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

ABSTRACT: Eosinophilic esophagitis (EoE) is an allergic disease of increasing worldwide incidence. Complications are due to tissue remodeling and involve TGF-?1-mediated fibrosis. Plasminogen activator inhibitor 1 (PAI-1/serpinE1) can be induced by TGF-?1, but its role in EoE is not known.We sought to understand the expression and role of PAI-1 in patients with EoE.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-?1, the relationship between PAI-1 and esophageal fibrosis, and the role of PAI-1 in fibrotic gene expression.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-?1 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-?1, collagen I, fibronectin, and matrix metalloproteases, and plasma PAI-1 levels correlated with plasma TGF-?1 levels. PAI-1 inhibition significantly decreased baseline and TGF-?1-induced fibrotic gene expression.PAI-1 expression is significantly increased in the epithelium in patients with EoE and reflects fibrosis, and its inhibition decreases TGF-?1-induced gene expression. Epithelial PAI-1 might serve as a marker of EoE severity and form part of a TGF-?1-induced profibrotic network.

SUBMITTER: Rawson R

PROVIDER: S-EPMC5014565 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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TGF-β1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis.

Rawson Renee R Yang Tom T Newbury Robert O RO Aquino Melissa M Doshi Ashmi A Bell Braxton B Broide David H DH Dohil Ranjan R Kurten Richard R Aceves Seema S SS

The Journal of allergy and clinical immunology 20160408 3

<h4>Background</h4>Eosinophilic esophagitis (EoE) is an allergic disease of increasing worldwide incidence. Complications are due to tissue remodeling and involve TGF-β1-mediated fibrosis. Plasminogen activator inhibitor 1 (PAI-1/serpinE1) can be induced by TGF-β1, but its role in EoE is not known.<h4>Objective</h4>We sought to understand the expression and role of PAI-1 in patients with EoE.<h4>Methods</h4>We used esophageal biopsy specimens and plasma samples from control subjects and patients ...[more]

PMID: 27212082

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Project description:Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the center of disease pathogenesis. In particular, the main EoE disease susceptibility loci at 2p23 and 5p22 encode for gene products that are produced by the esophageal epithelium: the intracellular protease calpain 14 and thymic stromal lymphopoietin, respectively. Furthermore, genetic and functional data establish a primary role for impaired epithelial barrier function in disease susceptibility and pathoetiology. Additionally, the EoE transcriptome, a set of genes dysregulated in the esophagi of patients with EoE, is enriched in genes that encode for proteins involved in esophageal epithelial cell differentiation. This transcriptome has a high proportion of esophagus-specific epithelial genes that are notable for the unexpected enrichment in genes encoding for proteases and protease inhibitors, as well as in IL-1 family genes, demonstrating a previously unappreciated role for innate immunity responses in the esophagus under homeostatic conditions. Among these pathways, basal production of the serine protease inhibitor, Kazal-type 7 (SPINK7) has been demonstrated to be part of the normal differentiation program of esophageal epithelium. Profound lost expression of SPINK7 occurs in patients with EoE and is sufficient for unleashing increased proteolytic activity (including urokinase plasminogen activator), impaired barrier function, and production of large quantities of proinflammatory and proallergic cytokines, including thymic stromal lymphopoietin. Collectively, we put forth a model in which the esophagus is normally equipped as an anti-inflammatory sensing organ and that defects in this pathway, mediated by epithelial protease/protease inhibitor imbalances, unleash inflammatory responses resulting in disorders, such as EoE.

Dataset Information

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

Publications

TGF-β1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis.

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