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 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-

• Chua, R. L.
• Veith, C.
• Schneider, M. A.
• Jechow, K.
• Kaufhold, G.
• Alkildani, S.
• Wild, M.
• Sudy, A.
• Xu, E. C.
• Kreuter, M.
• Boots, A.
• Eils, R.
• Kahn, N. C.
• Conrad, C.