Eosinophilic esophagitis (EoE) is an allergic disease characterized by esophageal infiltration of eosinophils, diagnosed from childhood through adulthood. Esophageal fibrosis is the most serious complication of EoE, leading to dysphagia and esophageal food impaction starting in the second decade of life. Elucidating the mechanisms which lead to fibrosis is critical to understanding the natural history of EoE. Our preliminary data suggests that cross-talk between primary EoE esophageal epithelial cells (EPCs) and primary fetal esophageal fibroblast cells (FEF3) enhances FEF3 expression of profibrotic cytokines. However, our model is limited by its use of fetal fibroblasts, which are functionally distinct from pediatric and adult fibroblasts. To date, characterization of esophageal fibroblasts spanning pediatric and adult EoE populations has never been described. Our overall hypothesis is that esophageal fibroblasts from EoE subjects are phenotypically distinct from fibroblasts from non-EoE subjects, and that fibro genic characteristics of EoE fibroblasts are enhanced during human maturation. Using primary esophageal fibroblasts, we will characterize fibroblast cytokine responses and contractility, comparing responses between age-matched EoE and non-EoE subjects (Aim 1a). Age-related differences in fibrotic responses in EoE subjects ages 1-9 years, 10-17 years, and adults will be examined (Aim 1b). We will determine fibroblast responses to epithelial-derived factors in the context of physiologically relevant epithelial stimuli including acid/bile and EoE triggers (food antigens) (Aim 2a). Finally, the effects of these stimuli upon fibrosis will be examined using novel organotypic cell culture models of """"""""living"""""""" esophageal tissue, constructed from primary EPCs and esophageal fibroblast cell lines (Aim 2b).
Eosinophilic esophagitis (EoE) is a chronic disease in which allergic inflammation and tissue damage eventually lead to scarring and fibrosis of the esophagus. This proposal seeks to better elucidate the changes that occur to fibroblasts during human maturation, to understand the natural course of EoE, and to predict and prevent these serious complications.
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