Objectives: 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.
*Allergy and Immunology, Department of Medicine
†Allergy and Immunology, Department of Pediatrics, 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: firstname.lastname@example.org).
Received 12 April, 2013
Accepted 12 February, 2014
This study was funded by Department of Defense grant W81XWH-10-1-0705 to D.B. D.B. is also supported by National Institutes of Health grants AI 38425, AI 70535, AI 72115, and AI107779. S.A. is supported by National Institutes of Health grant AI 092135. The other authors report no conflicts of interest.