title: N-desulfated non-anticoagulant heparin inhibits leukocyte adhesion and transmigration in vitro and attenuates acute peritonitis and ischemia and reperfusion injury in vivo.
abstract: OBJECTIVE
  Heparin, a highly sulfated proteoglycan, is known to have strong anticoagulant and anti-inflammatory activities. Here we sought to generate a heparin derivative, which had a significantly lower anticoagulant activity while retaining its strong anti-inflammatory activity.
  
  
  METHODS
  Heparin was chemically modified and this discrete set of the heparin derivatives was tested for their anticoagulant activities, such as activated partial thromboplastin time (APTT), and anti-inflammatory activities, such as leukocyte adhesion and transmigration in vitro and acute peritonitis and ischemia and reperfusion injury in vivo.
  
  
  RESULTS
  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 APTT. 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 and leukocyte deposition in a rabbit ear model of ischemia and reperfusion injury.
  
  
  CONCLUSIONS
  It is to our best knowledge that the N-desulfated heparin has the lowest anticoagulant activity among LMWH and chemically modified heparin derivatives, while preserving a potent anti-inflammatory activity. These combined properties appear to suggest it as a safer medicine for treatment of inflammation.
mesh_terms: D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004431:Ear, External / Q000098:blood supply; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007511:Ischemia / Q000473:pathology*; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D010537:Peritoneum / Q000187:drug effects / Q000503:physiopathology; D010538:Peritonitis / Q000473:pathology* / Q000503:physiopathology; D011817:Rabbits; D015427:Reperfusion Injury / Q000473:pathology*
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D006493:Heparin