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首页> 美国卫生研究院文献>International Journal of Molecular Medicine >BMS-345541 inhibits airway inflammation and epithelial-mesenchymal transition in airway remodeling of asthmatic mice
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BMS-345541 inhibits airway inflammation and epithelial-mesenchymal transition in airway remodeling of asthmatic mice

机译：BMS-345541抑制哮喘小鼠气道重塑中的气道炎症和上皮-间质转化

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The present study aimed to investigate the possible effects and regulatory mechanism of the inhibitor of nuclear factor-κB kinase complex β subunit (IKKβ) inhibitor BMS-345541 on airway inflammation, airway remodeling and epithelial-mesenchymal transition (EMT) in an ovalbumin (OVA) exposure asthma model in mice. The asthma mouse model was generated by sensitization and challenge with OVA. BMS-345541/dimethyl sulfoxide (DMSO) was administered perorally dairy in two therapeutic groups throughout the entire OVA challenge process. At 24 h following the last challenge, airway hyperresponsiveness (AHR) and airway inflammation were examined, and serum, bronchoalveolar lavage fluid (BALF) and lung samples were collected. Lung tissue was stained and assessed for pathological changes. The total number and classification of inflammatory cells in the BALF were examined. Levels of transforming growth factor β1 (TGFβ1) in the serum and BALF were measured using an enzyme-linked immunosorbent assay. The differential expression of EMT regulators E-cadherin and vimentin was detected by immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis. The results showed that OVA successfully induced allergic asthma. The asthmatic mice had AHR, airway inflammation, airway remodeling, a high expression of TGFβ1, and evidence of EMT. Following BMS-345541 treatment, there was significant inhibition of pathophysiological signs, including increased pulmonary eosinophilia infiltration, mucus hypersecretion and AHR. Treatment with BMS-345541 significantly reduced levels of TGFβ1. In addition, BMS-345541 notably downregulated the expression of vimentin and increased the expression of E-cadherin. These data suggested that the increased secretion of TGFβ1 induced by asthmatic inflammation can lead to EMT, and the IKKβ inhibitor BMS-345541 may alter airway remodeling by preventing EMT in an OVA asthma model. Therefore, IKKβ inhibitors require investigation as potential asthma therapies.
机译：本研究旨在探讨核因子-κB激酶复合物β亚基（IKKβ）抑制剂BMS-345541对卵清蛋白（OVA）中气道炎症，气道重塑和上皮-间质转化（EMT）的可能作用及其调控机制。 ）暴露于小鼠的哮喘模型。哮喘小鼠模型是通过OVA致敏和激发而产生的。在整个OVA攻击过程中，将BMS-345541 /二甲基亚砜（DMSO）分为两个治疗组经口乳制品给药。在最后一次攻击后24小时，检查气道高反应性（AHR）和气道炎症，并收集血清，支气管肺泡灌洗液（BALF）和肺部样本。肺组织被染色并评估病理变化。检查了BALF中炎性细胞的总数和分类。使用酶联免疫吸附测定法测量血清和BALF中转化生长因子β1（TGFβ1）的水平。通过免疫组织化学染色，逆转录定量聚合酶链反应分析和蛋白质印迹分析检测EMT调节剂E-钙黏着蛋白和波形蛋白的差异表达。结果表明，OVA成功诱发了过敏性哮喘。哮喘小鼠具有AHR，气道炎症，气道重塑，TGFβ1高表达和EMT证据。在BMS-345541治疗后，病理生理征兆受到明显抑制，包括增加的肺嗜酸性粒细胞浸润，粘液分泌过多和AHR。 BMS-345541处理可显着降低TGFβ1的水平。此外，BMS-345541显着下调波形蛋白的表达并增加E-钙粘蛋白的表达。这些数据表明，哮喘炎症引起的TGFβ1分泌增加可导致EMT，而IKKβ抑制剂BMS-345541可通过预防OVA哮喘模型中的EMT改变气道重塑。因此，IKKβ抑制剂需要作为潜在的哮喘治疗方法进行研究。

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