circRNA0001373/miR-212-3p上调METTL3介导STAT1 m6A动态修饰调控肺泡巨噬细胞极化在脓毒症急性肺损伤中的作用

脓毒症患者日益增多，急性肺损伤（ALI）是脓毒症患者死亡的重要原因；前期研究发现脓毒症肺组织circRNA0001373显著上调，伴METTL3和STAT1上调，M1巨噬细胞增加，与ALI严重程度正相关。体外实验LPS上调circRNA0001373，导致miR-212-3p下调，METTL3表达和STAT1mRNA m6A修饰增加，STAT1蛋白表达上调，促进巨噬细胞向M1极化。据此，提出“circRNA0001373/miR-212-3p上调METTL3表达介导STAT1 m6A动态修饰调控肺泡巨噬细胞极化介导脓毒症ALI”的假设。本项目建立野生型及CD11b-DRT转基因小鼠脓毒症模型，结合细胞学实验阐明circRNA0001373/miR-212-3p上调METTL3表达介导STAT1 m6A动态修饰调控巨噬细胞极化在脓毒症ALI的作用及机制，为脓毒症ALI防治提供理论依据。

The number of patients with sepsis is expanding. Acute lung injury is a major cause of acute respiratory distress syndrome (ARDS) and death among these patients. Our previous studies demonstrated that circRNA0001373 level in lung tissue increased significantly in sepsis, accompanied by the up-regulation of METTL3 and STAT1, increase of M1 macrophages, which was positively correlated with the severity of lung injury. In vitro, circRNA0001373 expression increased after LPS treatment, resulting in reduced miR-212-3p expression, increased METTL3 level and STAT1 mRNA m6A modification, and increased STAT1 protein expression, which promoted the polarization of macrophages to M1. Consequently, it is hypothesized that circRNA0001373/miR-212-3p might up-regulates METTL3-mediated STAT1 m6A dynamic modification, which induce lung injury with sepsis through regulating macrophage polarization. The current study was designed to clarify this hypothesis by establishing the model of normal and CD11b-DRT transgenic mice with acute lung injury in sepsis, which would provide potential targets for the prevention and treatment of acute lung injury in sepsis.