Atorvastatin improves survival in septic rats: effect on tissue inflammatory pathway and on insulin signaling.
Atorvastatin improves survival in septic rats: effect on tissue inflammatory pathway and on insulin signaling.
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DOI：
10.1371/journal.pone.0014232
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发表时间：
2010-12-06
期刊：
影响因子：
3.7
通讯作者：
Saad MJ
中科院分区：
文献类型：
--
作者：
Calisto KL;Carvalho Bde M;Ropelle ER;Mittestainer FC;Camacho AC;Guadagnini D;Carvalheira JB;Saad MJ
本研究的目的是研究阿托伐他汀在脓毒症中的生存改善作用是否伴随着炎症通路组织活化的减少，以及同时改善大鼠组织胰岛素信号传导。采用盲肠结扎穿孔术（CLP）诱导雄性Wistar大鼠弥漫性脓毒症。CLP后24 h测定血糖和炎性细胞因子水平。阿托伐他汀对脓毒症动物存活率的影响与肝脏、肌肉和脂肪组织中的胰岛素信号传导及其调节剂平行研究。阿托伐他汀改善脓毒症大鼠的存活率，这种改善伴随着胰岛素敏感性的显著改善，其特征在于胰岛素耐量试验期间葡萄糖消失率的增加。脓毒症诱导TLR 4表达/活化及其下游信号传导JNK和IKK/NF-κB活化增加，并减弱肝脏、肌肉和脂肪组织中胰岛素诱导的胰岛素信号传导;阿托伐他汀逆转所有这些变化，同时降低TNF-α和IL-6的循环水平。总之，本研究表明，阿托伐他汀治疗增加了存活率，对胰岛素敏感性有显著影响，改善了腹膜诱导脓毒症大鼠外周组织中的胰岛素信号传导。阿托伐他汀对TLR依赖性炎症通路的抑制作用可能在脓毒症损伤中胰岛素信号传导和存活的调节中发挥核心作用。
The aim of the present study was to investigate whether the survival-improving effect of atorvastatin in sepsis is accompanied by a reduction in tissue activation of inflammatory pathways and, in parallel, an improvement in tissue insulin signaling in rats. Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Serum glucose and inflammatory cytokines levels were assessed 24 h after CLP. The effect of atorvastatin on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle and adipose tissue. Atorvastatin improves survival in septic rats and this improvement is accompanied by a marked improvement in insulin sensitivity, characterized by an increase in glucose disappearance rate during the insulin tolerance test. Sepsis induced an increase in the expression/activation of TLR4 and its downstream signaling JNK and IKK/NF-κB activation, and blunted insulin-induced insulin signaling in liver, muscle and adipose tissue; atorvastatin reversed all these alterations in parallel with a decrease in circulating levels of TNF-α and IL-6. In summary, this study demonstrates that atorvastatin treatment increased survival, with a significant effect upon insulin sensitivity, improving insulin signaling in peripheral tissues of rats during peritoneal-induced sepsis. The effect of atorvastatin on the suppression of the TLR-dependent inflammatory pathway may play a central role in regulation of insulin signaling and survival in sepsis insult.
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