TGF-ß1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis.

ABSTRACT

BACKGROUND: Eosinophilic esophagitis (EoE) is an allergic disease of increasing worldwide incidence. Complications are due to tissue remodeling and involve TGF-ß1-mediated fibrosis. Plasminogen activator inhibitor 1 (PAI-1/serpinE1) can be induced by TGF-ß1, but its role in EoE is not known. OBJECTIVE: We sought to understand the expression and role of PAI-1 in patients with EoE. METHODS: We used esophageal biopsy specimens and plasma samples from control subjects and patients with EoE, primary human esophageal epithelial cells, and fibroblasts from patients with EoE in immunohistochemistry, quantitative PCR, and immunoassay experiments to understand the induction of PAI-1 by TGF-ß1, the relationship between PAI-1 and esophageal fibrosis, and the role of PAI-1 in fibrotic gene expression. RESULTS: PAI-1 expression was significantly increased in epithelial cells of biopsy specimens from patients with active EoE compared with that seen in biopsy specimens from patients with inactive EoE or control subjects (P < .001). Treatment of primary esophageal epithelial cells with recombinant TGF-ß1 increased PAI-1 transcription, intracellular protein expression, and secretion. Esophageal PAI-1 expression correlated with basal zone hyperplasia, fibrosis, and markers of esophageal remodeling, including vimentin, TGF-ß1, collagen I, fibronectin, and matrix metalloproteases, and plasma PAI-1 levels correlated with plasma TGF-ß1 levels. PAI-1 inhibition significantly decreased baseline and TGF-ß1-induced fibrotic gene expression. CONCLUSIONS: PAI-1 expression is significantly increased in the epithelium in patients with EoE and reflects fibrosis, and its inhibition decreases TGF-ß1-induced gene expression. Epithelial PAI-1 might serve as a marker of EoE severity and form part of a TGF-ß1-induced profibrotic network.