M2型巨噬细胞外泌体递送METTL3促进Axin2阳性肌成纤维祖细胞增殖与分化在急性肺损伤诱发肺纤维化中的致病机制

急性肺损伤(ALI)继发的急性呼吸窘迫综合征，常诱发肺纤维化，是患者死亡的主要因素，目前尚无有效治疗手段，亟需阐明ALI诱发肺纤维化分子机制。我们前期体内发现ALI晚期肺泡灌洗液中含大量M2型巨噬细胞(ALI-Mf)，ALI晚期清除巨噬细胞显著减轻肺纤维化。体外实验发现ALI-Mf及其外泌体(ALI-Mf-Exo)均显著激活肺间质中Axin2阳性肌成纤维祖细胞(AMP)增殖和分化。并且ALI-Mf-Exo中包含大量METTL3蛋白，刺激AMP后，显著上调AMP中METTL3蛋白水平及总RNA m6A。因此，我们推测ALI-Mf通过外泌体递送METTL3进入AMP调控m6A修饰，系统性激活AMP细胞增殖和分化，诱发肺纤维化。本项目拟从分子、细胞和动物平揭示ALI-Mf通过外泌体途径传递m6A信号，诱发肺纤维化的机制，丰富对ALI诱发肺纤维化机制的认知，为治疗ALI继发肺纤维化提供理论依据。

Acute lung injury (ALI) induced pulmonary fibrosis often lead to acute respiratory distress syndrome, which is the main cause of death in patients. There is no effective treatment, so that it is urgent to elucidate the molecular mechanism of ALI induced pulmonary fibrosis. Our previous in vivo study found a large number of M2-type macrophages (ALI-Mf) in the bronchoalveolar lavage fluid at the later stage of ALI, and the clearance of ALI-Mf significantly attenuated the pulmonary fibrosis. In vitro experiments found that both ALI-Mf and its exosomes significantly activated the proliferation and differentiation of lung stroma derived Axin2 positive myofibrogenic progenitor cell proliferation and differentiation (AMP). Moreover, ALI-Mf-Exo contains a large number of METTL3 proteins, and after stimulation of AMP with ALI-Mf-Exo, the METTL3 protein level and total RNAm6A in AMP were significantly up-regulated. Therefore, we speculate that ALI-Mf delivers METTL3 into AMP cells through the exosome pathway, activates the proliferation and differentiation of AMP cells, and induces pulmonary fibrosis. This project intends to reveal the mechanism of ALI-Mf transmitting m6A signal through exosome pathway to induce pulmonary fibrosis from molecules, cells and animals, which will enrich our understanding of the mechanism of ALI-Mf induced pulmonary fibrosis, and provide theoretical basis for targeted treatment of ALI induced pulmonary fibrosis.