TLR4-MyD88-NF-κB-p62自噬通路在烧伤脓毒症心肌损伤中作用的机制研究

The mortality of burn sepsis patients increased markedly when the patients suffered heart injury. With the development from MODS to MOF, autophagy signal pathways play very important roles in regulating the function of cells and tissues. As far as we know, macrophages play the key role in the uncontrolled inflammation during burn sepsis. Macrophages were activated in burn sepsis, and the inflammatory signal pathway of TLR4/MyD88/NF-κB was activated. TLR4/MyD88/NF-κB initiated inflammatory reaction, at the same time , it also activated autophagy signal pathway. More and more researches showed that autophagy regulated strictly the septic inflammation. P62 was one important part of autophagosomes. Lentiviral vector /RNAi will be applied to explore the possible mechanisms of TLR4-MyD88-NF-κB-p62 autophagy signal pathway on cardiac injury during burn sepsis in vivo and in vitro. It may provide a new theoretical basis and therapeutic targets to improve the treatment of burn sepsis.

烧伤脓毒症合并心肌损伤时患者的死亡率明显增加，自MODS向MOF发展的过程中，组织细胞的自噬水平起着重要的调节作用。巨噬细胞在烧伤脓毒症失控性炎症反应及组织损伤中起着关键的作用，烧伤脓毒症时巨噬细胞活化，TLR4/MyD88/NF-κB信号通路活化，启动炎症反应，同时激活自噬通路。越来越多的研究表明，自噬对脓毒症炎症反应起着严格调控作用。TLR4/MyD88/NF-κB/p62通路中p62蛋白是自噬小体的重要组成部分，本课题拟在烧伤脓毒症模型上，利用慢病毒增强/RNA干扰调节p62基因的表达，通过动物模型和体外实验，研究TLR4/MyD88/NF-κB/p62自噬通路在烧伤脓毒症心肌细胞损伤中的作用机制，为烧伤脓毒症心脏保护提供新的理论依据和治疗靶点。

烧伤脓毒症合并心肌损伤时患者的死亡率明显增加，自MODS向MOF发展的过程中，组织细胞的自噬水平起着重要的调节作用。巨噬细胞在烧伤脓毒症失控性炎症反应及组织损伤中起着关键的作用，烧伤脓毒症时巨噬细胞活化，TLR4-/MyD88- NF-κB信号通路活化，启动炎症反应，同时激活自噬通路。我们的的研究表明，脓毒症时TLR4-MyD88-NF-κB炎症通路激活，自噬相关蛋白 Beclin1、LC3B、Atg7等表达升高，但 p62 蛋白（自噬小体主要组成分子）表达降低，自噬可能在脓毒血症心肌损伤中扮演重要角色。同时我们研究发现在脓毒症心脏损害中，线粒体分裂失控过度活化引起心肌损害加重，而通过抑制线粒体分裂则可以减轻脓毒症导致的心脏损害。