Lipopolysaccharide promotes lung fibroblast proliferation through autophagy inhibition via activation of the PI3K-Akt-mTOR pathway
Lipopolysaccharide promotes lung fibroblast proliferation through autophagy inhibition via activation of the PI3K-Akt-mTOR pathway
复制标题
脂多糖通过激活 PI3K-Akt-mTOR 通路抑制自噬，促进肺成纤维细胞增殖
DOI：
10.1038/s41374-018-0160-2
复制
发表时间：
2019-05-01
影响因子：
5
通讯作者：
He, Zhengyu
中科院分区：
文献类型：
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作者：
Xie, Tingting;Xu, Qiaoyi;He, Zhengyu
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，据报道，肺成纤维细胞自噬的抑制在肺纤维化过程中也是至关重要的。然而，肺成纤维细胞增殖与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，我们报道了LPS刺激后小鼠肺成纤维细胞的自噬被抑制，并伴随着PI3K-Akt-mTOR信号通路的激活。LPS处理小鼠肺成纤维细胞导致mTOR和Akt磷酸化，p62上调，自噬体显著下调，PI3K-Akt抑制剂（Ly294002）或mTOR抑制剂（雷帕霉素，RAPA）可逆转这一过程。此外，LPS或自噬抑制剂羟氯喹（HCQ）均能促进小鼠肺成纤维细胞增殖，而RAPA可逆转这一作用。因此，本研究表明，LPS通过激活PI3K-Akt-mTOR通路，通过抑制自噬来促进肺成纤维细胞增殖。
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.