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1.
Clin Gastroenterol Hepatol ; 22(4): 732-740.e1, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37743034

RESUMO

BACKGROUND AND AIMS: The Index of Severity for Eosinophilic Esophagitis (I-SEE) was recently developed. We aimed to understand I-SEE scores in a longitudinal pediatric cohort and to determine the relationship between I-SEE and clinical features in children. METHODS: We performed a retrospective analysis on a prospectively enrolled cohort of children at a single center who were treated as part of routine clinical care. I-SEE was calculated at the diagnostic and follow-up endoscopies over a mean of 6.6 years. Scoring was 0 for inactive, 1-6 for mild, 7-14 for moderate, and ≥15 for severe eosinophilic esophagitis (EoE). We analyzed clinical, endoscopic, and histologic features at each instance. Symptoms were analyzed at the baseline, first follow-up, and last endoscopic instance. RESULTS: Of 67 children who met study criteria of at least 3 endoscopies over at least 2 years of follow-up time, 43%, 36%, and 21% had mild, moderate, and severe I-SEE scores at baseline, respectively. Between the first and second endoscopic instances, there was a decrease in the group mean I-SEE from 9.7 ± 7.2 to 6.1 ± 5.9 (P < .001). By the last instance, the overall I-SEE score dropped to 3.9 (P < .001). Body mass index <5% and poor feeding were more common in the children with severe I-SEE scores at baseline, and both improved by the last instance. Fibrosis was improved by the last instance biopsy (P < .01). CONCLUSIONS: I-SEE is a responsive severity metric in children treated long term during routine clinical care. Baseline low body mass index and poor feeding were more common in children with severe I-SEE scores.


Assuntos
Enterite , Eosinofilia , Esofagite Eosinofílica , Gastrite , Criança , Humanos , Esofagite Eosinofílica/patologia , Estudos Retrospectivos , Endoscopia , Biópsia
2.
Clin Gastroenterol Hepatol ; 20(1): 57-64.e3, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007513

RESUMO

BACKGROUND & AIMS: Esophageal remodeling in eosinophilic esophagitis (EoE) can lead to esophageal rigidity with eventual luminal compromise and stenoses. Gauging esophageal functional alterations in EoE is challenging. An epithelial marker of functional remodeling would impact EoE management. METHODS: Esophageal biopsy specimens from children with and without EoE and primary human esophageal epithelial cells were used for PAI-1 immunohistochemistry, and cell proliferation experiments. PAI-1 immunostaining and basal cell hyperplasia were assessed in the context of concurrently obtained esophageal compliance measures on endoscopic functional lumen imaging probe (EndoFLIP). RESULTS: EndoFLIPs were performed in 45 children (32 with and 13 without EoE). Epithelial PAI-1 was increased in patients with active EoE versus inactive or control patients (P < .01). Esophageal compliance was lower in EoE patients versus controls, particularly in the proximal esophagus (P < .001). Proximal compliance was the strongest predictor of EoE (AUROC 0.88, 95% CI 0.77, 0.98) with esophageal compliance of less than 2.6%mL/mmHg demonstrating 82% sensitivity and 84% specificity for EoE. PAI-1 inhibition significantly diminished esophageal epithelial cell proliferation, suggesting PAI-1 could trigger basal cell hyperplasia. A composite mid-esophageal BZH + PAI-1 score was the strongest predictor of altered compliance (P = .02, AUROC 0.89 (95% CI 0.80, 0.99). CONCLUSIONS: PAI-1 is significantly elevated in pediatric EoE and distinguishes altered compliance in children. PAI-1 may be a novel disease marker and therapeutic target.


Assuntos
Esofagite Eosinofílica , Criança , Esofagite Eosinofílica/patologia , Células Epiteliais/patologia , Humanos , Imuno-Histoquímica , Inibidor 1 de Ativador de Plasminogênio/uso terapêutico
3.
Clin Gastroenterol Hepatol ; 20(11): 2474-2484.e3, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35181570

