Remodeling and Fibrosis in Chronic Eosinophil Inflammation

Abstract

Chronic eosinophilic inflammation has been associated with tissue remodeling in a number of disease states including the hypereosinophilic syndrome (HES), asthma, and, more recently, eosinophilic esophagitis (EoE). Remodeling occurs in the epithelial and subepithelial esophageal tissue, and includes basal zone hyperplasia, epithelial mesenchymal transition, fibrosis, angiogenesis, and smooth muscle hypertrophy/hyperplasia. Previously, research on the clinical impacts of tissue remodeling has been limited by a paucity of human tissue. However, in EoE, recurrent biopsies are required for diagnosis and management. As such, investigators are able to study the associations between tissue changes and clinical disease features. A number of profibrotic and proangiogenic factors are elevated in EoE, including TGF-β1, CCL-18, FGF-9, VEGF, and VCAM-1. Both eosinophils and mast cells produce a number of these factors. TGF-β1 appears to be a master regulator of end-organ dysfunction in EoE and can cause esophageal epithelial mesenchymal transition, fibrosis, and smooth muscle contraction. The requirement for eosinophils, the eosinophilopoietic interleukin, IL-5, and the canonical TGF-β1 signaling pathway for EoE-associated fibrosis, has been invoked using gene-deficient mice. The clinical consequences of eosinophil-associated tissue fibrosis can be devastating, such as endomyocardial fibrosis and heart failure in HES. In EoE, tissue remodeling appears to be the mechanism for multiple cardinal disease complications including esophageal rigidity, strictures, narrowing, and food impactions, as well as the clinical hallmark of dysphagia. Therapies that may be able to reduce or reverse EoE-associated remodeling include topical corticosteroids, anti-IL-5, and food antigen avoidance.

A Player and Coordinator: The Versatile Roles of Eosinophils in the Immune System

“…IL-13, IL-4), MMPs, and granule proteins MBP and EDN, play crucial roles in promoting epithelial and/or smooth muscle cell hyperplasia, myofibroblast differentiation, extracellular matrix reorganization and tissue fibrosis [5]. These effects contribute to a variety of chronic inflammatory conditions associated with eosinophilia, including not only airway remodeling in severe asthma [38,40], stromal fibrosis in chronic rhinosinusitis with nasal polyposis [41] and esophageal subepithelial fibrosis in EoE [29] but also endomyocardial fibrosis in hypereosinophilic syndrome (HES) [42].…”

Eosinophilia: a pragmatic approach to diagnosis and treatment

“…Eosinophils have been implicated in the pathogenesis of tissue fibrosis, 11 thrombosis, 12 vasculitis, 13 and allergic inflammation. The propensity of eosinophils to cause these effects depends on a number of factors, including the number of eosinophils, their location, and degree of activation.…”

Eosinophilic Esophagitis: A Comprehensive Review

“…Transforming Growth Factor Beta 1 has been shown in in vitro studies to upregulate expression of epithelial mesenchymal transition (EMT) genes, such as N-Cadherin, vimentin and Fibronectin [45].…”

“…In one study the odds ratio for fibrosis more than doubled for every 10 years of disease [67], and that stricture prevalence increased with greater delays in diagnosis [61]. Most ominously, as the disease progresses in adulthood, there may be difficulties in reducing and reversing these remodeling changes [45]. Although measuring the quality of life impact of EoE is difficult and still being formulated, early studies in children suggest that the disease affects not only gastrointestinal issues, but result in social difficulties, anxiety, sleep difficulties, and depression, with an increasing incidence as these children age [68].…”