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

Ghebremariam YT, Cooke JP, Gerhart W, Griego C, Brower JB, Doyle-Eisele M, Moeller BC, Zhou Q, Ho L, de Andrade J, Raghu G, Peterson L, Rivera A, Rosen GD - J Transl Med (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave, R10-111, Houston, TX, 77030, USA. ytghebremariam@tmhs.org.

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.

No MeSH data available.


Related in: MedlinePlus

The effect of esomeprazole on a lung fibroblast and b alveolar epithelial cell proliferation. Cells were synchronized and then serum-stimulated to induce proliferation in the presence of vehicle or esomeprazole (5–50 µM). Incorporation of BrdU into newly synthesized DNA was quantified spectrophotometrically. Data is Mean ± SEM from duplicate experiments. *p < 0.05 compared to vehicle. BrdU Bromodeoxyuridine.
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Fig2: The effect of esomeprazole on a lung fibroblast and b alveolar epithelial cell proliferation. Cells were synchronized and then serum-stimulated to induce proliferation in the presence of vehicle or esomeprazole (5–50 µM). Incorporation of BrdU into newly synthesized DNA was quantified spectrophotometrically. Data is Mean ± SEM from duplicate experiments. *p < 0.05 compared to vehicle. BrdU Bromodeoxyuridine.

Mentions: Hyperplasia of alveolar epithelial (ATII) cells, although inconclusive, is reported to be pathologically involved in lung fibrosis through the process of epithelial-to-mesenchymal transition (EMT) [33, 34]; by serving as precursor cells for fibroblast-driven fibrosis. In addition, over-proliferation of fibroblasts contributes to pathological deposition of extracellular matrix in the lungs [35]. In this study, we found that esomeprazole dose-dependently attenuated serum-induced proliferation of both lung fibroblasts (by about 50% at 50 µM; p < 0.05) and epithelial cells (by over 90% at 50 µM; p < 0.05), as demonstrated by reduced BrdU incorporation into newly synthesized DNA (Fig. 2). These effects of esomeprazole occurred at doses that were not associated with cytotoxicity. Specifically, we treated lung fibroblasts and epithelial cells with increasing concentration of esomeprazole for 24 h and studied the release of lactate dehydrogenase (LDH) into the conditioned media. Treatment with esomeprazole at concentrations significantly higher than used in the proliferation assay was not associated with cytotoxicity (Additional file 1: Figure S1).Fig. 2


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

Ghebremariam YT, Cooke JP, Gerhart W, Griego C, Brower JB, Doyle-Eisele M, Moeller BC, Zhou Q, Ho L, de Andrade J, Raghu G, Peterson L, Rivera A, Rosen GD - J Transl Med (2015)

The effect of esomeprazole on a lung fibroblast and b alveolar epithelial cell proliferation. Cells were synchronized and then serum-stimulated to induce proliferation in the presence of vehicle or esomeprazole (5–50 µM). Incorporation of BrdU into newly synthesized DNA was quantified spectrophotometrically. Data is Mean ± SEM from duplicate experiments. *p < 0.05 compared to vehicle. BrdU Bromodeoxyuridine.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522053&req=5

Fig2: The effect of esomeprazole on a lung fibroblast and b alveolar epithelial cell proliferation. Cells were synchronized and then serum-stimulated to induce proliferation in the presence of vehicle or esomeprazole (5–50 µM). Incorporation of BrdU into newly synthesized DNA was quantified spectrophotometrically. Data is Mean ± SEM from duplicate experiments. *p < 0.05 compared to vehicle. BrdU Bromodeoxyuridine.
Mentions: Hyperplasia of alveolar epithelial (ATII) cells, although inconclusive, is reported to be pathologically involved in lung fibrosis through the process of epithelial-to-mesenchymal transition (EMT) [33, 34]; by serving as precursor cells for fibroblast-driven fibrosis. In addition, over-proliferation of fibroblasts contributes to pathological deposition of extracellular matrix in the lungs [35]. In this study, we found that esomeprazole dose-dependently attenuated serum-induced proliferation of both lung fibroblasts (by about 50% at 50 µM; p < 0.05) and epithelial cells (by over 90% at 50 µM; p < 0.05), as demonstrated by reduced BrdU incorporation into newly synthesized DNA (Fig. 2). These effects of esomeprazole occurred at doses that were not associated with cytotoxicity. Specifically, we treated lung fibroblasts and epithelial cells with increasing concentration of esomeprazole for 24 h and studied the release of lactate dehydrogenase (LDH) into the conditioned media. Treatment with esomeprazole at concentrations significantly higher than used in the proliferation assay was not associated with cytotoxicity (Additional file 1: Figure S1).Fig. 2

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave, R10-111, Houston, TX, 77030, USA. ytghebremariam@tmhs.org.

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.

No MeSH data available.


Related in: MedlinePlus