RESUMO

BACKGROUND & AIMS: Substantial heterogeneity in terminology used for eosinophilic gastrointestinal diseases (EGIDs), particularly the catchall term "eosinophilic gastroenteritis," limits clinical and research advances. We aimed to achieve an international consensus for standardized EGID nomenclature. METHODS: This consensus process utilized Delphi methodology. An initial naming framework was proposed and refined in iterative fashion, then assessed in a first round of Delphi voting. Results were discussed in 2 consensus meetings, and the framework was updated and reassessed in a second Delphi vote, with a 70% threshold set for agreement. RESULTS: Of 91 experts participating, 85 (93%) completed the first and 82 (90%) completed the second Delphi surveys. Consensus was reached on all but 2 statements. "EGID" was the preferred umbrella term for disorders of gastrointestinal (GI) tract eosinophilic inflammation in the absence of secondary causes (100% agreement). Involved GI tract segments will be named specifically and use an "Eo" abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The term "eosinophilic gastroenteritis" is no longer preferred as the overall name (96% agreement). When >2 GI tract areas are involved, the name should reflect all of the involved areas. CONCLUSIONS: This international process resulted in consensus for updated EGID nomenclature for both clinical and research use. EGID will be the umbrella term, rather than "eosinophilic gastroenteritis," and specific naming conventions by location of GI tract involvement are recommended. As more data are developed, this framework can be updated to reflect best practices and the underlying science.


Assuntos
Enterite , Eosinofilia , Esofagite Eosinofílica , Gastrite , Humanos , Consenso , Enterite/diagnóstico , Enterite/complicações , Gastrite/diagnóstico , Gastrite/complicações , Eosinofilia/diagnóstico , Eosinofilia/complicações , Esofagite Eosinofílica/complicações
4.
J Allergy Clin Immunol ; 148(2): 486-494, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33556465

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic TH2 disorder complicated by tissue fibrosis and loss of esophageal luminal patency. The fibrostenotic esophagus does not respond well to therapy, but profibrotic therapeutic targets are largely unclear. OBJECTIVE: Our aim was to utilize proteomics and primary cells as a novel approach to determine relevant profibrotic factors. METHODS: We utilized primary esophageal EoE and normal fibroblasts, their derivative extracellular matrixes (ECMs), an approach of fibroblast culture on autologous versus nonautologous ECM, and proteomics to elucidate EoE ECM proteins that dysregulate cellular function. RESULTS: We cultured esophageal fibroblasts from normal esophagi and esophagi from patients with severe EoE on autologous versus nonautologous ECM. The EoE ECM proteome shifted normal esophageal fibroblast protein expression. Proteomic analysis demonstrated that thrombospondin-1 is detected only in the EoE ECM, is central in the EoE ECM protein-protein interactome, is found at significantly elevated levels in biopsy specimens from patients with active EoE, and induces fibroblast collagen I production. CONCLUSION: Fibroblasts from patients with EoE secrete a unique ECM proteome that reflects their in vivo state and induces collagen I and α-smooth muscle actin protein expression from normal fibroblasts. Thrombospondin-1 is a previously unappreciated profibrotic molecule in EoE.


Assuntos
Esofagite Eosinofílica , Esôfago , Matriz Extracelular , Fibroblastos , Proteoma , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/metabolismo , Esofagite Eosinofílica/patologia , Esôfago/imunologia , Esôfago/metabolismo , Esôfago/patologia , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Proteoma/imunologia , Proteoma/metabolismo , Índice de Gravidade de Doença
5.
Gastroenterology ; 159(5): 1778-1792.e13, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32712105

