Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

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Abstract

Background

Ferroptosis is a newly recognized type of cell death, which is different from traditional necrosis, apoptosis or autophagic cell death. However, the position of ferroptosis in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored intensively so far. In this study, we mainly analyzed the relationship between ferroptosis and LPS-induced ALI.

Methods

In this study, a human bronchial epithelial cell line, BEAS-2B, was treated with LPS and ferrostatin-1 (Fer-1, ferroptosis inhibitor). The cell viability was measured using CCK-8. Additionally, the levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and iron, as well as the protein level of SLC7A11 and GPX4, were measured in different groups. To further confirm the in vitro results, an ALI model was induced by LPS in mice, and the therapeutic action of Fer-1 and ferroptosis level in lung tissues were evaluated.

Results

The cell viability of BEAS-2B was down-regulated by LPS treatment, together with the ferroptosis markers SLC7A11 and GPX4, while the levels of MDA, 4-HNE and total iron were increased by LPS treatment in a dose-dependent manner, which could be rescued by Fer-1. The results of the in vivo experiment also indicated that Fer-1 exerted therapeutic action against LPS-induced ALI, and down-regulated the ferroptosis level in lung tissues.

Conclusions

Our study indicated that ferroptosis has an important role in the progression of LPS-induced ALI, and ferroptosis may become a novel target in the treatment of ALI patients.

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Most cited references 47

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Ferroptosis: process and function.

Y Xie, W Hou, X Song … (2016)

Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.

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On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

Omkar Zilka, Ron Shah, Bo Li … (2017)

Ferroptosis is a form of regulated necrosis associated with the iron-dependent accumulation of lipid hydroperoxides that may play a key role in the pathogenesis of degenerative diseases in which lipid peroxidation has been implicated. High-throughput screening efforts have identified ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) as potent inhibitors of ferroptosis − an activity that has been ascribed to their ability to slow the accumulation of lipid hydroperoxides. Herein we demonstrate that this activity likely derives from their reactivity as radical-trapping antioxidants (RTAs) rather than their potency as inhibitors of lipoxygenases. Although inhibited autoxidations of styrene revealed that Fer-1 and Lip-1 react roughly 10-fold more slowly with peroxyl radicals than reactions of α-tocopherol (α-TOH), they were significantly more reactive than α-TOH in phosphatidylcholine lipid bilayers − consistent with the greater potency of Fer-1 and Lip-1 relative to α-TOH as inhibitors of ferroptosis. None of Fer-1, Lip-1, and α-TOH inhibited human 15-lipoxygenase-1 (15-LOX-1) overexpressed in HEK-293 cells when assayed at concentrations where they inhibited ferroptosis. These results stand in stark contrast to those obtained with a known 15-LOX-1 inhibitor (PD146176), which was able to inhibit the enzyme at concentrations where it was effective in inhibiting ferroptosis. Given the likelihood that Fer-1 and Lip-1 subvert ferroptosis by inhibiting lipid peroxidation as RTAs, we evaluated the antiferroptotic potential of 1,8-tetrahydronaphthyridinols (hereafter THNs): rationally designed radical-trapping antioxidants of unparalleled reactivity. We show for the first time that the inherent reactivity of the THNs translates to cell culture, where lipophilic THNs were similarly effective to Fer-1 and Lip-1 at subverting ferroptosis induced by either pharmacological or genetic inhibition of the hydroperoxide-detoxifying enzyme Gpx4 in mouse fibroblasts, and glutamate-induced death of mouse hippocampal cells. These results demonstrate that potent RTAs subvert ferroptosis and suggest that lipid peroxidation (autoxidation) may play a central role in the process.

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Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis.

Hirotaka Imai, Masaki Matsuoka, Takeshi Kumagai … (2017)

Glutathione peroxidase 4 (Phospholipid hydroperoxide glutathione peroxidase, PHGPx) can directly reduce phospholipid hydroperoxide. Depletion of GPx4 induces lipid peroxidation-dependent cell death in embryo, testis, brain, liver, heart, and photoreceptor cells of mice. Administration of vitamin E in tissue specific GPx4 KO mice restored tissue damage in testis, liver, and heart. These results indicate that suppression of phospholipid peroxidation is essential for cell survival in normal tissues in mice. Ferroptosis is an iron-dependent non-apoptotic cell death that can elicited by pharmacological inhibiting the cystine/glutamate antiporter, system Xc- (type I) or directly binding and loss of activity of GPx4 (Type II) in cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression, but not in normal cells. Ferroptosis by Erastin (Type I) and RSL3 (RAS-selective lethal 3, Type II) treatment was suppressed by an iron chelator, vitamin E and Ferrostatin-1, antioxidant compound. GPx4 can regulate ferroptosis by suppression of phospholipid peroxidation in erastin and RSL3-induced ferroptosis. Recent works have identified several regulatory factors of erastin and RSL3-induced ferroptosis. In our established GPx4-deficient MEF cells, depletion of GPx4 induce iron and 15LOX-independent lipid peroxidation at 26 h and caspase-independent cell death at 72 h, whereas erastin and RSL3 treatment resulted in iron-dependent ferroptosis by 12 h. These results indicated the possibility that the mechanism of GPx4-depleted cell death might be different from that of ferroptosis induced by erastin and RSL3.

