Esomeprazole attenuates inflammatory and fibrotic response in lung cells through the MAPK/Nrf2/HO1 pathway.

Autor: Ebrahimpour A; Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Wang M; Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Li L; Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Jegga AG; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA., Bonnen MD; Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Eissa NT; Department of Medicine, Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, 77030, USA., Raghu G; Division of Pulmonary and Critical Care Medicine, Center for Interstitial Lung Disease, University of Washington, Seattle, Washington, 98195, USA., Jyothula S; Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Kheradmand F; Department of Medicine, Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, 77030, USA., Hanania NA; Department of Medicine, Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, 77030, USA., Rosas IO; Department of Medicine, Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, 77030, USA., Ghebre YT; Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. yohannes.ghebre@bcm.edu.; Department of Medicine, Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. yohannes.ghebre@bcm.edu.
Jazyk: angličtina
Zdroj: Journal of inflammation (London, England) [J Inflamm (Lond)] 2021 May 19; Vol. 18 (1), pp. 17. Date of Electronic Publication: 2021 May 19.
DOI: 10.1186/s12950-021-00284-6
Abstrakt: Introduction: Idiopathic pulmonary fibrosis (IPF) is an orphan disease characterized by progressive loss of lung function resulting in shortness of breath and often death within 3-4 years of diagnosis. Repetitive lung injury in susceptible individuals is believed to promote chronic oxidative stress, inflammation, and uncontrolled collagen deposition. Several preclinical and retrospective clinical studies in IPF have reported beneficial outcomes associated with the use of proton pump inhibitors (PPIs) such as esomeprazole. Accordingly, we sought to investigate molecular mechanism(s) by which PPIs favorably regulate the disease process.
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.
Databáze: MEDLINE
Externí odkaz: