FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2056501262> ?p ?o ?g. }

• W2056501262 endingPage "1049" @default.
• W2056501262 startingPage "1047" @default.
• W2056501262 abstract "The concept of eosinophil-associated tissue remodeling and fibrosis has its roots in the hypereosinophilic syndrome and asthmatic airways.1Al-Muhsen S. Johnson J.R. Hamid Q. Remodeling in asthma.J Allergy Clin Immunol. 2011; 128: 451-462Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar In asthmatic patients TH2-associated eotaxins and interleukins activate eosinophils to release granule products and growth factors that propagate inflammation and cause tissue damage. Continual and recurrent dysregulated repair leads to tissue remodeling with subsequent fibrosis and end-organ dysfunction. The reversibility, natural history, and clinical consequences of eosinophil-associated remodeling have been largely debated, especially in human disease, in which the paucity of tissue for repeated analysis has been a rate-limiting factor in our understanding. The availability of adequate surrogate markers in patients with disorders such as asthma has obviated any clinical requirement for direct tissue assessment.In contrast, eosinophilic esophagitis (EoE), a relatively recently described antigen-driven disease of increasing worldwide prevalence, by its definition requires microscopic esophageal tissue evaluation for its diagnosis and management.2Liacouras C.A. Furuta G.T. Hirano I. Atkins D. Attwood S.E. Bonis P.A. et al.Eosinophilic esophagitis: updated consensus recommendations for children and adults.J Allergy Clin Immunol. 2011; 128: 3-20Abstract Full Text Full Text PDF PubMed Scopus (1548) Google Scholar This necessity for repeated histologic analysis allows EoE to function as a new model for studying allergic, eosinophil-associated remodeling over time. Although asthmatic airway remodeling has been hypothesized to begin in early childhood, the ability to study airway tissue in children remains elusive. EoE, on the other hand, affords the potential to monitor the genesis and evolution of remodeling in young children.1Al-Muhsen S. Johnson J.R. Hamid Q. Remodeling in asthma.J Allergy Clin Immunol. 2011; 128: 451-462Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar However, despite readily available esophageal tissue, remodeling analysis in patients with EoE still has its challenges. Esophageal biopsy specimens are small, approximately 3 mm. Although the esophageal epithelium is uniformly available from all biopsy specimens, only the minority of biopsy specimens contain adequate subepithelial lamina propria (LP) and muscularis mucosa for analysis. Because a large number of remodeling events, including fibrosis and angiogenesis, occur in the LP, this can generally only be studied in a subset of patients with EoE. Whether this required selection of biopsy specimens that have adequate LP introduces a phenotypic patient bias into studies of esophageal remodeling is unclear. In addition, whether any or all subepithelial findings are adequately reflected by epithelial changes remains to be systematically evaluated. Nonetheless, we have had multiple insights into esophageal remodeling from the current EoE literature. Human and animal model studies of EoE demonstrate that esophageal remodeling includes subepithelial fibrosis, angiogenesis, smooth muscle hypertrophy, and dysfunction; occurs both in children and adults; requires eosinophils, eotaxin-3, IL-5, and IL-13 for its pathogenesis; and involves eosinophil- and mast cell–derived TGF-β1.3Aceves S.S. Newbury R.O. Dohil R. Bastian J.F. Broide D.H. Esophageal remodeling in pediatric eosinophilic esophagitis.J Allergy Clin Immunol. 2007; 119: 206-212Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 4Fox V.L. Eosinophilic esophagitis: endoscopic findings.Gastrointest Endosc Clin N Am. 2008; 18: 45-57Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 5Nurko S. Rosen R. Furuta G.T. Esophageal dysmotility in children with eosinophilic esophagitis: a study using prolonged esophageal manometry.Am J Gastroenterol. 2009; 104: 3050-3057Crossref PubMed Scopus (77) Google Scholar, 6Straumann A. Conus S. Degen L. Felder S. Kummer M. Engel H. et al.Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.Gastroenterology. 