Conclusions
Taken together, PPIs may play antifibrotic role in IPF through direct regulation of the MAPK/Nrf2/HO1 pathway to favorably influence the disease process in IPF.
Methods
We stimulated oxidative stress, pro-inflammatory and profibrotic phenotypes in primary human lung epithelial cells and fibroblasts upon treatment with bleomycin or transforming growth factor β (TGFβ) and assessed the effect of a prototype PPI, esomeprazole, in regulating these processes.
Results
Our study shows that esomeprazole controls pro-inflammatory and profibrotic molecules through nuclear translocation of the transcription factor nuclear factor-like 2 (Nrf2) and induction of the cytoprotective molecule heme oxygenase 1 (HO1). Genetic deletion of Nrf2 or pharmacological inhibition of HO1 impaired esomeprazole-mediated regulation of proinflammatory and profibrotic molecules. Additional studies indicate that activation of Mitogen Activated Protein Kinase (MAPK) pathway is involved in the process. Our experimental data was corroborated by bioinformatics studies of an NIH chemical library which hosts gene expression profiles of IPF lung fibroblasts treated with over 20,000 compounds including esomeprazole. Intriguingly, we found 45 genes that are upregulated in IPF but downregulated by esomeprazole. Pathway analysis showed that these genes are enriched for profibrotic processes. Unbiased high throughput RNA-seq study supported antifibrotic effect of esomeprazole and revealed several novel targets. Conclusions: Taken together, PPIs may play antifibrotic role in IPF through direct regulation of the MAPK/Nrf2/HO1 pathway to favorably influence the disease process in IPF.