title: Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion-induced liver injury in rats.
abstract: OBJECTIVE
  To examine whether dalteparin, a low molecular weight heparin, prevents hepatic damage by inhibiting leukocyte activation, we analyzed its effect on ischemia/reperfusion (I/R) injury of rat liver in which activated leukocytes play a critical role.
  
  
  METHODS
  Prospective, randomized, controlled study.
  
  
  METHODS
  Research laboratory at a university medical center.
  
  
  METHODS
  Male Wistar rats weighing 220-280 g.
  
  
  METHODS
  Hepatic damage was evaluated by changes in serum transaminase concentrations after I/R. Coagulation abnormalities were evaluated by changes in serum concentrations of fragment E of fibrin and fibrinogen degradation products after I/R. Hepatic tissue blood flow was measured by laser-Doppler flow meter. Hepatic edema was evaluated by determination of the change in the wet/dry tissue weight ratio. Rats were intravenously injected with dalteparin or unfractionated heparin (300 units/kg) and subcutaneously injected with DX9056a, a selective inhibitor of activated factor X (3 mg/kg). To determine whether dalteparin inhibits leukocyte activation, we examined the effect of dalteparin on hepatic concentrations of interleukin-12, tumor necrosis factor-alpha, and hepatic myeloperoxidase activity after I/R in vivo. In addition, we examined increases in tumor necrosis factor-alpha production in rat monocytes and in intracellular calcium concentrations in neutrophils in vitro. We also examined the effect of dalteparin on endothelial production of prostacyclin using isolated rat hepatic sinusoidal cells in vitro.
  
  
  RESULTS
  Intravenous administration of dalteparin inhibited increases in serum levels of both transaminases and serum concentrations of fragment E of fibrin and fibrinogen degradation products in animals subjected to hepatic I/R. Hepatic tissue blood flow after reperfusion was increased by dalteparin. Dalteparin inhibited hepatic edema, increases in hepatic tissue levels of interleukin-12 and tumor necrosis factor-alpha, and accumulation of neutrophils in animals subjected to hepatic I/R. Neither DX9065a nor unfractionated heparin showed any therapeutic effects, despite potent inhibition of increases in serum levels of fragment E of fibrin and fibrinogen degradation products. Neither monocytic tumor necrosis factor-alpha production nor neutrophil activation was inhibited by dalteparin in vitro. Dalteparin enhanced the hepatic I/R-induced increases in hepatic tissue levels of 6-keto-prostaglandin (PG) F1alpha, a stable metabolite of prostacyclin, which is capable of inhibiting monocytic tumor necrosis factor-alpha production. Pretreatment with indomethacin completely reversed both of the therapeutic effects of dalteparin, whereas pretreatment with NS-398, a selective inhibitor of cyclooxygenase-2, did not. Dalteparin did not directly increase the endothelial production of prostacyclin in vitro.
  
  
  CONCLUSIONS
  Dalteparin might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects might be independent of its anticoagulant activity but dependent on its capacity to enhance endothelial production of prostacyclin via cyclooxygenase-1 activation. Furthermore, the mechanism or mechanisms by which dalteparin promotes the endothelial production of prostacyclin in vivo might involve unknown factors other than endothelial cells.
authors.affiliation: Department of Biodefense Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Harada
authors.forename: Kenji
authors.initials: K
authors.lastname: Okajima
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Uchiba
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D017985:Dalteparin / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000175:diagnosis; D004727:Endothelium / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D006493:Heparin / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy*; D018664:Interleukin-12 / Q000097:blood; D007962:Leukocytes / Q000502:physiology; D008099:Liver / Q000098:blood supply / Q000737:chemistry / Q000201:enzymology; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D009000:Monocytes / Q000737:chemistry / Q000201:enzymology; D009281:Naphthalenes / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D009195:Peroxidase / Q000032:analysis; D011422:Propionates / Q000494:pharmacology; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D052246:Cyclooxygenase 2 Inhibitors; D005338:Fibrin Fibrinogen Degradation Products; D009281:Naphthalenes; D009578:Nitrobenzenes; D011422:Propionates; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C072054:fibrin fragment E-2; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D018664:Interleukin-12; D015121:6-Ketoprostaglandin F1 alpha; D006493:Heparin; D011464:Epoprostenol; D009195:Peroxidase; D000637:Transaminases; D017985:Dalteparin; D002118:Calcium; D007213:Indomethacin