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Abstract
ObjectiveBesides reducing gastric acid secretion, proton pump inhibitors (PPIs) suppress Th2-cytokine-stimulated expression of an eosinophil chemoattractant (eotaxin-3) by esophageal epithelial cells through acid-independent, anti-inflammatory mechanisms. To explore acid-inhibitory and acid-independent, anti-inflammatory PPI effects in reducing esophageal eosinophilia, we studied eotaxin-3 expression by the proximal and distal esophagus of children with esophageal eosinophilia before and after PPI therapy. In vitro, we studied acid and bile salt effects on IL-13-stimulated eotaxin-3 expression by esophageal epithelial cells.DesignAmong 264 children with esophageal eosinophilia seen at a tertiary pediatric hospital from 2008 through 2012, we identified 10 with esophageal biopsies before and after PPI treatment alone. We correlated epithelial cell eotaxin-3 immunostaining with eosinophil numbers in those biopsies. In vitro, we measured eotaxin-3 protein secretion by esophageal squamous cells stimulated with IL-13 and exposed to acid and/or bile salt media, with or without omeprazole.ResultsThere was strong correlation between peak eosinophil numbers and peak eotaxin-3-positive epithelial cell numbers in esophageal biopsies. Eotaxin-3 expression decreased significantly with PPIs only in the proximal esophagus. In esophageal cells, exposure to acid-bile salt medium significantly suppressed IL-13-induced eotaxin-3 secretion; omeprazole added to the acid-bile salt medium further suppressed that eotaxin-3 secretion, but not as profoundly as at pH-neutral conditions.ConclusionIn children with esophageal eosinophilia, PPIs significantly decrease eotaxin-3 expression in the proximal but not the distal esophagus. In esophageal squamous cells, acid and bile salts decrease Th2 cytokine-stimulated eotaxin-3 secretion profoundly, possibly explaining the disparate PPI effects on the proximal and distal esophagus. In the distal esophagus, where acid reflux is greatest, a PPI-induced reduction in acid reflux (an effect that could increase eotaxin-3 secretion induced by Th2 cytokines) might mask the acid-independent, anti-inflammatory PPI effect of decreasing cytokine-stimulated eotaxin-3 secretion.
Highlights
In eosinophilic esophagitis (EoE), food allergens trigger a Thelper 2 (Th2) immune response with production of Th2 cytokines such as interleukin (IL)-13 and IL-4 [1,2]
Exposure to acid-bile salt medium significantly suppressed IL-13-induced eotaxin-3 secretion; omeprazole added to the acid-bile salt medium further suppressed that eotaxin-3 secretion, but not as profoundly as at pH-neutral conditions
In the distal esophagus, where acid reflux is greatest, a pump inhibitors (PPIs)-induced reduction in acid reflux might mask the acid-independent, anti-inflammatory PPI effect of decreasing cytokinestimulated eotaxin-3 secretion
Summary
In eosinophilic esophagitis (EoE), food allergens trigger a Thelper 2 (Th2) immune response with production of Th2 cytokines such as interleukin (IL)-13 and IL-4 [1,2]. Esophageal eosinophilia can be a manifestation of gastroesophageal reflux disease (GERD), which can cause symptoms and endoscopic abnormalities similar to those of EoE [9]. To distinguish these two disorders in patients with esophageal eosinophilia, authorities have recommended a trial of proton pump inhibitor (PPI) therapy with the assumption that gastric acid inhibition is the only important effect of PPIs and, only an acid-peptic disorder like GERD can respond to PPIs. a number of recent observations have challenged this assumption
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