Bletinib ameliorates neutrophilic inflammation and lung injury by inhibiting Src family kinase phosphorylation and activity. (14th July 2021)

• Record Type: Journal Article
• Authors: Kao, Ting‐I; Chen, Po‐Jen; Wang, Yi‐Hsuan; Tseng, Hsin‐Hui; Chang, Shih‐Hsin; Wu, Tian‐Shung; Yang, Sien‐Hung; Lee, Yen‐Tung; Hwang, Tsong‐Long
• Is Part Of: British journal of pharmacology. Volume 178:Number 20(2021)
• Page Start: 4069
• Page End: 4084
• Publication Date: 2021-07-14
• Subjects: acute lung injury -- acute respiratory distress syndrome -- bletinib -- inflammation -- neutrophil -- Src family kinase; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.15597
• Languages: English
• ISSNs: 0007-1188

Abstract

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. Abstract :