Complement c5a receptor antagonist attenuates multiple organ injury in a model of ruptured abdominal aortic aneurysm Denis W Harkin, MD,, Alex Romaschin,

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Complement c5a receptor antagonist attenuates multiple organ injury in a model of ruptured abdominal aortic aneurysm Denis W Harkin, MD,, Alex Romaschin, PhD, Stephen M Taylor, PhD, Barry B Rubin, MD, PhD, Thomas F Lindsay, PhD Journal of Vascular Surgery Volume 39, Issue 1, Pages 196-206 (January 2004) DOI: 10.1016/j.jvs.2003.07.001

Fig 1 Lung permeability index to iodine 125–labeled albumin was significantly increased in the shock and clamp group (s+c) compared with the sham group (*P < .01), and was significantly prevented with treatment with C5a receptor antagonist (C5aRA; #P < .03). MPO, Myeloperoxidase. Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)

Fig 2 Lung tissue myeloperoxidase (MPO) activity was significantly increased in the shock and clamp group (s+c) compared with the sham group (*P < .009), and was significantly attenuated with treatment with C5a receptor antagonist (C5aRA; #P < .006). Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)

Fig 3 Lung tissue necrosis factor-α (TNF-α) levels were significantly elevated in the shock and clamp group (s+c) compared with the sham group (*P < .03), but were not prevented with treatment with C5a receptor antagonist (C5aRA; P = NS). Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)

Fig 4 Rate of intraluminal intestinal albumin loss, intestinal permeability index (IPI), remained stable throughout the entire experimental period in sham animals. In shock and clamp animals (s+c), IPI remained stable during stabilization, hemorrhage, and clamp periods. During reperfusion IPI was significantly increased in s+c animals, compared with pre-shock levels (*P < .0001) and with control levels (*P < .0001), and remained at similar levels throughout the 120-minute reperfusion. Treatment with C5a receptor antagonist (C5aRA) significantly reduced the increased IPI in the first 60 minutes of (early) reperfusion, compared with untreated s+c animals (#P < .01). However, as reperfusion progressed IPI increased, even in the treated group, to mirror untreated s+c levels. s, Shock; c, clamping; r, reperfusion. Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)

Fig 5 Intestinal tissue myeloperoxidase (MPO) activity was not significantly increased in the shock and clamp group (s+c) compared with the sham group (P = NS). Of interest, intestinal MPO activity was significantly reduced in animals treated with C5a receptor antagonist (C5aRA) compared with untreated s+c animals (*P < .01) and the sham group (#P < .017). Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)

Fig 6 Intestinal tissue necrosis factor-α (TNF-α) levels were significantly elevated in the shock and clamp group (s+c) compared with the sham group (*P < .038), but were not prevented with treatment with C5a receptor antagonist (C5aRA; P = NS). Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)

Fig 7 Mean arterial blood pressure (MAP) remained stable throughout the entire experimental period in sham animals (A), requiring minimal intravenous fluid resuscitation with Ringer lactate solution (B). In shock and clamp animals (s+c), MAP was reduced during hemorrhagic shock to 50 mm Hg or less for 1 hour, as defined by the protocol. On application of the supramesenteric aortic clamp, MAP increased significantly compared with pre-shock levels (P < .001). In s+c animals after removal of the aortic clamp, MAP decreased progressively during reperfusion to a nadir after 120 minutes of reperfusion (#P < .001), despite vigorous fluid resuscitation with intravenous infusion of Ringer lactate solution (69.3 ± 8.5 mL). Animals treated with C5a receptor antagonist (C5aRA) maintained significantly better MAP during reperfusion compared with untreated s+c animals (#P < .01; A), and required less intravenous fluid resuscitation (P < .1, NS; B). s, Shock; c, clamping; r, reperfusion. Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)

Fig 8 Total serum hemolytic activity (CH50) measured at the end of the experimental period is expressed as a percentage of reference serum value. Significant reduction in serum hemolytic activity is noted in the shock and clamp group (s+c), and this was not significantly attenuated with treatment with C5a receptor antagonist (C5aRA; P < .004, analysis of variance). Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)

Fig 9 A, Expression of C5a receptor antagonist (C5aRA) in lung tissue is downregulated from control levels by shock and clamp injury (s+c), and this is only partially attenuated in the C5aRA-treated group. B, Densitometry analysis demonstrates significant downregulation of C5aRA in the s+c group, which is prevented in the C5aRA-treated group (P < .012, analysis of variance). Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)

Fig 10 A, Expression of tissue necrosis factor-α (TNF-α) in lung tissue is downregulated from control levels by shock and clamp injury (s+c), and this is only partially attenuated in the group treated with C5a receptor antagonist (C5aRA). B, Densitometry analysis demonstrates significant downregulation of TNF-α in the s+c group, which is not altered with treatment with C5aRA (P < .019, analysis of variance). Journal of Vascular Surgery 2004 39, 196-206DOI: (10.1016/j.jvs.2003.07.001)