Complement inhibitor, complement receptor 1-related gene/protein y-Ig attenuates intestinal damage after the onset of mesenteric ischemia/reperfusion injury in mice.
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 B(4) (LTB(4)). 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 PGE(2) generation despite the fact that it did not prevent local infiltration of neutrophils and did not have a significant effect on LTB(4) 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 LTB(4) inhibition.
Rehrig
S
S
Department of Surgery, Walter Reed Army Medical Center, Washington, DC 20307, USA.
Fleming
S D
SD
Anderson
J
J
Guthridge
J M
JM
Rakstang
J
J
McQueen
C E
CE
Holers
V M
VM
Tsokos
G C
GC
Shea-Donohue
T
T
D000818:Animals; D003169:Complement Inactivator Proteins / Q000235:genetics / Q000627:therapeutic use*; D015777:Eicosanoids / Q000096:biosynthesis; D004751:Enteritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007074:Immunoglobulin G / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008643:Mesentery; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011951:Receptors, Complement / Q000235:genetics / Q000627:therapeutic use*; D017463:Receptors, Complement 3b; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology
D003169:Complement Inactivator Proteins; C081470:Cr1l protein, mouse; D015777:Eicosanoids; D007074:Immunoglobulin G; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D011993:Recombinant Fusion Proteins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse