Soluble P-selectin moderates complement dependent injury

P-selectin is an adhesion molecule expressed on activated endothelial and p latelet membranes containing 9 short consensus repeats (SCRs) similar to th e composition of complement regulatory proteins. In our murine model of int estinal ischemia and reperfusion where local injury is mediated by the clas sical complement pathway we hypothesized the SCRs would moderate the comple ment response. Confirmatory data were sought following hindlimb ischemia an d reperfusion where injury is both complement- and neutrophil-mediated. Mic e deficient in P-selectin (P-/-) were found to have similar intestinal and hindlimb permeability compared to normal wild types mice (P+/+). When recon stituted with P+/+ platelets, but not P-/- platelets, P-/- mice subjected t o intestinal ischemia had a significant 29% decrease in permeability (P<0.0 5) and after hindlimb ischemia the decrease was 33% (P<0.05). Reperfusion a fter intestinal ischemia led to a 76% fall in CH50 in P-/- compared to sham animals (P<0.05) indicating complement activation and consumption, but onl y a 36% fall in animals reconstituted with P+/+ platelets (P<0.05). Full-le ngth, soluble P-selectin (sPsel) derived from processed platelets, but not the truncated version of sPsel has been shown to adhere to a heat labile fr action of serum and sensitized red blood cells thereby reducing Clq adheren ce to the sensitized red cell. From these data we conclude that sPsel moder ates complement activation by competing with Clq binding to antibody, there by limiting activation of the classical pathway that mediates murine reperf usion injury.