Department of Internal Medicine, FCM, State University of Campinas, Campinas, São Paulo, Brazil.
PLoS One. 2010 Dec 6;5(12):e14232. doi: 10.1371/journal.pone.0014232.
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.
本研究旨在探讨阿托伐他汀在脓毒症中的生存改善作用是否伴随着炎症途径的组织激活减少，以及在大鼠中组织胰岛素信号的改善。通过盲肠结扎和穿刺手术（CLP）在雄性 Wistar 大鼠中诱导弥漫性脓毒症。CLP 后 24 小时评估血清葡萄糖和炎症细胞因子水平。同时研究了阿托伐他汀对脓毒症动物生存的影响及其对肝、肌肉和脂肪组织中胰岛素信号及其调节剂的影响。阿托伐他汀可改善脓毒症大鼠的生存，这种改善伴随着胰岛素敏感性的显著改善，其特征是胰岛素耐量试验期间葡萄糖清除率增加。脓毒症诱导 TLR4 的表达/激活及其下游信号 JNK 和 IKK/NF-κB 激活增加，并使肝、肌肉和脂肪组织中的胰岛素诱导的胰岛素信号减弱；阿托伐他汀逆转了所有这些变化，同时降低了循环 TNF-α 和 IL-6 的水平。总之，这项研究表明，阿托伐他汀治疗可提高存活率，并显著提高腹膜炎诱导的脓毒症大鼠外周组织的胰岛素敏感性，改善胰岛素信号。阿托伐他汀对 TLR 依赖性炎症途径的抑制作用可能在脓毒症损伤中调节胰岛素信号和生存中发挥核心作用。
