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C5a causes limited, polymorphonuclear cell-independent, mesenteric ischemia/reperfusion-induced injury
Sherry D Fleming1, Dimitrios Mastellos, Georg Karpel-Massler
1Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA. sfleming@usuhs.mil
Abstract:
C5 is critical in the development of local mucosal damage and inflammation as well as in the development of remote organ injury after mesenteric ischemia/reperfusion (IR). To define the role of C5a in tissue injury, we treated wild-type mice with a cyclic hexapeptide C5a receptor antagonist (C5aRa) and administered recombinant C5a to C5 deficient (C5(-/-)) mice subjected to mesenteric IR. We demonstrate that at 2-h postreperfusion, C5a administered to C5-/- mice during IR induces limited intestinal mucosal injury but failed to cause remote lung injury despite the fact that it upregulated adhesion molecule expression. C5aRa treatment of C5+/+ mice undergoing IR limited local injury and prevented distant organ injury. We conclude that although C5a can trigger certain components of the IR induced injury, other mediators such as C5b-9 and local factors are needed for the complete expression of IR tissue damage.
Insights
Complement C5a plays a role in mesenteric ischemia/reperfusion (IR) injury, but other factors are also involved. Blocking C5a limits local and remote organ damage in IR mouse models.
Area of Science:
- Immunology
- Physiology
- Pathology
Background:
- Complement C5 is crucial for local mucosal damage and inflammation.
- C5 contributes to remote organ injury following mesenteric ischemia/reperfusion (IR).
Purpose of the Study:
- To elucidate the specific role of C5a in mediating tissue injury during mesenteric IR.
- To investigate the therapeutic potential of C5a receptor antagonism in IR-induced damage.
Main Methods:
- Wild-type mice were treated with a C5a receptor antagonist (C5aRa).
- Recombinant C5a was administered to C5-deficient mice subjected to mesenteric IR.
- Intestinal mucosal injury and remote lung injury were assessed at 2 hours postreperfusion.
Main Results:
- C5a administration in C5-deficient mice induced limited intestinal injury but not remote lung injury, despite upregulating adhesion molecules.
- C5aRa treatment in wild-type mice significantly limited both local intestinal injury and distant organ damage.
- C5a alone was insufficient to cause the full spectrum of IR-induced tissue damage.
Conclusions:
- C5a contributes to, but is not solely responsible for, IR-induced tissue injury.
- Complete IR tissue damage requires C5a in conjunction with other mediators like C5b-9 and local factors.