Li Zhenzhen, Zheng Beijie, Liu Chenchen, Zhao Xiang, Zhao Yupeng, Wang Xiangrui, Hou Lei, Yang Zhongwei
Department of Pharmacy, Zhongshan Hospital Wusong Branch, Fudan University, 200940 Shanghai, China.
Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127 Shanghai, China.
Stem Cells Int. 2023 Mar 31;2023:7072700. doi: 10.1155/2023/7072700. eCollection 2023.
Type II alveolar epithelial cell (AECII) apoptosis is one of the most vital causes of sepsis-induced acute respiratory distress syndrome (ARDS). Recent evidence has proved that bone mesenchymal stem cell-derived exosomes (BMSC-exos) can effectively reduce sepsis-induced ARDS. However, the function and molecular mechanism of BMSC-exos in sepsis-induced AECII apoptosis remain to be elucidated. In the present study, a more significant number of AECII apoptosis, high mitochondrial fission p-Drp1 protein levels, and low levels of mitochondrial biogenesis-related PGC1, Tfam, and Nrf1 proteins accompanied with ATP content depression were confirmed in AECIIs in response to sepsis. Surprisingly, BMSC-exos successfully recovered mitochondrial biogenesis, including the upregulated expression of PGC1, Tfam, Nrf1 proteins, and ATP contents, and prohibited p-Drp1-mediated mitochondrial fission by promoting Nrf2 expression. However, the aforementioned BMSC-exo reversal of mitochondrial dysfunction in AECIIs can be blocked by Nrf2 inhibitor ML385. Finally, BMSC-exos ameliorated the mortality rate, AECII apoptosis, inflammatory cytokine storm including HMGB1 and IL-6, and pathological lung damage in sepsis mice, which also could be prevented by ML385. These findings reveal a new mechanism of BMSC-exos in reversing mitochondrial dysfunction to alleviate AECII apoptosis, which may provide novel strategies for preventing and treating sepsis-induced ARDS.
II型肺泡上皮细胞（AECII）凋亡是脓毒症诱导的急性呼吸窘迫综合征（ARDS）的最重要原因之一。最近的证据表明，骨髓间充质干细胞来源的外泌体（BMSC-exos）可以有效减轻脓毒症诱导的ARDS。然而，BMSC-exos在脓毒症诱导的AECII凋亡中的功能和分子机制仍有待阐明。在本研究中，在脓毒症诱导的AECII中证实了更多数量的AECII凋亡、高线粒体裂变p-Drp1蛋白水平以及线粒体生物合成相关的PGC1、Tfam和Nrf1蛋白水平降低，同时伴有ATP含量降低。令人惊讶的是，BMSC-exos成功恢复了线粒体生物合成，包括PGC1、Tfam、Nrf1蛋白表达上调和ATP含量，并通过促进Nrf2表达抑制p-Drp1介导的线粒体裂变。然而，Nrf2抑制剂ML385可以阻断上述BMSC-exos对AECII中线粒体功能障碍的逆转作用。最后，BMSC-exos改善了脓毒症小鼠的死亡率、AECII凋亡、包括HMGB1和IL-6在内的炎性细胞因子风暴以及肺部病理损伤，而ML385也可以预防这些情况。这些发现揭示了BMSC-exos在逆转线粒体功能障碍以减轻AECII凋亡方面的新机制，这可能为预防和治疗脓毒症诱导的ARDS提供新策略。
