多酚类化合物LM49通过调控巨噬细胞表型治疗脓毒症肝损伤的作用及机制研究

调控肝脏巨噬细胞表型，调节致炎性M1型与抗炎性M2型巨噬细胞平衡是防治脓毒症肝脏过度炎性损伤的重要策略。前期研究发现多酚类化合物LM49在LPS/IFN-γ刺激的RAW264.7巨噬细胞和LPS诱导的脓毒症急性肝损伤小鼠中均可调控巨噬细胞表型，但调控机制尚不清楚。本项目通过研究LM49对脓毒症小鼠肝巨噬细胞（Kupffer）表型变化与肝损伤间的关系明确其通过调控Kupffer细胞表型治疗脓毒症肝损伤的作用；通过分子生物学技术研究LM49对巨噬细胞极化NF-κB、JAK/STAT3及JAK/STAT6通路的调控作用，利用RNA干扰方法进行反向验证；通过定量蛋白质组学进一步寻找调控Kupffer细胞极化的新信号调节靶蛋白，采用计算机辅助技术识别蛋白，从分子-细胞-动物三个层次分析探讨LM49治疗脓毒症肝损伤的作用及分子机制，为脓毒症寻找调控炎症反应的潜在治疗靶点提供科学依据。

It is an important strategy for preventing excessive inflammatory injury of sepsis liver by regulating the phenotype of liver macrophages and keeping the balance of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Previous studies have found that the polyphenol LM49 could regulate macrophage phenotype in LPS/IFN-γ stimulated RAW264.7 macrophages and LPS induced sepsis-associated acute hepatic injury mice , but the regulatory mechanism is unclear.The present study is to clarify the protective effect of polyphenol LM49 on sepsis-associated acute hepatic injury by regulating Kupffer cell phenotype and investigating the relationship between the the Kupffer cell phenotype in septic mice and changes in hepatic injury. The regulation of LM49 on macrophage polarization mediated by NF-κB,JAK/STAT3and JAK/STAT6 signaling pathways could be studied by molecular biology methods, which could be further verified by RNA interference method. By the proteomics technique,the changed proteins regulating the polarization of Kupffer cells can be founded after treatment with LM49.The target proteins can also be recognized by a computer-assisted technique.The regulatory mechanism of LM49 on macrophage polarization could be compositely analyzed and investigated from molecule-cell-whole animal levels to provide a scientific basis for regulating inflammation and finding potential therapeutic targets in sepsis.