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Glycosulfopeptides modeled on P‐selectin glycoprotein ligand‐1 inhibit P‐selectin‐dependent leukocyte rolling in vivo
Author(s) -
Hicks Anne E.R.,
Leppänen Anne,
Cummings Richard D.,
McEver Rodger P.,
Hellewell Paul G.,
Norman Keith E.
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0075fje
Subject(s) - intravital microscopy , in vivo , selectin , chemistry , cremaster muscle , ligand (biochemistry) , in vitro , glycoprotein , inflammation , p selectin , l selectin , microbiology and biotechnology , immunology , biology , biochemistry , receptor , platelet , platelet activation
Leukocytic inflammation can be limited by inhibiting selectin‐dependent leukocyte rolling. In spite of intensive efforts to develop small molecule selectin inhibitors with defined structure‐activity profiles, inhibition of P‐selectin‐dependent leukocyte rolling in vivo by such a compound has yet to be described. We recently reported that glycosulfopeptides (GSP), modeled on the high affinity selectin ligand PSGL‐1, inhibit leukocyte binding to P‐selectin in vitro. Here, we have used intravital microscopy to investigate whether GSP can inhibit P‐selectin‐dependent leukocyte rolling in vivo. Surgical preparation of the mouse cremaster muscle for intravital microscopy induced P‐selectin‐dependent leukocyte rolling. Baseline rolling was recorded for 1 min followed by i.v. injection of GSP. 2‐GSP‐6 and 4‐GSP‐6 substantially reversed P‐selectindependent leukocyte rolling, whereas control GSP, which are not fully glycosylated, did not. Inhibition of leukocyte rolling by 2‐ and 4‐GSP‐6 lasted 2–4 min. Clearance studies with 125 Ilabeled 4‐GSP‐6 demonstrated rapid reduction in its circulating levels concurrent with accumulation in urine. These data represent the first demonstration that a precisely defined structure based on a natural P‐selectin ligand can inhibit P‐selectin‐dependent leukocyte rolling in vivo.