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Author and article information

Contributors

Pengfei Liu:

ORCID: http://orcid.org/0000-0003-0172-189X

pengfeiliu2019@sina.com

Yetong Feng: fengyt17@sina.com

Hanwei Li: hanwei@szhospital.com

Xin Chen: chen_xin1979@163.com

Guangsuo Wang: wang_gs83825216@126.com

Shiyuan Xu: xsy9981@smu.edu.cn

Yalan Li: lyalan@jnu.edu.cn

Lei Zhao: zhao.lei@szhospital.com

Journal

Journal ID (nlm-ta): Cell Mol Biol Lett

Journal ID (iso-abbrev): Cell. Mol. Biol. Lett

Title: Cellular & Molecular Biology Letters

Publisher: BioMed Central (London )

ISSN (Print): 1425-8153

ISSN (Electronic): 1689-1392

Publication date (Electronic): 27 February 2020

Publication date PMC-release: 27 February 2020

Publication date Collection: 2020

Volume: 25

Electronic Location Identifier: 10

Affiliations

[1 ]GRID grid.263817.9, Department of Anesthesiology, , The 2nd Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, The 1st Affiliated Hospitals of Southern University of Science and Technology, ; Shenzhen, 518020 China

[2 ]GRID grid.258164.c, ISNI 0000 0004 1790 3548, Integrated Chinese and Western Medicine Postdoctoral Research Station, , Jinan University, ; Guangzhou, 510632 China

[3 ]GRID grid.263488.3, ISNI 0000 0001 0472 9649, Health Science Center, , School of Basic Medical Sciences, Shenzhen University, ; Shenzhen, 518037 China

[4 ]GRID grid.417404.2, ISNI 0000 0004 1771 3058, Department of Anesthesiology, , Zhujiang Hospital of Southern Medical University, ; Guangzhou, 510280 China

[5 ]GRID grid.263817.9, Department of Laboratory Medicine, , The 2nd Clinical Medicine College (Shenzhen People’s Hospital) of Jinan University, The 1st Affiliated Hospitals of Southern University of Science and Technology, ; Shenzhen, 518020 China

[6 ]GRID grid.263817.9, Department of Thoracic Surgery, , The 2nd Clinical Medicine College (Shenzhen People’s Hospital) of Jinan University, The 1st Affiliated Hospitals of Southern University of Science and Technology, ; Shenzhen, 518020 China

[7 ]GRID grid.412601.0, ISNI 0000 0004 1760 3828, Department of Anesthesiology, , First Affiliated Hospital of Jinan University, ; Guangzhou, 510632 China

Author information

Pengfei Liu http://orcid.org/0000-0003-0172-189X

Article

Publisher ID: 205

DOI: 10.1186/s11658-020-00205-0

PMC ID: 7045739

PubMed ID: 32161620

SO-VID: 6ae59f1e-50a9-4153-a478-9de3b69ec8a3

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 September 2019

Date accepted : 17 February 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 31900547

Award Recipient : Pengfei Liu

Funded by: FundRef http://dx.doi.org/10.13039/501100012234, Shenzhen Peacock Plan;

Award ID: KQTD2016113015442590

Award Recipient : Lei Zhao

Funded by: Project funded by China Postdoctoral Science Foundation

Award ID: 2019M653277

Award Recipient : Pengfei Liu

Funded by: FundRef http://dx.doi.org/10.13039/501100012245, Science and Technology Planning Project of Guangdong Province;

Award ID: 2016ZC0244

Award Recipient : Yalan Li

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Keywords: ferrostatin-1,ferroptosis,lipopolysaccharide,acute lung injury

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Keywords: ferrostatin-1, ferroptosis, lipopolysaccharide, acute lung injury

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Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

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Abstract

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Inflamed lung in vitro co-culture models

Most cited references 47

Ferroptosis: process and function.

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis.

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