RESUMO

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is an antigen-mediated eosinophilic disease of the esophagus that involves fibroblast activation and progression to fibrostenosis. Cytokines produced by T-helper type 2 cells and transforming growth factor beta 1 (TGFß1) contribute to the development of EoE, but other cytokines involved in pathogenesis are unknown. We investigate the effects of tumor necrosis factor superfamily member 14 (TNFSF14, also called LIGHT) on fibroblasts in EoE. METHODS: We analyzed publicly available esophageal CD3+ T-cell single-cell sequencing data for expression of LIGHT. Esophageal tissues were obtained from pediatric patients with EoE or control individuals and analyzed by immunostaining. Human primary esophageal fibroblasts were isolated from esophageal biopsy samples of healthy donors or patients with active EoE. Fibroblasts were cultured; incubated with TGFß1 and/or LIGHT; and analyzed by RNA sequencing, flow cytometry, immunoblots, immunofluorescence, or reverse transcription polymerase chain reaction. Eosinophils were purified from peripheral blood of healthy donors, incubated with interleukin 5, cocultured with fibroblasts, and analyzed by immunohistochemistry. RESULTS: LIGHT was up-regulated in the esophageal tissues from patients with EoE, compared with control individuals, and expressed by several T-cell populations, including T-helper type 2 cells. TNF receptor superfamily member 14 (TNFRSF14, also called HVEM) and lymphotoxin beta receptor are receptors for LIGHT that were expressed by fibroblasts from healthy donors or patients with active EoE. Stimulation of esophageal fibroblasts with LIGHT induced inflammatory gene transcription, whereas stimulation with TGFß1 induced transcription of genes associated with a myofibroblast phenotype. Stimulation of fibroblasts with TGFß1 increased expression of HVEM; subsequent stimulation with LIGHT resulted in their differentiation into cells that express markers of myofibroblasts and inflammatory chemokines and cytokines. Eosinophils tethered to esophageal fibroblasts after LIGHT stimulation via intercellular adhesion molecule-1. CONCLUSIONS: T cells in esophageal tissues from patients with EoE express increased levels of LIGHT compared with control individuals, which induces differentiation of fibroblasts into cells with inflammatory characteristics. TGFß1 increases fibroblast expression of HVEM, a receptor for LIGHT. LIGHT mediates interactions between esophageal fibroblasts and eosinophils via ICAM1. This pathway might be targeted for the treatment of EoE.


Assuntos
Diferenciação Celular , Esofagite Eosinofílica/metabolismo , Esôfago/metabolismo , Fibroblastos/metabolismo , Mediadores da Inflamação/metabolismo , Comunicação Parácrina , Linfócitos T/metabolismo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Adolescente , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/patologia , Esôfago/imunologia , Esôfago/patologia , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Fenótipo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Regulação para Cima
6.
J Allergy Clin Immunol ; 144(4): 1050-1057.e5, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31255641

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic and increasingly prevalent antigen-driven disease. There is a paucity of information on long-term course in children. OBJECTIVE: We sought to understand the longitudinal trajectory of pediatric EoE during routine clinical care. METHODS: We prospectively enrolled children into an EoE database and reviewed their medical and pathologic records over 13 years. RESULTS: From 2011 to 2015, 146 children with EoE seen for their first visit at our center had 2 or more years of follow-up and 3 or more endoscopies over an average follow-up period of 5.13 years (range, 2-13 years). Longitudinal eosinophilic inflammation during treatment demonstrated 3 patterns over time. Children with less than 15 eosinophils/high-power field (hpf) for greater than 75% of their follow-up period were termed continuous responders (CRs). Children with waxing and waning inflammation of less than 15 eosinophils/hpf for less than 75% but 25% or more of the follow-up period were termed intermittent responders (IRs). Nonresponders (NRs) were defined as having less than 15 eosinophils/hpf for less than 25% of their follow-up. Fifty-nine (40%) of 146 patients were CRs, 65 (45%) of 146 were IRs, and 22 (15%) of 146 were NRs. CRs differed from IRs and NRs on the parameter of male/female ratio (1:1 in CRs, 4:1 in IRs, and 6:1 in NRs; P < .001) and in their initial response to any therapy, including proton pump inhibitors (P < .001). Endoscopic severity correlated with esophageal eosinophilia (r = 0.73, P < .001). On multivariate analysis, female sex and initial therapeutic response to medications or elimination diet were associated with long-term control of esophageal eosinophilia. CONCLUSIONS: Long-term pediatric EoE followed 3 different longitudinal trajectories of inflammation. The long-term histologic groups differed significantly in biological sex and initial therapeutic response.


Assuntos
Esofagite Eosinofílica/patologia , Adolescente , Criança , Pré-Escolar , Esofagite Eosinofílica/terapia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Tempo , Resultado do Tratamento
7.
Gastroenterology ; 155(4): 1022-1033.e10, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30009819

RESUMO

BACKGROUND & AIMS: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis. METHODS: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences. RESULTS: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement. CONCLUSIONS: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm2) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.


