title: Smad3-deficient mice have reduced esophageal fibrosis and angiogenesis in a model of egg-induced eosinophilic esophagitis.
abstract: OBJECTIVE
  Eosinophilic esophagitis (EoE) is a food-triggered disease associated with esophageal fibrosis and stricture formation in a subset of patients. In the present study we used a murine model of egg (ovalbumin [OVA])-induced EoE to determine whether inhibiting transforming growth factor-β1 (TGF-β1) signaling through the Smad3 pathway would inhibit features of esophageal remodeling including fibrosis, angiogenesis, and basal zone hyperplasia.
  
  
  METHODS
  Wild-type (WT) and Smad3-deficient (KO [knockout]) mice were sensitized intraperitoneally and then challenged chronically with intraesophageal OVA for 1 month. Levels of esophageal eosinophils, esophageal TGF-β1+ and vascular endothelial growth factor (VEGF)+ cells, and features of esophageal remodeling (fibrosis, angiogenesis, basal zone hyperplasia) were quantitated by immunohistochemistry and image analysis.
  
  
  RESULTS
  OVA challenge induced a similar increase in the levels of esophageal major basic protein (MBP)+ eosinophils and esophageal TGF-β1+ cells in WT and Smad3 KO mice. Smad3 KO mice challenged with OVA had significantly less esophageal fibrosis and esophageal angiogenesis compared with OVA-challenged WT mice. The reduced esophageal angiogenesis in Smad3 KO mice was associated with reduced numbers of VEGF+ cells in the esophagus. There was a trend toward OVA-challenged Smad3 KO to have reduced basal zone hyperplasia, but this was not statistically significant.
  
  
  CONCLUSIONS
  In a mouse model of egg-induced EoE, Smad3-deficient mice have significantly less esophageal remodeling, especially fibrosis and angiogenesis that is associated with reduced expression of VEGF. Targeting the TGF-β1/Smad3 pathway may be a novel strategy to reduce esophageal fibrosis and its associated complications such as esophageal strictures in EoE.
authors.affiliation: *Allergy and Immunology, Department of Medicine †Allergy and Immunology, Department of Pediatrics, University of California, San Diego.
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Ashmi
authors.initials: A
authors.lastname: Doshi
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.forename: Andrew
authors.initials: A
authors.lastname: Beppu
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.forename: Seema
authors.initials: S
authors.lastname: Aceves
authors.forename: David
authors.initials: D
authors.lastname: Broide
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D047093:Eosinophil Major Basic Protein / Q000378:metabolism; D057765:Eosinophilic Esophagitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D004804:Eosinophils / Q000737:chemistry; D004947:Esophagus / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D006965:Hyperplasia; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000473:pathology; D010047:Ovalbumin; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000172:deficiency* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D010047:Ovalbumin; D047093:Eosinophil Major Basic Protein