Remodeling In Eosinophilic Esophagitis Research Articles

Measuring esophageal compliance using functional lumen imaging probe to assess remodeling in eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is associated with fibrostenotic remodeling that can be objectively assessed using the functional lumen imaging probe (FLIP). This is typically done using a metric called distensibility plateau (DP). We aimed to describe a novel measure of compliance of the esophageal body and evaluate the associated clinical characteristics in EoE. One hundred seventy-one adult patients with EoE (mean (SD) age 38 (12) years), 31% female and 35 healthy, asymptomatic controls who completed 16-cm functional luminal imaging probe (FLIP) during endoscopy, were evaluated in a cross-sectional study. The esophageal body DP and compliance were measured using a customized analysis program, with compliance calculated as (Δ esophageal body volume)/(Δ pressure) between two FLIP-filled volumes. In controls, the median (5-95th percentile) DP was 19.8 mm (17.9-21) and esophageal body compliance was 0.37 ml/mmHg (0.18-1.1), which was greater than in EoE (DP 19 (11-21)), compliance 0.19 (0.02-0.71), p-values <0.001. Among EoE patients, 70 (41%) had normal compliance (>0.2ml/mmHg) and normal DP (>17 mm); 11 (6%) had normal compliance and reduced DP; 34 (20%) had reduced compliance and normal DP; and 56 (33%) had reduced compliance and reduce DP. Patients with both reduced compliance and DP had the greatest proportion of severe rings (61% with EREFS score 2-3) and stricture (100%). FLIP provides an objective evaluation of biomechanical properties of the esophageal wall that appears enhanced by complementary application of metrics of DP and esophageal body compliance.

Esophageal remodeling in eosinophilic esophagitis: Relationships to luminal captured biomarkers of inflammation and periostin

Esophageal remodeling is a factor in disease progression and symptom severity for patients with eosinophilic esophagitis (EoE). Remodeling can begin early in children, resulting in stricture and food impaction. Detection of esophageal remodeling often depends on endoscopy and is appreciated only in its later stages. We sought to determine whether luminal eosinophil-associated and remodeling proteins captured by the esophageal string test (EST) correlate with measures of esophageal remodeling and biomarkers of the epithelial-mesenchymal transition (EMT). Patients with EoE (7-18 years old) were enrolled from 2 pediatric hospitals. Participants performed the EST and underwent endoscopy. Histology, distensibility measured by endoluminal functional lumen imaging probe, and symptoms were assessed. Protein quantitation by ELISA was performed on mucosal biopsy and EST samples. Tissue sections were evaluated for EMT. Outcome measures were summarized, and Spearman ρ was used to assess bivariate correlations. Forty patients (68% male) were enrolled (mean age, 12.5 years). Twenty-four (60%) had active disease (≥15 eosinophils per high-power field). EST-captured eotaxin-3, major basic protein 1, EDN, eosinophil peroxidase, and Charcot-Leyden crystal protein/galectin-10 showed significant correlations with peak eosinophils per high-power field (ρ 0.53-0.68, P< .001). Luminal proteins positively correlated with endoscopic features and markers of EMT, and negatively with esophageal distensibility. Periostin was captured by the EST and correlated with eosinophil density, basal zone hyperplasia, endoscopic appearance, and markers of EMT. Luminal markers of esophageal remodeling in addition to biomarkers of eosinophilic inflammation correlate with epithelial and functional remodeling in EoE.

