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P-selectin mediates intestinal ischemic injury by enhancing complement deposition
S A Gibbs1, M R Weiser, L Kobzik
1Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
Surgery
|June 1, 1996
Summary
P-selectin antagonism in rodent intestine ischemia reperfusion injury did not reduce neutrophil sequestration but did inhibit complement deposition. This suggests a novel protective mechanism beyond neutrophil adhesion.
Area of Science:
- Gastroenterology
- Immunology
- Vascular Biology
Background:
- Intestinal ischemia and reperfusion injury in rodents is mediated by the complement system.
- P-selectin antagonism shows promise in reducing local injury, but its mechanism remains unclear as neutrophil depletion does not confer protection.
Purpose of the Study:
- To investigate whether P-selectin antagonists protect against intestinal ischemia and reperfusion injury by inhibiting complement activation.
- To elucidate the role of P-selectin antagonism in modulating neutrophil sequestration and complement deposition during intestinal injury.
Main Methods:
- Rodents (n=86) underwent 50 minutes of mesenteric ischemia followed by 4 hours of reperfusion.
- Treatment groups included a monoclonal antibody against P-selectin (PB1.3), soluble sialyl Lewisx (sLex), saline control, and sham.
- Intestinal injury was assessed by 125I-albumin permeability and myeloperoxidase (MPO) assay; complement deposition (C5b-9) and neutrophil sequestration were evaluated via immunohistochemistry and MPO assays.
Main Results:
- PB1.3 treatment significantly reduced intestinal 125I-albumin permeability compared to saline controls (p < 0.05) but did not alter neutrophil sequestration.
- PB1.3 significantly reduced mucosal C5b-9 deposition, indicating complement inhibition.
- sLex reduced intestinal MPO activity (p < 0.05) but not permeability, while both PB1.3 and sLex showed effects on remote lung injury markers.
Conclusions:
- P-selectin antagonism, specifically targeting the lectin domain, does not confer local benefit by inhibiting neutrophil adhesion in this model.
- PB1.3 demonstrates a novel protective mechanism by antagonizing P-selectin and reducing complement deposition in the intestinal mucosa.
- The findings suggest that complement inhibition, rather than direct neutrophil adhesion blockade, may be the primary protective pathway for P-selectin antagonists in this context.