Complement C5a receptor antagonist attenuates multiple organ injury in a model of ruptured abdominal aortic aneurysm.
OBJECTIVE
Abdominal aortic aneurysm (AAA) rupture is associated with a systemic inflammatory response syndrome, characterized by increased microvascular permeability and neutrophil sequestration, leading to multiorgan dysfunction. We examined the role of a novel complement factor 5a (C5aR) receptor antagonist, the cyclic peptide AcF-(OpdChaWR), in attenuation of pathologic complement activation and tissue injury in a model of AAA rupture.


METHODS
Anesthetized rats were randomized to sham (control) or shock and clamp (s+c) groups. Animals in the s+c group underwent 1 hour of hemorrhagic shock (mean arterial blood pressure < or =50 mm Hg), followed by 45 minutes of supramesenteric aortic clamping, then 2 hours of resuscitated reperfusion. Animals in the s+c group were randomized to receive an intravenous bolus of C5aR antagonist at 1 mg/kg or saline solution control at the end of hemorrhagic shock. Intestinal and pulmonary permeability to iodine 125-labeled albumin was measured as an indicator of microvascular permeability. Tissue myeloperoxidase activity, proinflammatory cytokine tissue necrosis factor-alpha (TNF-alpha) protein and mRNA, and C5aR mRNA levels were measured as indicators of neutrophil sequestration and inflammatory signaling, respectively.


RESULTS
Lung permeability index was significantly increased in the s+c group compared with the sham group (4.43 +/- 0.96 vs 1.30 +/- 0.17; P <.01), and prevented with treatment with C5aR antagonist (1.74 +/- 0.50; P <.03). Lung myeloperoxidase activity was significantly increased in the the s+c group compared with the sham group (2.41 +/- 0.34 U/mg vs 1.03 +/- 0.29 U/mg; P <.009), and significantly attenuated with treatment with C5aR antagonist (1.11 +/- 0.09 U/mg; P <.006). Lung TNF-alpha protein levels were significantly elevated in both s+c groups, whereas lung TNF-alpha mRNA expression was significantly downregulated in both s+c groups compared with the sham group. Intestinal permeability index was significantly increased in animals in the s+c groups during reperfusion, compared with sham (P <.001), which was attenuated in early reperfusion with treatment with C5a receptor antagonist. Data represent mean +/- SEM, group comparisons with analysis of variance and post hoc Scheffé test.


CONCLUSIONS
These results indicate that a potent antagonist of C5a receptor protects the rat intestine and lung from neutrophil-associated injury in a model of AAA rupture. These data suggest that complement-mediated inflammation can be modulated at the C5a receptor level, independent of proinflammatory TNF-alpha production, and prevent acute local and remote organ injury.
Harkin
Denis W
DW
Division of Vascular Surgery, Department of Surgery, The Toronto Hospital (General Division), Faculty of Medicine, University of Toronto, Eaton Building 5-306, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. D.W.Harkin@qub.ac.uk
Romaschin
Alex
A
Taylor
Stephen M
SM
Rubin
Barry B
BB
Lindsay
Thomas F
TF
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000150:complications* / Q000503:physiopathology; D001019:Aortic Rupture / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D002199:Capillary Permeability; D003167:Complement Activation; D015941:Complement Hemolytic Activity Assay; D007422:Intestines / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D010539:Permeability; D009195:Peroxidase / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D010456:Peptides, Cyclic; D014409:Tumor Necrosis Factor-alpha; C041833:complement C5a-inhibitors; C412424:phenylalanyl(ornithinyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl); D009195:Peroxidase; D012697:Serine Endopeptidases