Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD

Abstract

Objective Eosinophilic oesophagitis (EoE) and gastrooesophageal reflux disease (GORD) can have similar clinical and histological features. Proton pump inhibitors (PPIs) are used to distinguish the disorders, with the assumption that only GORD can respond to PPIs. Oesophageal expression of eotaxin-3 stimulated by Th2 cytokines might contribute to oesophageal eosinophilia in EoE. Th2 cytokine effects on the oesophagus in GORD are not known. Our objective was to explore the molecular mechanisms of Th2 cytokines on eotaxin-3 expression by oesophageal squamous cells from patients with GORD and EoE, and the effects of omeprazole on that eotaxin-3 expression. Design Using telomerase-immortalised and primary cultures of oesophageal squamous cells from GORD and EoE patients, we measured eotaxin-3 protein secretion stimulated by Th2 cytokines (IL-4 and IL-13). Eotaxin-3 promoter constructs were used to study transcriptional regulation. Cytokine-induced eotaxin-3 mRNA and protein expression were measured in the presence or absence of omeprazole. Results There were no significant differences between EoE and GORD primary cells in cytokine-stimulated eotaxin-3 protein secretion levels. In EoE and GORD cell lines, IL-4 and IL-13 activated the eotaxin-3 promoter, and significantly increased eotaxin-3 mRNA and protein expression. Omeprazole blocked the cytokine-stimulated increase in eotaxin-3 mRNA and protein expression in EoE and GORD cell lines. Conclusion Oesophageal squamous cells from GORD and EoE patients express similar levels of eotaxin-3 when stimulated by Th2 cytokines, and omeprazole blocks that eotaxin-3 expression. These findings suggest that PPIs might have eosinophil-reducing effects independent of effects on acid reflux, and that response to PPIs might not distinguish EoE from GORD.

Development of urinary incontinence in a 7-year old boy after therapy with proton pump inhibitors and complete resolution of his clinicopathologic features of eosinophilic esophagitis after H2-receptor antagonist treatment: A case report

“…In addition to the inhibition of the proton pump in the parietal gastric cells, a number of potential direct anti-inflammatory effects of PPIs have been suggested (16)(17)(18)(19). It was demonstrated that PPIs inhibit the secretion of eotaxin-3, the most potent chemo-attractant for eosinophils, by esophageal epithelial cells (15). PPIs have been found to have anti-oxidant properties and direct effects on granulocytes, endothelial and epithelial cells that might prevent inflammation and they may reduce esophageal eosinophilia, at least in part, by inhibiting VCAM-1 production by esophageal endothelial cells (18).…”

“…It has been proposed that anti-inflammatory effects of PPIs in addition to their inhibition of acid secretion may be involved in PPI-REE (14)(15)(16)(17)(18)(19). To the best of our knowledge, resolution of extreme esophageal eosinophilia including other typical hallmarks of EoE with H2-receptor antagonists has never been reported.…”

Oesophageal baseline impedance values are decreased in patients with eosinophilic oesophagitis

“…Furthermore, recent papers have suggested that PPIs may have antiinflammatory effects besides their acid-suppressive effects. 22,23 Response to PPI therefore does not automatically translate to presence of gastro-oesophageal reflux.…”

Eosinophilic Esophagitis- Clinical Management in Adults

“…To exclude PPI-REE, patients with suspected EoE, a high dose PPI trial (20-40 mg twice daily of any of the available agents for 8 weeks) should be given followed by endoscopy with biopsies. Several studies reported response to PPIs treatment in up to 2/3 (75%) of cases as there is a speculation that PPIs may have anti-inflammatory or barrier-healing properties that contribute to resolution of esophageal eosinophilia [50,51]. If a patient responds to this regimen (clinical, endoscopic, and/or histologic response), then additional clinical evaluation should be performed to determine if GERD was the cause of the esophageal eosinophilia.…”