TGFβ1-Induced PAI-1 Contributes to a Pro-Fibrotic Network in Eosinophilic Esophagitis

Publication date: Available online 8 April 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Renee Rawson, Tom Yang, Robert O. Newbury, Melissa Aquino, Ashmi Doshi, Braxton Bell, David H. Broide, Ranjan Dohil, Richard Kurten, Seema S. Aceves
BackgroundEosinophilic esophagitis is an allergic disease of increasing worldwide incidence. Complications are due to tissue remodeling and involve transforming growth factor-β1 (TGFβ1) mediated fibrosis. Plasminogen Activator Inhibitor-1 (PAI-1/serpinE1) can be induced by TGFβ1 but its role in EoE is not known.ObjectiveTo understand the expression and role of PAI-1 in EoEMethodsWe used esophageal biopsy specimens and plasma samples from control and EoE subjects, primary human esophageal epithelial cells, and EoE fibroblasts in immunohistochemistry, quantitative PCR, and immunoassay experiments to understand the induction of PAI-1 by TGFβ1, the relationship between PAI-1 and esophageal fibrosis, and the role of PAI-1 in fibrotic gene expression.ResultsPAI-1 expression was significantly elevated in epithelial cells of active EoE biopsies as compared with inactive EoE or control biopsies (p<0.001). Treatment of primary esophageal epithelial cells with recombinant TGFβ1 increased PAI-1 transcription, intracellular protein expression, and secretion. Esophageal PAI-1 expression correlated with basal zone hyperplasia, a fibrosis, and markers of esophageal remodeling including vimentin, TGFβ1, collagen I, fibronectin, and matrix metalloproteases and plasma PAI-1 levels correlated with plasma TGFβ1. PAI-1 inhibition significantly decreased baseline and TGFβ1-induced fibrotic gene expression.ConclusionsPAI-1 is significantly elevated in the EoE epithelium, reflects fibrosis, and its inhibition decreases TGFβ1-induced gene expression. Epithelial PAI-1 may serve as a marker of EoE severity and form part of a TGFβ1-induced pro-fibrotic network.

Teaser

PAI-1 has not been previously studied in EoE. This study shows that PAI-1 may be an epithelial marker of fibrotic severity, and could be a new therapeutic target in EoE.


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