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

Abstract

AbstractCystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. CFTR controls chloride (Cl-) and bicarbonate (HCO3-) transport into the Airway Surface Liquid (ASL).We investigated the impact of F508del-CFTR correction on HCO3-secretion by studying transepithelial HCO3-fluxes.HCO3-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 HCO3-transporters ofairway epithelia such asSLC26A4 (Pendrin), SLC26A9 and NBCe1.CFTR-mediated HCO3-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 HCO3-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 HCO3-transport werenot differentbetween F508del homozygous and F508del heterozygous CF airway epithelia.Our studies show that correction of F508del-CFTRHCO3-is not sufficient to buffer acidic ASL and that inflammation is a key regulator of HCO3-secretion in CF airways. Prediction of the response to CFTR modulators by theratyping should take into account airway inflammation.