Complement Inhibitor, Complement Receptor 1-Related Gene/Protein y-Ig Attenuates Intestinal Damage After the Onset of Mesenteric Ischemia/Reperfusion Injury in Mice

Abstract

Complement receptor 1-related gene/protein y (Crry) is a murine membrane protein that regulates the activity of both classical and alternative complement pathways. We used a recombinant soluble form of Crry fused to the hinge, CH2, and CH3 domains of mouse IgG1 (Crry-Ig) to determine whether inhibition of complement activation prevents and/or reverses mesenteric ischemia/reperfusion-induced injury in mice. Mice were subjected to 30 min of ischemia, followed by 2 h of reperfusion. Crry-Ig was administered either 5 min before or 30 min after initiation of the reperfusion phase. Pretreatment with Crry-Ig reduced local intestinal mucosal injury and decreased generation of leukotriene B4 (LTB4). When given 30 min after the beginning of the reperfusion phase, Crry-Ig resulted in a decrease in ischemia/reperfusion-induced intestinal mucosal injury comparable to that occurring when it was given 5 min before initiation of the reperfusion phase. The beneficial effect of Crry-Ig administered 30 min after the initiation of reperfusion coincided with a decrease in PGE2 generation despite the fact that it did not prevent local infiltration of neutrophils and did not have a significant effect on LTB4 production. These data suggest that complement inhibition protects animals from reperfusion-induced intestinal damage even if administered as late as 30 min into reperfusion and that the mechanism of protection is independent of neutrophil infiltration or LTB4 inhibition.

TNF-α Is a Critical Effector and a Target for Therapy in Antiphospholipid Antibody-Induced Pregnancy Loss

“…Our results fit into a larger schema consistent with evidence from murine models of myocarditis, sepsis, and rheumatoid arthritis, and suggest that tissue damage induced as a result of complement activation is mediated by production of TNF-␣ (42,44). However, because blockade of TNF-␣ does not completely protect pregnancies, it is likely that other effector pathways contribute to fetal demise.…”

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

“…C, C9 is not detected in fB Ϫ/Ϫ mice subjected to I/R (ϫ200). (9) 0.0 Ϯ 0.0 0 Ϯ 0 a Tubular C3 deposition was graded on a scale from zero to four based upon the percentage of tubules with C3 along the basement membrane and the percentage of the circumference of individual tubules demonstrating C3. B6129F 1 mice had significantly greater C3 in the outer medulla after I/R when compared with unmanipulated B6129F 1 mice ( p Ͻ 0.001).…”

Complement, natural antibodies, autoantibodies and tissue injury

“…Treatment with soluble Crry-Ig allowed neutrophil infiltration without significant tissue damage indicating that the presence of neutrophils is not sufficient for tissue damage (2). These studies also showed complement activation is critical to the induction of local mucosal damage and resulted in decreased systemic neutrophil activation as well (2). Inflammatory mediators of the complement pathway, such as the anaphylotoxin C5a, are known to be required for damage to remote organs including the lungs in response to mesenteric IR (3, 4).…”