C5a, a therapeutic target in sepsis.
The complement activation product, C5a, is a potent inflammatory peptide with a broad spectrum of biological functions. Plasma levels of C5a are increased in sepsis, accompanied by increased content of C5a receptor (C5aR) in various organs. In the mouse and rat models of sepsis (cecal ligation and puncture, CLP), C5a blockade by anti-C5a antibody, anti-C5aR antibody or use of a C5aR antagonist (C5aRa) significantly improved survival in CLP animals. C5a blockade in sepsis attenuated the systemic inflammatory response syndrome (SIRS) by reducing plasma levels of IL-6 and decreasing bacteria counts in blood and organs. Anti-C5a treatment in CLP rodents markedly attenuated sepsis-induced defects in the coagulation/fibrinolytic system, while liver and kidney functions were remarkably preserved in contrast to CLP animals not receiving anti-C5a in which multi-organ failure occurs. In CLP rats treated with anti-C5a, thymus atrophy was diminished and thymocyte apoptosis was inhibited. Defective neutrophil functions (chemotaxis, phagocytosis, respiratory burst) caused by sepsis were significantly improved in CLP rats treated with anti-C5a. These data suggest during CLP-induced sepsis C5a has very harmful consequences and that its blockade might be a promising therapeutic strategy for the treatment of humans with sepsis. This review will summarize the beneficial effects of anti-C5a treatment in the rodent model of sepsis and will introduce the most recent patents on this line of research.
Guo
Ren-Feng
RF
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA. grf@med.umich.edu
Ward
Peter A
PA
D000818:Animals; D015936:Complement C5a / Q000037:antagonists & inhibitors*; D006801:Humans; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control; D009504:Neutrophils / Q000187:drug effects; D010330:Patents as Topic; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D013534:Survival; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy
D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a