The DOI matches its Crossref record; 72 of the 72 references it cites were found in a registry or an index.
Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins
Open accessAbstract
Heparin has been used clinically as an anticoagulant and antithrombotic agent for over 60 years.Here we show that the potent anti-inflammatory property of heparin results primarily from blockade of P-selectin and L-selectin.Unfractionated heparin and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis X and of cell adhesion to immobilized selectins or thrombin-activated endothelial cells.Compared with unfractionated heparin, the modified heparinoids had inhibitory activity in this general order: over-O-sulfated heparin > heparin > 2-O,3-O-desulfated ≥ N-desulfated/N-acetylated heparin ≥ carboxyl-reduced heparin ≥ N-,2-O,3-Odesulfated heparin >> 6-O-desulfated heparin.The heparinoids also showed similar differences in their ability to inhibit thioglycollate-induced peritonitis and oxazolone-induced delayed-type hypersensitivity.Mice deficient in P-or L-selectins showed impaired inflammation, which could be further reduced by heparin.However, heparin had no additional effect in mice deficient in both P-and L-selectins.We conclude that (a) heparin's anti-inflammatory effects are mainly mediated by blocking P-and L-selectin-initiated cell adhesion; (b) the sulfate groups at C6 on the glucosamine residues play a critical role in selectin inhibition; and (c) some non-anticoagulant forms of heparin retain anti-inflammatory activity.Such analogs may prove useful as therapeutically effective inhibitors of inflammation.
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“As a consequence of their antiselectin activity, these polysaccharides attenuated metastasis and inflammation [150,151,152].”
From Anticancer and Cancer Preventive Properties of Marine Polysaccharides: Some Results and Prospects (2013) · cites this paper as [152]
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“Some polysaccharides from the marine animals inhibited the binding of pro-inflammatory molecules, P- and L-selectins, to immobilized carbohydrate determinant sialyl Lewisx which is a component of cell surface glycoproteins presented in leukocytes and overexpressed in several tumor cells.”
From Anticancer and Cancer Preventive Properties of Marine Polysaccharides: Some Results and Prospects (2013) · cites this paper as [152]
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Cites
Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm
Springer, T. A. (1994) · Cell · doi:10.1016/0092-8674(94)90337-9 · Cited by 7,009
Lymphocyte Homing and Homeostasis
Butcher, E. C., & Picker, L. J. (1996) · Science · doi:10.1126/science.272.5258.60 · Cited by 2,846
Selectins and their ligands: Current concepts and controversies
Kansas, G. (1996) · Blood · doi:10.1182/blood.v88.9.3259.bloodjournal8893259 · Cited by 1,415
Molecular diversity of heparan sulfate
Esko, J. D., & Lindahl, U. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200113530 · Cited by 978
Self-citationVarki, A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.16.7390 · Cited by 946
Self-citationMechanisms That Regulate the Function of the Selectins and Their Ligands
VESTWEBER, D., & BLANKS, J. E. (1999) · Physiological Reviews · doi:10.1152/physrev.1999.79.1.181 · Cited by 932
Formation of anhydrosugars in the chemical depolymerization of heparin
Shively, J. E., & Conrad, H. E. (1976) · Biochemistry · doi:10.1021/bi00663a005 · Cited by 905
Malý, P., Thall, A. D., Petryniak, B., Rogers, C. E., Smith, P. L., Marks, R. M., Kelly, R. J., Gersten, K. M., Cheng, G., Saunders, T. L., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)80137-3 · Cited by 714
Borsig, L., Wong, R., Feramisco, J., Nadeau, D. R., Varki, N. M., & Varki, A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061615598 · Cited by 714
Self-citationKuschert, G. S. V., Coulin, F., Power, C. A., Proudfoot, A. E. I., Hubbard, R. E., Hoogewerf, A. J., & Wells, T. N. C. (1999) · Biochemistry · doi:10.1021/bi990711d · Cited by 575
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Heparin prevents antiphospholipid antibody–induced fetal loss by inhibiting complement activation
Girardi, G., Redecha, P. B., & Salmon, J. E. (2004) · Nature Medicine · doi:10.1038/nm1121 · Cited by 680
The role of heparan sulphate in inflammation
Parish, C. R. (2006) · Nature reviews. Immunology · doi:10.1038/nri1918 · Cited by 513
Wang, L., Fuster, M., Sriramarao, P., & Esko, J. D. (2005) · Nature Immunology · doi:10.1038/ni1233 · Cited by 413
Self-citationL-selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling
Ívetic, A., Green, H. L. H., & Hart, S. J. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01068 · Cited by 493
The anti-inflammatory effects of heparin and related compounds
Young, E. (2007) · Thrombosis Research · doi:10.1016/j.thromres.2006.10.026 · Cited by 397
Metadata
- Authors
- Wang, L., Brown, J. R., Varki, A., & Esko, J. D.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Esko, Jeffrey D.
- Venue
- Journal of Clinical Investigation
- Published
- 2002-07-01
- Volume
- 110
- Issue
- 1
- Pages
- 127-136
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W4250801983
- Cited by
- 288
- References
- 72
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 9 · 2023: 6 · 2022: 3 · 2021: 11 · 2020: 11 · 2019: 9 · 2018: 14 · 2017: 11 · 2016: 16 · 2015: 15 · 2014: 11 · 2013: 15 · 2012: 12
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Funders
- National Institutes of Health
- University of California, San Diego
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Keywords
- heparin, anti-inflammatory activity, P-selectin, L-selectin, cell adhesion, sialyl Lewis X, heparinoids, peritonitis, delayed-type hypersensitivity, inflammation
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