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Clin Exp Allergy. 2011 Jan;41(1):104-15. doi: 10.1111/j.1365-2222.2010.03564.x.

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

Author information

1
Department of Respiratory Medicine & Rheumatology Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan. ogawah@clin.med.tokushimau.ac.jp

Abstract

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.

[Indexed for MEDLINE]

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