Putting Bicarbonate on the spot. Implication for theratyping in Cystic Fibrosis

This is the authors' abstract. We don't add key points for this paper.

Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. CFTR controls chloride (Cl - ) and bicarbonate (HCO 3 - ) transport into the Airway Surface Liquid (ASL).We investigated the impact of F508del-CFTR correction on HCO 3 - secretion by studying transepithelial HCO 3 - fluxes. HCO 3 - secretion was measured by pH-stat techniquein primary human respiratory epithelial cells from healthy subjects (WT) and people with CF (pwCF)carrying at least oneF508del variant.Its changes after CFTR modulation by the triple combination VX445/661/770 and in the context of TNF-α+IL-17 induced inflammation were related to ASL pH and transcriptionnal levels of CFTRand other HCO 3 - transporters ofairway epithelia such asSLC26A4 (Pendrin), SLC26A9 and NBCe1. CFTR-mediated HCO 3 - secretion was not detected in F508del primary human respiratory epithelial cells. It was rescued up to ∼ 80% of the WT levelby VX-445/661/770. In contrast,TNF-α+IL-17 normalized transepithelial HCO 3 - transportand ASL acidic pH. This was related to anincrease in SLC26A4 and CFTR transcript levels.VX-445/661/770 induced an increase in pH only in the context of inflammation.Effects on HCO 3 - transport werenot differentbetween F508del homozygous and F508del heterozygous CF airway epithelia. Our studies show that correction of F508del-CFTRHCO 3 - is not sufficient to buffer acidic ASL and that inflammation is a key regulator of HCO 3 - secretion in CF airways. Prediction of the response to CFTR modulators by theratyping should take into account airway inflammation.