010587:Phagocytosis; D051381:Rats; D016897:Respiratory Burst; D018805:Sepsis / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
D015936:Complement C5a