Limits...
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

Sirius Red (collagen) stained lung sections showing the degree of accumulation of collagen fibers in lung tissue. Pulmonary fibrosis was induced by intra-tracheal instillation of bleomycin sulfate. The animals were treated with vehicle or low dose esomeprazole (prophylactic) for up to 28 days prior to harvesting and staining for collagen. Treatment with esomeprazole effectively prevented the accumulation of collagen compared to vehicle treatment as shown. Lower panel shows average lung fibrosis score of 10 animals per group. No bleomycin sham group was included as control. *p < 0.05 compared to vehicle. Representative images are shown.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig7: Sirius Red (collagen) stained lung sections showing the degree of accumulation of collagen fibers in lung tissue. Pulmonary fibrosis was induced by intra-tracheal instillation of bleomycin sulfate. The animals were treated with vehicle or low dose esomeprazole (prophylactic) for up to 28 days prior to harvesting and staining for collagen. Treatment with esomeprazole effectively prevented the accumulation of collagen compared to vehicle treatment as shown. Lower panel shows average lung fibrosis score of 10 animals per group. No bleomycin sham group was included as control. *p < 0.05 compared to vehicle. Representative images are shown.

Mentions: Subsequent to the robust anti-inflammatory and anti-fibrotic property of esomeprazole demonstrated in vitro, we examined these properties in vivo in an animal model characterized by inflammation and fibrosis (i.e. the bleomycin-induced acute lung injury model). Daily administration of esomeprazole starting 2 days after the induction of lung injury by bleomycin yielded dose dependent drug levels in the plasma and lung tissue (Additional file 1: Table S1) and resulted in robust suppression of inflammation (Fig. 6) and fibrotic changes (Fig. 7) to the lungs including maintenance of normal lung tissue with no microscopically detectable lesions in 35% of the animals in the low dose esomeprazole group and in 20% of the animals that received the high dose of esomeprazole. The overall inflammation and fibrosis score is shown as Table 2. In addition, stainings of the lung tissues for the smooth muscle cell marker alpha smooth muscle actin (α-SMA) and the extracellular matrix component Collagen type 1 (Collagen 1) showed that treatment with prophylactic esomeprazole reduced their expression levels (Additional file 1: Table S2). Furthermore, there was trend towards reduced levels of soluble collagen in the BALF and lung homogenates in the prophylactic esomeprazole group (Additional file 1: Figure S3).Fig. 6


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)

Sirius Red (collagen) stained lung sections showing the degree of accumulation of collagen fibers in lung tissue. Pulmonary fibrosis was induced by intra-tracheal instillation of bleomycin sulfate. The animals were treated with vehicle or low dose esomeprazole (prophylactic) for up to 28 days prior to harvesting and staining for collagen. Treatment with esomeprazole effectively prevented the accumulation of collagen compared to vehicle treatment as shown. Lower panel shows average lung fibrosis score of 10 animals per group. No bleomycin sham group was included as control. *p < 0.05 compared to vehicle. Representative images are shown.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig7: Sirius Red (collagen) stained lung sections showing the degree of accumulation of collagen fibers in lung tissue. Pulmonary fibrosis was induced by intra-tracheal instillation of bleomycin sulfate. The animals were treated with vehicle or low dose esomeprazole (prophylactic) for up to 28 days prior to harvesting and staining for collagen. Treatment with esomeprazole effectively prevented the accumulation of collagen compared to vehicle treatment as shown. Lower panel shows average lung fibrosis score of 10 animals per group. No bleomycin sham group was included as control. *p < 0.05 compared to vehicle. Representative images are shown.
Mentions: Subsequent to the robust anti-inflammatory and anti-fibrotic property of esomeprazole demonstrated in vitro, we examined these properties in vivo in an animal model characterized by inflammation and fibrosis (i.e. the bleomycin-induced acute lung injury model). Daily administration of esomeprazole starting 2 days after the induction of lung injury by bleomycin yielded dose dependent drug levels in the plasma and lung tissue (Additional file 1: Table S1) and resulted in robust suppression of inflammation (Fig. 6) and fibrotic changes (Fig. 7) to the lungs including maintenance of normal lung tissue with no microscopically detectable lesions in 35% of the animals in the low dose esomeprazole group and in 20% of the animals that received the high dose of esomeprazole. The overall inflammation and fibrosis score is shown as Table 2. In addition, stainings of the lung tissues for the smooth muscle cell marker alpha smooth muscle actin (α-SMA) and the extracellular matrix component Collagen type 1 (Collagen 1) showed that treatment with prophylactic esomeprazole reduced their expression levels (Additional file 1: Table S2). Furthermore, there was trend towards reduced levels of soluble collagen in the BALF and lung homogenates in the prophylactic esomeprazole group (Additional file 1: Figure S3).Fig. 6

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