Abstract
BACKGROUND: People with Cystic Fibrosis (pwCF) are prone to bacterial lung infections with P. aeruginosa, which have been linked to chronic inflammation in the lung. Although the highly effective CFTR modulator therapy (Elexacaftor-Tezacaftor-Ivacaftor, ETI) has dramatically improved respiratory outcomes in pwCF, airway inflammation and bacterial colonization persist in the upper and lower respiratory tracts. METHODS: We investigated the effect of ETI in both plasma and fresh primary nasal epithelial (HNE) cells obtained from pwCF pre- and post-three months of ETI treatment. Given that inflammation has been shown to upregulate NFKBIZ and the ATP12A proton pump, we measured their levels in fresh HNE cells and in cultured HNE cells exposed to clinical exoproducts (EXO) of P. aeruginosa or other inflammatory stimuli. RESULTS: ELISA analysis revealed a significant reduction of IL-6, IL-8, and IL-17C in both plasma and HNE cells after ETI treatment. NFKBIZ and ATP12A expression was increased after infection and inflammatory stimuli in CF bronchial epithelial (CFBE) and HNE cells, and this increase was reduced by Dimethyl-Fumarate, an anti-inflammatory drug. CONCLUSIONS: These preclinical studies, using patient-derived tissues, suggest that NFKBIZ and ATP12A may play a relevant role in the pathophysiology and inflammatory response of the CF airway epithelium.