title: Siglec-F inhibition reduces esophageal eosinophilia and angiogenesis in a mouse model of eosinophilic esophagitis.
abstract: OBJECTIVE
  Eosinophilic esophagitis (EoE) is a disorder characterized histologically by tissue eosinophilia. Sialic acid-binding immunoglobulin-like lectin (Siglec-F) is a receptor highly expressed on mouse eosinophils and mediates eosinophilic apoptosis. We investigated whether administration of an anti-Siglec-F Ab would reduce esophageal eosinophilic inflammation and remodeling in a mouse model of egg ovalbumin (OVA)-induced EoE.
  
  
  METHODS
  Three groups of mice were studied (no OVA, OVA + anti-Siglec-F Ab, and OVA + isotype control Ab). Mice were sensitized intraperitoneally and then challenged chronically with intraesophageal OVA. Levels of esophageal eosinophils and features of remodeling (angiogenesis, vascular endothelial growth factor expression, deposition of fibronectin, basal zone hyperplasia, and fibrosis) were quantitated by immunohistochemistry and image analysis.
  
  
  RESULTS
  Administration of an anti-Siglec-F Ab to OVA-challenged mice significantly reduced levels of esophageal eosinophils, down to levels noted in non-OVA-challenged mice. The anti-Siglec-F Ab also reduced features of OVA-induced remodeling, including angiogenesis, basal zone hyperplasia, and fibronectin deposition. The reduced angiogenesis in anti-Siglec-F Ab-treated mice was associated with reduced numbers of vascular endothelial growth factor-positive cells in the esophagus. The anti-Siglec-F antibody did not significantly reduce esophageal fibrosis as assessed by trichrome staining.
  
  
  CONCLUSIONS
  Administration of an anti-Siglec-F antibody significantly decreased the number of eosinophils in the esophagus in a mouse model of OVA-induced EoE. The reduction in eosinophilic inflammation was associated with a significant decrease in levels of angiogenesis, deposition of fibronectin, and basal zone hyperplasia. Studies in this pre-clinical model of EoE suggest that Siglec-F (and its human paralog Siglec-8) may be novel therapeutic targets to reduce eosinophilic inflammation in EoE.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California, San Diego, CA 92093-0635, USA.
authors.forename: Eitan
authors.initials: E
authors.lastname: Rubinstein
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.forename: James
authors.initials: J
authors.lastname: Chao
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.forename: Alexa
authors.initials: A
authors.lastname: Pham
authors.forename: Seema S
authors.initials: SS
authors.lastname: Aceves
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis; D004195:Disease Models, Animal; D057765:Eosinophilic Esophagitis / Q000097:blood / Q000473:pathology / Q000628:therapy*; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic; D010047:Ovalbumin / Q000378:metabolism; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000906:Antibodies; D015214:Antigens, Differentiation, Myelomonocytic; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C443130:Siglecf protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D010047:Ovalbumin