Non-anticoagulant Heparin In The Prevention And Treatment Of Inflammation And Heparin-p-selectin Interaction Affinity And Kinetic Study

Heparin, a highly sulfated proteoglycan, is known to have strong anticoagulant and anti-inflammatory activities. Here we generated a discrete set of the chemically modified heparin derivatives. Each of them was then tested for their anticoagulant and anti-inflammatory activities. We found that an N-desulfated heparin had 188-fold (compared to heparin) and 32-fold (compared to low molecular weight heparin; LMWH) reductions of anticoagulant activities as determined by measurements of activated partial thromboplastin time. The N-desulfated heparin inhibited adhesion of human promyeloid HL-60 cells to the stimulated human umbilical vein endothelial cells (HUVECs) under a physiological shear stress. It also prevented the transmigration of human neutrophils through the monolayers of the stimulated HUVECs. Further, intravenous administration of this compound attenuated the peritoneal infiltration of neutrophils in a mouse model of acute peritonitis, and reduced tissue edema, necrosis and leukocyte deposition in a rabbit ear model of ischemia and reperfusion injury. It is to our best knowledge that the N-desulfated heparin has the lowest anticoagulant activity between LMWH and chemically modified heparin derivatives, while preserving a potent anti-inflammatory activity. These combined properties appear to suggest it as a safer choice for treatment of inflammation.