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

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.

• Authors: H Ogawa, M Azuma, S Muto, Y Nishioka, A Honjo, T Tezuka, H Uehara, K Izumi, A Itai, S Sone
• Journal: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology (Clin Exp Allergy) Vol. 41 Issue 1 Pg. 104-15 (Jan 2011) ISSN: 1365-2222 [Electronic] England
• PMID: 20573155 (Publication Type: Journal Article)
• Copyright: © 2010 Blackwell Publishing Ltd.

Chemical References

• Antigens, Dermatophagoides
• Benzamides
• N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
• I-kappa B Kinase

Topics

• Airway Remodeling (drug effects, immunology)
• Animals
• Antigens, Dermatophagoides (immunology)
• Asthma (drug therapy, enzymology, pathology, physiopathology)
• Benzamides (chemistry, pharmacology, therapeutic use)
• Chronic Disease
• Disease Models, Animal
• Female
• I-kappa B Kinase (antagonists & inhibitors)
• Mice
• Mice, Inbred BALB C
• Molecular Structure