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

Ghebremariam, Yohannes T.; Cooke, John P.; Gerhart, William; Griego, Carol; Brower, Jeremy; Doyle-Eisele, Melanie; Moeller, Benjamin C.; Zhou, Qingtao; Ho, Lawrence; Andrade, Joao de; Raghu, Ganesh; Peterson, Leif E.; Rivera, Andreana L.; Rosen, Glenn D.

doi:10.1186/s12967-015-0614-x

Cited by 112 publications

(132 citation statements)

References 90 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…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).…”

Section: Ppis and Their Emerging Antiinflammatory-antifibrotic Rolementioning

confidence: 82%

“…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.…”

Section: Ppis and Their Emerging Antiinflammatory-antifibrotic Rolementioning

confidence: 93%

See 1 more Smart Citation

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

Ghebre

Raghu

2016

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

The prevalence of abnormal acid gastroesophageal reflux (GER) is higher in patients with idiopathic pulmonary fibrosis (IPF) than in matched control subjects. Several studies demonstrated that more than one-third of patients with IPF have abnormal esophageal acid exposures. In addition, many of these studies indicate that the majority of patients with IPF have silent reflux with no symptoms of GER. Findings of abnormal reflux persist in a large proportion of patients with IPF placed on antacid therapy such as proton pump inhibitors (PPIs). This seemingly paradoxical observation suggests that either patients with IPF are somehow resistant to PPI-based intervention or PPIs are inherently unable to suppress acid GER. By contrast, patients with IPF who undergo Nissen fundoplication surgery are effectively relieved from the complications of GER, and retrospective studies suggest improved lung function. Retrospective, anecdotal data suggest a beneficial role of PPIs in IPF including stabilization of lung function, reduction in episodes of acute exacerbation, and enhanced longevity. The recent evidence-based guidelines for treatment of IPF approved conditional recommendation of PPIs for all patients with IPF regardless of their GER status. Recently, we have reported that PPIs possess antiinflammatory and antifibrotic activities by directly suppressing proinflammatory cytokines, profibrotic proteins, and proliferation of lung fibroblasts. Our study provides an alternative explanation for the beneficial effect of PPIs in IPF. In this Perspective, we reviewed emerging progress on antifibrotic effect of PPIs using IPF as a disease model. In addition, we summarized surgical and pharmacological interventions for GER and their downstream effect on lung physiology.

show abstract

Section: Ppis and Their Emerging Antiinflammatory-antifibrotic Rolementioning

confidence: 82%

Section: Ppis and Their Emerging Antiinflammatory-antifibrotic Rolementioning

confidence: 93%

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

Ghebre

Raghu

2016

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…[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).…”

mentioning

confidence: 86%

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

Oriaifo¹

2017

WJPPS

View full text Add to dashboard Cite

Faced with the absence of suitable assays and/or kits for predictive biomarkers, medical practitioners in poor resource settings may be emasculated by the unrelenting upwards prevalence of and uncertain forecast associated with the pre-eclampsia/eclampsia and fetal growth restriction disease spectrum. Low-birth weight and pre-eclampsia due to placental malaria, multiple pregnancy and malnutrition may be reactive oxygen species -and anti-angiogenic factors -dependent.Adjunctive esomeprazole promises to be a treatment regimen that may lead to cure for it has been found to attenuate the known pathophysiologic mechanisms responsible for pre-eclampsia and IUGR which may be imbalance between pro-angiogenic and anti-angiogenic factors. The proton pump inhibitor, esomeprazole, decreases the excessive secretion of the anti-angiogenic factors soluble fmslike tyrosine kinase-I (sFlt-I) and soluble endoglin from the placenta responsible for the hypertension, endothelial dysfunction, multiorgan injury and foetal growth restriction in preeclampsia. sFlt-I binds the pro-angiogenic placenta growth factor (PIGF) and vascular endothelial growth factor (VEGF), the circulating free forms of which are low in preeclampsia. Case report is of a 32-year old Nigerian housewife who showed significant reduction in blood pressure, proteinuria and pedal oedema with esomeprazole add-on to a regimen of methyl-dopa for severe preeclampsia. The combination significantly (P < 0.05) This report corroborates the accumulating pre-clinical data on the safety and efficacy of esomeprazole in the treatment of preeclampsia, a precursor of eclampsia.

show abstract

“…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 .…”

Section: Methodsmentioning

confidence: 99%

Untitled

2017

IJPSR

View full text Add to dashboard Cite

Protein conformation and dynamics are influenced by various factors, including binding of ligands, their physico-chemical properties, etc. Every conformational change is dictated by an array of events, as making and breaking of bonds or change in interaction of protein residues. The three dimensional structure of protein molecules are widely investigated, based on small world network approaches, with an emphasis on different combinations of descriptors affecting the structure which have been tested on studies involving binding in protein ligand complexes and for protein-protein complexes. This application has revealed the benefits and success of the small world network approach which can change the focus from specific interactions in the local environment or to non-local phenomenon. Network analysis of interacting protein upon ligand binding is analysed. A similarity in interaction parameters among residues of the target protein, upon binding of particular ligands, is identified. This method differentiates ligands, on the basis of overall changes in interaction among residues of Target proteins in complex.

show abstract

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

Cited by 112 publications

References 90 publications

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

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

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

Untitled

Contact Info

Product

Resources

About