Protective effects of C5a blockade in sepsis

Sepsis in humans is a difficult condition to treat and is often associated with a high mortality rate. In this study, we induced sepsis in rats using cecal ligation and puncture (CLP). In rats depleted of the complement facto r C3, CLP led to very short survival times (about 4 days). Of the rats that underwent CLP ('CLP rats') that were C3-intact and treated with preimmune Igc, most (92%) were dead by 7 days. Blood neutrophils from these rats cont ained on their surfaces the powerful complement activation product C5a. Thi s group had high levels of bacteremia, and their blood neutrophils when sti mulated in vitro had greatly reduced production of H2O2 which is known to b e essential for the bactericidal function of neutrophils. In contrast, when companion CLP rats were treated with IgG antibody against C5a, survival ra tes were significantly improved, levels of bacteremia were considerably red uced, and the H2O2 response of blood neutrophils was preserved. Bacterial c olony-forming units in spleen and liver were very high in CLP rats treated with preimmune IgG and very low in CLP rats treated with IgG antibody again st C5a, similar to values obtained in rats that underwent 'sham' operations (without CLP). These data indicate that sepsis causes an excessive product ion of C5a, which compromises the bactericidal function of neutrophils. Thu s, C5a may be a useful target for the treatment of sepsis.