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Kasagi Y, Dods K, Wang JX, Chandramouleeswaran PM, Benitez AJ, Gambanga F, Kluger J, Ashorobi T, Gross J, Tobias JW, Klein-Szanto AJ, Spergel JM, Cianferoni A, Falk GW, Whelan KA, Nakagawa H, Muir AB
Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-alpha
J Allergy Clin Immunol (2019) 144:171-182.
Background: Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE. Objective: We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE. Methods: LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine-stimulated esophageal 3-dimensional organoids; and fibroblast epithelial cell coculture, the latter coupled with fluorescence-activated cell sorting. Results: Gene ontology and pathway analyses linked TNF-alpha and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-alpha-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-alpha stimulates epithelial LOX expression through activation of nuclear factor kappa B and TGF-beta-mediated signaling. In patients receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in patients with EoE. Conclusions: There is a novel positive feedback mechanism in epithelial LOX induction through fibroblast-derived TNF-alpha secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.
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Publication Date: 2019-07-01.
PMCID: PMC6586527
Last updated on Monday, August 10, 2020