title: Targeting granulocyte-macrophage colony-stimulating factor in epithelial and vascular remodeling in experimental eosinophilic esophagitis.
abstract: BACKGROUND
  Eosinophilic esophagitis (EoE) is a chronic antigen-mediated clinicopathologic disease of the esophagus characterized by an eosinophil-predominant inflammatory infiltrate. A clinical hallmark is extensive tissue remodeling including basal zone hyperplasia, fibrosis, and angiogenesis. However, the cellular mechanisms responsible for these processes are not fully defined. We hypothesized that targeting granulocyte-macrophage colony-stimulating factor (GM-CSF; an agonist cytokine linked with eosinophil survival and activation) would be protective in a preclinical model of EoE.
  
  
  METHODS
  Eosinophilic esophagitis-like esophageal inflammation was induced in the L2-IL5OXAEoE mouse model, and GM-CSF production was assessed by mRNA and protein analyses. Granulocyte-macrophage colony-stimulating factor-receptor-alpha expression patterns were examined by flow cytometric and immunofluorescence analysis. L2-IL5OXAEoE mice were treated with anti-GM-CSF neutralizing antibody or isotype control and assessed for histopathological indices of eosinophilia, epithelial hyperplasia, and angiogenesis by immunohistochemistry and RT-PCR.
  
  
  RESULTS
  Significantly increased levels of esophageal GM-CSF expression was detected in the L2-IL5OXAmouse EoE model during active inflammation. Granulocyte-macrophage colony-stimulating factor-receptor-alpha was predominantly expressed on esophageal eosinophils during EoE, in addition to select cells within the lamina propria. Anti-GM-CSF neutralization in L2-IL5OXAEoE mice resulted in a significant diminution of epithelial eosinophilia in addition to basal cell hyperplasia and vascular remodeling. This treatment response was independent of effects on esophageal eosinophil maturation or activation.
  
  
  CONCLUSIONS
  Granulocyte-macrophage colony-stimulating factor is a potential therapeutic target to reduce esophageal eosinophilia and remodeling.
authors.affiliation: Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA.|Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.|Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA.|Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: E N
authors.initials: EN
authors.lastname: McNamee
authors.affiliation: Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA.|Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.|Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Biette
authors.affiliation: Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA.|Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.|Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hammer
authors.affiliation: Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA.|Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.|Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: R
authors.initials: R
authors.lastname: Harris
authors.affiliation: Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA.|Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: H
authors.initials: H
authors.lastname: Miyazawa
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA.|Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.|Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: G T
authors.initials: GT
authors.lastname: Furuta
authors.affiliation: Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA.|Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.|Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Masterson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002461:Cell Line, Transformed; D002631:Chemotactic Factors, Eosinophil / Q000276:immunology; D004195:Disease Models, Animal; D057765:Eosinophilic Esophagitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000071041:Esophageal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D066253:Vascular Remodeling / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D002631:Chemotactic Factors, Eosinophil; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: GM-CSF receptor; eosinophil; epithelial; esophagitis; granulocyte-macrophage colony-stimulating factor (GM-CSF)