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Dalteparin Sodium Prevents Liver Injury Due to Lipopolysaccharide in Rat Through Suppression of Tumor Necrosis Factor‐α Production by Kupffer Cells
Author(s) -
Tsukada Shigeki,
Enomoto Nobuyuki,
Takei Yoshiyuki,
Hirose Miyoko,
Ikejima Kenichi,
Kitamura Tsuneo,
Sato Nobuhiro
Publication year - 2003
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1097/01.alc.0000078610.78390.2a
Subject(s) - lipopolysaccharide , tumor necrosis factor alpha , liver injury , medicine , endocrinology , necrosis , sepsis , chemistry , pharmacology , immunology
Background: Sensitization of Kupffer cells (KC) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF)‐α play important roles in the pathogenesis of alcoholic liver damage and sepsis‐associated organ injury. Therefore, suppression of TNF‐α should prove useful for treatment of LPS‐induced liver injury. Recently, heparin has been reported to diminish TNF‐α production from macrophages in response to LPS. Dalteparin sodium (DS) is a low‐molecular‐weight heparin with a mean molecular weight of 5000. 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 μg/ml) to the culture media, intracellular Ca 2+ 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 Ca 2+ 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‐α 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‐α production.