P-selectin mediates intestinal ischemic injury by enhancing complement deposition.
BACKGROUND
Ischemia and reperfusion injury of rodent intestine is complement mediated. P-selectin 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 125I-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-dependent remote lung injury assessed by 125I-albumin permeability and pulmonary myeloperoxidase assay were not significantly reduced by PB1.3. Treatment with a soluble form of P-selectin ligand, sialyl Lewisx (sLex), 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 sLex 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 exerted a novel antagonism of P-selectin and reduced complement deposition.
Gibbs
S A
SA
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
Weiser
M R
MR
Kobzik
L
L
Valeri
C R
CR
Shepro
D
D
Hechtman
H B
HB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000502:physiology*; D007422:Intestines / Q000098:blood supply*; D007511:Ischemia / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000502:physiology; D019007:P-Selectin / Q000502:physiology*; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D015938:Complement Membrane Attack Complex; D019007:P-Selectin; D009195:Peroxidase