LIGHT controls distinct homeostatic and inflammatory gene expression profiles in esophageal fibroblasts via differential HVEM and LT\u03b2R-mediated mechanisms

Fibroblasts mediate tissue remodeling in eosinophilic esophagitis (EoE), a chronic allergen-driven inflammatory pathology. Diverse fibroblast subtypes with homeostasis-regulating or inflammatory profiles have been recognized in various tissues, but which mediators induce these alternate differentiation states remain largely unknown. We recently identified that TNFSF14/LIGHT promotes an inflammatory esophageal fibroblast in vitro. Herein we used esophageal biopsies and primary fibroblasts to investigate the role of the LIGHT receptors, herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTβR), and their downstream activated pathways, in EoE. In addition to promoting inflammatory gene expression, LIGHT down-regulated homeostatic factors including WNTs, BMPs and type 3 semaphorins. In vivo, WNT2B+ fibroblasts were decreased while ICAM-1+ and IL-34+ fibroblasts were expanded in EoE, suggesting that a LIGHT-driven gene signature was imprinted in EoE versus normal esophageal fibroblasts. HVEM and LTβR overexpression and deficiency experiments demonstrated that HVEM regulates a limited subset of LIGHT targets, whereas LTβR controls all transcriptional effects. Pharmacologic blockade of the non-canonical NIK/p100/p52-mediated NF-κB pathway potently silenced LIGHT’s transcriptional effects, with a lesser role found for p65 canonical NF-κB. Collectively, our results show that LIGHT promotes differentiation of esophageal fibroblasts toward an inflammatory phenotype and represses homeostatic gene expression via a LTβR-NIK-p52 NF-κB dominant pathway.

Differential Contribution Of TNFSF14/LIGHT-Receptor Mediated Pathways To Inflammatory Fibroblast Phenotypes In Eosinophilic Esophagitis

Fibroblasts (FBL) mediate tissue remodeling in eosinophilic esophagitis (EoE), a chronic allergen driven inflammatory pathology. We recently defined a putative role of the cytokine TNFSF14/LIGHT as a promoter of an inflammatory esophageal FBL subtype. LIGHT can signal through two receptors, herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTßR). We investigated the relative contributions of each receptor to LIGHT-mediated inflammatory FBL differentiation.

Plasminogen Activator Inhibitor-1 as a Marker of Esophageal Functional Changes in Pediatric Eosinophilic Esophagitis

Esophageal remodeling in eosinophilic esophagitis (EoE) can lead to esophageal rigidity with eventual luminal compromise and stenoses. Gauging esophageal functional alterations in EoE is challenging. An epithelial marker of functional remodeling would impact EoE management. Esophageal biopsy specimens from children with and without EoE and primary human esophageal epithelial cells were used for PAI-1 immunohistochemistry, and cell proliferation experiments. PAI-1 immunostaining and basal cell hyperplasia were assessed in the context of concurrently obtained esophageal compliance measures on endoscopic functional lumen imaging probe (EndoFLIP). EndoFLIPs were performed in 45 children (32 with and 13 without EoE). Epithelial PAI-1 was increased in patients with active EoE versus inactive or control patients (P < .01). Esophageal compliance was lower in EoE patients versus controls, particularly in the proximal esophagus (P < .001). Proximal compliance was the strongest predictor of EoE (AUROC 0.88, 95% CI 0.77, 0.98) with esophageal compliance of less than 2.6%mL/mmHg demonstrating 82% sensitivity and 84% specificity for EoE. PAI-1 inhibition significantly diminished esophageal epithelial cell proliferation, suggesting PAI-1 could trigger basal cell hyperplasia. A composite mid-esophageal BZH+ PAI-1 score was the strongest predictor of altered compliance (P = .02, AUROC 0.89 (95% CI 0.80, 0.99). PAI-1 is significantly elevated in pediatric EoE and distinguishes altered compliance in children. PAI-1 may be a novel disease marker and therapeutic target.

Understanding fibrosis in eosinophilic esophagitis: Are we there yet?

Eosinophilic esophagitis (EoE) is an immune/antigen-mediated, progressive fibrostenotic disease characterized by symptoms of esophageal dysfunction and abnormal eosinophilic infiltration in the esophagus. Despite current treatment modalities of dietary antigen elimination or topical corticosteroids, a subset of patients do not have clinical or histologic response. Even with resolution of superficial epithelial eosinophilia, patients may still have progressive subepithelial fibrosis, which may lead to esophageal strictures over time. Histologic identification of subepithelial fibrosis requires deep esophageal biopsies, which are not routinely obtained. Herein, we review the challenges in diagnosing and treating fibrosis in EoE. We propose the novel concept of vitamin D supplementation to treat fibrosis in EoE through downregulation of profibrotic mediator, transforming growth factor-beta.