Assuntos
Técnicas de Diagnóstico do Sistema Digestório/normas , Esofagite Eosinofílica/diagnóstico , Gastroenterologia/normas , Inibidores da Bomba de Prótons/administração & dosagem , Algoritmos , Consenso , Esofagite Eosinofílica/tratamento farmacológico , Humanos , Valor Preditivo dos Testes , Prognóstico , Inibidores da Bomba de Prótons/efeitos adversos
8.
J Pediatr Gastroenterol Nutr ; 68(4): 559-565, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30418408

RESUMO

BACKGROUND: The management of eosinophilic esophagitis (EoE) relies on the severity of esophageal eosinophilia, yet there is poor evidence of its prediction of esophageal fibrotic remodeling and subsequent complications such as dysphagia, food impactions, or strictures. Functional luminal imaging planimetry (FLIP) has had limited use in pediatric patients to evaluate esophageal tissue mechanics. We aimed to standardize the FLIP technique and to measure esophageal compliance in children with EoE in comparison to controls. METHODS: Subjects were enrolled into a prospective observational study and had FLIP performed at the time of endoscopy. We calculated esophageal distensibility and compliance for the total and segmental esophagus independently (ie, proximal, middle, and distal esophageal segments). We evaluated esophageal biopsies for eosinophilia and epithelial remodeling, calculated endoscopy scores, and documented patient symptoms. RESULTS: We enrolled 11 EoE and 12 controls subjects, aged 5 to 18 years old. While EoE subjects had lower esophageal compliance (P = 0.004) than controls, the difference in distensibility did not reach significance (P = 0.151). Epithelial remodeling severity was more strongly correlated with compliance than with distensibility. Epithelial remodeling scores ≥2 had a significant association with lower compliance both segmentally and in the entire esophagus (P = 0.029), but not with distensibility. Compliance measures were more sensitive in detecting subjects with remodeling score ≥2 than distensibility (79% vs 64%). CONCLUSIONS: Compliance is a more sensitive measure of esophageal epithelial remodeling in children compared to distensibility, and a more appropriate measure of esophageal tissue mechanics. Standardized placement of the FLIP catheter is important to accurately assess esophageal compliance.


Assuntos
Esofagite Eosinofílica/fisiopatologia , Esôfago/fisiopatologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Manometria , Estudos Prospectivos , Sensibilidade e Especificidade
9.
J Pediatr Gastroenterol Nutr ; 68(2): 225-231, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30211842

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic TH2-assocated inflammatory condition accompanied by substantial impairments in epithelial barrier function and increased numbers of interleukin 9 (IL-9) expressing inflammatory cells. While IL-9 is known to affect barrier function in the intestine, the functional effects of IL-9 on the esophagus are unclear. Herein we aimed to understand the expression of the IL-9 receptor and effects of IL-9 on the epithelium in EoE. METHODS: We used esophageal biopsies from pediatric EoE patients with active and inactive disease to analyze the expression of the IL-9 receptor, the adherens junction protein E-cadherin and the tight junction protein claudin-1. We treated primary human esophageal epithelial cells with IL-9 to understand its effects on E-cadherin expression and function. RESULTS: Active EoE subjects had increased epithelial expression of IL-9 receptor mRNA and protein (P < 0.05) and decreased membrane bound E-cadherin (P < 0.01) and claudin-1 (P < 0.05) expression. IL-9 receptor expression and mislocalized claudin-1 positively correlated and while membrane bound E-cadherin expression negatively correlated with the degree of histologic epithelial remodeling (P < 0.05). IL-9 decreased epithelial resistance in stratified primary human esophageal epithelial cells (P < 0.01) and membrane bound E-cadherin in epithelial cell monolayers (P < 0.01). CONCLUSIONS: These data suggest that IL-9, its receptor, and its effects on E-cadherin may be important mechanisms for epithelial barrier disruption in EoE.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Esofagite Eosinofílica/metabolismo , Esôfago/metabolismo , Interleucina-9/metabolismo , Receptores de Interleucina-9/metabolismo , Biópsia , Criança , Esofagite Eosinofílica/patologia , Células Epiteliais/metabolismo , Epitélio/metabolismo , Epitélio/patologia , Esôfago/patologia , Feminino , Humanos , Masculino
10.
J Allergy Clin Immunol ; 137(1): 147-156.e8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26233926

