Back to Search
Start Over
Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization.
- Source :
-
International immunopharmacology [Int Immunopharmacol] 2024 May 10; Vol. 132, pp. 111991. Date of Electronic Publication: 2024 Apr 06. - Publication Year :
- 2024
-
Abstract
- 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.<br />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.<br />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.<br />Conclusion: Our study suggested that targeting BRD4 using ARV-825 is a potential therapeutic approach for ALI.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024. Published by Elsevier B.V.)
- Subjects :
- Animals
Mice
Male
Mice, Inbred C57BL
Humans
Proteolysis drug effects
Anti-Inflammatory Agents pharmacology
Anti-Inflammatory Agents therapeutic use
Lung pathology
Lung drug effects
Lung immunology
Nuclear Proteins metabolism
Nuclear Proteins genetics
Cell Cycle Proteins metabolism
Cell Cycle Proteins genetics
Disease Models, Animal
Macrophage Activation drug effects
Acute Lung Injury drug therapy
Acute Lung Injury chemically induced
Acute Lung Injury pathology
Acute Lung Injury immunology
Transcription Factors metabolism
Transcription Factors genetics
Lipopolysaccharides
Macrophages, Alveolar drug effects
Macrophages, Alveolar immunology
Macrophages, Alveolar metabolism
Bromodomain Containing Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1705
- Volume :
- 132
- Database :
- MEDLINE
- Journal :
- International immunopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38581996
- Full Text :
- https://doi.org/10.1016/j.intimp.2024.111991