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

Abstract

BackgroundThe 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.MethodsHere, 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.ResultsThe 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).ConclusionsOverall, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0614-x) contains supplementary material, which is available to authorized users.

Idiopathic Pulmonary Fibrosis: Novel Concepts of Proton Pump Inhibitors as Antifibrotic Drugs

“…Our preclinical in vivo study revealed that oral esomeprazole mitigates inflammatory and fibrotic responses (about 50% reduction of each parameter) in a rodent model of bleomycin-induced lung injury (47). Overall, the reported data from in vitro and in vivo studies demonstrating the beneficial role of PPIs on processes involved in lung inflammation and fibrogenesis suggest that PPIs, in contrast to antireflux surgery, may exert favorable effects in measures of lung function and survival in IPF through biological regulation of inflammatory and fibrotic processes rather than suppression of gastric reflux or microaspiration (Figure 3).…”

“…Our recent mechanistic study demonstrated that an archetype PPI, esomeprazole, possesses a pleiotropic salutary effect in regulating processes involved in the development and progression of lung inflammation and fibrosis (47). We demonstrated this effect of esomeprazole using in vitro studies of primary lung fibroblasts, endothelial and epithelial cells exposed to bleomycin or ionizing radiation.…”

Adjunctive Use of Esomeprazole in the Treatment of Pre-Eclampsia: A Case Report and Literature Review

“…[106] Esomeprazole has been observed to be antiinflammatory, anti-oxidant and anti-apoptotic via directly down-regulating ROS, upregulating the anti-oxidants nuclear factor 2-related factor-2 (Nrf 2 ) and heme oxygenase-I (HO-I). [107] In conclusion, case report points esomeprazole out as a drug that may contribute to a favourable forecast in the pre-eclampsia syndrome and safely attenuate the major ultrasonic and biochemical indices of pre-eclampsia. Appropriate national and international trials would delineate its place not only in the treatment but also in the prevention of pre-eclampsia and intra-uterine growth restriction (IUGR).…”

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“…However, esomeprazole is also found to control Inflammation, by suppressing the expression of pro-inflammatory molecules and vascular cell molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6) in cell culture studies. This function was identified, based on strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1), and the anti-fibrotic 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) 14 .…”