%0 Journal Article %A N Lang %A M Ansari %A D Porras-Gonzalez %A A Agami %A B Hooshiar Kashani %A S Zhou %A L Yang %A M Gerckens %A X Wei %A C H Mayr %A J Schniering %A M Stoleriu %A R Hatz %A J Behr %A G Burgstaller %A H B Schiller %T Ex vivo modelling of human lung fibrogenesis and drug mode of action screens using single-cell RNA-seq in precision-cut lung slices %D 2022 %R 10.1183/13993003.congress-2022.LSC-0072 %J European Respiratory Journal %P LSC-0072 %V 60 %N suppl 66 %X IPF is a lethal chronic lung disease characterized by progressive alveolar fibrogenesis. There are currently no effective therapies that halt or reverse IPF progression underlining the need for better disease models to facilitate drug testing. Human precision-cut lung slices (hPCLS) treated with a pro-fibrotic cytokine mix (fibrotic cocktail - FC) are a promising new ex vivo model of human lung fibrogenesis (Alsafadi et al. AJP Lung, 2017). Here we investigate at single-cell resolution which aspects of in vivo IPF pathogenesis can be modelled in hPCLS in order to apply drug mode of action screens.We performed single-cell RNA-seq of hPCLS treated with FC, FC+Nintedanib (clinically approved drug) or FC+CMP4 (novel drug candidate). First, we compared our ex vivo data against in vivo data from an integrated IPF cell atlas. Second, drug mode of actions were dissected systematically using Differential Gene Expression and Gene Set Enrichtment analysis.Analysis of 23,000 cells revealed that FC induces characteristic cell state shifts that are key cellular hallmarks of IPF lungs (Adams, Schupp et al. Sci Adv, 2020) including the induction of myofibroblasts, aberrant basaloid and ectopic endothelial cells. We identify drug specific effects on these IPF associated cell states and describe drug effects on specific cell-cell communication routes within the fibrogenic niche of human lung parenchyma.In summary, our study validates hPCLS as a powerful ex vivo model that recapitulates aspects of IPF pathogenesis and demonstrates its potential for scalable, high-resolution drug testing.FootnotesCite this article as Eur Respir J 2022; 60: Suppl. 66, LSC-0072.This article was presented at the 2022 ERS International Congress, in session “-”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only). %U