Melatonin protects against PM2.5-induced lung injury by inhibiting ferroptosis of lung epithelial cells in a Nrf2-dependent manner

Fan, Guohua; Tong, Zhu; Min, Xinping; Juan, Xiong

doi:10.1016/j.ecoenv.2021.112588

Cited by 58 publications

(32 citation statements)

References 33 publications

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“…Nrf2 then binds to antioxidant responsive element (ARE) in the nucleus to promote the expression of antioxidant enzyme genes (such as GPx4, heme oxygenase-1 (HO-1)) [ 42 ]; meanwhile, Nrf2 can also regulate the expression of ferritin heavy chain 1 (FTH1), a gene associated with iron ion storage [ 43 ]. Previous studies demonstrated that inhibition of Nrf2 abolished the protective effect of tanshinone IIA on human coronary artery endothelial cell ferroptosis and that Nrf2 knockdown inhibited the anti-ferroptosis effect of melatonin on lung epithelial cells, suggesting a role of Nrf2 in inhibiting ferroptosis [ 44 ]. As previously mentioned, GPx4 is known to regulate inflammatory responses and apoptosis in humans and mammals, in addition to its antioxidant capacity [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

1,25(OH)2D3 Inhibited Ferroptosis in Zebrafish Liver Cells (ZFL) by Regulating Keap1-Nrf2-GPx4 and NF-κB-hepcidin Axis

Cheng

Huang

Wang

2021

IJMS

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Ferroptosis is a kind of iron-dependent programed cell death. Vitamin D has been shown to be an antioxidant and a regulator of iron metabolism, but the relationship between vitamin D and ferroptosis is poorly studied in fish. This study used zebrafish liver cells (ZFL) to establish a ferroptosis model to explore the effect of 1,25(OH)2D3 on cell ferroptosis and its mechanism of action. The results showed that different incubation patterns of 1,25(OH)2D3 improved the survival rate of ZFL, mitigated mitochondrial damage, enhanced total glutathione peroxidase (GPx) activity, and reduced intracellular reactive oxygen species (ROS), lipid peroxidation (LPO), and malondialdehyde (MDA), as well as iron ion levels, with the best effect at 200 pM 1,25(OH)2D3 preincubation for 72 h. Preincubation of ZFL at 200 pM 1,25(OH)2D3 for 72 h downgraded keap1 and ptgs2 gene expression, increased nrf2, ho-1, fth1, gpx4a,b expression, and lowered the expression of the nf-κb p65,il-6,il-1β gene, thus reducing the expression of hamp1. The above results indicate that different incubation patterns of 1,25(OH)2D3 have protective effects on ferroptosis of ZFL induced by ferroptosis activator RSL3 and 1,25(OH)2D3 can inhibit ferroptosis of ZFL by regulating Keap1–Nrf2–GPx4 and NF-κB–hepcidin axis.

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Section: Discussionmentioning

confidence: 99%

1,25(OH)2D3 Inhibited Ferroptosis in Zebrafish Liver Cells (ZFL) by Regulating Keap1-Nrf2-GPx4 and NF-κB-hepcidin Axis

Cheng

Huang

Wang

2021

IJMS

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“…PM2.5 samples were obtained with a high flow PM2.5 sampler (Ecotech, Australia) in the Wuhan Environment Surveillance Centre. The extraction and analysis of PM2.5 sampling were carried out based on our previous study [ 23 ]. The PM2.5 particles were stored at −20°C and detached from filters by sonication, which were next desiccated by lyophilization.…”

Section: Methodsmentioning

confidence: 99%

“…The cells were cultured in DMEM/F-12 supplemented with FBS (10%) at 37°C in an incubator with 5% CO 2 . To establish an in vitro model of PM2.5-induced lung injury, the MLE-12 lung epithelial cells were stimulated with PM2.5 (100 μ g/mL) with or without EG (20 μ M) for 24 hours as described [ 23 ]. To activate AKT in MLE-12 lung epithelial cells constitutively, the adenoviral (Ad) vectors generated by Hanbio Biotechnology Co. (Shanghai, China) were used in the present study [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

Epigallocatechin Gallate Relieved PM2.5-Induced Lung Fibrosis by Inhibiting Oxidative Damage and Epithelial-Mesenchymal Transition through AKT/mTOR Pathway

