Protective effect of pioglitazone against endotoxin-induced liver injury through prevention of Kupffer cell sensitization.
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]i) is involved in LPS-stimulated cytokine production. TNF-alpha is produced exclusively by the monocyte-macrophage lineage, including Kupffer cells, and pioglitazone has been shown to reduce TNF-alpha production from macrophages. On the other hand, there is increasing evidence that TNF-alpha 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 microg/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]i was measured using a microspectrofluorometer with the fluorescent indicator, fura-2, and TNF-alpha 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]i and TNF-alpha 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-alpha production from Kupffer cells.
Enomoto
Nobuyuki
N
Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Takei
Yoshiyuki
Y
Yamashima
Shunhei
S
Ikejima
Kenichi
K
Kitamura
Tsuneo
T
Sato
Nobuhiro
N
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007728:Kupffer Cells / Q000187:drug effects* / Q000473:pathology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D047495:PPAR gamma / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000627:therapeutic use*; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D004731:Endotoxins; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000637:Transaminases; D000077205:Pioglitazone