Elexacaftor/Tezacaftor/Ivacaftor Disrupts Respiratory Tract Development in a Murine Fetal Lung Explant Model

• Published in: American journal of respiratory cell and molecular biology Vol. 67; no. 6; pp. 723 - 726
• Main Authors: Lhuillier, Mickaël, Aoust, Laura, Dreano, Elise, Franco-Montoya, Marie-Laure, Landry-Truchon, Kim, Houde, Nicolas, Chhun, Stéphanie, Hinzpeter, Alexandre, Edelman, Aleksander, Delacourt, Christophe, Jeannotte, Lucie, Sermet-Gaudelus, Isabelle, Hadchouel, Alice
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.12.2022
• Subjects: Animals; Chronic obstructive pulmonary disease; Correspondence; Developmental stages; Epithelium; Fetuses; Heterozygosity; Kidneys; Lung; Lung cancer; Lung diseases; Medical screening; Mice; Morphogenesis; Neonates; Obstructive lung disease; Pyrazoles; Respiratory function; Respiratory tract; Smoking
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/RCMB.2022-0175LE

We demonstrate that acute exposure to ETI has a detrimental effect on lung branching and causes aberrant terminal dilations during the pseudoglandular stage of lung development. Our findings indicate that, as seen in the kidney epithelium, the pharmacological activation of WT CFTR may cause changes in lung branching and the development of epithelial cyst-like structures via increasing fluid secretion. This would combine excessive and ongoing activation of both the WT and the corrected F508 del CFTR in the context of F508 del heterozygosity. Our findings imply that bronchial morphogenesis pathways may be affected by ETI exposure during lung development. Prematurity and maternal smoking, which are linked to aberrant lung growth and a risk of chronic obstructive pulmonary disease in adulthood, demonstrate how antenatal exposure may influence the future lung function trajectories of healthy heterozygous carrier newborns with expression later in life (17). These results support close monitoring of such pregnancies and postpartum monitoring of the ensuing youngsters.