A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury.

Abstract

Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in an antithrombin-dependent fashion. This newly developed anticoagulant is used in the prevention and treatment of venous thromboembolism. Recently, we showed that fondaparinux reduces inflammation and protects the kidney from ischemia-reperfusion (I/R) injury. However, the relative contributions of the anticoagulant and anti-inflammatory activities of fondaparinux to the observed protection is unknown. To address this, we chemically modified fondaparinux to abolish its affinity for antithrombin and analyzed the effect of this non-anticoagulant (NAC)-pentasaccharide on binding of U937 cells to P-selectin in vitro and on inflammation in a murine model of kidney I/R injury. NAC-pentasaccharide was as effective as fondaparinux at inhibiting the binding of U937 cells to P-selectin. In addition, NAC-pentasaccharide significantly reduced IL-6 and MIP-2 expression and injury in the kidney I/R model. These findings indicate that the anti-inflammatory activity of fondaparinux can be dissociated from its anticoagulant activity and that NAC-pentasaccharide is protective in kidney I/R injury.

• Authors: Rolf Dario Frank, Todd Holscher, Gernot Schabbauer, Michael Tencati, Rafal Pawlinski, Jeffrey I Weitz, Nigel Mackman
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 96 Issue 6 Pg. 802-6 (Dec 2006) ISSN: 0340-6245 [Print] Germany
• PMID: 17139376 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Anticoagulants
• Ccl2 protein, mouse
• Chemokine CCL2
• Chemokine CXCL2
• Chemokines
• Cxcl2 protein, mouse
• Factor Xa Inhibitors
• Interleukin-6
• NAC-pentasaccharide
• Oligosaccharides
• P-Selectin
• Polysaccharides
• Creatinine
• Fondaparinux

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Anticoagulants (pharmacology, therapeutic use)
• Blood Coagulation (drug effects)
• Cell Adhesion (drug effects)
• Chemokine CCL2 (blood)
• Chemokine CXCL2
• Chemokines (metabolism)
• Creatinine (blood)
• Disease Models, Animal
• Factor Xa Inhibitors
• Fondaparinux
• Humans
• Inflammation (blood, metabolism, prevention & control)
• Interleukin-6 (blood)
• Kidney (blood supply, drug effects, metabolism, pathology)
• Kidney Tubules (drug effects, pathology)
• Macrophages (drug effects, metabolism)
• Mice
• Neutrophil Infiltration (drug effects)
• Oligosaccharides (pharmacology, therapeutic use)
• P-Selectin (metabolism)
• Partial Thromboplastin Time
• Polysaccharides (pharmacology, therapeutic use)
• Reperfusion Injury (blood, metabolism, pathology, prevention & control)
• U937 Cells