Department of Respiratory Medicine & Rheumatology Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
Clin Exp Allergy. 2011 Jan;41(1):104-15. doi: 10.1111/j.1365-2222.2010.03564.x.
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.
We examined the effects of a newly synthesized IKKβ inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice.
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.
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.
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.
核因子 (NF)-κB 是一种转录因子，可调节包括支气管哮喘在内的各种炎症性疾病中的细胞因子和趋化因子的产生。IKKβ 在炎症条件下对 NF-κB 的激活很重要，并且可能与气道重塑有关。因此，抑制 IKKβ-NF-κB 途径可能是治疗气道重塑的理想策略。
我们在小鼠慢性变应原暴露的哮喘模型中研究了一种新合成的 IKKβ 抑制剂 IMD-0354 的作用。
通过用屋尘螨抗原（Dermatophagoides pteronyssinus）激发来建立慢性小鼠模型。在治疗组中通过腹腔内给药给予 IMD-0354。测定肺组织病理学、高反应性以及肺匀浆上清液中介质和分子的浓度。
长时间给予 IMD-0354 可抑制 NF-κB 激活。IMD-0354 减少了支气管嗜酸性粒细胞的数量。IMD-0354 还抑制了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 通过抑制 IKKβ 抑制了与重塑相关的介质（如 TGF-β）的产生和激活，从而抑制了这些结构变化。IMD-0354 抑制了 IL-13 和 IL-1β 的产生，并恢复了 IFN-γ 的产生。它还改善了气道高反应性。
IKKβ 在哮喘慢性小鼠模型中气道炎症和重塑中发挥关键作用。一种特定的 IKKβ 抑制剂 IMD-0354 可能对治疗慢性哮喘中的气道炎症和重塑具有治疗益处。
