The STAT3 inhibitor B9 alleviates lipopolysaccharide-induced acute lung injury through its anti-inflammatory effects.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 100965259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1705 (Electronic) Linking ISSN: 15675769 NLM ISO Abbreviation: Int Immunopharmacol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam ; New York : Elsevier Science, c2001-
    • Subject Terms:
      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; 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
    • 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.
      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.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Acute lung injury; B9; Inflammation; Macrophage; STAT3
    • Accession Number:
      0 (Lipopolysaccharides)
      0 (STAT3 Transcription Factor)
      0 (Anti-Inflammatory Agents)
      0 (Cytokines)
      0 (Stat3 protein, mouse)
      0 (Sulfonamides)
    • Publication Date:
      Date Created: 20240519 Date Completed: 20240606 Latest Revision: 20240606
    • Publication Date:
      20240607
    • Accession Number:
      10.1016/j.intimp.2024.112221
    • Accession Number:
      38762924