Relationships between eosinophilic inflammation, tissue remodeling, and fibrosis in eosinophilic esophagitis

Abstract

The clinical and pathologic features of eosinophilic esophagitis (EE) include extensive tissue remodeling. Increasing evidence supports a key role for the eosinophil in multiple aspects of the esophageal remodeling and fibrosis seen in this allergic disease. This article reviews the clinical implications of esophageal remodeling and fibrosis in EE and discusses the possible pathogenic mechanisms inducing and regulating these responses. The focus is specifically on eosinophil and cytokine interactions with the esophageal epithelium, vascular endothelium, resident fibroblasts, and smooth muscle. Current and potential therapeutic interventions are discussed that may impact the development or resolution of chronic esophageal remodeling and fibrosis in EE.

Figures

Figure 1. Eosinophil induction of esophageal remodeling and fibrosis in EE: relationships to endoscopic and histologic pathologies

Eosinophil activation during recruitment to the esophagus occurs in response to eotaxin-3, periostin, IL-5 and interactions with vascular endothelium, epithelium and fibroblasts, leading to their expression of fibrogenic factors such as TGF-β. Eosinophil-expressed TGF-β and granule proteins (MBP, EPO) induce epithelial basal zone hyperplasia, contributing to esophageal thickening and luminal narrowing. Eosinophil-derived TGF-β induces fibroblast activation, with transdifferentiation to myofibroblasts and consequent over-production of ECM leading to subepithelial fibrosis, fixed narrowings/rings, strictures and food impactions. Alternatively, TGF-β expressed by eosinophils or MBP/EPO damaged epithelium itself may induce epithelial to mesenchymal (myofibroblast) transition (EMT) contributing to subepithelial fibrosis. Eosinophil-expressed TGF-β may induce smooth muscle cell hypertrophy/hyperplasia leading to thickening of the esophageal muscularis propria, contributing to dysmotility, dysphagia, transient rings and non-stricture food impactions. Eosinophil expression of VEGF likely supports increased angiogenic responses of vascular endothelium with VCAM-1 activation by IL-13 and TNF-α, contributing to increased eosinophil trafficking, dilated intercellular spaces, esophageal thickening, furrowing, luminal narrowing and non-stricture food impactions.