Soluble P-selectin moderates complement-dependent reperfusion injury of ischemic skeletal muscle

P-selectin is an adhesion molecule expressed on activated endothelial and p latelet surfaces. The function of the short consensus repeats (SCRs) of P-s electin, homologous with the SCRs of complement regulatory proteins is larg ely unknown. In a model of murine hindlimb ischemia where local reperfusion injury is partly mediated by IgM natural antibody and classical complement pathway activation, we hypothesized that human soluble P-selectin (sP-sel) would moderate the complement component of the inflammatory response. Infu sion of sP-sel supernatant or purified (p) sP-sel prepared from activated h uman platelets, reduced ischemic muscle vascular permeability by 48% and 43 %, respectively, following reperfusion. Hindlimb immunohistochemistry demon strated negligible C3 staining colocalized with IgM in these groups compare d with intense staining in the untreated injured mice. In vitro studies of mouse serum complement hemolytic activity showed that psP-sel inhibited the classical but not alternative complement pathway. Flow cytometry demonstra ted that psP-sel inhibited C1q adherence to sensitized red blood cells. Fro m these data we conclude that sP-sel moderates skeletal muscle reperfusion injury by inhibition of the classical complement pathway.