Zhongyin

Wang

Juan

et al. 2022

Oxidative Medicine and Cellular Longevity

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Oxidative damage and epithelial-mesenchymal transition (EMT) are main pathological processes leading to the development of PM2.5-induced lung fibrosis. Epigallocatechin gallate (EG), a natural polyphenol extracted from green tea, possesses the ability to combat oxidative stress and inflammation. However, the potential roles of EG in PM2.5-induced lung fibrosis have not been reported yet. In the present study, we investigated whether EG could relieve PM2.5-induced lung injury and fibrosis in vivo and in vitro. To mimic PM2.5-induced lung fibrosis, C57/BL6 mice were intranasally instilled with PM2.5 suspension, and MLE-12 lung epithelial cells were stimulated with PM2.5 (100 μg/mL) in vitro. The results showed that intragastric administration of EG (20 mg/kg/d or 80 mg/kg/d for 8 weeks) significantly prevented lung injury, inflammation, and oxidative stress in PM2.5-induced mice, apart from inhibiting collagen deposition. Additionally, EG treatment also suppressed the activation of AKT/mTOR signaling pathway in lung tissues challenged with PM2.5. In vitro experiments further demonstrated that EG treatment could enhance cell viability in a concentration-dependent manner in PM2.5-treated MLE-12 lung epithelial cells. Also, the overexpression of constitutively active AKT could offset the inhibitory effects of EG on EMT and oxidative stress in PM2.5-treated MLE-12 lung epithelial cells. Finally, AKT overexpression also blocked the inhibitory effect of EG on the phosphorylation of mTOR in PM2.5-treated MLE-12 lung epithelial cells. In conclusion, EG could improve PM2.5-induced lung fibrosis by decreasing oxidative damage and EMT through AKT/mTOR pathway, which might be a potential candidate for the treatment of PM2.5-induced lung fibrosis.

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“…However, in the course of ALI/ARDS caused by various pathological factors, several studies have revealed the relationship between alveolar epithelial cell injury and ferroptosis, and that inhibition of ferroptosis in alveolar epithelial cells can alleviate lung injury. For example, Fan et al (28) found that melatonin inhibits ferroptosis in epithelial cells and attenuates PM2.5-related lung injury by regulating nuclear factor-erythroid 2-related Factor 2 (Nrf2). Xu et al (26) reported that puerarin can suppress the ferroptosis of lung epithelial cells and alleviate the inflammatory response of sepsis-induced lung injury, and Xu et al (29) confirmed that ischaemia-reperfusion (IR)-induced lung injury can be improved by inhibiting ferroptosis and acyl-CoA synthetase long-chain family member 4 (ACSL4).…”

Section: Introductionmentioning

confidence: 99%

“…For example, Fan et al. ( 28 ) found that melatonin inhibits ferroptosis in epithelial cells and attenuates PM2.5-related lung injury by regulating nuclear factor-erythroid 2-related Factor 2(Nrf2). Xu et al.…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture Alleviates LPS-Induced ARDS Through α7 Nicotinic Acetylcholine Receptor-Mediated Inhibition of Ferroptosis

et al. 2022

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Acute respiratory distress syndrome (ARDS) is an uncontrollable, progressive pulmonary inflammatory disease, and as a common clinical critical disease, there is no effective treatment available. Electroacupuncture (EA) therapy is a type of traditional Chinese medicine physiotherapy that can alleviate the inflammatory response. However, the potential mechanism of EA in the treatment of ARDS is not yet clear. Ferroptosis is a new type of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation. Recently, emerging evidence has shown that ferroptosis is closely related to the occurrence and development of ARDS caused by various pathological factors. Here, we further investigated whether EA-mediated inhibition of ferroptosis in lung tissue could attenuate lipopolysaccharide (LPS)-induced ARDS and explored its underlying mechanisms. In this study, mice were administered LPS intraperitoneally to establish a model of LPS-induced ARDS. We found that EA stimulation could not only reduce the exudation of inflammatory cells and proteins in the alveolar lumen but also significantly alleviate the pathological changes of lung tissue, inhibit the production of proinflammatory cytokines and improve the survival rate of mice. Concurrently, we also found that ferroptosis events occurred in the lung tissue of LPS-induced ARDS mice, manifested by elevated iron levels, ROS production and lipid peroxidation. Intriguingly, our results showed that EA stimulation at the Zusanli (ST36) acupoint activated α7 nicotinic acetylcholine receptor (α7nAchR) in lung tissue mainly through the sciatic nerve and cervical vagus nerve, thus exerting anti-ferroptosis and pulmonary protective effects. Additionally, these effects were eliminated by methyllycaconitine (MLA), a selective antagonist of α7nAchR. In vitro experiments, activation of α7nAchR protected alveolar epithelial cells from LPS-induced ferroptosis. Furthermore, our experiments showed that the pulmonary protective effects of EA stimulation were effectively reversed by erastin, a ferroptosis activator. Collectively, we demonstrated that EA stimulation could alleviate LPS-induced ARDS by activating α7nAchR to inhibit LPS-induced ferroptosis in alveolar epithelial cells. Targeting and regulating ferroptosis in alveolar epithelial cells may be a potential intervention approach for the treatment of LPS-induced ALI/ARDS in the future.

show abstract

Melatonin protects against PM2.5-induced lung injury by inhibiting ferroptosis of lung epithelial cells in a Nrf2-dependent manner

Cited by 58 publications

References 33 publications

1,25(OH)2D3 Inhibited Ferroptosis in Zebrafish Liver Cells (ZFL) by Regulating Keap1-Nrf2-GPx4 and NF-κB-hepcidin Axis

1,25(OH)2D3 Inhibited Ferroptosis in Zebrafish Liver Cells (ZFL) by Regulating Keap1-Nrf2-GPx4 and NF-κB-hepcidin Axis

Epigallocatechin Gallate Relieved PM2.5-Induced Lung Fibrosis by Inhibiting Oxidative Damage and Epithelial-Mesenchymal Transition through AKT/mTOR Pathway

Electroacupuncture Alleviates LPS-Induced ARDS Through α7 Nicotinic Acetylcholine Receptor-Mediated Inhibition of Ferroptosis

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