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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 PPI esomeprazole regulates ionizing radiation-induced changes in gene expression in primary lung epithelial cells cultured in 3D matrix. In a inhibition of the spike in the pro-inflammatory cytokines TNF-α, NFκB and IL-6 is shown. b shows downregulation of the proapoptotic protein p53 and c shows the upregulation of the antioxidant gene HO1 by esomeprazole. Data is Mean ± SEM from duplicate experiments. *p < 0.05 compared to vehicle.
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Fig3: The PPI esomeprazole regulates ionizing radiation-induced changes in gene expression in primary lung epithelial cells cultured in 3D matrix. In a inhibition of the spike in the pro-inflammatory cytokines TNF-α, NFκB and IL-6 is shown. b shows downregulation of the proapoptotic protein p53 and c shows the upregulation of the antioxidant gene HO1 by esomeprazole. Data is Mean ± SEM from duplicate experiments. *p < 0.05 compared to vehicle.

Mentions: A typical cellular response to bleomycin or ionizing radiation is a burst in markers of inflammation [36, 37]. Interestingly, pre-incubation of primary lung epithelial cells with esomeprazole prior to exposure to ionizing radiation significantly (by about 50%; p < 0.05) suppressed the expression of pro-inflammatory markers including TNF-α, IL-6 and nuclear factor kappa B (NFκB) (Fig. 3a). Moreover, esomeprazole downregulated the expression of p53 (Fig. 3b) and upregulated the anti-inflammatory molecule HO1 (Fig. 3c) (p < 0.05 at 50 µM). Furthermore, pre-incubation of lung epithelial cells, fibroblasts or endothelial cells with esomeprazole substantially inhibited bleomycin-induced inflammatory response, as well as markers of fibrotic response including components of the TGFβ/MMP pathway (Fig. 4a–c). In addition, the expression of HO1 was increased in each of these lung cell types (Fig. 4d–f) (p < 0.05 at 50 µM).Fig. 3


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 PPI esomeprazole regulates ionizing radiation-induced changes in gene expression in primary lung epithelial cells cultured in 3D matrix. In a inhibition of the spike in the pro-inflammatory cytokines TNF-α, NFκB and IL-6 is shown. b shows downregulation of the proapoptotic protein p53 and c shows the upregulation of the antioxidant gene HO1 by esomeprazole. Data is Mean ± SEM from duplicate experiments. *p < 0.05 compared to vehicle.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: The PPI esomeprazole regulates ionizing radiation-induced changes in gene expression in primary lung epithelial cells cultured in 3D matrix. In a inhibition of the spike in the pro-inflammatory cytokines TNF-α, NFκB and IL-6 is shown. b shows downregulation of the proapoptotic protein p53 and c shows the upregulation of the antioxidant gene HO1 by esomeprazole. Data is Mean ± SEM from duplicate experiments. *p < 0.05 compared to vehicle.
Mentions: A typical cellular response to bleomycin or ionizing radiation is a burst in markers of inflammation [36, 37]. Interestingly, pre-incubation of primary lung epithelial cells with esomeprazole prior to exposure to ionizing radiation significantly (by about 50%; p < 0.05) suppressed the expression of pro-inflammatory markers including TNF-α, IL-6 and nuclear factor kappa B (NFκB) (Fig. 3a). Moreover, esomeprazole downregulated the expression of p53 (Fig. 3b) and upregulated the anti-inflammatory molecule HO1 (Fig. 3c) (p < 0.05 at 50 µM). Furthermore, pre-incubation of lung epithelial cells, fibroblasts or endothelial cells with esomeprazole substantially inhibited bleomycin-induced inflammatory response, as well as markers of fibrotic response including components of the TGFβ/MMP pathway (Fig. 4a–c). In addition, the expression of HO1 was increased in each of these lung cell types (Fig. 4d–f) (p < 0.05 at 50 µM).Fig. 3

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