Tissue remodeling in eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a recently recognized, immune-mediated disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. The chronic esophageal eosinophilia of EoE is associated with tissue remodeling that includes epithelial hyperplasia, subepithelial fibrosis, and hypertrophy of esophageal smooth muscle. This remodeling causes the esophageal rings and strictures that frequently complicate EoE and underlies the mucosal fragility that predisposes to painful mucosal tears in the EoE esophagus. The pathogenesis of tissue remodeling in EoE is not completely understood, but emerging studies suggest that secretory products of eosinophils and mast cells, as well as cytokines produced by other inflammatory cells, epithelial cells, and stromal cells in the esophagus, all contribute to the process. Interleukin (IL)-4 and IL-13, Th2 cytokines overproduced in allergic disorders, have direct profibrotic and remodeling effects in EoE. The EoE esophagus exhibits increased expression of transforming growth factor (TGF)-β1, which is a potent activator of fibroblasts and a strong inducer of epithelial-mesenchymal transition. In addition, IL-4, IL-13, and TGF-β all have a role in regulating periostin, an extracellular matrix protein that might influence remodeling by acting as a ligand for integrins, by its effects on eosinophils or by activating fibrogenic genes in the esophagus. Presently, few treatments have been shown to affect the tissue remodeling that causes EoE complications. This report reviews the potential roles of fibroblasts, eosinophils, mast cells, and profibrotic cytokines in esophageal remodeling in EoE and identifies potential targets for future therapies that might prevent EoE complications.

BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis

“…EoE is characterized by basal cell hyperplasia and subepithelial fibrosis (53). We propose that follistatin inhibits BMP activities during disease progression, thereby blocking the differentiation of basal progenitor cells.…”

“…In the esophagus, basal cells serve as progenitor cells to maintain the stratified squamous epithelium (2,3). Disruption of the balance of basal cell activities underlies multiple pathological conditions, including eosinophilic esophagitis (EoE), in which basal cells become hyperplastic in the setting of high levels of the inflammatory cytokines eotaxin-3, IL-5, and IL-13 (4)(5)(6). Studies have shown that these hyperplastic basal cells serve as an important source of cytokines and chemokines that facilitate EoE disease progression (7,8).…”

Eosinophilic Esophagitis: A Comprehensive Review

“…These processes lead to sub epithelial fibrosis and alternation in smooth muscle contraction, which in result in the rings and strictures seen on endoscopy and the dysphagia experienced by patients [47].…”

Eosinophilic Esophagitis–More than Two Decades of Progress

“…It is believed that the mechanism in which EoE occurs is by food or environmental allergens contacting a possible leaky esophageal epithelium and triggering a T-helper 2 (Th2) cell-mediated immune response (involving interleukin [IL]-4, IL-5, IL-9 and IL-13). This response stimulates the epithelium to produce eotaxin-3, a potent chemokine that recruits eosinophils, which promotes local inflammation, injury, and tissue remodeling via increased expression of transforming growth factor (TGF)-β1 leading to smooth muscle dysfunction [22][23][24].…”