Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization
Copyright © 2024. Published by Elsevier B.V..
OBJECTIVES: Acute lung injury (ALI) is a highly inflammatory condition with the involvement of M1 alveolar macrophages (AMs) polarization, eventually leading to the development of non-cardiogenic edema in alveolar and interstitial regions, accompanied by persistent hypoxemia. Given the significant mortality rate associated with ALI, it is imperative to investigate the underlying mechanisms of this condition so as to identify potential therapeutic targets. The therapeutic effects of the inhibition of bromodomain containing protein 4 (BRD4), an epigenetic reader, has been proven with high efficacy in ameliorating various inflammatory diseases through mediating immune cell activation. However, little is known about the therapeutic potential of BRD4 degradation in acute lung injury.
METHODS: This study aimed to assess the protective efficacy of ARV-825, a novel BRD4-targeted proteolysis targeting chimera (PROTAC), against ALI through histopathological examination in lung tissues and biochemical analysis in bronchoalveolar lavage fluid (BALF). Additionally, the underlying mechanism by which BRD4 regulated M1 AMs was elucidated by using CUT & Tag assay.
RESULTS: In this study, we found the upregulation of BRD4 in a lipopolysaccharide (LPS)-induced ALI model. Furthermore, we observed that intraperitoneal administration of ARV-825, significantly alleviated LPS-induced pulmonary pathological changes and inflammatory responses. These effects were accompanied by the suppression of M1 AMs. In addition, our findings revealed that the administration of ARV-825 effectively suppressed M1 AMs by inhibiting the expression of IRF7, a crucial transcriptional factor involved in M1 macrophages.
CONCLUSION: Our study suggested that targeting BRD4 using ARV-825 is a potential therapeutic approach for ALI.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:132 |
|---|---|
| Enthalten in: |
International immunopharmacology - 132(2024) vom: 10. Apr., Seite 111991 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Li, Difei [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 30.04.2024 Date Revised 30.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.intimp.2024.111991 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370714059 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370714059 | ||
| 003 | DE-627 | ||
| 005 | 20240430232308.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240407s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.intimp.2024.111991 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1393.xml |
| 035 | |a (DE-627)NLM370714059 | ||
| 035 | |a (NLM)38581996 | ||
| 035 | |a (PII)S1567-5769(24)00509-5 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Difei |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 30.04.2024 | ||
| 500 | |a Date Revised 30.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024. Published by Elsevier B.V. | ||
| 520 | |a OBJECTIVES: Acute lung injury (ALI) is a highly inflammatory condition with the involvement of M1 alveolar macrophages (AMs) polarization, eventually leading to the development of non-cardiogenic edema in alveolar and interstitial regions, accompanied by persistent hypoxemia. Given the significant mortality rate associated with ALI, it is imperative to investigate the underlying mechanisms of this condition so as to identify potential therapeutic targets. The therapeutic effects of the inhibition of bromodomain containing protein 4 (BRD4), an epigenetic reader, has been proven with high efficacy in ameliorating various inflammatory diseases through mediating immune cell activation. However, little is known about the therapeutic potential of BRD4 degradation in acute lung injury | ||
| 520 | |a METHODS: This study aimed to assess the protective efficacy of ARV-825, a novel BRD4-targeted proteolysis targeting chimera (PROTAC), against ALI through histopathological examination in lung tissues and biochemical analysis in bronchoalveolar lavage fluid (BALF). Additionally, the underlying mechanism by which BRD4 regulated M1 AMs was elucidated by using CUT & Tag assay | ||
| 520 | |a RESULTS: In this study, we found the upregulation of BRD4 in a lipopolysaccharide (LPS)-induced ALI model. Furthermore, we observed that intraperitoneal administration of ARV-825, significantly alleviated LPS-induced pulmonary pathological changes and inflammatory responses. These effects were accompanied by the suppression of M1 AMs. In addition, our findings revealed that the administration of ARV-825 effectively suppressed M1 AMs by inhibiting the expression of IRF7, a crucial transcriptional factor involved in M1 macrophages | ||
| 520 | |a CONCLUSION: Our study suggested that targeting BRD4 using ARV-825 is a potential therapeutic approach for ALI | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ARV-825 | |
| 650 | 4 | |a Acute lung injury | |
| 650 | 4 | |a Alveolar macrophage polarization | |
| 650 | 4 | |a Bromodomain-containing protein 4 | |
| 650 | 4 | |a CUT & Tag assay | |
| 650 | 4 | |a Interferon regulator factor 7 | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Brd4 protein, mouse |2 NLM | |
| 650 | 7 | |a Anti-Inflammatory Agents |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a Bromodomain Containing Proteins |2 NLM | |
| 700 | 1 | |a Deng, Yao |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Guanxi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lingwei |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Xing |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shanze |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Rongchang |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t International immunopharmacology |d 2001 |g 132(2024) vom: 10. Apr., Seite 111991 |w (DE-627)NLM112639542 |x 1878-1705 |7 nnns |
| 773 | 1 | 8 | |g volume:132 |g year:2024 |g day:10 |g month:04 |g pages:111991 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.intimp.2024.111991 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 132 |j 2024 |b 10 |c 04 |h 111991 | ||