204 Epithelial Lysyl Oxidase Is an Early Mediator of Fibrotic Remodeling in Eosinophilic Esophagitis

204 Epithelial Lysyl Oxidase Is an Early Mediator of Fibrotic Remodeling in Eosinophilic Esophagitis

Eosinophilic Esophagitis: An Autoimmune Esophageal Disorder

Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal inflammatory disease associated with esophageal dysfunction resulting from severe inflammation. The incidence and prevalence of EoE have been increasing in the past decade; however, the reason for this increase is unclear. There is a chronic inflammatory infiltrate that is present in EoE which promotes inflammation, symptoms, and dysfunction. In addition to eosinophils, interleukin (IL)-5 expressing T cells, B cells, eotaxin-3, IL-13, and IgE-bearing mast cells are present in EoE and are thought to contribute to the disease process. Eosinophils are pro-inflammatory and modulate multiple aspects of the immune response. Eosinophils produce a wide range of inflammatory cytokines, chemokines, granulocyte-monocyte colony-stimulating factors, and tumor necrosis factors. Once activated, eosinophils release granule components, which are toxic to a variety of tissues. Transforming growth factor β1 is a pro-fibrotic molecule produced by epithelial and inflammatory cells, is overexpressed in EoE, and plays a role in esophageal remodeling. Fibrous remodeling in EoE could be associated with symptoms of dysphagia and may explain and predict future esophageal strictures and dysmotility. EoE is a complex disease involving multiple activation pathways, a large number of cells, and various inflammatory molecules. It, along with other atopic disease, is becoming increasingly prevalent and has an important genetic load and may represent as an immunological tolerance disorder of the GI tract.

The pathophysiology of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an emerging disease characterized by esophageal eosinophilia (>15eos/hpf), lack of responsiveness to acid-suppressive medication and is managed by allergen elimination and anti-allergy therapy. Although the pathophysiology of EoE is currently unsubstantiated, evidence implicates food and aeroallergen hypersensitivity in genetically predisposed individuals as contributory factors. Genome-wide expression analyses have isolated a remarkably conserved gene-expression profile irrespective of age and gender, suggesting a genetic contribution. EoE has characteristics of mainly TH2 type immune responses but also some TH1 cytokines, which appear to strongly contribute to tissue fibrosis, with esophageal epithelial cells providing a hospitable environment for this inflammatory process. Eosinophil-degranulation products appear to play a central role in tissue remodeling in EoE. This remodeling and dysregulation predisposes to fibrosis. Mast-cell-derived molecules such as histamine may have an effect on enteric nerves and may also act in concert with transforming growth factor-β to interfere with esophageal musculature. Additionally, the esophageal epithelium may facilitate the inflammatory process under pathogenic contexts such as in EoE. This article aims to discuss the contributory factors in the pathophysiology of EoE.

Tissue remodeling in eosinophilic esophagitis

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.

Eosinophils in the gastrointestinal tract: friends or foes?

