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The STAT3 inhibitor B9 alleviates lipopolysaccharide-induced acute lung injury through its anti-inflammatory effects.
- Source :
-
International immunopharmacology [Int Immunopharmacol] 2024 Jun 30; Vol. 135, pp. 112221. Date of Electronic Publication: 2024 May 19. - Publication Year :
- 2024
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Abstract
- The development of acute lung injury (ALI), a common respiratory condition with multiple causes, is significantly influenced by the pro-inflammatory environment of signal transducer and activator of transcription 3 (STAT3) in macrophages. Our study aimed to evaluate the anti-inflammatory effects of B9 (N-(4-hydroxyphenyl)-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonamide), a novel inhibitor targeting the STAT3 SH2 domain, in macrophages and to assess its therapeutic potential for ALI using a mouse model of lipopolysaccharide (LPS)-induced ALI. We found that B9 (30 mg/kg) significantly reduced lung pathological damage and neutrophil infiltration caused by the intratracheal administration of LPS. Additionally, the high expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in alveolar lavage fluid was also inhibited by B9 treatment. The decreased expression of CD86 and increased CD206 in lung tissue demonstrated the anti-inflammatory effect of B9, which was due to its inhibition of the STAT3 signaling pathway in macrophages of ALI mice. Furthermore, B9 suppressed the activation of RAW264.7 cells induced by LPS, characterized by its ability to inhibit the activation of iNOS and STAT3 in a dose-dependent manner, as well as reduce the secretion of IL-6 and IL-1β. The in vivo preliminary safety evaluation indicated that B9 had a favorable safety profile at the administered doses. These results suggest that B9 exerts a therapeutic effect on LPS-induced ALI, potentially by preventing the phosphorylation of STAT3 Y705 and S727 without affecting the STAT3 protein level. Taken together, these findings provide a foundation for developing B9 as a novel anti-inflammatory agent for ameliorating LPS-induced 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 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Mice
RAW 264.7 Cells
Male
Lung pathology
Lung drug effects
Lung immunology
Sulfonamides pharmacology
Sulfonamides therapeutic use
Mice, Inbred C57BL
Signal Transduction drug effects
Disease Models, Animal
Acute Lung Injury drug therapy
Acute Lung Injury chemically induced
Acute Lung Injury immunology
Acute Lung Injury pathology
Lipopolysaccharides
STAT3 Transcription Factor metabolism
STAT3 Transcription Factor antagonists & inhibitors
Anti-Inflammatory Agents therapeutic use
Anti-Inflammatory Agents pharmacology
Macrophages drug effects
Macrophages immunology
Cytokines metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1705
- Volume :
- 135
- Database :
- MEDLINE
- Journal :
- International immunopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38762924
- Full Text :
- https://doi.org/10.1016/j.intimp.2024.112221