IκB kinase β inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma
IκB kinase β inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma
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DOI：
10.1111/j.1365-2222.2010.03564.x
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发表时间：
2011-01-01
影响因子：
6.1
通讯作者：
Sone, S.
中科院分区：
文献类型：
--
作者：
Ogawa, H.;Azuma, M.;Sone, S.
核因子（NF）-κ B（B）是一种转录因子，在包括支气管哮喘在内的多种炎症性疾病中调节细胞因子和趋化因子的产生。I κ B激酶（IKK）β在炎症状态下对NF-κ B活化很重要，并且可能与气道重塑有关。因此，IKK β-NF-κ B通路的抑制可能是一个理想的策略，用于管理气道remodeling. ESTA我们研究了一种新合成的IKK β抑制剂，IMD-0354，在慢性过敏原暴露模型的支气管asthma in mice.MethodsA慢性小鼠模型产生的挑战与屋尘螨抗原（Dermatophagoides pteronyssinus）。治疗组腹腔注射IMD-0354。肺组织病理学，高反应性和介质和肺匀浆上清液中的分子的浓度进行了determined. ResultsNF-κ B激活抑制IMD-0354管理的延长时间。IMD-0354减少了支气管嗜酸性粒细胞的数量。IMD-0354还抑制气道重塑的病理特征，包括杯状细胞增生、上皮下纤维化、胶原沉积和平滑肌肥大。IMD-0354对这些结构变化的抑制是通过抑制IKK β抑制重塑相关介质（如TGF-β）的产生和活化的结果。IMD-0354抑制IL-13和IL-1 β的产生，并恢复IFN-γ的产生。结论IKK β在慢性哮喘小鼠模型气道炎症和气道重塑中起重要作用。一种特异性IKK β抑制剂IMD-0354可能对治疗慢性哮喘的气道炎症和重塑有益。Ogawa，M.东，S. Muto，Y. Nishioka，A.本约，T.手冢，H。Uehara，K. Izumi，A. Itai和S. Sone，临床与实验过敏，2011（41）104-115。
P>BackgroundNuclear 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.ObjectiveWe examined the effects of a newly synthesized IKK beta inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice.MethodsA 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.ResultsNF-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.ConclusionIKK 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.