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Open Access | 10.1172/jci.insight.154719
1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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Stritt, M.
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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Blattmann, P.
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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White, E.
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America
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Nayler, O.
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Published December 15, 2022 - More info
In the progression phase of idiopathic pulmonary fibrosis (IPF) the normal alveolar structure of the lung is lost and replaced by remodeled fibrotic tissue and by bronchiolized cystic airspaces. Although these are characteristic features of IPF, knowledge of specific interactions between these pathological processes is limited. Here, the interaction of lung epithelial and lung mesenchymal cells was investigated in a co–culture model of human primary airway epithelial cells (EC) and lung fibroblasts (FB). Single–cell RNA sequencing (sc–RNA–seq) revealed that the starting EC population was heterogenous and enriched for cells with a basal cell signature. Furthermore, fractions of the initial EC and FB cell populations adopted distinct pro–fibrotic cell differentiation states upon co-cultivation, resembling specific cell populations that were previously identified in lungs of IPF patients. Transcriptomic analysis revealed active nuclear factor NF–kappa–B (NF–κB) signaling early in the co–cultured EC and FB cells and the identified NF–κB expression signatures were also found in “HAS1 High FB” and “PLIN2+ FB” populations from IPF patient lungs. Pharmacological blockade of NF–κB signaling attenuated specific phenotypic changes of EC and prevented FB–mediated interleukin–6 (IL6), interleukin–8 (IL–8) and C–X–C motif chemokine ligand 6 (CXCL6) cytokine secretion, as well as collagen alpha–1(I) chain (COL1A1) and alpha–smooth muscle actin (α–SMA) accumulation. Thus, we identified NF–κB as a potential mediator, linking epithelial pathobiology with fibrogenesis.