ABSTRACT
BACKGROUND & AIMS: Patients with eosinophilic esophagitis (EoE) often become dysphagic from the combination of organ fibrosis and motor abnormalities. We investigated mechanisms of dysphagia, assessing the response of human esophageal fibroblasts (HEFs), human esophageal muscle cells (HEMCs), and esophageal muscle strips to eosinophil-derived products. METHODS: Biopsy specimens were collected via endoscopy from the upper, middle, and lower thirds of the esophagus of 18 patients with EoE and 21 individuals undergoing endoscopy for other reasons (controls). Primary cultures of esophageal fibroblasts and muscle cells were derived from 12 freshly resected human esophagectomy specimens. Eosinophil distribution was investigated by histologic analyses of full-thickness esophageal tissue. Active secretion of EoE-related mediators was assessed from medium underlying mucosal biopsy cultures. We quantified production of fibronectin and collagen I by HEF and HEMC in response to eosinophil products. We also measured the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by, and adhesion of human eosinophils to, HEFs and HEMCs. Eosinophil products were tested in an esophageal muscle contraction assay. RESULTS: Activated eosinophils were present in all esophageal layers. Significantly higher concentrations of eosinophil-related mediators were secreted spontaneously in mucosal biopsy specimens from patients with EoE than controls. Exposure of HEFs and HEMCs to increasing concentrations of eosinophil products or co-culture with eosinophils caused HEFs and HEMCs to increase secretion of fibronectin and collagen I; this was inhibited by blocking transforming growth factor ß1 and p38 mitogen-activated protein kinase signaling. Eosinophil binding to HEFs and HEMCs increased after incubation of mesenchymal cells with eosinophil-derived products, and decreased after blockade of transforming growth factor ß1 and p38 mitogen-activated protein kinase blockade. Eosinophil products reduced electrical field-induced contraction of esophageal muscle strips, but not acetylcholine-induced contraction. CONCLUSIONS: In an analysis of tissues samples from patients with EoE, we linked the presence and activation state of eosinophils in EoE with altered fibrogenesis and motility of esophageal fibroblasts and muscle cells. This process might contribute to the development of dysphagia.
Subject(s)
Cytokines/metabolism , Deglutition Disorders/etiology , Deglutition , Eosinophilic Esophagitis/complications , Eosinophils/immunology , Muscle Contraction , Th2 Cells/immunology , Transforming Growth Factor beta1/metabolism , Aged , Biopsy , Case-Control Studies , Cell Adhesion , Cell Communication , Cells, Cultured , Coculture Techniques , Collagen Type I/metabolism , Deglutition Disorders/immunology , Deglutition Disorders/metabolism , Deglutition Disorders/pathology , Deglutition Disorders/physiopathology , Eosinophilic Esophagitis/immunology , Eosinophilic Esophagitis/metabolism , Eosinophilic Esophagitis/pathology , Eosinophilic Esophagitis/physiopathology , Eosinophils/metabolism , Esophagoscopy , Female , Fibroblasts/immunology , Fibroblasts/metabolism , Fibroblasts/pathology , Fibronectins/metabolism , Fibrosis , Humans , Intercellular Adhesion Molecule-1/metabolism , Male , Middle Aged , Mucous Membrane/immunology , Mucous Membrane/metabolism , Mucous Membrane/pathology , Myocytes, Smooth Muscle/immunology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Th2 Cells/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Eosinophilic esophagitis is an increasingly recognized cause of a variety of esophageal symptoms, including dysphagia, food impaction, atypical chest pain, and heartburn that does not respond to medical therapy. Its cause is unknown, but allergic and immune-mediated mechanisms similar to those of asthma and other atopic diseases are implicated.