2010; 139: 1526-1537Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 7Blanchard C. Wang N. Stringer K.F. Mishra A. Fulkerson P.C. Abonia J.P. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (696) Google Scholar, 8Zuo L. Fulkerson P.C. Finkelman F.D. Mingler M. Fischetti C.A. Blanchard C. et al.IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R alpha 2-inhibited pathway.J Immunol. 2010; 185: 660Crossref PubMed Scopus (156) Google Scholar, 9Mishra A. Wang M. Pemmaraju V.R. Collins M.H. Fulkerson P.C. Abonia J.P. et al.Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia.Gastroenterology. 2008; 134: 204-214Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 10Aceves S.S. Chen D. Newbury R.O. Dohil R. Bastian J. Broide D.H. Mast cells infiltrate the esophageal smooth muscle in eosinophilic esophagitis, express TGFβ1, and increase esophageal smooth muscle contraction.J Allergy Clin Immunol. 2010; 126: 1198-1204Abstract Full Text Full Text PDF PubMed Scopus (191) Google ScholarIn this issue of the Journal, Lucendo et al11Lucendo A.J. Arias A. De Rezende L.C. Yagüe-Compadre J.L. Mota-Huertas T. González-Castillo S. et al.Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: a prospective study.J Allergy Clin Immunol. 2011; 128: 1037-1046Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar report their findings in 10 adult patients treated for 1 year with topical esophageal fluticasone propionate. Using large-volume forceps, the investigators were able to overcome the problem of having only a subset of patients whose biopsy specimens contain adequate subepithelial tissue. All 10 consecutive patients’ biopsy specimens had LP and muscularis mucosa, allowing a nonbiased approach to those patients who could be evaluated for fibrotic changes. The adult patients with EoE in their cohort had a relatively severe phenotype with prolonged symptoms (mean, >5 years), with 40% having esophageal rings or stricture indicative of decreased esophageal caliber, 60% having dysphagia, and 80% having food impactions. Patients with EoE were treated with a nonthickened, swallowed liquid formulation of fluticasone for which efficacy and safety have not been documented in prior clinical trials and that might not have the same mucosal penetration, adherence, or transit-time properties of a thickened suspension or particulate.Similar to prior studies in adults and children, IL-59Mishra A. Wang M. Pemmaraju V.R. Collins M.H. Fulkerson P.C. Abonia J.P. et al.Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia.Gastroenterology. 2008; 134: 204-214Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar and fibroblast growth factor 912Mulder D.J. Pacheco I. Hurlbut D.J. Mak N. Furuta G.T. MacLeod R.J. et al.FGF9-induced proliferative response to eosinophilic inflammation in oesophagitis.Gut. 2009; 58: 166-173Crossref PubMed Scopus (62) Google Scholar levels were increased in patients with EoE compared with levels seen in the control groups, who had normal esophageal histology or gastroesophageal reflux disease. Unlike other reports, there were increased levels of CCL-18, a factor associated with M2 macrophages and fibrous diseases. After esophageal fluticasone treatment, the overall group showed significant decreases in CCL-18 levels. In contrast, the effects on the overall fibrosis score and mRNA levels of IL-5, fibroblast growth factor 9, and TGF-β1 were less striking, and a degree of subepithelial eosinophilia persisted despite epithelial eosinophil resolution. As such, although CCL18 levels were significantly decreased, its potential contribution to esophageal fibrosis is complicated by the lack of a corresponding significant decrease in LP fibrosis. TGF-β1 and IL-5 mRNA levels correlated to one another, and like fibrosis, neither was significantly reduced after therapy. This is in contrast to shorter-duration studies in children and adults in whom the resolution of epithelial eosinophilia after topical corticosteroids is accompanied by improvements in fibrosis, TGF-β1 (levels of which are increased at baseline), phosphorylated Smad2/3 protein, and vascular activation.6Straumann A. Conus S. Degen L. Felder S. Kummer M. Engel H. et al.Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.Gastroenterology. 2010; 139: 1526-1537Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 13Aceves S.S. Newbury R.O. Chen D. Dohil R. Mueller J. Hoffman H. et al.Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids.Allergy. 2010; 65: 109-116Crossref PubMed Scopus (239) Google Scholar These disparate results could stem from an incomplete fluticasone penetration into the LP, the use of deeper biopsies with proportionally more subepithelial tissue, the analysis of transcript versus protein levels, an overall variability that is missed in other studies caused by a lack of unbiased LP procurement, and/or the use of a distinct TGF-β1–independent fibrotic pathway in a subset of adults.In patients with diseases such as idiopathic pulmonary fibrosis, there are accumulating data that epithelial injury is a substantive force for orchestrating fibrosis.14Hardie W.D. Hagood J.S. Dave V. Perl A.K. Whitsett J.A. Korfhagen T.R. et al.Signaling pathways in the epithelial origins of pulmonary fibrosis.Cell Cycle. 2010; 9: 2769-2776Crossref PubMed Scopus (54) Google Scholar Consistent with this hypothesis, there is alignment of epithelial healing and subepithelial inflammation in children whereby only patients with epithelial EoE resolution have improved LP findings and children with epithelial nonresponsive EoE have persistent LP fibrosis and inflammation.13Aceves S.S. Newbury R.O. Chen D. Dohil R. Mueller J. Hoffman H. et al.Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids.Allergy. 2010; 65: 109-116Crossref PubMed Scopus (239) Google Scholar However, the cohort of Lucendo et al11Lucendo A.J. Arias A. De Rezende L.C. Yagüe-Compadre J.L. Mota-Huertas T. González-Castillo S. et al.Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: a prospective study.J Allergy Clin Immunol. 2011; 128: 1037-1046Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar has a subset of adult patients with epithelial eosinophil resolution, symptom improvements, and endoscopic normalization who show continued fibrosis and profibrotic gene expression after therapy. A few patients have progressive fibrosis despite apparent disease resolution in the epithelium. The propagation of fibrosis in these patients might be guided by LP signals that function independently from the epithelium and that are unable to limit the fibrotic cascade. These findings might also point to differences in the mechanisms of pediatric versus adult fibrosis.Interestingly, patient age, but not symptom duration, was directly associated with the severity of fibrosis. This brings up 2 important points about EoE. First, it suggests that active disease duration can be associated with progressive fibrosis, an observation that is supported by limited pediatric data. Second, it suggests that symptom activity does not accurately reflect fibrotic severity or endoscopic appearance. Patients with chronic EoE likely have compensatory behaviors that mask symptom severity. As such, there is a pressing need for new modalities to assess the potential clinical consequences of remodeling, including validated symptom-scoring tools and a systematic assessment of esophageal dysmotility and rigidity15Kwiatek M.A. Hirano I. Kahrilas P.J. Rothe J. Luger D. Pandolfino J.E. Mechanical properties of the esophagus in eosinophilic esophagitis.Gastroenterology. 2011; 140: 82-90Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar in adults and children.The most severe consequence of EoE is stricture formation.2Liacouras C.A. Furuta G.T. Hirano I. Atkins D. Attwood S.E. Bonis P.A. et al.Eosinophilic esophagitis: updated consensus recommendations for children and adults.J Allergy Clin Immunol. 2011; 128: 3-20Abstract Full Text Full Text PDF PubMed Scopus (1548) Google Scholar Currently, the natural history, phenotypes, genotypes, and gene-environment interactions that predispose to severe fibrosis remain unclear. However, unlike in asthmatic patients, in whom there are no clear data that inhaled corticosteroids reverse remodeling, current EoE data show that remodeling features can be reversed in a subset of patients.6Straumann A. Conus S. Degen L. Felder S. Kummer M. Engel H. et al.Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.Gastroenterology. 2010; 139: 1526-1537Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 13Aceves S.S. Newbury R.O. Chen D. Dohil R. Mueller J. Hoffman H. et al.Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids.Allergy. 