title: Protective effect of thalidomide on endotoxin-induced liver injury.
abstract: BACKGROUND
  Activation of Kupffer cells by lipopolysaccharide (LPS) plays a pivotal role in the onset of pathophysiological events that occur during endotoxemia, and intracellular calcium concentration ([Ca2+]i) is involved in LPS-stimulated cytokine production. Tumor necrosis factor (TNF)-alpha is produced exclusively by the monocyte-macrophage lineage, which is mostly made up of Kupffer cells, and thalidomide has been shown to reduce TNF-alpha production from macrophages. However, there is increasing evidence that TNF-alpha may play a role in the initiation or progression of multiple organ failure syndrome. Therefore, the purpose of this work was to determine whether thalidomide could prevent LPS-induced liver injury.
  
  
  METHODS
  Rats were given a single oral dose of thalidomide (5 mg/kg). To assess the sensitization of Kupffer cells, LPS (5 or 10 mg/kg) was administered intravenously, and mortality, liver histology, and transaminases were evaluated 24 hr later. Kupffer cells were isolated 2 hr after thalidomide treatment. After the addition of LPS, [Ca2+]i was measured by using a microspectrofluorometer with the fluorescent indicator fura-2, and TNF-alpha was measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  LPS caused focal necrosis with neutrophil infiltration in the liver. Moreover, LPS dramatically increased transaminases. These pathologic parameters and increases of serum transaminases were diminished markedly by thalidomide. In isolated Kupffer cells, LPS-induced increases in [Ca2+]i and TNF-alpha production were suppressed by treatment with thalidomide. To further explore the mechanism by which thalidomide directly abrogated Kupffer cell sensitivity to LPS, we determined the effect of thalidomide (5 microM) in vitro on LPS-induced [Ca2+]i response and TNF-alpha production. With the addition of thalidomide (5 microM) in vitro to the culture media for 2 hr before LPS, these parameters were suppressed.
  
  
  CONCLUSIONS
  Thalidomide prevents LPS-induced liver injury via mechanisms dependent on the suppression of TNF-alpha production from Kupffer cells.
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
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: Tsuneo
authors.initials: T
authors.lastname: Kitamura
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ikejima
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Sato
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D018450:Disease Progression; D004926:Escherichia coli / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008106:Liver Cirrhosis, Experimental / Q000276:immunology* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D009102:Multiple Organ Failure / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D002118:Calcium