Identification of anoctamin 1 (ANO1) as a key driver of esophageal epithelial proliferation in eosinophilic esophagitis.

BACKGROUND: The pathology of eosinophilic esophagitis (EoE) is characterized by eosinophil-rich inflammation, basal zone hyperplasia (BZH), and dilated intercellular spaces, and the underlying processes that drive the pathologic manifestations of the disease remain largely unexplored. OBJECTIVE: We sought to investigate the involvement of the calcium-activated chloride channel anoctamin 1 (ANO1) in esophageal proliferation and the histopathologic features of EoE. METHODS: We examined mRNA and protein expression of ANO1 in esophageal biopsy samples from patients with EoE and in mice with EoE. We performed molecular and cellular analyses and ion transport assays on an in vitro esophageal epithelial 3-dimensional model system (EPC2-ALI) and murine models of EoE to define the relationship between expression and function of ANO1 and esophageal epithelial proliferation in patients with EoE. RESULTS: We observed increased ANO1 expression in esophageal biopsy samples from patients with EoE and in mice with EoE. ANO1 was expressed within the esophageal basal zone, and expression correlated positively with disease severity (eosinophils/high-power field) and BZH. Using an in vitro esophageal epithelial 3-dimensional model system revealed that ANO1 undergoes chromatin modification and rapid upregulation of expression after IL-13 stimulation, that ANO1 is the primary apical IL-13-induced Cl- transport mechanism within the esophageal epithelium, and that loss of ANO1-dependent Cl- transport abrogated esophageal epithelial proliferation. Mechanistically, ANO1-dependent regulation of basal cell proliferation was associated with modulation of TP63 expression and phosphorylated cyclin-dependent kinase 2 levels. CONCLUSIONS: These data identify a functional role for ANO1 in esophageal cell proliferation and BZH in patients with EoE and provide a rationale for pharmacologic intervention of ANO1 function in patients with EoE.

Dissociation between symptoms and histological severity in pediatric eosinophilic esophagitis.

OBJECTIVES: The relation between patient symptoms and histological severity of eosinophilic esophagitis (EE) is not known. We created a pediatric EE symptom score (PEESS) and compared the results with histological findings in the esophagus. PATIENTS AND METHODS: Subjects ages 3 to 18 years with a histological diagnosis of EE or their parent completed a survey rating the frequency and severity of their gastrointestinal symptoms. Scores ranged from 0 to 98. Eosinophil numbers in esophageal biopsy specimens were correlated with the PEESS. RESULTS: A total of 49 subjects completed the PEESS. The symptom score did not correlate with the peak eosinophil count (r = 0.079). Newly diagnosed, untreated EE subjects (N = 15) had a mean score of 24.7 +/- 16.4 with a modest correlation between the PEESS and the number of eosinophils in the distal esophagus (r = 0.37). The mean PEESS score in the 34 treated patients was lower than in untreated patients (15.6 +/- 12.9; P = 0.046). The mean score for treated patients in histological remission was the same as for treated patients with active EE, regardless of treatment type. Abdominal pain was the most frequent and severe symptom reported. Among 20 of the 34 subjects (58.8%) in histological remission, 17 (85%) continued to report symptoms with a mean score of 17.4 +/- 9.9 (range 1-38). Three children with active histological EE (10%) reported no symptoms. CONCLUSIONS: Children with untreated EE had a higher PEESS than treated subjects. Symptoms persisted in 85% of EE patients despite histological resolution and 10% with active EE reported no symptoms. Our data indicate a dissociation between symptoms and histology in pediatric EE.