Eotaxin and FGF enhance signaling through an Extracellular signal-related kinase (ERK)-dependent pathway in the pathogenesis of Eosinophilic Esophagitis

Jennifer J Huang,Anup Patel,John Kerner,Kenneth Cox,Neha Reshamwala,Lisa Hoyte,Christine Nguyen,Scott Seki,William Berquist,Eric Sibley,Dorsey Bass,Tammie Nguyen,Jae Won Joh,Judy Fuentebella,Kari C Nadeau,Anthony Quiros

doi:10.1186/1710-1492-6-25

Abstract

BackgroundEosinophilic esophagitis (EoE) is characterized by the inflammation of the esophagus and the infiltration of eosinophils into the esophagus, leading to symptoms such as dysphagia and stricture formation. Systemic immune indicators like eotaxin and fibroblast growth factor were evaluated for possible synergistic pathological effects. Moreover, blood cells, local tissue, and plasma from EoE and control subjects were studied to determine if the localized disease was associated with a systemic effect that correlated with presence of EoE disease.MethodReal-time polymerase chain reaction from peripheral blood mononuclear cells (PBMC), immunohistochemistry from local esophageal biopsies, fluid assays on plasma, and fluorescence-activated cell sorting on peripheral blood cells from subjects were used to study the systemic immune indicators in newly diagnosed EoE (n = 35), treated EoE (n = 9), Gastroesophageal reflux disease (GERD) (n = 8), ulcerative colitis (n = 5), Crohn's disease (n = 5), and healthy controls (n = 8).ResultOf the transcripts tested for possible immune indicators, we found extracellular signal-regulated kinase (ERK), Bcl-2, bFGF (basic fibroblast growth factor), and eotaxin levels were highly upregulated in PBMC and associated with disease presence of EoE. Increased FGF detected by immunohistochemistry in esophageal tissues and in PBMC was correlated with low levels of pro-apoptotic factors (Fas, Caspase 8) in PBMC from EoE subjects. Plasma-derived bFGF was shown to be the most elevated and most specific in EoE subjects in comparison to healthy controls and disease control subjects.ConclusionWe describe for the first time a possible mechanism by which increased FGF is associated with inhibiting apoptosis in local esophageal tissues of EoE subjects as compared to controls. Eotaxin and FGF signaling pathways share activation through the ERK pathway; together, they could act to increase eosinophil activation and prolong the half-life of eosinophils in local tissues of the esophagus in EoE subjects.

Highlights

Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus that can be characterized by feeding difficulties, heartburn, regurgitation, vomiting, abdominal pain, dysphagia, and food impaction [1,2,3]
Result: Of the transcripts tested for possible immune indicators, we found extracellular signal-regulated kinase (ERK), B cell lymphoma protein 2 (Bcl-2), bFGF, and eotaxin levels were highly upregulated in peripheral blood mononuclear cells (PBMC) and associated with disease presence of EoE
Demographics Data were analyzed from newly diagnosed EoE (n = 35), treated EoE (n = 9), gastroesophageal reflux disease (GERD) (n = 8), ulcerative colitis (UC, n = 5), and Crohn’s disease (CD, n = 5), healthy controls (HC, n = 8) respectively

Summary

Introduction

Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus that can be characterized by feeding difficulties, heartburn, regurgitation, vomiting, abdominal pain, dysphagia, and food impaction [1,2,3]. The symptoms do not resolve with gastric acid suppression, and EoE presents with esophageal abnormalities during endoscopy, showing eosinophil infiltration in the esophagus. Endoscopy of the subjects often shows signs of longitudinal linear furrows, trachealization, white plaques, and strictures but usually with a negative pH probe result. Subjects with more severe disease status present with severe stricturing, furrowing, and/or trachealization, which may lead to mechanical dilation of the esophagus or food impaction that requires surgical removal [13]. Eosinophilic esophagitis (EoE) is characterized by the inflammation of the esophagus and the infiltration of eosinophils into the esophagus, leading to symptoms such as dysphagia and stricture formation. Blood cells, local tissue, and plasma from EoE and control subjects were studied to determine if the localized disease was associated with a systemic effect that correlated with presence of EoE disease

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