Inhibition of selectin-mediated cell adhesion and prevention of acute inflammation by nonanticoagulant sulfated saccharides. Studies with carboxyl-reduced and sulfated heparin and with trestatin a sulfate.
Selectins play a major role in the inflammatory reaction by initiating neutrophil attachment to activated vascular endothelium. Some heparin preparations can interact with L- and P-selectin; however, the determinants required for inhibiting selectin-mediated cell adhesion have not yet been characterized. We now report that carboxyl-reduced and sulfated heparin (prepared by chemical modifications of porcine intestinal mucosal heparin leading to the replacement of carboxylates by O-sulfate groups) and trestatin A sulfate (obtained by sulfation of trestatin A, a non-uronic pseudo-nonasaccharide extracted from Streptomyces dimorphogenes) exhibit strong anti-P-selectin and anti-L-selectin activity while lacking antithrombin-mediated anticoagulant activity. In vitro experiments revealed that both compounds inhibited P-selectin- and L-selectin-mediated cell adhesion under laminar flow conditions. Moreover, carboxyl-reduced and sulfated heparin and trestatin A sulfate were also active in vivo, as assessed by experiments showing 1) that microinfusion of trestatin A sulfate reduced by 96% leukocyte rolling along rat mesenteric postcapillary venules and 2) that both compounds inhibited (by 58-81%) neutrophil migration into thioglycollate-inflamed peritoneum of BALB/c mice. These results indicate that nonanticoagulant sulfated saccharides targeted at P-selectin and L-selectin may have therapeutic potential in inflammatory disorders.
Xie
X
X
Division and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois, Bugnon 46, 1011 Lausanne, Switzerland.
Rivier
A S
AS
Zakrzewicz
A
A
Bernimoulin
M
M
Zeng
X L
XL
Wessel
H P
HP
Schapira
M
M
Spertini
O
O
D000906:Antibodies / Q000276:immunology; D002448:Cell Adhesion / Q000502:physiology*; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control*; D019087:Selectins / Q000276:immunology / Q000502:physiology*; D013431:Sulfates / Q000737:chemistry; D014312:Trisaccharides / Q000737:chemistry / Q000494:pharmacology*
D000906:Antibodies; D019087:Selectins; D013431:Sulfates; D014312:Trisaccharides; C038505:trestatin; D006493:Heparin