Soluble P-selectin moderates complement dependent injury.
P-selectin is an adhesion molecule expressed on activated endothelial and platelet membranes containing 9 short consensus repeats (SCRs) similar to the composition of complement regulatory proteins. In our murine model of intestinal ischemia and reperfusion where local injury is mediated by the classical complement pathway we hypothesized the SCRs would moderate the complement response. Confirmatory data were sought following hindlimb ischemia and reperfusion where injury is both complement- and neutrophil-mediated. Mice deficient in P-selectin (P-/-) were found to have similar intestinal and hindlimb permeability compared to normal wild types mice (P+/+). When reconstituted with P+/+ platelets, but not P-/- platelets, P-/- mice subjected to intestinal ischemia had a significant 29% decrease in permeability (P < 0.05) and after hindlimb ischemia the decrease was 33% (P<0.05). Reperfusion after intestinal ischemia led to a 76% fall in CH50 in P-/- compared to sham animals (P < 0.05) indicating complement activation and consumption, but only a 36% fall in animals reconstituted with P+/+ platelets (P < 0.05). Full-length, soluble P-selectin (sPsel) derived from processed platelets, but not the truncated version of sPsel has been shown to adhere to a heat labile fraction of serum and sensitized red blood cells thereby reducing Clq adherence to the sensitized red cell. From these data we conclude that sPsel moderates complement activation by competing with C1q binding to antibody, thereby limiting activation of the classical pathway that mediates murine reperfusion injury.
Woodcock
S A
SA
Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Kyriakides
C
C
Wang
Y
Y
Austen
W G
WG
Moore
F D
FD
Valeri
R
R
Hartwell
D
D
Hechtman
H B
HB
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D003171:Complement Pathway, Classical; D003165:Complement System Proteins / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply / Q000293:injuries; D007422:Intestines / Q000098:blood supply / Q000293:injuries; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000097:blood* / Q000235:genetics; D015427:Reperfusion Injury / Q000097:blood / Q000276:immunology; D012995:Solubility
D019007:P-Selectin; D003165:Complement System Proteins