Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Lab Invest. 2019 May;99(5):625-633. doi: 10.1038/s41374-018-0160-2. Epub 2019 Feb 13.
Pulmonary fibrosis is a major cause of death in patients with acute respiratory distress syndrome (ARDS). Our previous study revealed that lipopolysaccharide (LPS) challenge could lead to mouse lung fibroblast proliferation. Additionally, inhibition of autophagy in lung fibroblasts was also reported to be crucial during the process of pulmonary fibrosis. However, the correlation between proliferation and inhibition of autophagy of lung fibroblasts and the underlying mechanism remain unknown. In this study, we report that autophagy was inhibited in mouse lung fibroblasts after LPS challenge, and was accompanied by activation of the PI3K-Akt-mTOR signaling pathway. Treating mouse lung fibroblasts with LPS resulted in mTOR and Akt phosphorylation, p62 up-regulation, and significant down-regulation of autophagosomes, which could be reversed by PI3K-Akt inhibitors (Ly294002) or mTOR inhibitors (rapamycin, RAPA). Furthermore, either LPS or hydroxychloroquine (HCQ), an autophagy inhibitor, could promote mouse lung fibroblast proliferation, which could be reversed by RAPA application. The present research therefore reveals that LPS promotes lung fibroblast proliferation through autophagy inhibition via activation of the PI3K-Akt-mTOR pathway.
肺纤维化是急性呼吸窘迫综合征（ARDS）患者死亡的主要原因。我们之前的研究表明，脂多糖（LPS）刺激可导致小鼠肺成纤维细胞增殖。此外，有报道称肺成纤维细胞中自噬的抑制在肺纤维化过程中也是至关重要的。然而，肺成纤维细胞增殖和自噬抑制之间的相关性及其潜在机制尚不清楚。在本研究中，我们报道 LPS 刺激后，小鼠肺成纤维细胞中的自噬受到抑制，同时伴随着 PI3K-Akt-mTOR 信号通路的激活。用 LPS 处理小鼠肺成纤维细胞后，mTOR 和 Akt 发生磷酸化，p62 上调，自噬体明显下调，这可以被 PI3K-Akt 抑制剂（Ly294002）或 mTOR 抑制剂（雷帕霉素，RAPA）逆转。此外，LPS 或羟氯喹（HCQ），一种自噬抑制剂，均可促进小鼠肺成纤维细胞增殖，而 RAPA 的应用可逆转这一现象。因此，本研究揭示了 LPS 通过激活 PI3K-Akt-mTOR 通路抑制自噬从而促进肺成纤维细胞增殖。