2010; 65: 109-116Crossref PubMed Scopus (239) Google Scholar Whereas in asthmatic patients the age of remodeling onset is unclear,1Al-Muhsen S. Johnson J.R. Hamid Q. Remodeling in asthma.J Allergy Clin Immunol. 2011; 128: 451-462Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar EoE studies show us that children less than 2 years old can have remodeling and that long-standing EoE in children can be associated with higher numbers of TGF-β1+ cells (unpublished data).14Hardie W.D. Hagood J.S. Dave V. Perl A.K. Whitsett J.A. Korfhagen T.R. et al.Signaling pathways in the epithelial origins of pulmonary fibrosis.Cell Cycle. 2010; 9: 2769-2776Crossref PubMed Scopus (54) Google Scholar On the molecular level, remodeling in patients with EoE implicates antigen induction of subepithelial inflammation and fibrovascular changes, which are postulated to lead to clinical sequelae, such as strictures, dysmotility, and dysphagia (Fig 1). We hope that the removal of antigens and/or treatment with biologic agents, topical corticosteroids, or both can halt the fibroinflammatory cascade and intervene in the natural history and clinical complications related to remodeling in patients with EoE. If this is the case, then earlier aggressive therapy to control epithelial and subepithelial inflammation, especially in children during a “developmental window of opportunity,”1Al-Muhsen S. Johnson J.R. Hamid Q. Remodeling in asthma.J Allergy Clin Immunol. 2011; 128: 451-462Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar might be indicated. Future pediatric and adult studies that systematically evaluate remodeling in the context of clinical EoE features will be paramount in providing an understanding of the mechanisms and true clinical sequelae of what lies beneath the surface in patients with EoE. The concept of eosinophil-associated tissue remodeling and fibrosis has its roots in the hypereosinophilic syndrome and asthmatic airways.1Al-Muhsen S. Johnson J.R. Hamid Q. Remodeling in asthma.J Allergy Clin Immunol. 2011; 128: 451-462Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar In asthmatic patients TH2-associated eotaxins and interleukins activate eosinophils to release granule products and growth factors that propagate inflammation and cause tissue damage. Continual and recurrent dysregulated repair leads to tissue remodeling with subsequent fibrosis and end-organ dysfunction. The reversibility, natural history, and clinical consequences of eosinophil-associated remodeling have been largely debated, especially in human disease, in which the paucity of tissue for repeated analysis has been a rate-limiting factor in our understanding. The availability of adequate surrogate markers in patients with disorders such as asthma has obviated any clinical requirement for direct tissue assessment. In contrast, eosinophilic esophagitis (EoE), a relatively recently described antigen-driven disease of increasing worldwide prevalence, by its definition requires microscopic esophageal tissue evaluation for its diagnosis and management.2Liacouras C.A. Furuta G.T. Hirano I. Atkins D. Attwood S.E. Bonis P.A. et al.Eosinophilic esophagitis: updated consensus recommendations for children and adults.J Allergy Clin Immunol. 2011; 128: 3-20Abstract Full Text Full Text PDF PubMed Scopus (1548) Google Scholar This necessity for repeated histologic analysis allows EoE to function as a new model for studying allergic, eosinophil-associated remodeling over time. Although asthmatic airway remodeling has been hypothesized to begin in early childhood, the ability to study airway tissue in children remains elusive. EoE, on the other hand, affords the potential to monitor the genesis and evolution of remodeling in young children.1Al-Muhsen S. Johnson J.R. Hamid Q. Remodeling in asthma.J Allergy Clin Immunol. 