Raised plasma soluble P-selectin in peripheral arterial occlusive disease enhances leukocyte adhesion.
Raised levels of soluble P-selectin (sP-selectin) have been reported in the plasma of patients with vascular diseases; however, the functional importance of this ligand remains unclear. In this study we have examined a potential role for plasma sP-selectin in regulating neutrophil adhesion in patients with peripheral arterial occlusive disease (PAOD). Patients with PAOD had significantly higher levels of sP-selectin (mean+/-SD: 73.3+/-13.0 versus 16.7+/-6.4 ng/mL) and enhanced whole blood leukocyte adhesion to platelets under shear. To examine whether the raised sP-selectin levels can directly influence leukocyte adhesion, isolated neutrophils were incubated with plasma from PAOD patients before and after immunodepletion of sP-selectin. Neutrophil adhesion to fibrinogen increased 2-fold following incubation with PAOD plasma, which was abrogated on sP-selectin immunodepletion. We subsequently demonstrated that recombinant sP-selectin dose-dependently (75 to 250 ng/mL) increased leukocyte adhesion to fibrinogen and platelet monolayers. This increase was PSGL-1 and Src kinase-dependent and correlated with an increase in sP-selectin-mediated Mac-1 activation. sP-selectin-stimulated neutrophil adhesion to platelet monolayers was inversely correlated with shear, such that at low shear (50 s(-1)) a 92.7%+/-15.7 increase in adhesion was observed decreasing to 38.5%+/-11.9 at 150 s(-1) and 10.1%+/-7.4 at 300 s(-1). These studies suggest a potentially important role for sP-selectin in modulating neutrophil adhesion in patients with PAOD, particularly at sites of low shear, where it raises the possibility that raised plasma sP-selectin levels may enhance leukocyte recruitment to vascular injury and promote disease progression.
Woollard
K J
KJ
Alfred and Baker Medical Unit, Wynn Domain, Baker Heart Research Institute, Melbourne, Australia. Kevin.Woollard@baker.edu.au
Kling
D
D
Kulkarni
S
S
Dart
A M
AM
Jackson
S
S
Chin-Dusting
J
J
D000368:Aged; D001157:Arterial Occlusive Diseases / Q000097:blood*; D002448:Cell Adhesion; D005260:Female; D005340:Fibrinogen / Q000502:physiology; D006801:Humans; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000502:physiology; D019007:P-Selectin / Q000097:blood*; D016491:Peripheral Vascular Diseases / Q000097:blood*
D019007:P-Selectin; D005340:Fibrinogen