Eosinophils play an important role in the mucosal immune system of the gastrointestinal tract under resting and under inflammatory conditions. Under steady-state conditions, the mucosa of the digestive tract is the only organ harboring a substantial number of eosinophils, which, if need be, get activated and exert several effector and immunoregulatory functions. The precise function of these late-phase inflammatory cells is not yet completely understood. Nevertheless, it has recently been demonstrated that lipopolysaccharides from gram-negative bacteria activate eosinophils to rapidly release mitochondrial DNA in the extracellular space. Released mitochondrial DNA and eosinophil granule proteins form extracellular structures able to bind and inactivate bacteria. These findings suggest a novel mechanism of eosinophil-mediated innate immune responses that might be important in maintaining the intestinal barrier function. Moreover, eosinophils also play a crucial role in several inflammatory conditions, such as intestinal infections, immune-mediated inflammations and hypersensitivity reactions. Under chronic inflammatory conditions, the ability of the eosinophils to induce repair can lead to pathological sequelae in the tissue, such as esophageal remodeling in eosinophilic esophagitis. It is established that the uncontrolled eosinophilic inflammation induces fibrosis, esophageal wall thickening and strictures leading to damage that results in a loss of esophageal function. One potential mechanism of this remodeling is so-called 'epithelial mesenchymal transition', which is triggered by eosinophils and is potentially reversible under successful anti-eosinophil treatment. Therefore, eosinophils may act either as friends or as foes, depending on the microenvironment.

Epithelial Mesenchymal Transition Induced Esophageal Remodeling in Eosinophilic Esophagitis Reverses With Treatment

Epithelial Mesenchymal Transition Induced Esophageal Remodeling in Eosinophilic Esophagitis Reverses With Treatment

Epithelial Mesenchymal Transition in Eosinophilic Esophagitis: Identification and Contributions to Esophageal Remodeling and Fibrosis

RATIONALE: Esophageal remodeling in Eosinophilic Esophagitis (EoE), a food-allergic disease, includes epithelial hyperplasia and subepithelial fibrosis. Epithelial Mesenchymal Transition (EMT) is a process whereby non-motile epithelial cells de-differentiate into motile mesenchymal-like cells during chronic inflammation, and can further differentiate into myofibroblasts. Since the mechanism of esophageal fibrosis in EoE is poorly understood, our objective was to determine whether EMT occurs in EoE and contributes to its pathogenesis.

Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids

Esophageal remodeling occurs in eosinophilic esophagitis (EE) patients but whether the components of remodeling in the subepithelium are reversible by administration of topical oral corticosteroids is unknown. We quantitated the degree of lamina propria remodeling in esophageal biopsies obtained before and after at least 3 months of therapy with budesonide in 16 pediatric EE subjects. In addition, we investigated whether corticosteroid therapy modulated vascular activation (expression of VCAM-1; level of interstitial edema), TGFbeta(1) activation (levels of TGFbeta(1), phosphorylated Smad2/3), and performed a pilot analysis of a polymorphism in the TGFbeta(1) promoter in relation to EE subjects who had reduced remodeling with budesonide therapy. EE subjects were stratified based on the presence (n = 9) or absence (n = 7) of decreased epithelial eosinophilia following budesonide. Patients with residual eosinophil counts of <or=7 eosinophils per high power field in the epithelial space (responders) demonstrated significantly reduced esophageal remodeling with decreased fibrosis, TGFbeta(1) and pSmad2/3 positive cells, and decreased vascular activation in association with budesonide therapy. Responders were more likely to have a CC genotype at the -509 position in the TGFbeta(1) promoter. Reductions in epithelial eosinophils following budesonide therapy were associated with significantly reduced esophageal remodeling.

Esophageal Remodeling Develops as a Consequence of Tissue Specific Interleukin (IL)-5 Induced Eosinophilia

Eosinophilic esophagitis (EE) has been associated with esophageal remodeling, but the mechanisms involved are poorly understood. We examined the mechanism of the induction of esophageal remodeling in EE.

Translational Research on the Pathogenesis of Eosinophilic Esophagitis

Eosinophilic esophagitis (EE) is an inflammatory disease of the esophagus characterized by eosinophilic infiltration of the esophageal epithelium. EE is a relatively new disease from clinical and research standpoints. A recent surge in basic and translational studies has emerged to understand its pathogenesis since its recognition as a separate entity from acid-induced gastroesophageal reflux disease in 1995. Our understanding of this disease is still limited, however. In this article, available evidence from translational studies on EE is discussed, focusing on the allergic nature of the disease and highlighting the role of various inflammatory cells found in the esophagus of patients who have EE. Esophageal remodeling in EE is also discussed.