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Inflammation Research

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24-07-2022 | Acute Respiratory Distress-Syndrome | Original Research Article

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

Authors: Fei He, Lina Gu, Nan Cai, Jun Ni, Yong Liu, Quan Zhang, Chao Wu

Published in: Inflammation Research | Issue 10-11/2022

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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Title: The HMGB1-RAGE axis induces apoptosis in acute respiratory distress syndrome through PERK/eIF2α/ATF4-mediated endoplasmic reticulum stress
Authors: Fei He
Lina Gu
Nan Cai
Jun Ni
Yong Liu
Quan Zhang
Chao Wu
Publication date: 24-07-2022
Publisher: Springer International Publishing
Keyword: Acute Respiratory Distress-Syndrome
Published in: Inflammation Research / Issue 10-11/2022
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-022-01613-y

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

Abstract

Objective

Methods

Results

Conclusion

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Abstract

Objective

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Results

Conclusion

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