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Rosmarinic acid alleviates septic acute respiratory distress syndrome in mice by suppressing the bronchial epithelial RAS-mediated ferroptosis.
- Source :
-
International immunopharmacology [Int Immunopharmacol] 2024 Jun 30; Vol. 135, pp. 112304. Date of Electronic Publication: 2024 May 21. - Publication Year :
- 2024
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Abstract
- Activating angiotensin-converting enzyme 2 (ACE2) is an important player in the pathogenesis of septic-related acute respiratory distress syndrome (ARDS). Rosmarinic acid (RA) as a prominent polyphenolic secondary metabolite derived from Rosmarinus officinalis modulates ACE2 in sepsis remains unclear, although its impact on ACE inhibition and septic-associated lung injury has been explored. The study investigated the ACE2 expression in lipopolysaccharide (LPS)-induced lungs in mice and BEAS2B cells. Additionally, molecular docking, protein-protein interaction (PPI) network analysis, and western blotting were employed to predict and evaluate the molecular mechanism of RA on LPS-induced ferroptosis in vivo and in vitro. LPS-induced glutathione peroxidase 4 (GPX4) downregulation, ACE/ACE2 imbalance, and alteration of frequency of breathing (BPM), minute volume (MV), and the expiratory flow at 50% expired volume (EF <subscript>50</subscript> ) were reversed by captopril pretreatment in vitro and in vivo. RA notably inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of GPX4 and ACE2 proteins, lung function improvement, and decreased inflammatory cytokines levels and ER stress in LPS-induced ARDS in mice. Molecular docking showed RA was able to interact with ACE and ACE2. Moreover, combined with different pharmacological inhibitors to block ACE and ferroptosis, RA still significantly inhibited inflammatory cytokines Interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and C-X-C motif chemokine 2 (CXCL2) levels, as well as improved lung function, and enhanced GPX4 expression. Particularly, the anti-ferroptosis effect of RA in LPS-induced septic ARDS is RAS-dependent.<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 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Humans
Mice
Male
Molecular Docking Simulation
Peptidyl-Dipeptidase A metabolism
Mice, Inbred C57BL
Bronchi drug effects
Bronchi pathology
Cell Line
Captopril pharmacology
Captopril therapeutic use
Disease Models, Animal
Cytokines metabolism
Rosmarinic Acid
Depsides therapeutic use
Depsides pharmacology
Ferroptosis drug effects
Cinnamates therapeutic use
Cinnamates pharmacology
Respiratory Distress Syndrome drug therapy
Lipopolysaccharides
Sepsis drug therapy
Angiotensin-Converting Enzyme 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1705
- Volume :
- 135
- Database :
- MEDLINE
- Journal :
- International immunopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38776851
- Full Text :
- https://doi.org/10.1016/j.intimp.2024.112304