Ibrutinib Prevents Acute Lung Injury via Multi-Targeting BTK, FLT3 and EGFR in Mice

Abstract

Ibrutinib has potential therapeutic or protective effects against viral- and bacterial-induced acute lung injury (ALI), likely by modulating the Bruton tyrosine kinase (BTK) signaling pathway. However, ibrutinib has multi-target effects. Moreover, immunity and inflammation targets in ALI treatment are poorly defined. We investigated whether the BTK-, FLT3-, and EGFR-related signaling pathways mediated the protective effects of ibrutinib on ALI. The intratracheal administration of poly I:C or LPS after ibrutinib administration in mice was performed by gavage. The pathological conditions of the lungs were assessed by micro-CT and HE staining. The levels of neutrophils, lymphocytes, and related inflammatory factors in the lungs were evaluated by ELISA, flow cytometry, immunohistochemistry, and immunofluorescence. Finally, the expression of proteins associated with the BTK-, FLT3-, and EGFR-related signaling pathways were evaluated by Western blotting. Ibrutinib (10 mg/kg) protected against poly I:C-induced (5 mg/kg) and LPS-induced (5 mg/kg) lung inflammation. The wet/dry weight ratio (W/D) and total proteins in the bronchoalveolar lavage fluid (BALF) were markedly reduced after ibrutinib (10 mg/kg) treatment, relative to the poly I:C- and LPS-treated groups. The levels of ALI indicators (NFκB, IL-1β, IL-6, TNF-α, IFN-γ, neutrophils, and lymphocytes) were significantly reduced after treatment. Accordingly, ibrutinib inhibited the poly I:C- and LPS-induced BTK-, FLT3-, and EGFR-related pathway activations. Ibrutinib inhibited poly I:C- and LPS-induced acute lung injury, and this may be due to its ability to suppress the BTK-, FLT3-, and EGFR-related signaling pathways. Therefore, ibrutinib is a potential protective agent for regulating immunity and inflammation in poly I:C- and LPS-induced ALI.

BTK and MMP9 regulate NLRP3 inflammasome-dependent cytokine and NET responses in primary neutrophils

“…A positive regulatory role of BTK was also observed in in experimental murine models of NLRP3 activation, e.g. stroke 23 , acute lung Injury 24 , sepsis 25 and neuroinflammation 26 . On the molecular level, BTK interacts constitutively with NLRP3 in macrophages and promoted TGN dissociation and NLRP3 oligomerization via direct phosphorylation of NLRP3 at three adjacent tyrosine residues 19 .…”

Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models

“…Ibrutinib treatment effectively inhibits Poly I:C and lipopolysaccharide (LPS)-induced activation of BTK, fms-like tyrosine kinase 3 (FLT3), and epidermal growth factor receptor (EGFR)-related pathways and significantly reduces acute lung injury in mice (Rao et al, 2022). These findings suggest that BTK inhibitors may serve as potential therapeutic agents in regulating SARS-CoV-2-induced acute lung injury.…”

Preliminary PET imaging of [11C]evobrutinib in mouse models of colorectal cancer, SARS‐CoV‐2, and lung damage: Radiosynthesis via base‐aided palladium‐NiXantphos‐mediated 11C‐carbonylation

“…BTK is increased in lung tissue following exposure to lipopolysaccharide (LPS). 35 C57BL6 male mice received an intranasal challenge of 10 μL of 2 mg/mL LPS (L2630, serotype O111:B4; Sigma-Aldrich) in saline (n = 2) or a control of 10 μL saline (n = 1). PET imaging was performed at 24 h postintranasal LPS challenge.…”