Heparin Oligosaccharides Bind P- and L-Selectin and Inhibit Acute Inflammation

Authors
Nelson, R.M.
Cecconi, O.
Roberts, W.G.
Aruffo, A.
Linhardt, Robert J.
Bevilacqua, M.P.
ORCID
https://orcid.org/0000-0003-2219-5833
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Issue Date
1993
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Full Citation
Heparin Oligosaccharides Bind P- and L-Selectin and Inhibit Acute Inflammation, R.M. Nelson, O. Cecconi, W.G. Roberts, A. Aruffo, R.J. Linhardt, M.P. Bevilacqua, Blood, 82, 3253-3258 (1993).
Abstract
Initial attachment of leukocytes to the vessel wall at sites of inflammation is supported by a family of carbohydrate-binding adhesion molecules called the selectins. Selectin ligands include sialyl-Lewis x (sLex, Neu5Ac alpha 2-3Gal beta 1-4[Fuc alpha 1-3]GlcNAc--) and related structures. We report here that defined heparin oligosaccharides interact with the selectins. Heparin chains containing four or more monosaccharide residues inhibited the function of L- and P-selectin, but not E-selectin, in vitro. In a competition enzyme-linked immunosorbent assay measuring inhibition of solution-phase selectin-Ig fusion proteins (selectin-Ig) binding to immobilized bovine serum albumin-sLex neoglycoprotein, a heparin-derived tetrasaccharide mixture inhibited 50% of L- and P-selectin-Ig binding (IC50) at 200 +/- 40 mumol/L and 850 +/- 110 mumol/L, respectively. A single hexasulfated tetrasaccharide (delta UA2S alpha 1-4GlcNS6S alpha 1-4IdoA2S alpha 1-4GlcNS6S) was particularly active against L- and P-selectin-Ig (IC50 = 46 +/- 5 mumol/L and 341 +/- 24 mumol/L). By comparison, the tetrasaccharide sLex was not inhibitory at concentrations up to 1 mmol/L. In cell adhesion assays, heparin tetrasaccharides reduced binding of neutrophils to COS cells expressing P-selectin but not to COS cells expressing E-selectin. They also blocked colon cancer cell adhesion to L- and P-selectin but not E-selectin. In a model of acute inflammation, intravenously administered heparin tetrasaccharides diminished influx of neutrophils into the peritoneal cavities of thioglycollate-treated mice. We conclude that heparin oligosaccharides, including non-anticoagulant tetrasaccharides, are effective L- and P-selectin inhibitors in vitro and have anti-inflammatory activity in vivo.
Description
Blood, 82, 3253-3258
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Department
The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
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Relationships
The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
https://harc.rpi.edu/
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