IκB kinase β inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma

• Published in: Clinical and experimental allergy 2011-01, Vol.41 (1), p.104-115
• Main Authors: Ogawa, H., Azuma, M., Muto, S., Nishioka, Y., Honjo, A., Tezuka, T., Uehara, H., Izumi, K., Itai, A., Sone, S.
• Format: Article
• Language: English
• Subjects: airway inflammation; Airway Remodeling - drug effects; Airway Remodeling - immunology; airway remodelling; Animals; Antigens, Dermatophagoides - immunology; Asthma - drug therapy; Asthma - enzymology; Asthma - pathology; Asthma - physiopathology; Benzamides - chemistry; Benzamides - pharmacology; Benzamides - therapeutic use; Biological and medical sciences; Chronic Disease; Chronic obstructive pulmonary disease, asthma; Disease Models, Animal; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; I-kappa B Kinase - antagonists & inhibitors; IKKβinhibitor; IMD-0354; Indexing in process; Medical sciences; Mice; Mice, Inbred BALB C; Molecular Structure; NF-κB; Pneumology; TGF-β
• ISSN: 0954-7894; 1365-2222
• DOI: 10.1111/j.1365-2222.2010.03564.x

Summary Background Nuclear factor (NF)‐κB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IκB kinase (IKK) β is important for NF‐κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKβ–NF‐κB pathway may be an ideal strategy for the management of airway remodelling. Objective We examined the effects of a newly synthesized IKKβ 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‐κB 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‐β, via inhibition of IKKβ. IMD‐0354 inhibited IL‐13 and IL‐1β production, and it restored the production of IFN‐γ. It also ameliorated airway hyperresponsiveness. Conclusion IKKβ plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKβ 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.