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Transcriptomic signatures of IPF in ALI-cultured airway cells and their therapeutic implications

Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Most single-cell studies rely on end-stage explant lungs, leaving early disease mechanisms poorly understood. Profiling earlier stages may reveal distinct cellular phenotypes t...

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Hauptverfasser: Chua, Robert Lorenz (VerfasserIn) , Veith, Carmen (VerfasserIn) , Schneider, Marc (VerfasserIn) , Jechow, Katharina (VerfasserIn) , Kaufhold, Gelsomina (VerfasserIn) , Alkildani, Said (VerfasserIn) , Wild, Michelle (VerfasserIn) , Sudy, Alexander (VerfasserIn) , Chang Xu, Elizabeth (VerfasserIn) , Kreuter, Michael (VerfasserIn) , Boots, Agnes (VerfasserIn) , Eils, Roland (VerfasserIn) , Kahn, Nicolas (VerfasserIn) , Conrad, Christian (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: February 18, 2026
In: Thorax
Year: 2026, Pages: 1-12
ISSN:1468-3296
DOI:10.1136/thorax-2025-223325
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1136/thorax-2025-223325
Verlag, kostenfrei, Volltext: https://thorax.bmj.com/content/early/2026/02/17/thorax-2025-223325
Volltext
Verfasserangaben:Robert Lorenz Chua, Carmen Veith, Marc A. Schneider, Katharina Jechow, Gelsomina Kaufhold, Said Alkildani, Michelle Wild, Alexander Sudy, Elizabeth Chang Xu, Michael Kreuter, Agnes Boots, Roland Eils, Nicolas C. Kahn, Christian Conrad
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Zusammenfassung:Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Most single-cell studies rely on end-stage explant lungs, leaving early disease mechanisms poorly understood. Profiling earlier stages may reveal distinct cellular phenotypes that could be pharmacologically targeted. Recent evidence also implicates airway epithelial cells in IPF disease development and progression. - Methods To investigate early-stage IPF mechanisms, we profiled the airway mucosa of newly diagnosed, treatment-naïve patients using single-cell RNA-sequencing of air-liquid interface cultures. We further assessed the transcriptional and functional responses of these cells to antifibrotic drugs (nintedanib and pirfenidone) and a Src kinase inhibitor (saracatinib). - Results Profiling of 129 986 transcriptomes identified primed fibroblasts (PDGFRA+, SPP1+), dysregulated basal cells (TP63+, KRT5+, FN1+), and proinflammatory airway epithelial cells (SAA, CXCL, CCL). Integrative analyses with explant-derived IPF atlases revealed different basal and fibroblast phenotypes spanning tissue regions and disease stages. In vitro, bronchial epithelial cells stimulated fibroblast proliferation and activation, and fibroblasts remained sensitive to TGF-β. While all three drugs attenuated many IPF signatures, saracatinib most effectively suppressed fibroblast activation and epithelial proliferation. - Conclusions This study defines epithelial-mesenchymal programmes of the airway mucosa at an early, diagnostic stage of IPF and demonstrates distinct drug responses at single-cell resolution. By linking airway-derived phenotypes to antifibrotic efficacy, our findings highlight the therapeutic potential of saracatinib and may inform future treatment strategies.
Beschreibung:Gesehen am 13.04.2026
Beschreibung:Online Resource
ISSN:1468-3296
DOI:10.1136/thorax-2025-223325

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