Bletinib ameliorates neutrophilic inflammation and lung injury by inhibiting Src family kinase phosphorylation and activity

Ting I. Kao, Po Jen Chen, Yi Hsuan Wang, Hsin Hui Tseng, Shih Hsin Chang, Tian Shung Wu, Sien Hung Yang, Yen Tung Lee, Tsong Long Hwang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

29 Scopus citations

Abstract

Background and Purpose: Neutrophil overactivation is crucial in the pathogenesis of acute lung injury (ALI). Bletinib (3,3′-dihydroxy-2′,6′-bis(p-hydroxybenzyl)-5-methoxybibenzyl), a natural bibenzyl, extracted from the Bletilla plant, exhibits anti-inflammatory, antibacterial, and antimitotic effects. In this study, we evaluated the therapeutic effects of bletinib in human neutrophilic inflammation and LPS-mediated ALI in mice. Experimental Approach: In human neutrophils activated with the formyl peptide (fMLP), we assessed integrin expression, superoxide anion production, degranulation, neutrophil extracellular trap (NET) formation, and adhesion through flow cytometry, spectrophotometry, and immunofluorescence microscopy. Immunoblotting was used to measure phosphorylation of Src family kinases (SFKs) and downstream proteins. Finally, a LPS-induced ALI model in male BALB/c mice was used to investigate the potential therapeutic effects of bletinib treatment. Key Results: In activated human neutrophils, bletinib reduced degranulation, respiratory burst, NET formation, adhesion, migration, and integrin expression; suppressed the enzymic activity of SFKs, including Src, Lyn, Fgr, and Hck; and inhibited the phosphorylation of SFKs as well as Vav and Bruton's tyrosine kinase (Btk). In mice with ALI, the pulmonary sections demonstrated considerable amelioration of prominent inflammatory changes, such as haemorrhage, pulmonary oedema, and neutrophil infiltration, after bletinib treatment. Conclusion and Implications: Bletinib regulates neutrophilic inflammation by inhibiting the SFK-Btk-Vav pathway. Bletinib ameliorates LPS-induced ALI in mice. Further biochemical optimisation of bletinib may be a promising strategy for the development of novel therapeutic agents for inflammatory diseases.

Original languageEnglish
Pages (from-to)4069-4084
Number of pages16
JournalBritish Journal of Pharmacology
Volume178
Issue number20
DOIs
StatePublished - 10 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Keywords

  • Src family kinase
  • acute lung injury
  • acute respiratory distress syndrome
  • bletinib
  • inflammation
  • neutrophil

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