2011; 128: 451-462Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar However, despite readily available esophageal tissue, remodeling analysis in patients with EoE still has its challenges. Esophageal biopsy specimens are small, approximately 3 mm. Although the esophageal epithelium is uniformly available from all biopsy specimens, only the minority of biopsy specimens contain adequate subepithelial lamina propria (LP) and muscularis mucosa for analysis. Because a large number of remodeling events, including fibrosis and angiogenesis, occur in the LP, this can generally only be studied in a subset of patients with EoE. Whether this required selection of biopsy specimens that have adequate LP introduces a phenotypic patient bias into studies of esophageal remodeling is unclear. In addition, whether any or all subepithelial findings are adequately reflected by epithelial changes remains to be systematically evaluated. Nonetheless, we have had multiple insights into esophageal remodeling from the current EoE literature. Human and animal model studies of EoE demonstrate that esophageal remodeling includes subepithelial fibrosis, angiogenesis, smooth muscle hypertrophy, and dysfunction; occurs both in children and adults; requires eosinophils, eotaxin-3, IL-5, and IL-13 for its pathogenesis; and involves eosinophil- and mast cell–derived TGF-β1.3Aceves S.S. Newbury R.O. Dohil R. Bastian J.F. Broide D.H. Esophageal remodeling in pediatric eosinophilic esophagitis.J Allergy Clin Immunol. 2007; 119: 206-212Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 4Fox V.L. Eosinophilic esophagitis: endoscopic findings.Gastrointest Endosc Clin N Am. 2008; 18: 45-57Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 5Nurko S. Rosen R. Furuta G.T. Esophageal dysmotility in children with eosinophilic esophagitis: a study using prolonged esophageal manometry.Am J Gastroenterol. 2009; 104: 3050-3057Crossref PubMed Scopus (77) Google Scholar, 6Straumann A. Conus S. Degen L. Felder S. Kummer M. Engel H. et al.Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.Gastroenterology. 2010; 139: 1526-1537Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 7Blanchard C. Wang N. Stringer K.F. Mishra A. Fulkerson P.C. Abonia J.P. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (696) Google Scholar, 8Zuo L. Fulkerson P.C. Finkelman F.D. Mingler M. Fischetti C.A. Blanchard C. et al.IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R alpha 2-inhibited pathway.J Immunol. 2010; 185: 660Crossref PubMed Scopus (156) Google Scholar, 9Mishra A. Wang M. Pemmaraju V.R. Collins M.H. Fulkerson P.C. Abonia J.P. et al.Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia.Gastroenterology. 2008; 134: 204-214Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 10Aceves S.S. Chen D. Newbury R.O. Dohil R. Bastian J. Broide D.H. Mast cells infiltrate the esophageal smooth muscle in eosinophilic esophagitis, express TGFβ1, and increase esophageal smooth muscle contraction.J Allergy Clin Immunol. 2010; 126: 1198-1204Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar In this issue of the Journal, Lucendo et al11Lucendo A.J. Arias A. De Rezende L.C. Yagüe-Compadre J.L. Mota-Huertas T. González-Castillo S. et al.Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: a prospective study.J Allergy Clin Immunol. 2011; 128: 1037-1046Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar report their findings in 10 adult patients treated for 1 year with topical esophageal fluticasone propionate. Using large-volume forceps, the investigators were able to overcome the problem of having only a subset of patients whose biopsy specimens contain adequate subepithelial tissue. All 10 consecutive patients’ biopsy specimens had LP and muscularis mucosa, allowing a nonbiased approach to those patients who could be evaluated for fibrotic changes. The adult patients with EoE in their cohort had a relatively severe phenotype with prolonged symptoms (mean, >5 years), with 40% having esophageal rings or stricture indicative of decreased esophageal caliber, 60% having dysphagia, and 80% having food impactions. Patients with EoE were treated with a nonthickened, swallowed liquid formulation of fluticasone for which efficacy and safety have not been documented in prior clinical trials and that might not have the same mucosal penetration, adherence, or transit-time properties of a thickened suspension or particulate. Similar to prior studies in adults and children, IL-59Mishra A. Wang M. Pemmaraju V.R. Collins M.H. Fulkerson P.C. Abonia J.P. et al.Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia.Gastroenterology. 