Role of the complement in experimental sepsis

Abstract

At the Trauma, Shock, Inflammation and Sepsis 2007 conference, the roles of complement activation products and relevant receptors were stressed in the setting of experimental sepsis [cecal ligation and puncture (CLP)] in mice and rats. In addition, some limited evidence was presented related to humans with septic shock (requiring vasopressor support). Collectively, the data suggested that events found in CLP also occur in human sepsis. Experimental sepsis (CLP) in rodents is associated with robust complement consumption and appearance of activation products (C3a, C5a) in plasma. During sepsis, there is up-regulation of C5a receptors (C5aR, C5L2) on blood polymorphonuclear neutrophils (PMNs) and in lungs, liver, kidneys, and heart. CLP also leads to dramatic reductions of C5aRs on blood PMNs, the intensity of which correlates with lethality. Interception in vivo of C5a or C5aR dramatically improves survival after CLP, preserves innate immune functions of blood PMNs, and greatly attenuates the intensity of consumptive coagulopathy and activation of the fibrinolytic system after CLP. In humans with septic shock, there is evidence of complement activation products in plasma along with loss of C5aRs on blood PMNs. These data suggest that in septic humans, interception of C5a or C5aR might be clinically efficacious.