TY - JOUR
T1 - Eosinophilic esophagitis
T2 - Epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatment
AU - Kagalwalla, Amir F.
AU - Akhtar, Noorain
AU - Woodruff, Samantha A.
AU - Rea, Bryan A.
AU - Masterson, Joanne C.
AU - Mukkada, Vincent
AU - Parashette, Kalyan R.
AU - Du, Jian
AU - Fillon, Sophie
AU - Protheroe, Cheryl A.
AU - Lee, James J.
AU - Amsden, Katie
AU - Melin-Aldana, Hector
AU - Capocelli, Kelley E.
AU - Furuta, Glenn T.
AU - Ackerman, Steven J.
N1 - Funding Information:
Disclosure of potential conflict of interest: A. F. Kagalwalla is on the speakers' bureau for Abbott Nutrition and has received research support from the Campaign Urging Research on Eosinophil Diseases, the Buckeye Foundation, and the University of Illinois at Chicago Department of Pediatrics . G. T. Furuta has received research support from the American Gastroenterological Association . The rest of the authors declare that they have no relevant conflicts of interest.
Funding Information:
Supported in part by a translational research award from the AGA (to S.J.A. and G.T.F.), National Institutes of Health (NIH) grant R21AI079925 (to G.T.F. and S.J.A.), unrestricted gifts from the Campaign Urging Research on Eosinophilic Diseases (CURED; to S.J.A., G.T.F., and A.F.K.) and the Buckeye Foundation (to A.F.K.), and research funds from the UIC Department of Pediatrics (to A.F.K. and S.J.A.) and the Mayo Foundation and its NIH grant NCRR K26 RR0109709 (J.J.L.). B.A.R. was supported in part by a Craig Medical Student Summer Research Fellowship from the UIC COM . The CURED and Buckeye Foundations did not play any role in development of the study or in the preparation of this manuscript aside from providing research funding. This project was also supported in part by NIH/NCRR Colorado CTSI grant UL1 RR025780 (to G.T.F., S.A.W., and J.C.M.). Its contents are the authors' sole responsibility and do not necessarily represent official NIH views. S.J.A. and G.T.F. are members of the Medical Advisory Panel of the American Partnership for Eosinophilic Diseases.
PY - 2012/5
Y1 - 2012/5
N2 - Background: Mechanisms underlying esophageal remodeling with subepithelial fibrosis in subjects with eosinophilic esophagitis (EoE) have not been delineated. Objectives: We sought to explore a role for epithelial mesenchymal transition (EMT) in subjects with EoE and determine whether EMT resolves with treatment. Methods: Esophageal biopsy specimens from 60 children were immunostained for epithelial (cytokeratin) and mesenchymal (vimentin) EMT biomarkers, and EMT was quantified. Subjects studied had EoE (n = 17), indeterminate EoE (n = 15), gastroesophageal reflux disease (n = 7), or normal esophagus (n = 21). EMT was analyzed for relationships to diagnosis, eosinophil counts, and indices of subepithelial fibrosis, eosinophil peroxidase, and TGF-β immunostaining. EMT was assessed in pretreatment and posttreatment biopsy specimens from 18 subjects with EoE treated with an elemental diet, 6-food elimination diet, or topical corticosteroids (n = 6 per group). Results: TGF-β1 treatment of esophageal epithelial cells in vitro for 24 hours induced upregulation of mesenchymal genes characteristic of EMT, including N-cadherin (3.3-fold), vimentin (2.1-fold), and fibronectin (7.5-fold). EMT in esophageal biopsy specimens was associated with EoE (or indeterminate EoE) but not gastroesophageal reflux disease or normal esophagus and was correlated to eosinophil counts (r = 0.691), eosinophil peroxidase (r = 0.738), and TGF-β (r = 0.520) immunostaining and fibrosis (r = 0.644) indices. EMT resolved with EoE treatments that induced clinicopathologic remission with reduced eosinophil counts. EMT decreased significantly after treatment by 74.1% overall in the 18 treated subjects with EoE; pretreatment versus posttreatment EMT scores were 3.17 ± 0.82 versus 0.82 ± 0.39 (P <.001), with similar decreases within treatment groups. Pretreatment/posttreatment EMT was strongly correlated with eosinophil counts for combined (r = 0.804, P <.001) and individual treatment groups. Conclusions: EMT likely contributes to subepithelial fibrosis in subjects with EoE and resolves with treatments that decrease esophageal inflammation, and its resolution correlates with decreased numbers of esophageal eosinophils.
AB - Background: Mechanisms underlying esophageal remodeling with subepithelial fibrosis in subjects with eosinophilic esophagitis (EoE) have not been delineated. Objectives: We sought to explore a role for epithelial mesenchymal transition (EMT) in subjects with EoE and determine whether EMT resolves with treatment. Methods: Esophageal biopsy specimens from 60 children were immunostained for epithelial (cytokeratin) and mesenchymal (vimentin) EMT biomarkers, and EMT was quantified. Subjects studied had EoE (n = 17), indeterminate EoE (n = 15), gastroesophageal reflux disease (n = 7), or normal esophagus (n = 21). EMT was analyzed for relationships to diagnosis, eosinophil counts, and indices of subepithelial fibrosis, eosinophil peroxidase, and TGF-β immunostaining. EMT was assessed in pretreatment and posttreatment biopsy specimens from 18 subjects with EoE treated with an elemental diet, 6-food elimination diet, or topical corticosteroids (n = 6 per group). Results: TGF-β1 treatment of esophageal epithelial cells in vitro for 24 hours induced upregulation of mesenchymal genes characteristic of EMT, including N-cadherin (3.3-fold), vimentin (2.1-fold), and fibronectin (7.5-fold). EMT in esophageal biopsy specimens was associated with EoE (or indeterminate EoE) but not gastroesophageal reflux disease or normal esophagus and was correlated to eosinophil counts (r = 0.691), eosinophil peroxidase (r = 0.738), and TGF-β (r = 0.520) immunostaining and fibrosis (r = 0.644) indices. EMT resolved with EoE treatments that induced clinicopathologic remission with reduced eosinophil counts. EMT decreased significantly after treatment by 74.1% overall in the 18 treated subjects with EoE; pretreatment versus posttreatment EMT scores were 3.17 ± 0.82 versus 0.82 ± 0.39 (P <.001), with similar decreases within treatment groups. Pretreatment/posttreatment EMT was strongly correlated with eosinophil counts for combined (r = 0.804, P <.001) and individual treatment groups. Conclusions: EMT likely contributes to subepithelial fibrosis in subjects with EoE and resolves with treatments that decrease esophageal inflammation, and its resolution correlates with decreased numbers of esophageal eosinophils.
KW - Eosinophil
KW - cytokeratin
KW - epithelium
KW - esophagitis
KW - fibrosis
KW - mesenchymal
KW - remodeling
KW - vimentin
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U2 - 10.1016/j.jaci.2012.03.005
DO - 10.1016/j.jaci.2012.03.005
M3 - Article
C2 - 22465212
AN - SCOPUS:84860490159
VL - 129
SP - 1387-1396.e6
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 5
ER -