CIP2A promotes bronchiolitis obliterans by activating the NF‑κB pathway

Area of Science:

• Toxicology
• Pulmonology
• Molecular Biology

Background:

• Bronchiolitis obliterans (BO) is a severe fibrotic lung disease linked to 2,3-butanedione (diacetyl, DA) exposure.
• The precise mechanisms by which DA induces BO remain unclear.
• Bioinformatics analysis revealed increased cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) in DA-exposed lung tissue.

Purpose of the Study:

• To investigate the role of CIP2A in the pathogenesis of DA-induced BO.
• To explore the therapeutic potential of inhibiting CIP2A in DA-induced lung injury.

Main Methods:

• Established rat and cellular models of DA-induced BO.
• Utilized ethoxysanguinarine, a CIP2A inhibitor, to reduce CIP2A levels.
• Assessed pathological changes using H&E, Masson, and Giemsa staining.
• Quantified gene and protein expression of CIP2A and related markers via RT-qPCR, Western blotting, IHC, IF, and ELISA.
• Investigated the involvement of the nuclear factor-κB (NF-κB) signaling pathway.

Main Results:

• CIP2A inhibition significantly ameliorated BO pathology, reducing intraluminal occlusion, inflammation, and fibrosis.
• Reduced expression of inflammation, fibrosis, and epithelial-mesenchymal transition (EMT) markers was observed following CIP2A inhibition.
• CIP2A inhibition suppressed NF-κB pathway activation, evidenced by decreased IκBα phosphorylation and p65 nuclear translocation.

Conclusions:

• CIP2A promotes DA-induced BO by enhancing inflammation, fibrosis, and EMT via activation of the NF-κB signaling pathway.
• Inhibition of CIP2A represents a promising therapeutic strategy for treating diacetyl-induced lung disease.