Putting bicarbonate on the spot: pharmacological insights for CFTR correction in the airway epithelium

Miroslaw Zajac; Agathe Lepissier; Elise Dréano; Benoit Chevalier; Aurélie Hatton; Mairead Kelly-Aubert; Daniela Guidone; Gabrielle Planelles; Aleksander Edelman; Emmanuelle Girodon; Alexandre Hinzpeter; Gilles Crambert; Iwona Pranke; Luis J V Galietta; Isabelle Sermet-Gaudelus

doi:10.3389/fphar.2023.1293578

Putting bicarbonate on the spot: pharmacological insights for CFTR correction in the airway epithelium

Front Pharmacol. 2023 Dec 11:14:1293578. doi: 10.3389/fphar.2023.1293578. eCollection 2023.

Authors

Miroslaw Zajac^{1

2

3

4}, Agathe Lepissier^{1

2

3}, Elise Dréano^{1

2

3}, Benoit Chevalier^{1

2

3}, Aurélie Hatton^{1

2

3}, Mairead Kelly-Aubert^{1

2

3}, Daniela Guidone⁵, Gabrielle Planelles⁶, Aleksander Edelman^{1

2

3}, Emmanuelle Girodon^{2

7}, Alexandre Hinzpeter^{1

2

3}, Gilles Crambert⁶, Iwona Pranke^{1

2

3}, Luis J V Galietta⁵, Isabelle Sermet-Gaudelus^{1

2

3

8}

Affiliations

¹ INSERM U1151, Institut Necker Enfants Malades, Paris, France.
² Université de Paris-Cité, Paris, France.
³ Centre de Référence Maladie Rare Pour La Mucoviscidose et Maladies de CFTR, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France.
⁴ Department of Physics and Biophysics, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland.
⁵ Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
⁶ U1138/CNRS ERL 8228, Centre de Recherche des Cordeliers, Paris, France.
⁷ Service de Médecine Génomique des Maladies de Système et d'Organe, Hôpital Cochin, Paris, France.
⁸ European Reference Network for Rare Diseases, Frankfurt, Belgium.

Abstract

Introduction: Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) proteins. 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. Methods: HCO₃ ^- secretion was measured by pH-stat technique in primary human respiratory epithelial cells from healthy subjects (WT) and people with CF (pwCF) carrying at least one F508del 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 correlated to ASL pH and transcriptional levels of CFTR and other HCO₃ ^- transporters of airway epithelia such as SLC26A4 (Pendrin), SLC26A9 and NBCe1. Results: CFTR-mediated HCO₃ ^- secretion was not detected in F508del primary human respiratory epithelial cells. It was rescued up to ∼ 80% of the WT level by VX-445/661/770. In contrast, TNF-α+IL-17 normalized transepithelial HCO₃ ^- transport and increased ASL pH. This was related to an increase 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 were not different between F508del homozygous and F508del compound heterozygous CF airway epithelia. Conclusion: Our studies show that correction of F508del-CFTR HCO₃ ^- is not sufficient to buffer acidic ASL and 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.

Keywords: TRIKAFTA; bicarbonate; cystic fibrosis transmembrane conductance regulator; inflammation; ion transport across membrane.

Grants and funding

The authors declare that financial support was received for the research, authorship, and/or publication of this article. This research was funded by the Vertex Innovation Award-2017 cycle, The Association ABCF, and the Vaincre La Mucoviscidose - RC20200502648-2020 Award (Correction du transport de chlorure et de bicarbonate au sein de l'épithélium respiratoire par les modulateurs de CFTR). Application aux mutants rares et perspectives thérapeutiques). MZ was financed by the Polish National Agency for Academic Exchange within the Bekker Program no. BPN/BEK/2021/1/00284 and by the National Science Center (NCN), Poland, no. 2019/35/B/NZ1/02546.