Soluble P-selectin antagonist mediates rolling velocity and adhesion of leukocytes in acutely inflamed venules.
OBJECTIVE
Leukocyte rolling is recognized as an important event in facilitating the extravasation of leukocytes from the vascular to the interstitial compartment, and is mediated by the selectin family of cell adhesion molecules. The aim of this study was to evaluate and characterize the rolling behavior of leukocytes in a model of acute inflammation using a novel soluble selectin ligand directed against P-selectin.


METHODS
Feline mesenteric postcapillary venules were visualized using intravital microscopy prior to and following exposure to leukotriene C4 (LTC4) in animals pretreated with vehicle (saline) and the P-selectin antagonist rPSGL-Ig.


RESULTS
A concentration of 500 pM LTC4 induced a threefold and sixfold elevation in leukocyte rolling flux and adhesion, respectively, compared to baseline values (p < 0.05). Administration of rPSGL-Ig had no effect on LTC4-induced leukocyte rolling flux but significantly attenuated the increase in the fraction of rolling leukocytes (p < 0.05). In addition, rPSGL-Ig inhibited the LTC4-induced reductions in leukocyte rolling velocity (p < 0.001). Finally, LTC4-induced leukocyte adhesion in animals pretreated with rPSGL-Ig was reduced by 60%, compared to vehicle-treated animals (p < 0.05).


CONCLUSIONS
LTC4 induces leukocyte rolling and adhesion in feline mesenteric venules in a dose-dependent manner. Administration of rPSGL-Ig inhibits LTC4-induced reductions in leukocyte rolling velocity and attenuates the elevation in the fraction of rolling leukocytes produced by LTC4 stimulation. This suggests that rPSGL-Ig may be used to reduce leukocyte rolling and adhesion, and subsequently attenuate tissue injury during inflammation.
Eppihimer
M J
MJ
Wyeth/Genetics Institute, Andover, MA 01810, USA. meppihimer@genetics.com
Schaub
R G
RG
D000595:Amino Acid Sequence; D000818:Animals; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology*; D017997:Leukotriene C4 / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D008642:Mesenteric Veins / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008969:Molecular Sequence Data; D019007:P-Selectin / Q000187:drug effects* / Q000502:physiology*; D010689:Phlebitis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D012995:Solubility; D014699:Venules / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011994:Recombinant Proteins; D017997:Leukotriene C4