Protective effect of pioglitazone against endotoxin-induced liver injury through prevention of Kupffer cell sensitization
Protective effect of pioglitazone against endotoxin-induced liver injury through prevention of Kupffer cell sensitization
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DOI：
10.1097/01.alc.0000192394.26573.10
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发表时间：
2005-12-01
影响因子：
3.2
通讯作者：
Sato, N
中科院分区：
文献类型：
--
作者：
Enomoto, N;Takei, Y;Sato, N
背景资料：由脂多糖（LPS）激活枯否细胞在内毒素血症期间发生的病理生理事件的发作中起关键作用，并且细胞内钙（[Ca 2 +]（i））参与LPS刺激的细胞因子产生。TNF-α仅由单核细胞-巨噬细胞谱系（包括枯否细胞）产生，吡格列酮已显示可减少巨噬细胞产生TNF-α。另一方面，越来越多的证据表明TNF-α在多器官衰竭综合征的发生和/或进展中起主要作用。因此，本工作的目的是确定吡格列酮是否可以预防LPS诱导的肝损伤方法：大鼠单次口服吡格列酮（500 μ g/kg）。为了评估枯否细胞的致敏性，IV施用LPS（5 mg/kg），24小时后评价转氨酶。在吡格列酮处理后2小时分离枯否细胞。加入LPS后，以荧光指示剂Fura-2为指示剂，用显微荧光分光光度计测定[Ca ~（2+）]（i），用ELISA法测定TNF-α。在离体枯否细胞中，吡格列酮可抑制LPS诱导的[Ca 2 +]（i）和TNF-α产生的增加。结论：吡格列酮通过抑制枯否细胞TNF-α产生来预防LPS诱导的肝损伤。
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 ([Ca2+](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-a 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 injuryMethods: Rats were given a single oral dose of pioglitazone (500 mu g/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, [Ca2+](i) was measured using a microspectrofluorometer with the fluorescent indicator, fura-2, and TNF-a was measured by ELISAResults: LPS increased transaminases dramatically and elevation of serum transaminases were diminished markedly by pioglitazone. In isolated Kupffer cells, the LPS-induced increase in [Ca2+](i) and TNF-alpha production were suppressed by treated with pioglitazoneConclusions: Therefore, it is concluded that pioglitazone prevents LPS induced liver injury via a mechanism dependent on suppression of TNF-alpha production from Kupffer cells.