Elimination of C5aR prevents intestinal mucosal damage and attenuates neutrophil infiltration in local and remote organs.
The complement C5a pathway has been shown to be an important mediator of inflammation and tissue injury. To further understand the role of C5a receptor (C5aR) pathway in ischemia/reperfusion (I/R) injury, and to evaluate the potential of antagonizing C5aR to protect from I/R injury, we tested the effect of eliminating C5aR using C5aR knockout (KO) mice and their wild-type (WT) littermates in a superior mesenteric artery occlusion (SMAO) intestinal I/R injury model. C5aR KO and WT mice were subjected to SMAO or sham for 45 min. After 3 h of reperfusion, the percentage of injured ileal villi was twice as high in WT mice subjected to SMAO as compared with the C5aR KO mice. In addition, the number of neutrophils was 34% higher in WT mice subjected to SMAO as compared with the C5aR KO mice. Moreover, ileum and lung myeloperoxidase activities after SMAO were significantly higher in WT than C5aR KO mice. Apoptotic cell death was induced after reperfusion in WT-SMAO and was reduced by more than 50% in C5aR KO mice. The plasma level of TNF-alpha was increased approximately 3.74-fold in WT subjected to SMAO compared with sham. In contrast, the level was increased only approximately 1.18-fold in the C5aR KO mice subjected to SMAO. In conclusion, this study demonstrates that elimination of the C5aR pathway protects the intestine from I/R injury and diminishes intestine-derived pulmonary neutrophil sequestration. Blocking C5aR may be considered as a potential therapeutic intervention for I/R injury.
Xu
Da-Zhong
DZ
Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
Zaets
Sergey B
SB
Chen
Ruihua
R
Lu
Qi
Q
Rajan
Harini
H
Yang
Xiaoman
X
Zhang
John
J
Feketova
Eleonora
E
Bogdan
Nancy
N
Deitch
Edwin A
EA
Cao
Yang
Y
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D007082:Ileum / Q000098:blood supply / Q000378:metabolism; D007413:Intestinal Mucosa / Q000098:blood supply* / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000235:genetics / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase
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