Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins
Year: 2002
Type: article
Abstract: 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.
DOI: 10.1172/jci0214996
Institution: University of California San Diego
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4250801983