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic TH2 inflammatory disease characterized by tissue remodeling that leads to esophageal strictures and food impactions. Effects of therapy on long-term remodeling in patients with pediatric eosinophil-associated diseases have not been previously described. OBJECTIVE: We sought to understand the long-term control of esophageal remodeling in patients with EoE. METHODS: We assessed endoscopic and histologic remodeling and TGF-ß1 expression in esophageal biopsy specimens from children (n = 32) with EoE treated with topical corticosteroids (TCSs) over 10 years (mean, 4.5 years). We used standardized EoE scoring tools to gauge endoscopic and symptom features. RESULTS: Seven hundred thirty-eight biopsy specimens from 246 endoscopic procedures were evaluated over 10 years. Four hundred eighty-six biopsy specimens had adequate lamina propria for evaluation of subepithelial remodeling. The severity of epithelial esophageal eosinophilia correlated with epithelial remodeling (basal zone hyperplasia, desquamation, and dilated intercellular spaces; P < .0001), lamina propria eosinophilia (P < .0001), and fibrosis (P < .0001). Sixteen subjects were initial responders (<15 eosinophils/high-power field) to TCSs. Responders and nonresponders spent 54% and 97% of their total disease duration with active EoE (P < .001) and 23% and 53% (P < .02) with maximal fibrosis scores, respectively. Responders had lower endoscopy scores during their disease duration (P = .013). Having less than 15 eosinophils/high-power field at any time correlated with lower fibrosis and endoscopic severity. TGF-ß1(+) cell counts decreased in responders at the first biopsy, but this was not sustained. Symptoms did not correlate with other disease features. CONCLUSIONS: Children with EoE have substantial esophageal remodeling, which associates with inflammation and can improve in a sustainable manner with TCSs. Although endoscopic features correspond to histologic features, symptoms did not correlate with inflammation or fibrosis.


Assuntos
Esofagite Eosinofílica/tratamento farmacológico , Esofagite Eosinofílica/patologia , Esôfago/patologia , Glucocorticoides/uso terapêutico , Administração Tópica , Adolescente , Criança , Pré-Escolar , Esofagite Eosinofílica/metabolismo , Esôfago/metabolismo , Feminino , Glucocorticoides/administração & dosagem , Humanos , Lactente , Masculino , Inibidores da Bomba de Prótons/uso terapêutico , Fator de Crescimento Transformador beta1/metabolismo
11.
J Allergy Clin Immunol ; 138(3): 791-800.e4, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27212082

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is an allergic disease of increasing worldwide incidence. Complications are due to tissue remodeling and involve TGF-ß1-mediated fibrosis. Plasminogen activator inhibitor 1 (PAI-1/serpinE1) can be induced by TGF-ß1, but its role in EoE is not known. OBJECTIVE: We sought to understand the expression and role of PAI-1 in patients with EoE. METHODS: 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-ß1, the relationship between PAI-1 and esophageal fibrosis, and the role of PAI-1 in fibrotic gene expression. RESULTS: 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-ß1 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-ß1, collagen I, fibronectin, and matrix metalloproteases, and plasma PAI-1 levels correlated with plasma TGF-ß1 levels. PAI-1 inhibition significantly decreased baseline and TGF-ß1-induced fibrotic gene expression. CONCLUSIONS: PAI-1 expression is significantly increased in the epithelium in patients with EoE and reflects fibrosis, and its inhibition decreases TGF-ß1-induced gene expression. Epithelial PAI-1 might serve as a marker of EoE severity and form part of a TGF-ß1-induced profibrotic network.


Assuntos
Esofagite Eosinofílica/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adolescente , Criança , Pré-Escolar , Esofagite Eosinofílica/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Esôfago/citologia , Esôfago/metabolismo , Esôfago/patologia , Feminino , Fibroblastos/metabolismo , Fibrose , Humanos , Lactente , Masculino
12.
J Pediatr Gastroenterol Nutr ; 61(2): 194-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25539192

