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首页> 外文期刊>Clinical and experimental allergy : >IkappaB kinase beta inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma.
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IkappaB kinase beta inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma.

机译：IkappaB激酶β抑制剂IMD-0354在慢性哮喘的Dermatophagoides蕨类植物致敏小鼠模型中抑制气道重塑。

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BACKGROUND: Nuclear factor (NF)-kappaB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IkappaB kinase (IKK) beta is important for NF-kappaB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKbeta-NF-kappaB pathway may be an ideal strategy for the management of airway remodelling. OBJECTIVE: We examined the effects of a newly synthesized IKKbeta 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-kappaB 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 IKKbeta. IMD-0354 inhibited IL-13 and IL-1beta production, and it restored the production of IFN-gamma. It also ameliorated airway hyperresponsiveness. CONCLUSION: IKKbeta plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKbeta inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.
机译：背景：核因子（NF）-κB是一种转录因子，可调节各种炎症性疾病（包括支气管哮喘）中的细胞因子和趋化因子的产生。 IkappaB激酶（IKK）beta对于炎症条件下的NF-kappaB激活很重要，并且可能与气道重塑有关。因此，抑制IKKbeta-NF-kappaB途径可能是治疗气道重塑的理想策略。目的：我们研究了一种新合成的IKKbeta抑制剂IMD-0354在小鼠支气管哮喘的慢性过敏原暴露模型中的作用。方法：用室内尘螨抗原（Dermatophagoides pteronyssinus）攻击产生慢性小鼠模型。在治疗组中腹膜内施用IMD-0354。测定了肺匀浆上清液的肺组织病理学，高反应性以及介质和分子的浓度。结果：延长的IMD-0354施用抑制了NF-κB的活化。 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，胶原蛋白沉积和平滑肌肥大。 IMD-0354对这些结构变化的抑制是通过抑制IKKbeta来抑制重塑相关介体（例如TGF-beta）的产生和激活的结果。 IMD-0354抑制IL-13和IL-1beta的产生，并恢复IFN-γ的产生。它还改善了气道高反应性。结论：IKKbeta在慢性哮喘小鼠模型的气道炎症和重塑中起关键作用。特定的IKKbeta抑制剂IMD-0354对于治疗慢性哮喘中的气道炎症和重塑可能在治疗上有益。

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