C5 complement inhibition attenuates shock and acute lung injury in an experimental model of ruptured abdominal aortic aneurysm.
BACKGROUND
Ruptured abdominal aortic aneurysm (RAAA) is associated with a systemic inflammatory response syndrome and multiple organ dysfunction. The potential role of a novel C5 complement inhibitor in attenuation of pathological complement activation and tissue injury was explored in a model of RAAA.


METHODS
Anaesthetized rats were randomized to sham (control) or shock and clamp (SC) groups. Animals in the SC group underwent 1 h of haemorrhagic shock (mean arterial pressure 50 mmHg or less), 45 min of supramesenteric aortic clamping and 2 h of reperfusion. They were randomized to receive an intravenous bolus of a functionally blocking anti-C5 monoclonal antibody (C5 inhibitor), at a dose of 20 mg/kg, or saline. Lung injury was assessed by permeability to 125I-labelled albumin, tissue myeloperoxidase (MPO) activity, and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) for mRNAs encoding tumour necrosis factor (TNF) alpha and interleukin (IL) 6.


RESULTS
The lung permeability index was significantly increased in the SC compared with the sham group (P = 0.032); this was prevented by the C5 inhibitor (P = 0.015). Lung MPO activity was significantly increased in the SC compared with the sham group (P < 0.001), and this increase was attenuated by treatment with the C5 inhibitor (P < 0.001). Semiquantitative RT-PCR in SC group demonstrated downregulation of TNF-alpha mRNA (P = 0.050) and upregulation of IL-6 mRNA (P < 0.001), which were both prevented by the C5 inhibitor (P = 0.014 and P < 0.001 respectively).


CONCLUSIONS
These results indicated that C5 complement inhibition can reduce shock and acute lung injury in an experimental model of RAAA.
Harkin
D W
DW
Division of Vascular Surgery, Department of Surgery, Toronto Hospital (General Division), Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. D.W.Harkin@qub.ac.uk
Marron
C D
CD
Rother
R P
RP
Romaschin
A
A
Rubin
B B
BB
Lindsay
T F
TF
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology / Q000276:immunology*; D001019:Aortic Rupture / Q000201:enzymology / Q000276:immunology*; D001794:Blood Pressure; D003167:Complement Activation / Q000276:immunology; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012771:Shock, Hemorrhagic / Q000276:immunology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D003182:Complement C5; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D009195:Peroxidase