IκB kinase ß inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma.
Clin Exp Allergy
; 41(1): 104-15, 2011 Jan.
Article
em En
| MEDLINE
| ID: mdl-20573155
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) ß is important for NF-κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKß-NF-κB pathway may be an ideal strategy for the management of airway remodelling.OBJECTIVE:
We examined the effects of a newly synthesized IKKß 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-ß, via inhibition of IKKß. IMD-0354 inhibited IL-13 and IL-1ß production, and it restored the production of IFN-γ. It also ameliorated airway hyperresponsiveness.CONCLUSION:
IKKß plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKß inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Asma
/
Benzamidas
/
Antígenos de Dermatophagoides
/
Modelos Animais de Doenças
/
Quinase I-kappa B
/
Remodelação das Vias Aéreas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Clin Exp Allergy
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Japão