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.