Melatonin ameliorates bleomycin-induced pulmonary fibrosis via activating NRF2 and inhibiting galectin-3 expression

Yue-jiao Lan1,2, Ming-han Cheng1, Hui-min Ji3, Yu-qian Bi3, Yong-yue Han1, Chong-yang Yang3, Xuan Gu4, Jian Gao1, Hong-liang Dong1
1 Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200120, China
2 Jilin Province People’s Hospital, Changchun 130021, China
3 Dalian Medical University, Dalian 116023, China
4 3201 Hospital, Hanzhong 723000, China
Correspondence to: Jian Gao:, Hong-liang Dong:,
DOI: 10.1038/s41401-022-01018-x
Received: 1 July 2022
Accepted: 19 October 2022
Advance online: 4 November 2022


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.
Keywords: pulmonary fibrosis; fibroblast-myofibroblast differentiation; galectin-3; NRF2; ROS; melatonin

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