ABSTRACT
Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barrier is limited, particularly in allergy. Here, we identified a regulatory axis whereby the oxygen-sensing transcription factor HIF-1α orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1α-dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL5OXA mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1α/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1α. EoE patient biopsy analysis identified a repressed HIF-1α/claudin-1 axis, which was restored via pharmacologic HIF-1α stabilization ex vivo. Collectively, these studies reveal HIF-1α's critical role in maintaining barrier and highlight the HIF-1α/claudin-1 axis as a potential therapeutic target for EoE.
Subject(s)
Claudin-1/metabolism , Eosinophilic Esophagitis/metabolism , Epithelial Cells/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Signal Transduction , Tight Junctions/metabolism , Adolescent , Adult , Animals , Cell Line, Transformed , Child , Child, Preschool , Claudin-1/genetics , Eosinophilic Esophagitis/genetics , Eosinophilic Esophagitis/pathology , Epithelial Cells/pathology , Female , Gene Expression Regulation , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Male , Mice , Mice, Transgenic , Protein Stability , Tight Junctions/genetics , Tight Junctions/pathologyABSTRACT
OBJECTIVE: Children with eosinophilic esophagitis (EoE) experience daily challenges related to coping with symptoms and the psychosocial effect of this chronic disease. The aim of this study was to identify features of psychosocial dysfunction experienced by children with EoE who were evaluated in a tertiary care program. METHODS: We performed a retrospective review of EoE patients and their families' psychosocial evaluations performed in a tertiary care EoE program. Consecutive evaluations were analyzed to document reports of patients' disease-related pain/discomfort; feeding/appetite symptoms; sleep, social, and school problems; depression, anxiety; and overall psychological adjustment. RESULTS: Sixty-four patients received psychosocial evaluation during an 18-month period and were analyzed. Sixty-nine percent of children evaluated experienced some form of psychosocial problems, including social difficulties (64%), anxiety (41%), sleep difficulties (33%), depression (28%), and school problems (26%). Adjustment problems were identified in 44% of the sample. Older children experienced more adjustment difficulties than younger children (P = 0.05). Sleep disturbances and feeding problems predominated in the younger children. Anxious behavior and depressive feelings increased with age. Children with gastrostomy tubes (G-tubes) had more social, school, and psychological adjustment problems than those without. CONCLUSIONS: The majority of children with EoE who underwent health and behavior evaluation in a tertiary care program experienced psychosocial adjustment and coping problems. Evaluation and management by mental health professionals would likely benefit a majority of patients with this chronic disease.
