Nrf2-PPARγ通路参与电针平衡M1/M2极化保护急性肺损伤的相关机制

Acute lung injury is the common organ dysfunction in the process of sepsis，which would progress into ARDS if deteriorating and seriously endanger patients’ lives and health. Recent studies have suggested that the balance of macrophage M1/M2 polarization could play a vital regulatory role in the process of various inflammation and tissue repair. Acute lung injury is often accompanied with macrophage dysfunction, which may be due to the macrophage polarization disorder. In our previous studies, we have found that electroacupuncture significantly reduced mortality of mice with acute lung injury and promoted macrophage polarization toward M2 and meanwhile, Nrf2-PPARγin lung macrophages was up-regulated. But, Nrf2 deficiency abolished the protection by electroacupuncture. These indicated that Nrf2-PPARγ involved in the macrophage polarization regulated by electroacupuncture to attenuated acute lung injury induced by sepsis. Based on these findings, the current project is devoted to carry out the following studies:1) to investigate the mechanism by which Nrf2-PPARγmediates the balance of macrophage polarization toward M1/M2; 2) to explore the correlation of the balance of M1/M2 polarization and the severity and prognosis of acute lung injury; 3) to clarify the effectiveness of electroacupuncture on patients with acute lung injury. Collectively, our project will not only provide critical consequence to help clarify the correlation of the macrophage polarization balance regulated by electroacupuncture and the progression of acute lung injury, but aslo harbor the potential to provide novel strategies for the treatment against acute lung injury.

急性肺损伤是脓毒症进程中常见的器官功能不全表现，重者可发展为ARDS，严重威胁患者的生命健康。近年的研究发现巨噬细胞M1/M2的极化平衡在多种炎症反应与组织损伤修复过程中发挥着重要调节作用。脓毒症肺损伤患者多伴有巨噬细胞功能紊乱现象，可能与巨噬细胞极化失调有关。我们前期研究发现电针可显著降低小鼠急性肺损伤死亡率，促进肺泡巨噬细胞向M2方向极化，同时伴有巨噬细胞内Nrf2-PPARγ表达上调，而Nrf2缺陷消除电针的保护作用，提示Nrf2-PPARγ参与电针调节巨噬细胞极化进而保护脓毒症急性肺损伤。在以上工作基础上，本项目拟开展以下研究：1）阐明Nrf2-PPARγ通路参与调节巨噬细胞M1/M2极化平衡的相关机制；2）研究M1/M2极化的平衡与脓毒症急性肺损伤严重程度及预后的相关性；3）明确电针治疗脓毒症急性肺损伤患者的有效性。本项目可能为脓毒症急性肺损伤的治疗提供新的策略。

急性呼吸窘迫综合征（acute respiratory distress syndrome, ARDS）是围术期常见的呼吸系统并发症之一，死亡率高达40%。免疫功能紊乱以及过度的炎症反应是其发生发展的关键机制。过氧化物酶增殖激活受体γ（peroxisome proliferators-activated receptors γ, PPARγ）在抗炎和脏器保护中发挥了重要的作用，核因子E2相关因子2（nuclear factor erythroid-2, Nrf2）在抗炎过程中的作用也非常重要，激活Nrf2通路可发挥肺保护作用，我们也发现了电针可通过激活PPARγ发挥抗炎和对ARDS的保护作用，减轻急性肺损伤，但其具体机制还不清楚。本项目主要从分子水平、动物实验等层次研究探讨了Nrf2-PPARγ通路在急性肺损伤中扮演的作用，是否可以成为急性肺损伤的潜在靶点。研究发现，激活Nrf2可以促进PPARγ的表达，激活巨噬细胞向M2方向极化，减轻肺损伤。在上皮细胞中下调Nrf2，对炎症基因的表达没有影响，Nrf2-PPARγ通路可能在巨噬细胞中发挥抗炎作用。在动物水平中，我们得到了同样的结果。研究结果提示，Nrf2-PPARγ通路可能是作为有效的抗ARDS的通路，可为ARDS的防治提供有效的潜在干预手段。