TY - JOUR T1 - PGE2 and PGI2 restore defective lung epithelial progenitors induced by cigarette smoke JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.congress-2020.4785 VL - 56 IS - suppl 64 SP - 4785 AU - Xinhui Wu AU - Sophie Bos AU - Lars Verkleij AU - Angela D’Ambrosi AU - Martina Schmidt AU - Loes Kiestemaker AU - Reinoud Gosens Y1 - 2020/09/07 UR - http://erj.ersjournals.com/content/56/suppl_64/4785.abstract N2 - Background: COPD is characterized by irreversible airflow limitation and emphysema development associated with defective lung repair. Currently, there is no pharmacological treatment targeting lung repair in COPD.Methods: 2 microarray datasets of lung tissue from CS exposed mice and COPD patients were analyzed to select potential novel drug targets for lung repair. Murine lung organoids were set up by co-culturing epithelial cells (EpCAM+/CD45-/CD31-) with CCL206 fibroblasts in Matrigel.Results: Several common genes and pathways were identified in the experimental CS model and COPD patients. 38 upregulated and 30 downregulated genes were identified that showed concordant regulation in CS exposed mice and in COPD patients. We further filtered these genes for expression in alveolar epithelial type II cells and fibroblasts and for their potential as drug targets, yielding 19 targets which we screened in CSE-exposed lung organoids. 6 targets showed potential as drug targets for repair including PGE2 (target gene PTGES) and PGI2 (target gene PGIR), both of which completely restored the reduced alveolar epithelial organoid number in response to CSE. Progenitors isolated from CS exposed murine lungs had significantly repressed organoid formation; however, both in vivo and in vitro treatment with PGE2 (misoprostol)/PGI2 (iloprost) agonists restored organoid numbers. For PGE2, the effects were mimicked by an EP4 agonist but not by an EP2 agonist.Conclusion: A transcriptomics-guided drug discovery strategy yielded 6 potential targets that potentially restore lung repair. Of these, PGE2 and PGI2 had the most significant therapeutic potential in correcting the response to CS both in vitro and in vivo.FootnotesCite this article as: European Respiratory Journal 2020; 56: Suppl. 64, 4785.This abstract was presented at the 2020 ERS International Congress, in session “Respiratory viruses in the "pre COVID-19" era”.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). ER -