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The HMGB1-RAGE axis induces apoptosis in acute respiratory distress syndrome through PERK/eIF2α/ATF4-mediated endoplasmic reticulum stress

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Abstract

Objective

Apoptosis plays a major role in the progression of acute respiratory distress syndrome (ARDS) that may involve the interaction of the high mobility group box 1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). However, the underlying mechanism remains unclear. Thus, we aimed to explore the mechanisms of HMGB1-RAGE axis-induced apoptosis in ARDS.

Methods

Blood samples from ARDS patients and healthy volunteers were collected to investigate the correlation between serum HMGB1 levels and the severity of ARDS in patients. Mouse models of ARDS induced by caecal ligation and perforation and A549 cell models established by stimulation with recombinant human HMGB1 (rHMGB1) were designed to explore lung inflammatory injury and apoptosis.

Results

Serum HMGB1 levels were significantly increased in ARDS patients compared to controls, and HMGB1 levels in the Severe group and Nonsurvival group were significantly higher than those in the Mild and Moderate group and Survival group. In vivo, compared to sham mice, ARDS mice showed significant lung inflammatory injury and apoptosis as well as upregulation of HMGB1 and RAGE and endoplasmic reticulum stress (ERs) protein expression. All injury was attenuated by treatment with an HMGB1 inhibitor GA, a RAGE blocker FPS-ZM1, and an ERs inhibitor 4-PBA. In vitro, A549 cells challenged with rHMGB1 exhibited significant increases in the levels of proteins in the RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway and in apoptosis, all of which were significantly inhibited by pre-treatment with lenti-shPERK and an anti-RAGE antibody.

Conclusion

The HMGB1-RAGE axis induces apoptotic injury during ARDS, possibly through PERK/eIF2α/ATF4-mediated ERs.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ARDS:

Acute respiratory distress syndrome

ATF4:

Activating transcription factor 4

Bip:

Binding immunoglobulin protein

BALF:

Bronchoalveolar lavage fluid

CHOP:

C/EBP homologous protein

CLP:

Caecal ligation and puncture

eIF2α:

Eukaryotic translation-initiation factor 2α

GA:

Glycyrrhizic acid

HMGB1:

High mobility group protein

IRE1α:

Inositol-requiring enzyme 1α

IL-6:

Interleukin 6

IL-1β:

Interleukin 1β

PERK:

Protein kinase R-like ER kinase

4-PBA:

4-Phenylbutyricacid

RAGE:

Receptor for advanced glycation end-products

rHMGB1:

Recombinant high mobility group protein

TNF-α:

Tumour necrosis factor-α

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Acknowledgements

This study was supported by Nanjing Medical Science and technique Development Foundation (QRX17124). We would like to thank Mr. Xiangeng He and Ms. Xiaoshun Fang for giving us so much encouragement and support during this research period.

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    Authors and Affiliations

    1. Department of Emergency Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China

      Fei He

    2. Department of Pulmonary and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China

      Lina Gu

    3. Department of Infectious Disease, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China

      Nan Cai

    4. Department of Clinical Laboratory, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China

      Jun Ni

    5. Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China

      Yong Liu & Quan Zhang

    6. Department of Infectious Disease, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China

      Chao Wu

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    Contributions

    CW and FH contributed to the conception and design of the study; NG, NC, JN, YL and FH performed research; NG, NC, JN and FH performed analysis and interpretation of data; YL, QZ and Fei He contributed to drafting the article or revising it critically for important intellectual content; all authors approve the final version to be submitted.

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    Correspondence to Fei He or Chao Wu.

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    The authors declare that they have no competing interests.

    Ethical approval

    The clinical investigation in this study was approved by the Ethics Committee of Nanjing Drum Tower Hospital (EC 2020-089). All procedures for animal in this study were approved by the Institutional Animal Care and Use Committee at Nanjing Drum Tower Hospital, Nanjing University Medical School and conducted in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (NIH, Publication No. 86-23, revised 1996).

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    Fei He, Lina Gu and Nan Cai contributed equally to this work.

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    He, F., Gu, L., Cai, N. et al. The HMGB1-RAGE axis induces apoptosis in acute respiratory distress syndrome through PERK/eIF2α/ATF4-mediated endoplasmic reticulum stress. Inflamm. Res. 71, 1245–1260 (2022). https://doi.org/10.1007/s00011-022-01613-y

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