Complement C5a receptor antagonist attenuates multiple organ injury in a model of ruptured abdominal aortic aneurysm.

Abstract

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.

• Authors: Denis W Harkin, Alex Romaschin, Stephen M Taylor, Barry B Rubin, Thomas F Lindsay
• Journal: Journal of vascular surgery (J Vasc Surg) Vol. 39 Issue 1 Pg. 196-206 (Jan 2004) ISSN: 0741-5214 [Print] United States
• PMID: 14718840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Peptides, Cyclic
• Tumor Necrosis Factor-alpha
• complement C5a-inhibitors
• phenylalanyl(ornithinyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)
• Peroxidase
• Serine Endopeptidases

Topics

• Animals
• Aortic Aneurysm, Abdominal (complications, physiopathology)
• Aortic Rupture (complications, immunology, physiopathology)
• Capillary Permeability
• Complement Activation
• Complement Hemolytic Activity Assay
• Intestines (physiopathology)
• Lung (blood supply, metabolism)
• Male
• Multiple Organ Failure (etiology, physiopathology, prevention & control)
• Peptides, Cyclic (therapeutic use)
• Permeability
• Peroxidase (analysis)
• Rats
• Rats, Sprague-Dawley
• Serine Endopeptidases (therapeutic use)
• Tumor Necrosis Factor-alpha (analysis)