TIME OF C5a RECEPTOR ANTAGONIST ADMINISTRATION INFLUENCES LOCAL AND REMOTE ORGAN INJURY IN A MOUSE MODEL OF RUPTURED ABDOMINAL AORTIC ANEURYSM

WS. Johnson, S Nicholson, BB. Rubin, TF. Lindsay 
Division of Vascular Surgery, Toronto General Hospital, Department of Surgery, University of Toronto

Objective: Complement is an essential mediator of organ injury that contributes to the 40% to 75% mortality of Ruptured Abdominal Aortic Aneurysm (RAAA). We sought to determine if a C5a receptor antagonist (C5aRa) reduces organ injury in a mouse model of RAAA and the time of maximal effect.

Methods: C57BL/6 mice were assigned to one of 4 experimental groups: 1) sham, 2) shock, 3) clamp, and 4) shock + clamp (SC).  The SC group (simulating RAAA repair) was further assigned to 3 treatment groups: 1) SC+C5aRa administered prior to shock, 2) SC+C5aRa administered at the end of shock, and 3) SC+C5aRa administered at the end of aortic clamping.  All animals in the SC groups experienced 1 hour of hemorrhagic shock followed by 30 minutes of surpramesenteric aortic clamping and 2 hours of resuscitated reperfusion.  Animals in treatment groups received an intravenous bolus of C5aRa (2mg/kg) at the different time points.  Lung and gut injury was assessed by the permeability to I125 - labeled albumin.  Neutrophil sequestration was assessed by levels of tissue myeloperoxidase and proinflammatory cytokines by the tissue levels of TNF-α.

Results:

 * p<0.05 vs. sham; + p<0.05 vs. SC;  ‡ p<0.05 vs. all except C5aRa aftshock;   # p<0.05 vs. SC, C5aRa preshock, and C5aRa aftclamp; † p<0.05 vs. SC and C5aRa preshock

CONCLUSIONS: These data characterize the mouse model of RAAA and establish it as an investigational tool for further molecular intervention.  Complement inhibition via C5aRa successfully attenuates both local and remote organ injury.  C5aRa is most effective when given after the period of hemorrhagic shock, the timing of which holds significant clinical promise.