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

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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 2years). 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.

Original languageEnglish (US)
Article number249
JournalJournal of Translational Medicine
Volume13
Issue number1
DOIs
StatePublished - Aug 1 2015
Externally publishedYes

Fingerprint

Esomeprazole
Idiopathic Pulmonary Fibrosis
Proton Pump Inhibitors
Pneumonia
Fibrosis
Transplants
Fibroblasts
Survival
Pulmonary diseases
Interstitial Lung Diseases
Bleomycin
Inflammation
Interleukin-1
Lung
Databases
Intestinal Diseases
Heme Oxygenase-1
Vascular Cell Adhesion Molecule-1
Acute Lung Injury
Interleukins

Keywords

  • Fibrosis
  • Inflammation
  • Oxidative stress
  • Proton pump inhibitors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ghebremariam, Y. T., Cooke, J. P., Gerhart, W., Griego, C., Brower, J. B., Doyle-Eisele, M., ... Rosen, G. D. (2015). Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. Journal of Translational Medicine, 13(1), [249]. https://doi.org/10.1186/s12967-015-0614-x

Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. / Ghebremariam, Yohannes T.; Cooke, John P.; Gerhart, William; Griego, Carol; Brower, Jeremy B.; Doyle-Eisele, Melanie; Moeller, Benjamin; Zhou, Qingtao; Ho, Lawrence; de Andrade, Joao; Raghu, Ganesh; Peterson, Leif; Rivera, Andreana; Rosen, Glenn D.

In: Journal of Translational Medicine, Vol. 13, No. 1, 249, 01.08.2015.

Research output: Contribution to journalArticle

Ghebremariam, YT, Cooke, JP, Gerhart, W, Griego, C, Brower, JB, Doyle-Eisele, M, Moeller, B, Zhou, Q, Ho, L, de Andrade, J, Raghu, G, Peterson, L, Rivera, A & Rosen, GD 2015, 'Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis', Journal of Translational Medicine, vol. 13, no. 1, 249. https://doi.org/10.1186/s12967-015-0614-x
Ghebremariam, Yohannes T. ; Cooke, John P. ; Gerhart, William ; Griego, Carol ; Brower, Jeremy B. ; Doyle-Eisele, Melanie ; Moeller, Benjamin ; Zhou, Qingtao ; Ho, Lawrence ; de Andrade, Joao ; Raghu, Ganesh ; Peterson, Leif ; Rivera, Andreana ; Rosen, Glenn D. / Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. In: Journal of Translational Medicine. 2015 ; Vol. 13, No. 1.
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AU - Ghebremariam, Yohannes T.

AU - Cooke, John P.

AU - Gerhart, William

AU - Griego, Carol

AU - Brower, Jeremy B.

AU - Doyle-Eisele, Melanie

AU - Moeller, Benjamin

AU - Zhou, Qingtao

AU - Ho, Lawrence

AU - de Andrade, Joao

AU - Raghu, Ganesh

AU - Peterson, Leif

AU - Rivera, Andreana

AU - Rosen, Glenn D.

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N2 - 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 2years). 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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