2008; 134: 204-214Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar and fibroblast growth factor 912Mulder D.J. Pacheco I. Hurlbut D.J. Mak N. Furuta G.T. MacLeod R.J. et al.FGF9-induced proliferative response to eosinophilic inflammation in oesophagitis.Gut. 2009; 58: 166-173Crossref PubMed Scopus (62) Google Scholar levels were increased in patients with EoE compared with levels seen in the control groups, who had normal esophageal histology or gastroesophageal reflux disease. Unlike other reports, there were increased levels of CCL-18, a factor associated with M2 macrophages and fibrous diseases. After esophageal fluticasone treatment, the overall group showed significant decreases in CCL-18 levels. In contrast, the effects on the overall fibrosis score and mRNA levels of IL-5, fibroblast growth factor 9, and TGF-β1 were less striking, and a degree of subepithelial eosinophilia persisted despite epithelial eosinophil resolution. As such, although CCL18 levels were significantly decreased, its potential contribution to esophageal fibrosis is complicated by the lack of a corresponding significant decrease in LP fibrosis. TGF-β1 and IL-5 mRNA levels correlated to one another, and like fibrosis, neither was significantly reduced after therapy. This is in contrast to shorter-duration studies in children and adults in whom the resolution of epithelial eosinophilia after topical corticosteroids is accompanied by improvements in fibrosis, TGF-β1 (levels of which are increased at baseline), phosphorylated Smad2/3 protein, and vascular activation.6Straumann A. Conus S. Degen L. Felder S. Kummer M. Engel H. et al.Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.Gastroenterology. 2010; 139: 1526-1537Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 13Aceves S.S. Newbury R.O. Chen D. Dohil R. Mueller J. Hoffman H. et al.Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids.Allergy. 2010; 65: 109-116Crossref PubMed Scopus (239) Google Scholar These disparate results could stem from an incomplete fluticasone penetration into the LP, the use of deeper biopsies with proportionally more subepithelial tissue, the analysis of transcript versus protein levels, an overall variability that is missed in other studies caused by a lack of unbiased LP procurement, and/or the use of a distinct TGF-β1–independent fibrotic pathway in a subset of adults. In patients with diseases such as idiopathic pulmonary fibrosis, there are accumulating data that epithelial injury is a substantive force for orchestrating fibrosis.14Hardie W.D. Hagood J.S. Dave V. Perl A.K. Whitsett J.A. Korfhagen T.R. et al.Signaling pathways in the epithelial origins of pulmonary fibrosis.Cell Cycle. 2010; 9: 2769-2776Crossref PubMed Scopus (54) Google Scholar Consistent with this hypothesis, there is alignment of epithelial healing and subepithelial inflammation in children whereby only patients with epithelial EoE resolution have improved LP findings and children with epithelial nonresponsive EoE have persistent LP fibrosis and inflammation.13Aceves S.S. Newbury R.O. Chen D. Dohil R. Mueller J. Hoffman H. et al.Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids.Allergy. 2010; 65: 109-116Crossref PubMed Scopus (239) Google Scholar However, the cohort of Lucendo et al11Lucendo A.J. Arias A. De Rezende L.C. Yagüe-Compadre J.L. Mota-Huertas T. González-Castillo S. et al.Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: a prospective study.J Allergy Clin Immunol. 2011; 128: 1037-1046Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar has a subset of adult patients with epithelial eosinophil resolution, symptom improvements, and endoscopic normalization who show continued fibrosis and profibrotic gene expression after therapy. A few patients have progressive fibrosis despite apparent disease resolution in the epithelium. The propagation of fibrosis in these patients might be guided by LP signals that function independently from the epithelium and that are unable to limit the fibrotic cascade. These findings might also point to differences in the mechanisms of pediatric versus adult fibrosis. Interestingly, patient age, but not symptom duration, was directly associated with the severity of fibrosis. This brings up 2 important points about EoE. First, it suggests that active disease duration can be associated with progressive fibrosis, an observation that is supported by limited pediatric data. Second, it suggests that symptom activity does not accurately reflect fibrotic severity or endoscopic appearance. Patients with chronic EoE likely have compensatory behaviors that mask symptom severity. As such, there is a pressing need for new modalities to assess the potential clinical consequences of remodeling, including validated symptom-scoring tools and a systematic assessment of esophageal dysmotility and rigidity15Kwiatek M.A. Hirano I. Kahrilas P.J. Rothe J. Luger D. Pandolfino J.E. Mechanical properties of the esophagus in eosinophilic esophagitis.Gastroenterology. 