Renee Rawson, BS, Tom Yang, BS, Robert O

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TGF-β1–induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis Renee Rawson, BS, Tom Yang, BS, Robert O. Newbury, MD, Melissa Aquino, BA, Ashmi Doshi, MD, Braxton Bell, David H. Broide, MB, ChB, Ranjan Dohil, MD, Richard Kurten, PhD, Seema S. Aceves, MD, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 3, Pages 791-800.e4 (September 2016) DOI: 10.1016/j.jaci.2016.02.028 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 PAI-1 is expressed in the esophageal epithelium in patients with EoE. A-C, Representative images of PAI-1 immunohistochemistry on esophageal biopsy specimens from a nondiseased control subject (Fig 1, A), a patient with active EoE (Fig 1, B), and a patient with inactive EoE (Fig 1, C). D and E, Epithelial staining was quantified as a percentage of total epithelial height in control subjects and patients with active EoE (Fig 1, D) and in paired biopsy specimens from patients with inactive and active EoE (Fig 1, E). Lines represent means. Journal of Allergy and Clinical Immunology 2016 138, 791-800.e4DOI: (10.1016/j.jaci.2016.02.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Actively proliferating cells express PAI-1. A and B, Representative images of double immunofluorescence for PAI-1 (green; Fig 2, A and B) and cytokeratin 14 (Krt14; red; Fig 2, A) or nuclear Ki67 (red; Fig 2, B) show that PAI-1 colocalizes with cytokeratin 14–positive (yellow; Fig 2, A) and Ki67-positive (green cytoplasm, red nucleus; Fig 2, B) cells. C and D, Quantification of cells that are KRT14/PAI-1 (Fig 2, C) and Ki67/PAI-1 (Fig 2, D) double positive in the basal (BZ) and nonbasal (NBZ) zones of a subset of biopsy specimens. E, Epithelial PAI-1 expression correlates with BZH severity. F and G, PAI-1 mRNA expression correlates with Ki67 (Fig 2, F) and cytokeratin 5 (Krt5; Fig 2, G) levels in esophageal biopsy specimens from patients with active EoE, patients with inactive EoE, and control subjects. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2016 138, 791-800.e4DOI: (10.1016/j.jaci.2016.02.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 PAI-1 expression associates with fibrosis and remodeling gene expression. A, Epithelial expression of PAI-1 correlates with the severity of LP fibrosis. B-E, PAI-1 mRNA expression correlates with mRNA expression of the profibrotic genes collagen I (Fig 3, B), MMP-14 (Fig 3, C), and MMP-2 (Fig 3, D) and the epithelial mesenchymal transformation marker vimentin (VIM; Fig 3, E). F and G, PAI-1 expression correlates with numbers of tryptase-positive cells (Fig 3, F) and eosinophils (Fig 3, G). Journal of Allergy and Clinical Immunology 2016 138, 791-800.e4DOI: (10.1016/j.jaci.2016.02.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TGF-β1 induces PAI-1 expression in epithelial esophageal cells. Treatment of primary human esophageal epithelial cells with recombinant human TGF-β1 significantly induces PAI-1 gene expression (A), increases intracellular PAI-1 protein expression (B and D), and induces PAI-1 release into the supernatant (C). Journal of Allergy and Clinical Immunology 2016 138, 791-800.e4DOI: (10.1016/j.jaci.2016.02.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 PAI-1 expression associates with the degree of TGF-β1 expression. A and B, Representative images of epithelial PAI-1 expression (left) and LP TGF-β1–positive cells (right) in biopsy specimens from a control subject (Fig 5, A) and a patient with EoE (Fig 5, B). C, Epithelial PAI-1 expression correlates with the numbers LP TGF-β1–positive cells. D, mRNA expression of PAI-1 correlates with TGF-β1 levels in esophageal biopsy specimens. E, Plasma PAI-1 levels correlate with plasma TGF-β1 levels. Journal of Allergy and Clinical Immunology 2016 138, 791-800.e4DOI: (10.1016/j.jaci.2016.02.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 PAI-1 inhibition decreases gene expression in fibroblasts from patients with EoE. A and B, Treatment with the PAI-1 inhibitor TM5275 decreases baseline (Fig 6, A) and TGF-β1–induced (Fig 6, B) expression of profibrotic and myofibroblast genes. C and D, Biopsy specimens from patients with active EoE (Fig 6, C) and primary human esophageal fibroblasts (Fig 6, D) shows the presence of low-density lipoprotein–like receptor 1. Journal of Allergy and Clinical Immunology 2016 138, 791-800.e4DOI: (10.1016/j.jaci.2016.02.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 PAI-1 is increased in patients with EoE. Quantification of the percentage of “high positive” cells in control subjects, patients with active EoE (A), and patients with active and inactive EoE (B) shows higher numbers of PAI-1–positive cells. Bars represent means. Journal of Allergy and Clinical Immunology 2016 138, 791-800.e4DOI: (10.1016/j.jaci.2016.02.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions