Soluble P-selectin moderates complement-dependent reperfusion injury of ischemic skeletal muscle.
P-selectin is an adhesion molecule expressed on activated endothelial and platelet surfaces. The function of the short consensus repeats (SCRs) of P-selectin, homologous with the SCRs of complement regulatory proteins is largely 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. Infusion of sP-sel supernatant or purified (p) sP-sel prepared from activated human platelets, reduced ischemic muscle vascular permeability by 48% and 43%, respectively, following reperfusion. Hindlimb immunohistochemistry demonstrated negligible C3 staining colocalized with IgM in these groups compared 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 demonstrated that psP-sel inhibited C1q adherence to sensitized red blood cells. From these data we conclude that sP-sel moderates skeletal muscle reperfusion injury by inhibition of the classical complement pathway.
Kyriakides
C
C
Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston 02115, USA.
Woodcock
S A
SA
Wang
Y
Y
Favuzza
J
J
Austen
W G
WG
Kobzik
L
L
Moore
F D
FD
Valeri
R C
RC
Shepro
D
D
Hechtman
H B
HB
D000818:Animals; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D003171:Complement Pathway, Classical / Q000187:drug effects*; D006614:Hindlimb / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects*; D019007:P-Selectin / Q000494:pharmacology* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*
D019007:P-Selectin