Function-selective targeting of the extracellular signal-regulated kinase (ERK1/2) mitigates multiple pathophysiological features of allergen-induced asthma in mice. Function-selective targeting of the extracellular signal-regulated kinase (ERK1/2) mitigates multiple pathophysiological features of allergen-induced asthma in mice

Purpose: To test the in vivo effectiveness of a novel function-selective inhibitor of ERK1/2 in a murine model of house dust mite (HDM)-induced allergic asthma. Methods: Mice challenged with HDM for 3 weeks were treated with SF-3-030 or vehicle and asthma phenotype was assessed by histology and lung function measurements. Total RNA from lung samples were subjected to RNAseq analysis to determine the molecular signature perturbed by SF-3-030 treatment in mice. Results: RNA-seq analysis revealed modulation (up- or down-regulation) of expression of a number of genes by HDM challenge. SF-3-030 treatment significantly modulated the expression of genes involved in HDM-induced airway inflammation, cell proliferation, and extracellular matrix production. Conclusion: Function-selective inhibitor of ERK1/2 SF-3-030 mitigates multiple features of asthma in a murine model by modulating expression of genes involved in the regulation of key pathological functions in airway cells. Overall design: BALB/c mice were treated with HDM every day for 5 days/week for 3 weeks. A group of mice was treated with vehicle or 10 mg/kg SF-3-030 intranasally 30 min prior to the HDM challenge. Lung functions and histology were assessed after 3 weeks. Lung tissues harvested from mice were used for total RNA extraction and subjected to RNA-seq analysis. Differential gene expression and pathway analysis were performed. Asthma phenotype data in mice were also generated by histology, biochemical analysis, and lung mechanics studies.

研究目的：在屋尘螨（house dust mite, HDM）诱导的过敏性哮喘小鼠模型中，评估新型ERK1/2功能选择性抑制剂的体内有效性。实验方法：将经屋尘螨致敏3周的小鼠分别予以SF-3-030或溶剂处理，通过组织病理学检测与肺功能测定评估哮喘表型；提取肺组织总RNA进行RNA测序（RNA-seq）分析，以明确SF-3-030处理对小鼠体内基因表达分子特征的扰动情况。实验结果：RNA测序分析显示，屋尘螨致敏可调控多个基因的表达水平（上调或下调）；SF-3-030处理可显著调控参与屋尘螨诱导的气道炎症、细胞增殖与细胞外基质生成相关基因的表达。研究结论：ERK1/2功能选择性抑制剂SF-3-030可通过调控气道细胞关键病理功能相关基因的表达，缓解小鼠哮喘模型中哮喘的多种病理特征。整体实验方案：将BALB/c小鼠每周5天、每日予以屋尘螨刺激，持续3周；其中一组小鼠于屋尘螨致敏前30分钟经鼻内给予溶剂或10 mg/kg的SF-3-030。处理3周后，检测小鼠肺功能与组织病理学特征。收集小鼠肺组织用于总RNA提取，并开展RNA测序分析，进行差异基因表达分析与通路富集分析。此外，通过组织病理学检测、生化分析与肺力学研究，获取小鼠哮喘表型相关数据。