P-selectin mediates intestinal ischemic injury by enhancing complement deposition

Background. Ischemia and reperfusion injury of rodent intestine is complement mediated. P-seletin antagonism reduces local injury, yet neutrophil depletion does not. This study tests the thesis that the protective mechanism of P-selectin antagonists involves complement inhibition. Methods. We subjected rats (n=86) to 50 minutes of complete mesenteric ischemia and 4 hours of reperfusion. Treatment with a monoclonal antibody (PB1.3) against P-selectin reduced intestinal injury as judged by I-125-albumin permeability index (7.33 +/- 0.40) compared with saline solution treatment (11.4 +/- 0.49) (p <0.05). Results. However, intestinal neutrophil sequestration assessed by myeloperoxidase assay was unchanged. Immunohistochemistry revealed that mucosal C5b-9 was deposited in animals treated with saline solution and was absent in the sham group. PB1.3 treatment reduced C5b-9 deposition in the intestinal mucosa compared with that in animals treated with saline solution (p <0.05). Neutrophil-dependant remote lung injury assessed by I-125-albumin permeability and pulmonary myeloperoxidase assay were not significantly reduced by PB1.3. Treatment with a soluble form of P-selectin ligand, sialyl Lewis(x) (sLe(x)), reduced intestinal myeloperoxidase (0.065 +/- 0.006) compared with saline solution treatment (0.136 +/- 0.02) (p <0.05), but it did not reduce permeability. Remote lung permeability was reduced (4.52 +/- 0.65 x 10(-3)) by sLe(x) compared with saline solution treatment (6.11 +/- 0.41 x 10(-3)) (p <0.05). Conclusions. Antagonizing the lectin domain of P-selectin and thereby neutrophil adhesion was without local benefit in this model. In contrast, PB1.3 extend a novel antagonism of P-selectin and reduced complement deposition.