title: Dalteparin sodium prevents liver injury due to lipopolysaccharide in rat through suppression of tumor necrosis factor-alpha production by Kupffer cells.
abstract: BACKGROUND
  Sensitization of Kupffer cells (KC) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF)-alpha play important roles in the pathogenesis of alcoholic liver damage and sepsis-associated organ injury. Therefore, suppression of TNF-alpha should prove useful for treatment of LPS-induced liver injury. Recently, heparin has been reported to diminish TNF-alpha production from macrophages in response to LPS. Dalteparin sodium (DS) is a low-molecular-weight heparin with a mean molecular weight of 5,000. DS elicits an antithrombotic effect through a mechanism depending on anti-factor Xa activity but not on the antithrombin activity. DS is thus suitable for treatment of disseminated intravascular coagulation because it has a much smaller prohemorrhagic property. In this study, we evaluated whether DS could prevent LPS-induced liver injury.
  
  
  METHODS
  Female Wistar rats were administered DS (50 IU/kg intraperitoneally) followed by challenge with LPS (5 mg/kg intravenously) 2 hr later. Livers and sera were collected 24 hr later. KC from rats were isolated and cultured in RPMI 1640 supplemented with 10% fetal bovine serum. After the addition of LPS (10 microg/ml) to the culture media, intracellular Ca2+ was measured by using a fluorescent indicator, fura-2.
  
  
  RESULTS
  LPS (5 mg/kg intravenously) caused focal necrosis and neutrophil infiltration in the control liver. The histological changes and increased alanine aminotransferase levels caused by LPS injection were diminished by treatment with DS. LPS increased intracellular Ca2+ of KC in control rats from the basal level (26 +/- 6 nmol/liter) to 280 +/- 18 nmol/liter. This increase was blunted by DS (126 +/- 28 nmol/liter). The DS treatment decreased the LPS-induced TNF-alpha production by KC from 911 +/- 78 pg/ml to 309 +/- 45 pg/ml (p < 0.05).
  
  
  CONCLUSIONS
  These results indicate that DS reduces the LPS-induced liver injury through suppression of TNF-alpha production.
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tsukada
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takei
authors.forename: Miyoko
authors.initials: M
authors.lastname: Hirose
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ikejima
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kitamura
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Sato
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D017985:Dalteparin / Q000494:pharmacology*; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology*; D008106:Liver Cirrhosis, Experimental / Q000276:immunology* / Q000473:pathology; D008111:Liver Function Tests; D011292:Premedication; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D005343:Fibrinolytic Agents; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D017985:Dalteparin; D002118:Calcium