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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2015

Open Access 01-12-2015 | Research

Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis

Authors: Yohannes T Ghebremariam, John P Cooke, William Gerhart, Carol Griego, Jeremy B Brower, Melanie Doyle-Eisele, Benjamin C Moeller, Qingtao Zhou, Lawrence Ho, Joao de Andrade, Ganesh Raghu, Leif Peterson, Andreana Rivera, Glenn D Rosen

Published in: Journal of Translational Medicine | Issue 1/2015

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Abstract

Background

The beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (IPF) has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated.

Methods

Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and fibrosis. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and fibrosis. In addition, we cultured lung fibroblasts from IPF patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease (ILD) databases to examine the effect of PPIs on transplant-free survival.

Results

The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6). The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1) and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor β (TGFβ), fibronectin and matrix metalloproteinases (MMPs). Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in IPF patients. Intriguingly, this data demonstrated that IPF patients on PPIs had prolonged survival over controls (median survival of 3.4 vs 2 years).

Conclusions

Overall, these data indicate the possibility that PPIs may have protective function in IPF by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.
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Metadata
Title
Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis
Authors
Yohannes T Ghebremariam
John P Cooke
William Gerhart
Carol Griego
Jeremy B Brower
Melanie Doyle-Eisele
Benjamin C Moeller
Qingtao Zhou
Lawrence Ho
Joao de Andrade
Ganesh Raghu
Leif Peterson
Andreana Rivera
Glenn D Rosen
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2015
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-015-0614-x

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