Development of Inflammatory Models Using Differentiated Human Bronchial Epithelial (HBE) Cells from Cystic Fibrosis Patients for the Pre-Clinical Evaluation of Novel Therapeutic Compounds

Background There is a persistent need for effective anti-inflammatory therapies for people with cystic fibrosis (pwCF), even in the era of highly effective modulator therapy (hEMT). Although hEMT improves clinical outcomes, this treatment does not fully resolve the chronic airway inflammation that contributes to progressive lung damage and recurrent pulmonary exacerbations. Existing anti-inflammatory drugs have shown benefit, but their severe side effects limit long-term use. To address this therapeutic gap, we aimed to establish a robust ex vivo model of CF airway inflammation based on the differentiation of primary bronchial epithelial cells from pwCF. This model, induced by biological and biochemical stimuli, represents a potentially valuable tool for preclinical studies of novel anti-inflammatory agents. Methods To evaluate the efficacy of this model, we analyzed the expression and release of pro-inflammatory cytokines and chemokines in primary human bronchial epithelial (HBE) cells obtained ex vivo from different pwCF carrying the F508del mutation, exposed to Pseudomonas aeruginosa (PAO-1), its secretome, TNF-α, IL-17, and their combination. Results Both bacterial and biochemical stimuli induced a strong inflammatory response, characterized by marked upregulation of pro-inflammatory cytokine gene expression. Protein analysis confirmed increased secretion of inflammatory mediators, demonstrating that differentiated air liquid interface -HBE cells cultures reproduce key features of CF airway inflammation and provide a reliable ex vivo model for studying inflammation-driven molecular responses. Conclusions This ex vivo model of inflammation shows strong potential as a tool for preclinical evaluation of new therapeutic strategies for people with cystic fibrosis and for other lung inflammatory diseases.