Premium
Protective Effect of Thalidomide on Endotoxin‐Induced Liver Injury
Author(s) -
Enomoto Nobuyuki,
Takei Yoshiyuki,
Hirose Miyoko,
Kitamura Tsuneo,
Ikejima Kenichi,
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.0000078606.59842.01
Subject(s) - thalidomide , tumor necrosis factor alpha , lipopolysaccharide , cytokine , liver injury , medicine , kupffer cell , endocrinology , necrosis , macrophage , immunology , pharmacology , in vitro , biology , biochemistry , multiple myeloma
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 ([Ca 2+ ] i ) is involved in LPS‐stimulated cytokine production. Tumor necrosis factor (TNF)‐α is produced exclusively by the monocyte‐macrophage lineage, which is mostly made up of Kupffer cells, and thalidomide has been shown to reduce TNF‐α production from macrophages. However, there is increasing evidence that TNF‐α 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, [Ca 2+ ] i was measured by using a microspectrofluorometer with the fluorescent indicator fura‐2, and TNF‐α 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 [Ca 2+ ] i and TNF‐α 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 μM) in vitro on LPS‐induced [Ca 2+ ] i response and TNF‐α production. With the addition of thalidomide (5 μM) 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‐α production from Kupffer cells.