BMS‑345541 inhibits airway inflammation and epithelial‑mesenchymal transition in airway remodeling of asthmatic mice.

Abstract

The present study aimed to investigate the possible effects and regulatory mechanism of the inhibitor of nuclear factor-κB kinase complex β subunit (IKKβ) inhibitor BMS-345541 on airway inflammation, airway remodeling and epithelial-mesenchymal transition (EMT) in an ovalbumin (OVA) exposure asthma model in mice. The asthma mouse model was generated by sensitization and challenge with OVA. BMS-345541/dimethyl sulfoxide (DMSO) was administered perorally dairy in two therapeutic groups throughout the entire OVA challenge process. At 24 h following the last challenge, airway hyperresponsiveness (AHR) and airway inflammation were examined, and serum, bronchoalveolar lavage fluid (BALF) and lung samples were collected. Lung tissue was stained and assessed for pathological changes. The total number and classification of inflammatory cells in the BALF were examined. Levels of transforming growth factor β1 (TGFβ1) in the serum and BALF were measured using an enzyme-linked immunosorbent assay. The differential expression of EMT regulators E-cadherin and vimentin was detected by immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis. The results showed that OVA successfully induced allergic asthma. The asthmatic mice had AHR, airway inflammation, airway remodeling, a high expression of TGFβ1, and evidence of EMT. Following BMS-345541 treatment, there was significant inhibition of pathophysiological signs, including increased pulmonary eosinophilia infiltration, mucus hypersecretion and AHR. Treatment with BMS-345541 significantly reduced levels of TGFβ1. In addition, BMS-345541 notably downregulated the expression of vimentin and increased the expression of E-cadherin. These data suggested that the increased secretion of TGFβ1 induced by asthmatic inflammation can lead to EMT, and the IKKβ inhibitor BMS-345541 may alter airway remodeling by preventing EMT in an OVA asthma model. Therefore, IKKβ inhibitors require investigation as potential asthma therapies.