Abstract
Cystic fibrosis (CF) lung disease is characterized by the presence of marked, neutrophil-dominant inflammation that contributes to tissue injury and the development of irreversible structural lung disease. Here, we describe a dysregulated, neutrophil-dominant inflammation and an accompanying pro-inflammatory airway epithelium in the pediatric CF lung through the application of single-cell RNA sequencing (scRNA-seq) to minimally invasive respiratory specimens collected during flexible bronchoscopy. These findings were present in both an infant and an adolescent with CF, the latter on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, suggesting a common pathological program that starts early in life and may be challenging to reverse once structural lung disease is established. Intercellular communication network analysis further revealed potential mechanisms whereby airway epithelial cells modulate the ongoing, destructive airway inflammation present in the CF lung. Importantly, the scRNA-seq workflow leveraged in this study provides a unique opportunity to investigate and monitor disease-related changes in the composition, function, and interaction of the immune and airway epithelial cell populations in CF and other respiratory diseases across the life course.
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Data availability
Raw FASTQ and processed matrix data that support the findings of this study have been deposited in the National Center for Biotechnology Information’s Gene Expression Omnibus at the National Institutes of Health with the accession number GSE271984. Additional data and code required to analyze the results and generate the figures included in this manuscript are available from the corresponding authors upon reasonable request.
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Acknowledgements
We would like to thank our pediatric patients and their families for their generous participation in this study, and we would like to thank the Cystic Fibrosis Center at Lenox Hill Hospital/Northwell Health for graciously entrusting us with the care of their pediatric patients with CF. We would additionally like to thank the Genomics Core Facility and the Mount Sinai Biorepository at the Icahn School of Medicine at Mount Sinai for their essential contributions.
Funding
This work was supported by the Cystic Fibrosis Foundation (JANUSK21D0; awarded to MNJ) as well as the National Center for Advancing Translational Sciences (KL2TR004421; awarded to MNJ) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118946; awarded to MJW) at the National Institutes of Health.
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YS: Methodology, investigation, data curation, formal analysis, visualization, and writing – review and editing; AGV: Writing – review and editing and resources; MBB: Writing – review and editing; MJW: Supervision, methodology, writing – review and editing, funding acquisition, and resources; and MNJ: Conceptualization, methodology, investigation, visualization, writing – original draft, writing – review and editing, funding acquisition, and resources.
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Sun, Y., Vicencio, A.G., Beasley, M.B. et al. The single-cell transcriptional landscape of the pediatric cystic fibrosis lung from minimally invasive respiratory specimens. Sci Rep (2026). https://doi.org/10.1038/s41598-026-36125-w
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DOI: https://doi.org/10.1038/s41598-026-36125-w