RESUMO

OBJECTIVES: Eosinophilic esophagitis (EoE) is a chronic, antigen-mediated disease in children and adults associated with substantial esophageal remodeling and fibrosis. The expression of the remodeling-associated matrix metalloproteinases (MMPs) has not been previously detailed in EoE. METHODS: MMP-2 and -14 expression and cellular localization were assessed using real-time quantitative polymerase chain reaction and immunohistochemistry/immunofluorescence in EoE fibroblasts, active and inactive pediatric EoE biopsies, and nondiseased control biopsies. The effect of transforming growth factor (TGF)-ß1 treatment on MMP-2 expression in cultured esophageal epithelial (HET1A) cells was analyzed. RESULTS: MMP-2 and -14 mRNA were expressed in EoE fibroblasts and biopsies. Proliferating epithelial cells produced MMP-14 more abundantly in EoE than in controls (P < 0.001) and the degree of epithelial MMP-14 expression correlated positively with basal zone hyperplasia (r = 0.65, P = 0.002). EoE lamina propria had higher numbers of MMP-2- and -14-positive cells (906 ±â€Š167 and 701 ±â€Š93 cells/mm²) as compared with controls (258 ±â€Š93 cells/mm², P < 0.01 and 232 ±â€Š54 cells/mm², P < 0.01), and MMP-14 expression correlated with the severity of fibrosis. Following therapy with topical corticosteroids, MMP-14 and -2 were significantly diminished (P < 0.01). TGF-ß1 increased the expression and secretion of MMP-2 from esophageal epithelial HET1A cells. CONCLUSIONS: MMP-2 and -14 are elevated in pediatric patients with EoE and significantly decrease following topical corticosteroid therapy. TGF-ß1 increases MMP-2 in esophageal epithelial cells. This alludes to previously unappreciated role for MMPs in EoE-associated esophageal remodeling and a potential positive feedback loop via TGF-ß1.


Assuntos
Corticosteroides/uso terapêutico , Esofagite Eosinofílica/enzimologia , Metaloproteinase 14 da Matriz/análise , Metaloproteinase 2 da Matriz/análise , Biópsia , Criança , Esofagite Eosinofílica/tratamento farmacológico , Esofagite Eosinofílica/patologia , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Feminino , Fibroblastos/enzimologia , Imunofluorescência , Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 14 da Matriz/efeitos dos fármacos , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/genética , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Fator de Crescimento Transformador beta1/farmacologia
13.
J Allergy Clin Immunol ; 134(5): 1100-1107.e4, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24835503

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease characterized by esophageal eosinophilia, remodeling, and fibrosis. TGF-ß1 is a central regulator of EoE remodeling and increases esophageal smooth muscle (ESM) cell contraction. OBJECTIVE: In this study we aimed to understand the molecular mechanisms by which TGF-ß1 could induce ESM cell contraction. METHODS: We used primary human ESM cells and esophageal myofibroblasts (EMFs) to assess the mechanisms of TGF-ß1-induced contraction. We analyzed the expression, phosphorylation, and function of phospholamban (PLN), a sarcoendoplasmic reticulum regulatory protein induced by TGF-ß1. Expression of PLN, phospho-PLN, and its regulatory pathway was analyzed in the ESM of biopsy specimens from patients with EoE and control subjects. Gene silencing in EMFs from patients with EoE was used to understand the role of PLN in contraction. RESULTS: TGF-ß1 induced and phosphorylated PLN in primary human ESM cells and EMFs from patients with EoE. PLN and phospho-PLN levels were increased in smooth muscle from patients with EoE compared with that seen in smooth muscle from control subjects in vivo. PLN inhibition significantly diminished TGF-ß1-induced EMF contraction in patients with EoE. PLN expression and ESM/EMF contraction depended on TGF-ß receptor I signals. CONCLUSION: We describe a previously unrecognized mechanism for ESM cell contraction that depends on TGF-ß1, its receptors, and PLN. Because PLN levels are increased in smooth muscle from patients with EoE and PLN silencing diminishes contraction, we provide a novel potential mechanistic framework and therapeutic target for ESM dysfunction in patients with EoE.


Assuntos
Proteínas de Ligação ao Cálcio/biossíntese , Esofagite Eosinofílica/metabolismo , Esôfago/metabolismo , Contração Muscular , Proteínas Musculares/metabolismo , Miócitos de Músculo Liso/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Células Cultivadas , Esofagite Eosinofílica/patologia , Esofagite Eosinofílica/fisiopatologia , Esôfago/patologia , Esôfago/fisiopatologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Miócitos de Músculo Liso/patologia , Fosforilação
14.
Nephrol Dial Transplant ; 29 Suppl 4: iv87-94, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25165189

RESUMO

Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.


