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Suppressing Endoplasmic Reticulum Stress Alleviates LPS-Induced Acute Lung Injury via Inhibiting Inflammation and Ferroptosis

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Abstract

Acute lung injury (ALI) is a life-threatening clinical disorder with high mortality rate. Ferroptosis is a new type of programmed cell death with lipid peroxidation and iron ion overloading as the main characteristics. Endoplasmic reticulum (ER) stress and ferroptosis play pivotal roles in the pathogenesis of ALI. The study aimed to investigate the underlying relationship between ER stress and ferroptosis in ALI. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated LPS-induced inflammation, and decreased IL-1β, IL-6, and TNF-α levels in BALF and lungs. The increased MDA and decreased GSH induced by LPS were partially reversed by 4-PBA, which also inhibited the expressions of ferroptosis-related protein ACSL4, COX-2, and FTH1. TEM further confirmed the ferroptosis within airway epithelia cells was ameliorated by 4-PBA. Moreover, 4-PBA reduced the production of ROS and lipid ROS in LPS-exposed BEAS-2B cells in a concentration-dependent way. Meanwhile, 4-PBA mitigated LPS-induced cell apoptosis in vivo and in vitro. Mechanistically, the MAPK signaling pathway activated by LPS was downregulated by 4-PBA. Collectively, these findings suggested that 4-PBA protected against ALI by inhibiting inflammation and ferroptosis through downregulating ER stress, thus providing a potential intervention for ALI and revealing the possible interaction between ER stress and ferroptosis in ALI.

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AVAILABILITY OF DATA AND MATERIALS

All supporting the findings of this report are included in this article. The data and materials are fully available upon reasonable request.

Abbreviations

ALI:

Acute lung injury

ER:

Endoplasmic reticulum

4-PBA:

4-Phenylbutyric acid

HE:

Hematoxylin and eosin

LPS:

Lipopolysaccharide

ARDS:

Acute respiratory distress syndrome

IL:

Interleukin

TNF:

Tumor necrosis factor

BALF:

Bronchoalveolar lavage fluid

MDA:

Malondialdehyde

GSH:

Glutathione

ACSL4:

Acyl-CoA synthetase long-chain family member 4

COX-2:

Cyclooxygenase-2

FTH1:

Ferritin heavy chain 1

TEM:

Transmission electron microscopy

ROS:

Reactive oxygen species

IRE1α:

Inositol-requiring enzyme 1α

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

ATF6:

Activating transcription factor 6

GRP78:

Glucose-regulated protein 78

4-HNE:

4-Hydroxynonenal

ATF4:

Activating transcription factor 4

TUNEL:

TdT-mediated dUTP nick end labeling

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Funding

This study was funded by the National Natural Science Foundation of China ([81873420] and [82070075]) and National Key Research and Development Plan, Ministry of Science and Technology of China (2018YFC0309502).

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Authors and Affiliations

  1. Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China

    Sijiao Wang, Fan Xu, Hanhan Liu, Yue Shen, Lijuan Hu & Lei Zhu

  2. Department of Pulmonary Medicine, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Jun Zhang

  3. Department of Pulmonary Medicine, Huadong Hospital, Fudan University, Shanghai, 200040, China

    Lei Zhu

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  1. Sijiao Wang
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  3. Hanhan Liu
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Contributions

Sijiao Wang and Fan Xu conceptualized and designed the study, validated the data, analyzed and curated the data, performed the experiments, performed software-related analysis, and wrote and revised the manuscript. Lei Zhu and Lijuan Hu conceptualized the study, validated and curated the data, acquired funding, obtained resources, revised the manuscript, supervised the study, and performed visualization and administration of the project. Hanhan Liu, Yue Shen and Jun Zhang performed the experiments and wrote the original draft of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Lijuan Hu or Lei Zhu.

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Wang, S., Xu, F., Liu, H. et al. Suppressing Endoplasmic Reticulum Stress Alleviates LPS-Induced Acute Lung Injury via Inhibiting Inflammation and Ferroptosis. Inflammation (2024). https://doi.org/10.1007/s10753-023-01962-8

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