MMPs‐2 and ‐14 Are Elevated in Eosinophilic Esophagitis and Reduced Following Topical Corticosteroid Therapy

Beppu, Lisa; Yang, Tom; Luk, Michelle; Newbury, Robert; Palmquist, Jacob; Dohil, Ranjan; Kurten, Richard C.; Broide, David H.; Aceves, Seema S.

doi:10.1097/mpg.0000000000000668

Cited by 21 publications

(17 citation statements)

References 26 publications

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“…We have previously reported that MMP-14 is also increased in the epithelium of pediatric EoE subjects (16). Like PAI-1, MMP-14 expression and release is increased in epithelial cells by TGFβ1 (16).…”

Section: Discussionmentioning

confidence: 89%

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

Rawson

Yang

Newbury

et al. 2016

Journal of Allergy and Clinical Immunology

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Background Eosinophilic 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. Objective To understand the expression and role of PAI-1 in EoE. Methods We 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. Results PAI-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. Conclusions PAI-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.

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Section: Discussionmentioning

confidence: 89%

“…Like PAI-1, MMP-14 expression and release is increased in epithelial cells by TGFβ1 (16). Indeed, PAI-1 gene expression correlates positively with MMP-14 gene expression as well as with the expression of a number of other remodeling genes including collagen I, MMP-2, Ki67, vimentin, and TGFβ1.…”

Section: Discussionmentioning

confidence: 99%

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

Rawson

Yang

Newbury

et al. 2016

Journal of Allergy and Clinical Immunology

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“…Mast cells are produce of TGFβ1 in EoE. TGFβ1 increases pro-fibrotic gene expression and induces esophageal smooth muscle cell contraction [ 31 , 32 ]. We found that there was a step-wise gradient of mast cell numbers by genotype with TT genotype being the highest in the context of SPT positivity to foods.…”

Section: Discussionmentioning

confidence: 99%

The TGFβ1 Promoter SNP C-509T and Food Sensitization Promote Esophageal Remodeling in Pediatric Eosinophilic Esophagitis

et al. 2015

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BackgroundEosinophilic esophagitis (EoE) is a chronic antigen mediated disease associated with substantial esophageal remodeling and fibrosis. The functional TGFβ1 promoter SNP C-509 associates with renal fibrosis and asthma. The effect of TGFβ1 genotype and EoE severity or potential gene-environment interactions have not been previously reported in EoE.MethodsGenotype at TGFβ1 C-509T and remodeling was analyzed in 144 subjects with EoE. The severity of remodeling and inflammation was analyzed in the context of IgE sensitization to food antigens and C-509T genotype.ResultsThe TGFβ1 promoter C-509 genotypes CC, CT, and TT were 35%, 52%, and 13%, respectively. Sixty-six percent of subjects were sensitized to foods by positive skin prick test (SPT) or serum specific IgE. TT genotype subjects had significantly more TGFβ1 (CC subjects = 1300 per mm2; TT = 2250 per mm2) (p<0.05) and tryptase (CC subjects = 145 per mm2: TT = 307 per mm2) (p<0.05) positive cells and higher epithelial remodeling scores (2.4 vs 3.7, p<0.001) than CC subjects. The differences in TGFβ1 and tryptase positive cells as well as fibrosis were significantly increased when there was concurrent food sensitization. Food sensitization alone did not associate with any parameters of inflammation or remodeling.ConclusionsOur data support a gene-environment interaction between food and genotype at C-509 that modulates disease severity in EoE. Since EoE subjects often continue to consume foods to which they are sensitized, these findings may have clinical relevance for disease management.

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“…TGFβ also induces a number of other profibrotic tissue remodeling factors including MMPs, plasminogen activator inhibitor 1 (PAI-1) and Periostin. MMP2 and MMP14 are upregulated in EoE and in patients responding to corticosteroid therapy [39]. PAI-1 has also been found to be upregulated in active EoE patient biopsies and its expression correlates with lamina propria fibrosis.…”

Section: Mechanisms Of Fibrosis In Eoementioning

confidence: 99%

Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis

2018

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Eosinophilic esophagitis (EoE) is a food allergen-induced inflammatory disorder. EoE is increasingly recognized as a cause of swallowing dysfunction, food impaction and esophageal stricture. Inflammation of the esophageal mucosa involves immune cell infiltrate, reactive epithelial changes and fibroblast activation, culminating in robust tissue remodeling toward esophageal fibrosis characterized by excess collagen deposition in the subepithelial lamina propria. Fibrosis contributes to a unique mechanical property of the EoE-affected esophagus that is substantially stiffer than the normal esophagus. There is a great need to better understand the processes behind esophageal fibrosis in order to foster improved diagnostic tools and novel therapeutics for EoE-related esophageal fibrosis. In this review, we discuss the role of esophageal inflammatory microenvironment that promotes esophageal fibrosis, with specific emphasis upon cytokines-mediated functional epithelial-stromal interplays, recruitment and activation of a variety of effector cells, and tissue stiffness. We then explore the current state of clinical methodologies to detect and treat the EoE-related esophageal stricture.

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MMPs‐2 and ‐14 Are Elevated in Eosinophilic Esophagitis and Reduced Following Topical Corticosteroid Therapy

Cited by 21 publications

References 26 publications

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

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

The TGFβ1 Promoter SNP C-509T and Food Sensitization Promote Esophageal Remodeling in Pediatric Eosinophilic Esophagitis

Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis

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