2011; 140: 82-90Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar in adults and children. The most severe consequence of EoE is stricture formation.2Liacouras C.A. Furuta G.T. Hirano I. Atkins D. Attwood S.E. Bonis P.A. et al.Eosinophilic esophagitis: updated consensus recommendations for children and adults.J Allergy Clin Immunol. 2011; 128: 3-20Abstract Full Text Full Text PDF PubMed Scopus (1548) Google Scholar Currently, the natural history, phenotypes, genotypes, and gene-environment interactions that predispose to severe fibrosis remain unclear. However, unlike in asthmatic patients, in whom there are no clear data that inhaled corticosteroids reverse remodeling, current EoE data show that remodeling features can be reversed in a subset of patients.6Straumann A. Conus S. Degen L. Felder S. Kummer M. Engel H. et al.Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.Gastroenterology. 2010; 139: 1526-1537Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 13Aceves S.S. Newbury R.O. Chen D. Dohil R. Mueller J. Hoffman H. et al.Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids.Allergy. 2010; 65: 109-116Crossref PubMed Scopus (239) Google Scholar Whereas in asthmatic patients the age of remodeling onset is unclear,1Al-Muhsen S. Johnson J.R. Hamid Q. Remodeling in asthma.J Allergy Clin Immunol. 2011; 128: 451-462Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar EoE studies show us that children less than 2 years old can have remodeling and that long-standing EoE in children can be associated with higher numbers of TGF-β1+ cells (unpublished data).14Hardie W.D. Hagood J.S. Dave V. Perl A.K. Whitsett J.A. Korfhagen T.R. et al.Signaling pathways in the epithelial origins of pulmonary fibrosis.Cell Cycle. 2010; 9: 2769-2776Crossref PubMed Scopus (54) Google Scholar On the molecular level, remodeling in patients with EoE implicates antigen induction of subepithelial inflammation and fibrovascular changes, which are postulated to lead to clinical sequelae, such as strictures, dysmotility, and dysphagia (Fig 1). We hope that the removal of antigens and/or treatment with biologic agents, topical corticosteroids, or both can halt the fibroinflammatory cascade and intervene in the natural history and clinical complications related to remodeling in patients with EoE. If this is the case, then earlier aggressive therapy to control epithelial and subepithelial inflammation, especially in children during a “developmental window of opportunity,”1Al-Muhsen S. Johnson J.R. Hamid Q. Remodeling in asthma.J Allergy Clin Immunol. 2011; 128: 451-462Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar might be indicated. Future pediatric and adult studies that systematically evaluate remodeling in the context of clinical EoE features will be paramount in providing an understanding of the mechanisms and true clinical sequelae of what lies beneath the surface in patients with EoE. I thank Drs Glenn Furuta and David Broide for critical reading. Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: A prospective studyJournal of Allergy and Clinical ImmunologyVol. 128Issue 5PreviewRecent research shows that both pediatric and adult patients with eosinophilic esophagitis (EoE) experience esophageal remodeling marked by increased collagen deposition in which TGF-β plays an important role. However, limited data are available on the intensity and reversibility of fibrous remodeling in adults with EoE. Full-Text PDF" @default.
• W2056501262 created "2016-06-24" @default.
• W2056501262 creator A5089210937 @default.
• W2056501262 date "2011-11-01" @default.
• W2056501262 modified "2023-10-18" @default.
• W2056501262 title "Tissue remodeling in patients with eosinophilic esophagitis: What lies beneath the surface?" @default.
