期刊
GASTROENTEROLOGY
卷 162, 期 2, 页码 439-453出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2021.10.016
关键词
Endothelium; Eosinophil; Eosinophilic Esophagitis; Fibrosis; Transcriptome
资金
- NIH [K99/R00 AI158660]
- CEGIR, Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS) [U54 AI117804]
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- NCATS
- American Partnership for Eosinophilic Disorders
- Campaign Urging Research for Eosinophilic Disease
- Eosinophilic Family Coalition
- Data Management and Coordinating Center [U2CTR002818]
Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. IL-13 may promote tissue remodeling in EoE through fibroblast-endothelial cell crosstalk.
BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. METHODS: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. RESULTS: TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P < .001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling. CONCLUSIONS: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据