I kappa B kinase beta inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma

P>Background Nuclear factor (NF)-kappa B is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. I kappa B kinase (IKK) beta is important for NF-kappa B activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKK beta-NF-kappa B pathway may be an ideal strategy for the management of airway remodelling. Objective We examined the effects of a newly synthesized IKK beta inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice. Methods A chronic mouse model was generated by challenge with house dust mite antigen (Dermatophagoides pteronyssinus). IMD-0354 was administrated intraperitoneally in therapeutic groups. Lung histopathology, hyperresponsiveness and the concentrations of mediators and molecules in supernatants of lung homogenates were determined. Results NF-kappa B activation was inhibited by prolonged periods of IMD-0354 administration. IMD-0354 reduced the numbers of bronchial eosinophils. IMD-0354 also inhibited the pathological features of airway remodelling, including goblet cell hyperplasia, subepithelial fibrosis, collagen deposition and smooth muscle hypertrophy. Inhibition of these structural changes by IMD-0354 was the result of the suppressing the production and activation of remodelling-related mediators, such as TGF-beta, via inhibition of IKK beta. IMD-0354 inhibited IL-13 and IL-1 beta production, and it restored the production of IFN-gamma. It also ameliorated airway hyperresponsiveness. Conclusion IKK beta plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKK beta inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma. Cite this as: H. Ogawa, M. Azuma, S. Muto, Y. Nishioka, A. Honjo, T. Tezuka, H. Uehara, K. Izumi, A. Itai and S. Sone, Clinical & Experimental Allergy, 2011 (41) 104-115.