Department of Clinical Laboratory, Yunnan Molecular Diagnostic Center, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
Department of Respiratory, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
J Cell Physiol. 2020 Feb;235(2):1759-1768. doi: 10.1002/jcp.29094. Epub 2019 Jul 12.
Oxidative stress is a key regulator of idiopathic pulmonary fibrosis. Paraquat (PQ)-induced pulmonary fibrosis seriously endangers people's health. Rapamycin has been reported to alleviate PQ-induced pulmonary fibrosis, but its underlying mechanism is unclear. The nuclear factor E2-related factor 2 (Nrf2) plays an important regulatory role in the antioxidant therapy of PQ-induced pulmonary fibrosis. In this study, we tried to confirm that rapamycin attenuates PQ-induced pulmonary fibrosis by regulating Nrf2 pathway. In vivo, we proved that rapamycin could inhibit the degree of PQ-induced oxidant stress as well as enhanced the expression of Nrf2. In vitro, rapamycin decreased the upregulated effects of cell death and apoptosis, fibrosis-related factors expression and fibroblast-to-myofibroblast transformation by PQ treatment. In vivo, rapamycin treatment reduced fibrosis degree and the expression of fibrosis-related factors in lung tissues of rat treated PQ. Furthermore, we also found that Nrf2 knockdown reduced the inhibitory effect of rapamycin on PQ-induced pulmonary fibrosis, as well as decreased Nrf2 transfer from the cytoplasm into the nucleus. Our findings demonstrated that the protective effect of rapamycin is associated with the activation of the Nrf2 pathway in pulmonary fibrosis induced by PQ poisoning.
氧化应激是特发性肺纤维化的关键调节因子。百草枯（PQ）诱导的肺纤维化严重危害人们的健康。雷帕霉素已被报道可减轻 PQ 诱导的肺纤维化，但其潜在机制尚不清楚。核因子 E2 相关因子 2（Nrf2）在 PQ 诱导的肺纤维化抗氧化治疗中发挥重要调节作用。在本研究中，我们试图证实雷帕霉素通过调节 Nrf2 通路来减轻 PQ 诱导的肺纤维化。在体内，我们证明雷帕霉素可以抑制 PQ 诱导的氧化应激程度，并增强 Nrf2 的表达。在体外，雷帕霉素降低了 PQ 处理对细胞死亡和凋亡、纤维化相关因子表达和成纤维细胞向肌成纤维细胞转化的上调作用。在体内，雷帕霉素处理减轻了 PQ 处理大鼠肺组织中的纤维化程度和纤维化相关因子的表达。此外，我们还发现 Nrf2 敲低降低了雷帕霉素对 PQ 诱导的肺纤维化的抑制作用，并减少了 Nrf2 从细胞质向核内的转移。我们的研究结果表明，雷帕霉素的保护作用与 PQ 中毒诱导的肺纤维化中 Nrf2 通路的激活有关。
