Melatonin ameliorates bleomycin-induced pulmonary fibrosis via activating NRF2 and inhibiting galectin-3 expression.
Melatonin ameliorates bleomycin-induced pulmonary fibrosis via activating NRF2 and inhibiting galectin-3 expression.
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褪黑素通过激活 NRF2 和抑制 galectin-3 表达来改善博莱霉素诱导的肺纤维化。
DOI：
10.1038/s41401-022-01018-x
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发表时间：
2023-05
影响因子：
8.2
通讯作者：
Dong, Hong-liang
中科院分区：
文献类型：
--
作者：
Lan, Yue-Jiao;Cheng, Ming-han;Ji, Hui-min;Bi, Yu-qian;Han, Yong-yue;Yang, Chong-yang;Gu, Xuan;Gao, Jian;Dong, Hong-liang
肺纤维化是一种慢性间质性肺疾病，目前尚无有效的治疗方法。半乳糖凝集素-3(Galectin-3，Gal-3)是氧化应激的标志，在PF的发病机制中起着关键作用。成纤维细胞-肌成纤维细胞分化(FMD)是PF中纤维细胞的重要来源。以往的研究表明，褪黑素(MT)通过其抗氧化活性在包括PF在内的多种疾病中发挥抗纤维化作用。本研究探讨了Gal-3、NRF2、ROS在口蹄疫发病中的相互关系及MT对它们的调节作用。我们建立了经转化生长因子-β-1处理的人胎肺成纤维细胞FMD的体外模型和气管内滴注博莱霉素的PF小鼠模型。我们发现Gal-3在体外和体内的表达都显著增加。Gal-3基因敲除可明显抑制转化生长因子-β-1诱导的FMD过程和ROS积聚。β特异性抑制剂ML385(5 μM)可显著上调Gal-3、α-SMA和ROS的表达，提示Gal-3的表达受NRF2的调控。NRF2激活剂MT(250μM)可抑制α-SMA和ROS的积聚，同时减少Gal-3的表达。在博莱霉素性肺纤维化模型中，MT(5 mg·kg−1·d−1，ip 14或2 8d)通过上调肺组织中NRF2和下调肺组织GAL3的表达而显著减轻肺纤维化的进展。这些结果提示Gal-3调节转化生长因子-NRF1诱导的促纤维化反应和FMD中ROS的产生，MT通过下调Gal-3的表达而激活β，从而阻断FMD的进程。这项研究为临床预防肺纤维化提供了有用的线索。机构的图形摘要。MT通过激活NRF2和抑制Gal-3的表达而减弱博莱姆诱导的PF。
Pulmonary fibrosis (PF) is a chronic interstitial lung disease with no effective therapies. Galectin-3 (Gal-3), a marker of oxidative stress, plays a key role in the pathogenesis of PF. Fibroblast-myofibroblast differentiation (FMD) is an important source of fibrotic cells in PF. Previous studies showed that melatonin (MT) exerted anti-fibrotic effect in many diseases including PF through its antioxidant activity. In the present study we investigated the relationships among Gal-3, NRF2, ROS in FMD and their regulation by MT. We established an in vitro model of FMD in TGF-β1-treated human fetal lung fibroblast1 (HFL1) cells and a PF mouse model via bleomycin (BLM) intratracheal instillation. We found that Gal-3 expression was significantly increased both in vitro and in vivo. Knockdown of Gal-3 in HFL1 cells markedly attenuated TGF-β1-induced FMD process and ROS accumulation. In TGF-β1-treated HFL1 cells, pretreatment with NRF2-specific inhibitor ML385 (5 μM) significantly increased the levels of Gal-3, α-SMA and ROS, suggesting that the expression of Gal-3 was regulated by NRF2. Treatment with NRF2-activator MT (250 μM) blocked α-SMA and ROS accumulation accompanied by reduced Gal-3 expression. In BLM-induced PF model, administration of MT (5 mg·kg−1·d−1, ip for 14 or 28 days) significantly attenuated the progression of lung fibrosis through up-regulating NRF2 and down-regulating Gal-3 expression in lung tissues. These results suggest that Gal-3 regulates TGF-β1-induced pro-fibrogenic responses and ROS production in FMD, and MT activates NRF2 to block FMD process by down-regulating Gal-3 expression. This study provides a useful clue for a clinical strategy to prevent PF. Graphic abstract of the mechanisms. MT attenuated BLM-induced PF via activating NRF2 and inhibiting Gal-3 expression.
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DOI：
10.1165/rcmb.2014-0116ps
发表时间：
2014-05-01
影响因子：
6.4
作者：
Cho, Hye-Youn;Kleeberger, Steven R.
通讯作者：
Kleeberger, Steven R.
影响因子：
3.8
作者：
Cho, Hye-Youn;Kleeberger, Steven R.
通讯作者：
Kleeberger, Steven R.
影响因子：
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作者：
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通讯作者：
Fei, Guanghe
影响因子：
6.6
作者：
Fulton, David J. R.;Li, Xueyi;Barman, Scott A.
通讯作者：
Barman, Scott A.
影响因子：
9
作者：
Jia W;Wang Z;Gao C;Wu J;Wu Q
通讯作者：
Wu Q