• W2056501262 cites W1603709335 @default.
• W2056501262 cites W1967926844 @default.
• W2056501262 cites W1972578247 @default.
• W2056501262 cites W1995481725 @default.
• W2056501262 cites W1997015714 @default.
• W2056501262 cites W2005895346 @default.
• W2056501262 cites W2007046473 @default.
• W2056501262 cites W2063903627 @default.
• W2056501262 cites W2069688346 @default.
• W2056501262 cites W2075782740 @default.
• W2056501262 cites W2079587357 @default.
• W2056501262 cites W2086283601 @default.
• W2056501262 cites W2117673476 @default.
• W2056501262 cites W2137304500 @default.
• W2056501262 cites W2144846148 @default.
• W2056501262 doi "https://doi.org/10.1016/j.jaci.2011.09.026" @default.
• W2056501262 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22036097" @default.
• W2056501262 hasPublicationYear "2011" @default.
• W2056501262 type Work @default.
• W2056501262 sameAs 2056501262 @default.
• W2056501262 citedByCount "46" @default.
• W2056501262 countsByYear W20565012622012 @default.
• W2056501262 countsByYear W20565012622013 @default.
• W2056501262 countsByYear W20565012622014 @default.
• W2056501262 countsByYear W20565012622015 @default.
• W2056501262 countsByYear W20565012622016 @default.
• W2056501262 countsByYear W20565012622017 @default.
• W2056501262 countsByYear W20565012622018 @default.
• W2056501262 countsByYear W20565012622019 @default.
• W2056501262 countsByYear W20565012622020 @default.
• W2056501262 countsByYear W20565012622021 @default.
• W2056501262 countsByYear W20565012622022 @default.
• W2056501262 countsByYear W20565012622023 @default.
• W2056501262 crossrefType "journal-article" @default.
• W2056501262 hasAuthorship W2056501262A5089210937 @default.
• W2056501262 hasConcept C126322002 @default.
• W2056501262 hasConcept C142724271 @default.
• W2056501262 hasConcept C2776581183 @default.
• W2056501262 hasConcept C2776914184 @default.
• W2056501262 hasConcept C2779134260 @default.
• W2056501262 hasConcept C2781065132 @default.
• W2056501262 hasConcept C71924100 @default.
• W2056501262 hasConceptScore W2056501262C126322002 @default.
• W2056501262 hasConceptScore W2056501262C142724271 @default.
• W2056501262 hasConceptScore W2056501262C2776581183 @default.
• W2056501262 hasConceptScore W2056501262C2776914184 @default.
• W2056501262 hasConceptScore W2056501262C2779134260 @default.
• W2056501262 hasConceptScore W2056501262C2781065132 @default.
• W2056501262 hasConceptScore W2056501262C71924100 @default.
• W2056501262 hasIssue "5" @default.
• W2056501262 hasLocation W20565012621 @default.
• W2056501262 hasLocation W20565012622 @default.
• W2056501262 hasOpenAccess W2056501262 @default.
• W2056501262 hasPrimaryLocation W20565012621 @default.
• W2056501262 hasRelatedWork W1995494242 @default.
• W2056501262 hasRelatedWork W2046222341 @default.
• W2056501262 hasRelatedWork W2056501262 @default.
• W2056501262 hasRelatedWork W2356801597 @default.
• W2056501262 hasRelatedWork W2899084033 @default.
• W2056501262 hasRelatedWork W3196749034 @default.
• W2056501262 hasRelatedWork W3198887863 @default.
• W2056501262 hasRelatedWork W3215714328 @default.
• W2056501262 hasRelatedWork W4244954286 @default.
• W2056501262 hasRelatedWork W4311068385 @default.
• W2056501262 hasVolume "128" @default.
• W2056501262 isParatext "false" @default.
• W2056501262 isRetracted "false" @default.
• W2056501262 magId "2056501262" @default.
• W2056501262 workType "article" @default.