title: Proton pump inhibitors decrease eotaxin-3 expression in the proximal esophagus of children with esophageal eosinophilia.
abstract: OBJECTIVE
  Besides 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.
  
  
  METHODS
  Among 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.
  
  
  RESULTS
  There 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Esophageal Diseases Center, Department of Pathology, Children's Medical Center, Eugene McDermott Center for Human Growth and Development, and the University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Jason Y
authors.initials: JY
authors.lastname: Park
authors.affiliation: Esophageal Diseases Center, Department of Pathology, Children's Medical Center, Eugene McDermott Center for Human Growth and Development, and the University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Children's Medical Center, and the University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Esophageal Diseases Center, Department of Internal Medicine, VA North Texas Health Care System, Harold C. Simmons Comprehensive Cancer Center, and the University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Rhonda F
authors.initials: RF
authors.lastname: Souza
authors.affiliation: Esophageal Diseases Center, Department of Internal Medicine, VA North Texas Health Care System, Harold C. Simmons Comprehensive Cancer Center, and the University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Spechler
authors.affiliation: Esophageal Diseases Center, Department of Internal Medicine, VA North Texas Health Care System, and the University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Department of Pediatrics, Children's Medical Center, and the University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Edaire
authors.initials: E
authors.lastname: Cheng
mesh_terms: D000293:Adolescent; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000032:analysis / Q000276:immunology*; D002648:Child; D015536:Down-Regulation / Q000187:drug effects; D057765:Eosinophilic Esophagitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004947:Esophagus / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology; D008297:Male; D009853:Omeprazole / Q000627:therapeutic use*; D054328:Proton Pump Inhibitors / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; C120429:CCL26 protein, human; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D018793:Interleukin-13; D054328:Proton Pump Inhibitors; D009853:Omeprazole