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Siglec-F Inhibition Reduces Esophageal Eosinophilia and Angiogenesis in a Mouse Model of Eosinophilic Esophagitis

Rubinstein, Eitan*; Cho, Jae Youn; Rosenthal, Peter; Chao, James; Miller, Marina; Pham, Alexa; Aceves, Seema S.; Varki, Ajit; Broide, David H.

Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e3182182ff8
Original Articles: Gastroenterology
Abstract

Objectives: 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.

Subjects and 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.

Author Information

*Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California, San Diego

Department of Medicine, University of California, San Diego.

Address correspondence and reprint requests to David Broide, MB, ChB, University of California, San Diego, Biomedical Sciences Building, Room 5090, 9500 Gilman Dr, La Jolla, CA 92093-0635 (e-mail: dbroide@ucsd.edu).

Received 20 October, 2010

Accepted 23 February, 2011

This study was supported by NIH grants T32 DK07202-33 (E.R.), AI 38425 (D.B.), AI 70535 (D.B.), AI 72115 (D.B., A.V.), and PO1-HL057345 (A.V.).

The authors report no conflicts of interest.

Copyright 2011 by ESPGHAN and NASPGHAN