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Protective Effect of Pioglitazone Against Endotoxin‐Induced Liver Injury through Prevention of Kupffer Cell Sensitization
Author(s) -
Enomoto Nobuyuki,
Takei Yoshiyuki,
Yamashima Shunhei,
Ikejima Kenichi,
Kitamura Tsuneo,
Sato Nobuhiro
Publication year - 2005
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.0000192394.26573.10
Subject(s) - pioglitazone , kupffer cell , lipopolysaccharide , liver injury , cytokine , tumor necrosis factor alpha , medicine , sensitization , macrophage , endocrinology , monocyte , immunology , chemistry , in vitro , biochemistry , type 2 diabetes , diabetes mellitus
A bstract : 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 ([Ca 2+ ] i ) is involved in LPS‐stimulated cytokine production. TNF‐α is produced exclusively by the monocyte‐macrophage lineage, including Kupffer cells, and pioglitazone has been shown to reduce TNF‐α production from macrophages. On the other hand, there is increasing evidence that TNF‐α plays a major role in the initiation and/or progression of multiple organ failure syndrome. Therefore, the purpose of this work was to determine whether pioglitazone could prevent LPS‐induced liver injury Methods: Rats were given a single oral dose of pioglitazone (500 μg/kg). To assess the sensitization of Kupffer cells, LPS (5 mg/kg) was administered IV and transaminases were evaluated 24 hr later. Kupffer cells were isolated 2 hr after pioglitazone treatment. After addition of LPS, [Ca 2+ ] i was measured using a microspectrofluorometer with the fluorescent indicator, fura‐2, and TNF‐α was measured by ELISA Results: LPS increased transaminases dramatically and elevation of serum transaminases were diminished markedly by pioglitazone. In isolated Kupffer cells, the LPS‐induced increase in [Ca 2+ ] i and TNF‐α production were suppressed by treated with pioglitazone Conclusions: Therefore, it is concluded that pioglitazone prevents LPS induced liver injury via a mechanism dependent on suppression of TNF‐α production from Kupffer cells.