Amifostine ameliorates bleomycin-induced murine pulmonary fibrosis via NAD <sup>+</sup>/SIRT1/AMPK pathway-mediated effects on mitochondrial function and cellular metabolism

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Abstract

Background

Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions aimed at mitigating several different molecular aspects of the disease, only two drugs with limited clinical efficacy have so far been approved for IPF therapy.

Objective

We investigated the therapeutic efficacy of amifostine, a detoxifying drug clinically used for radiation-caused cytotoxicity, in bleomycin-induced murine pulmonary fibrosis.

Methods

C57BL6/J mice were intratracheally instilled with 3 U/kg of bleomycin. Three doses of amifostine (WR-2721, 200 mg/kg) were administered intraperitoneally on days 1, 3, and 5 after the bleomycin challenge. Bronchoalveolar lavage fluid (BALF) was collected on day 7 and day 21 for the assessment of lung inflammation, metabolites, and fibrotic injury. Human fibroblasts were treated in vitro with transforming growth factor beta 1 (TGF-β1), followed by amifostine (WR-1065, 1–4 µg/mL) treatment. The effects of TGF-β1 and amifostine on the mitochondrial production of reactive oxygen species (ROS) were assessed by live cell imaging of MitoSOX. Cellular metabolism was assessed by the extracellular acidification rate (ECAR), the oxygen consumption rate (OCR), and the concentrations of various energy-related metabolites as measured by mass spectrum (MS). Western blot analysis was performed to investigate the effect of amifostine on sirtuin 1 (SIRT1) and adenosine monophosphate activated kinase (AMPK).

Results

Three doses of amifostine significantly attenuated lung inflammation and pulmonary fibrosis. Pretreatment and post-treatment of human fibroblast cells with amifostine blocked TGF-β1-induced mitochondrial ROS production and mitochondrial dysfunction in human fibroblast cells. Further, treatment of fibroblasts with TGF-β1 shifted energy metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) and towards glycolysis, as observed by an altered metabolite profile including a decreased ratio of NAD + /NADH and increased lactate concentration. Treatment with amifostine significantly restored energy metabolism and activated SIRT1, which in turn activated AMPK. The activation of AMPK was required to mediate the effects of amifostine on mitochondrial homeostasis and pulmonary fibrosis. This study provides evidence that repurposing of the clinically used drug amifostine may have therapeutic applications for IPF treatment.

Conclusion

Amifostine inhibits bleomycin-induced pulmonary fibrosis by restoring mitochondrial function and cellular metabolism.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40001-023-01623-4.

Related collections

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Author and article information

Contributors

Zaichun Deng: dengzaichun@nbu.edu.cn

Panfeng Fu: fupanfeng@nbu.edu.cn

Journal

Journal ID (nlm-ta): Eur J Med Res

Journal ID (iso-abbrev): Eur J Med Res

Title: European Journal of Medical Research

Publisher: BioMed Central (London )

ISSN (Print): 0949-2321

ISSN (Electronic): 2047-783X

Publication date (Electronic): 20 January 2024

Publication date PMC-release: 20 January 2024

Publication date Collection: 2024

Volume: 29

Electronic Location Identifier: 68

Affiliations

[1 ]GRID grid.203507.3, ISNI 0000 0000 8950 5267, Department of Biochemistry, Health Science Center, , Ningbo University, ; Ningbo, 315041 China

[2 ]GRID grid.460077.2, ISNI 0000 0004 1808 3393, Central Laboratory of the Medical Research Center, , The First Affiliated Hospital of Ningbo University, ; Ningbo, China

[3 ]GRID grid.203507.3, ISNI 0000 0000 8950 5267, Department of Respiratory and Critical Care Medicine, , The First Affiliated Hospital of Ningbo University, Ningbo University, ; Ningbo, 315041 China

[4 ]GRID grid.460077.2, ISNI 0000 0004 1808 3393, Department of Laboratory Medicine, , The First Affiliated Hospital of Ningbo University, ; Ningbo, China

[5 ]GRID grid.460077.2, ISNI 0000 0004 1808 3393, Department of Emergency Medicine, , The First Affiliated Hospital of Ningbo University, ; Ningbo, China

[6 ]GRID grid.460077.2, ISNI 0000 0004 1808 3393, Department of Dermatology, , The First Affiliated Hospital of Ningbo University, ; Ningbo, China

[7 ]Department of Pulmonary and Critical Care Medicine, South China Hospital Affiliated to Shenzhen University, ( https://ror.org/01me2d674) Shenzhen, China

Article

Publisher ID: 1623

DOI: 10.1186/s40001-023-01623-4

PMC ID: 10799491

PubMed ID: 38245795

SO-VID: 3721449b-8e95-40ef-9299-52b83ebd2127

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

History

Date received : 27 January 2023

Date accepted : 25 December 2023

Funding

Funded by: Medical Health Science and Technology Project of Zhejiang Province

Award ID: 2022KY1145

Award ID: 2021KY1046

Award ID: 2022KY333

Award Recipient : Feng Xu Yongxiong Gan Zaichun Deng

Funded by: Ningbo Nature Science

Award ID: 2021J243

Award ID: 202003N4023

Award ID: 2021J244

Award Recipient : Yun Zhang Dan Lv Zaichun Deng

Funded by: PAN3315 Innovative Individual of Ningbo Government

Award ID: 2020B-31-G

Award Recipient : Zaichun Deng

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: amifostine,ipf,tgf-β1,mitochondria,metabolism,ros,sirt1,nad+

Data availability:

ScienceOpen disciplines: Medicine

Keywords: amifostine, ipf, tgf-β1, mitochondria, metabolism, ros, sirt1, nad+