胰岛素强化治疗介导Akt/FoxO1/TLR4/NF-κB信号通路而抑制烧伤后炎症反应的机制研究

过度炎症反应是危重烧伤患者临床常见的并发症之一，由炎症介质过度释放引发，也是制约临床危重烧伤患者救治的关键因素。研究显示胰岛素治疗不仅可以降低患者血糖水平，同时能发挥免疫调控功效，抑制烧伤后过度炎症反应发生。我们前期的多中心临床试验研究发现，与胰岛素常规治疗相比，胰岛素强化治疗可明显降低烧伤患者的炎症因子表达，但发挥该作用的具体分子机制尚不明确。我们前期的动物实验研究也显示烧伤后TLR4蛋白表达上调，NF-κB活性增强可能促进炎症因子表达，而胰岛素通路下游蛋白Akt、FoxO有参与调控TLR4蛋白表达。因此，本项目拟通过建立动物及细胞模型，采用分子及细胞生物学手段，揭示胰岛素强化治疗通过调控Akt/FoxO/TLR4/NF-κB信号通路活性而抑制炎症因子表达并最终下调烧伤后炎症反应的具体分子机制，为临床危重烧伤患者过度炎症反应治疗提供新思路。

Excessive inflammation is one of the most common complications of critically burned patients, which is caused by excessive release of inflammatory mediators. Studies have shown that insulin treatment can not only reduce the level of blood glucose, but also play a critical role in immune regulation, inhibiting burn-induced excessive inflammation. Our previous multicenter clinical trial found that compared with the conventional insulin therapy, intensive insulin therapy can significantly reduce the expression of inflammatory cytokines in burn patients, but the molecular mechanism is still unclear. Previous animal studies from our group have also shown that the expression of TLR4 protein is up-regulated after burn, and the enhancement of NF-κB activity may promote the expression of inflammatory factors, while the downstream protein Akt and FoxO of insulin pathway are involved in regulating the expression of TLR4 protein. Therefore, this project aims to reveal the molecular mechanism of intensive insulin therapy by regulating Akt/FoxO/TLR4/NF-κB signaling pathway, inhibiting the expression of inflammatory factors and attenuating the expression of inflammatory reaction, which might provide new ideas for clinical treatment of severe burn-induced inflammation.