PGE2 and PGI2 restore defective lung epithelial progenitors induced by cigarette smoke

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. Lung organoids were set up by co-culturing epithelial cells (EpCAM+/CD45-/CD31-) with fibroblasts in Matrigel. Results: The transcriptomic-guided drug discovery strategy identified 15 targets expressed in alveolar progenitors that showed concordant regulation in CS exposed mice and in COPD patients. We screened these in CSE-exposed lung organoids and found PGE2 (target gene PTGES) and PGI2 (target gene PGIR) to show the most significant repair potential, completely restoring the reduced alveolar epithelial organoid number. Progenitors isolated from CS exposed murine lungs had significantly repressed organoid formation as well, and both in vivo and in vitro treatments with PGE2 (misoprostol)/PGI2 (iloprost) agonists restored this. For PGE2, the effects were mimicked by an EP4 agonist but not by an EP2 agonist. RNA-sequencing on the epithelial progenitors from mice exposed to air, CS, CS+misoprostol or CS+iloprost, showed differentially expressed gene signatures for circadian clock (downregulated) and cell cycle (upregulated) signaling pathways, which was prevented by in vivo misoprostol/iloprost treatment. Conclusion: Our findings are the first to identify the use of PGE2 and PGI2 analogues as a potential therapeutic strategy to improve defective lung repair in COPD.