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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

Hierarchical clustering of over 700 genes that are significantly regulated during the process of lung inflammation and fibrosis. Total RNA was extracted from the lungs of bleomycin-injured animals that received vehicle or esomeprazole (prophylactic or therapeutic course) treatment. Subsequent Genechip microarray analysis of the rat exon revealed that several transcripts are differentially regulated by esomeprazole and the prophylactic esomeprazole treatment group closely clustered with uninjured sham group. S sham, P prophylactic esomeprazole, V vehicle, T therapeutic esomeprazole.
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Fig10: Hierarchical clustering of over 700 genes that are significantly regulated during the process of lung inflammation and fibrosis. Total RNA was extracted from the lungs of bleomycin-injured animals that received vehicle or esomeprazole (prophylactic or therapeutic course) treatment. Subsequent Genechip microarray analysis of the rat exon revealed that several transcripts are differentially regulated by esomeprazole and the prophylactic esomeprazole treatment group closely clustered with uninjured sham group. S sham, P prophylactic esomeprazole, V vehicle, T therapeutic esomeprazole.

Mentions: Here, we carried out unbiased and comprehensive interrogation of signaling pathways involved in the regulation of lung inflammation and fibrosis and how these pathways are affected by esomeprazole. We conducted GeneChip array of lung tissue homogenates using a bioanalyzer as described above. Intriguingly, cluster analysis of the rat exon revealed that several signaling pathways that are known to be involved in inflammation and fibrosis including members of the Collagen family (such as Col1α2, Col3α1, Col16α1), fibronectin (FN1) and MMPs (MMP12) are regulated by esomeprazole. Interestingly, the cluster analysis of over 700 significantly regulated genes (by twofold or more at p < 0.05) indicates that prophylactic regimen of esomeprazole treatment closely resembled the gene expression signature of the uninjured sham controls (Fig. 10). Meanwhile, we also identified novel transcripts that are differentially regulated by the PPI (Additional file 1: Figure S7). One of the genes that is significantly downregulated by PPI treatment was gremlin 1 (GREM 1). Recent studies indicate that GREM1 is an endogenous inhibitor of Bone Morphogenetic Proteins (BMPs; BMP-2, BMP-4 and BMP-7) and is highly upregulated in fibrotic diseases including in IPF [39–41].Fig. 10


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)

Hierarchical clustering of over 700 genes that are significantly regulated during the process of lung inflammation and fibrosis. Total RNA was extracted from the lungs of bleomycin-injured animals that received vehicle or esomeprazole (prophylactic or therapeutic course) treatment. Subsequent Genechip microarray analysis of the rat exon revealed that several transcripts are differentially regulated by esomeprazole and the prophylactic esomeprazole treatment group closely clustered with uninjured sham group. S sham, P prophylactic esomeprazole, V vehicle, T therapeutic esomeprazole.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig10: Hierarchical clustering of over 700 genes that are significantly regulated during the process of lung inflammation and fibrosis. Total RNA was extracted from the lungs of bleomycin-injured animals that received vehicle or esomeprazole (prophylactic or therapeutic course) treatment. Subsequent Genechip microarray analysis of the rat exon revealed that several transcripts are differentially regulated by esomeprazole and the prophylactic esomeprazole treatment group closely clustered with uninjured sham group. S sham, P prophylactic esomeprazole, V vehicle, T therapeutic esomeprazole.
Mentions: Here, we carried out unbiased and comprehensive interrogation of signaling pathways involved in the regulation of lung inflammation and fibrosis and how these pathways are affected by esomeprazole. We conducted GeneChip array of lung tissue homogenates using a bioanalyzer as described above. Intriguingly, cluster analysis of the rat exon revealed that several signaling pathways that are known to be involved in inflammation and fibrosis including members of the Collagen family (such as Col1α2, Col3α1, Col16α1), fibronectin (FN1) and MMPs (MMP12) are regulated by esomeprazole. Interestingly, the cluster analysis of over 700 significantly regulated genes (by twofold or more at p < 0.05) indicates that prophylactic regimen of esomeprazole treatment closely resembled the gene expression signature of the uninjured sham controls (Fig. 10). Meanwhile, we also identified novel transcripts that are differentially regulated by the PPI (Additional file 1: Figure S7). One of the genes that is significantly downregulated by PPI treatment was gremlin 1 (GREM 1). Recent studies indicate that GREM1 is an endogenous inhibitor of Bone Morphogenetic Proteins (BMPs; BMP-2, BMP-4 and BMP-7) and is highly upregulated in fibrotic diseases including in IPF [39–41].Fig. 10

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