TY - JOUR
T1 - Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis
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 C.
AU - Zhou, Qingtao
AU - Ho, Lawrence
AU - de Andrade, Joao
AU - Raghu, Ganesh
AU - Peterson, Leif
AU - Rivera, Andreana
AU - Rosen, Glenn D.
N1 - Funding Information:
YTG was a recipient of the Stanford School of Medicine Dean’s fellowship (grant number 1049528‑149‑ KAVFB) and the Tobacco‑Related Disease Research Program of the University of California (grant number 20FT‑0090). He is currently supported by the National Institutes of Health National Heart, Lung, and Blood Institute (grant number 5K01HL118683) and by intramural funding from the Houston Methodist Research Institute (project ID 25150001). YTG and JPC acknowledge support from the Stanford SPARK Translational Research Program. JA is supported by the National Institutes of Health National Heart, Lung, and Blood Institute (grant number P01HL114470).
Funding Information:
We are grateful to Ms. Yuelan Ren and Houston Methodist Hospital’s Research Pathology Core for assistance with immunohistochemical studies. We also thank Dr. Tej Pandita’s lab in the Department of Radiation Oncology at Houston Methodist for allowing us to use their X‑ray machine for irradia‑ tion studies. This project was supported by the Genomic and RNA Profiling Core (G.A.R.P.) at Baylor College of Medicine and the expert assistance of the Core Director Dr. Lisa D. White, Ph.D. in our microarray study. We also thank the Methodist Hospital’s Center for Biostatistics for analysis of the microarray data. Finally, we are grateful to Houston Methodist Research Institute (HMRI), Stanford University Cardiovascular Institute (CVI) and the Division of Pulmo‑ nary Medicine as well as the Lovelace Respiratory Research Institute (LRRI) for overall support and Ms. Julie Hutt at LRRI for her assistance with histopathol‑ ogy needs of the project.
Publisher Copyright:
© 2015 Ghebremariam et al.
PY - 2015/8/1
Y1 - 2015/8/1
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.
AB - 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.
KW - Fibrosis
KW - Inflammation
KW - Oxidative stress
KW - Proton pump inhibitors
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U2 - 10.1186/s12967-015-0614-x
DO - 10.1186/s12967-015-0614-x
M3 - Article
C2 - 26231702
AN - SCOPUS:84938094276
VL - 13
JO - Journal of Translational Medicine
JF - Journal of Translational Medicine
SN - 1479-5876
IS - 1
M1 - 249
ER -