430 Different Effects of Proton Pump Inhibitors (PPIs) on Eotaxin-3 Protein Expression by the Proximal and Distal Esophagus of Children With Esophageal Eosinophilia

Abstract

Introduction: PPIs can reduce esophageal eosinophilia, an effect usually attributed to decreased acid reflux. However, PPIs can suppress Th2-cytokine-stimulated expression of an eosinophil chemoattractant (eotaxin-3) by esophageal cells through mechanisms independent of effects on gastric acid. To explore the relative contributions of these acid-suppressive and acid-independent PPI actions, 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 effects on Th2-cytokine-stimulated eotaxin-3 expression by esophageal epithelial cells.Methods:We identified 10 children with initial esophageal biopsies showing ≥15 eos/hpf who had follow-up endoscopy after PPI treatment alone for ≥8 weeks. Eosinophils were quantified on HE eotaxin-3 secretion was determined by ELISA. Results: For the group as a whole, mean maximum eos/hpf decreased with PPI treatment (50 to 40 eos/hpf); in 5 of the 10 patients, counts fell to <15 eos/hpf. There was strong correlation between maximum eos/hpf and maximum eotaxin-3-positive epithelial cells/hpf (R=0.8332, P<0.0001). Although PPI effects in reducing acid reflux are strongest in the distal esophagus, eotaxin-3 expression decreased significantly with PPIs only in the proximal esophagus (28 to 6 cells/hpf proximal, P=0.049; 14 to 24 cells/hpf distal esophagus, P=0.41). In vitro, EoE1-T and EoE2-T cells stimulated with IL-13 showed strong suppression of eotaxin-3 secretion at pH4; weakly acidic pH levels had no consistent effects on eotaxin3 in the same cell lines (Table). Treatment with omeprazole at weakly acidic pH did not suppress IL-13-stimulated eotaxin-3 secretion as profoundly as exposure to pH4 alone (Table). Conclusions: In children with esophageal eosinophilia, PPIs significantly decrease expression of eotaxin-3 protein in the proximal but not distal esophagus. In esophageal squamous cells in vitro, acid at pH4 decreases eotaxin-3 secretion significantly. This in vitro finding might explain the disparate PPI effects on the proximal and distal esophagus. In the distal esophagus, where acid exposure that inhibits eotaxin-3 secretion is greatest, suppression of acid reflux by PPIs might increase eotaxin-3 secretion and mask acid-independent PPI suppressive effects on the protein. In the proximal esophagus, where acid exposure is least, acid-independent PPI effects in suppressing eotaxin-3 secretion are manifest most greatly. Acid pH Effects on IL-13-Driven Eotaxin-3 Protein Secretion by Esophageal Squamous Cell Lines (EoE1-T and EoE2-T)