Assuntos
Cistinose/diagnóstico , Cistinose/terapia , Criança , Cistinose/genética , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/terapia , Humanos , Guias de Prática Clínica como Assunto , Sociedades Médicas
15.
J Allergy Clin Immunol ; 131(6): 1576-82, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23623266

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is a clinicopathologic entity of increasing worldwide prevalence. IL-5 is essential for eosinophil trafficking, and anti-IL-5 therapy decreases esophageal eosinophilia. EoE is associated with prominent mast cell infiltration. OBJECTIVE: We investigated whether anti-IL-5 (mepolizumab) treatment reduced esophageal mast cell accumulation in biopsy specimens from pediatric patients with EoE from a previous randomized anti-IL-5 trial. METHODS: A subanalysis was completed for children treated with 0.55, 2.5, or 10 mg/kg mepolizumab monthly for 12 weeks followed by no treatment until week 24. Quantitative immunochemistry was used to assess the numbers of eosinophils, tryptase-positive mast cells, IL-9(+) cells, and mast cell-eosinophil couplets before and after treatment. RESULTS: Forty-three biopsy specimens had adequate tissue for paired analysis. Forty percent of subjects responded to anti-IL-5 (defined as <15 eosinophils per high-power field [hpf] after mepolizumab therapy), and 77% of all subjects had decreased numbers of mast cells after anti-IL-5. In responders epithelial mast cell numbers decreased from 62 to 19 per hpf (P < .001), were significantly lower than in nonresponders after therapy (P < .05), and correlated with eosinophil numbers (r = 0.75, P < .0001). Mast cells and eosinophils were found in couplets before therapy, and these were significantly decreased only in responders after anti-IL-5 (P < .001). Esophageal eosinophils comprised the majority of cells that made the mast cell growth factor IL-9. IL-9(+) cell numbers decreased from 102 to 71 per hpf (P < .001) after anti-IL-5. CONCLUSIONS: Pediatric patients with EoE had significantly fewer mast cells, IL-9(+) cells, and mast cell-eosinophil couplets in the esophageal epithelium after anti-IL-5 therapy. Because eosinophils were one source of IL-9, they might support esophageal mastocytosis.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Esofagite Eosinofílica/tratamento farmacológico , Interleucina-5/antagonistas & inibidores , Interleucina-9/metabolismo , Mastócitos/imunologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Eosinofilia/imunologia , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/metabolismo , Esôfago/metabolismo , Humanos , Mucosa/metabolismo , Triptases/metabolismo
16.
Mucosal Immunol ; 17(3): 315-322, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38423390

RESUMO

The gastrointestinal system is a hollow organ affected by fibrostenotic diseases that cause volumetric compromise of the lumen via smooth muscle hypertrophy and fibrosis. Many of the driving mechanisms remain unclear. Yes-associated protein-1 (YAP) is a critical mechanosensory transcriptional regulator that mediates cell hypertrophy in response to elevated extracellular rigidity. In the type 2 inflammatory disorder, eosinophilic esophagitis (EoE), phospholamban (PLN) can induce smooth muscle cell hypertrophy. We used EoE as a disease model for understanding a mechanistic pathway in which PLN and YAP interact in response to rigid extracellular substrate to induce smooth muscle cell hypertrophy. PLN-induced YAP nuclear sequestration in a feed-forward loop caused increased cell size in response to a rigid substrate. This mechanism of rigidity sensing may have previously unappreciated clinical implications for PLN-expressing hollow systems such as the esophagus and heart.


Assuntos
Proteínas de Ligação ao Cálcio , Hipertrofia , Mecanotransdução Celular , Miócitos de Músculo Liso , Proteínas de Sinalização YAP , Humanos , Miócitos de Músculo Liso/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Sinalização YAP/metabolismo , Animais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição/metabolismo , Camundongos
17.
Pediatr Nephrol ; 28(3): 507-10, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23001048

RESUMO

BACKGROUND: Patients with nephropathic cystinosis are required to take 6-hourly immediate-release cysteamine (Cystagon®) to reduce disease progression. This arduous regimen affects quality of life, disrupts sleep, and may result in non-compliance with therapy. Enteric-coated cysteamine bitartrate (EC-cysteamine) was developed as a "proof-of-concept" formulation for twice-daily ingestion. Previous reports have shown this therapy to be effective up to a mean of 14 months. CASE-DIAGNOSIS/TREATMENT: Two subjects (aged 13 and 15 years) received EC-cysteamine for 5-6 years at 60-65 % of their previous total daily dose of immediate-release cysteamine given at 6-h intervals. White blood cell (WBC) cystine levels were monitored every 1-3 months. CONCLUSION: The administration of EC-cysteamine did not result in any change in mean trough WBC cystine levels or any deterioration in the estimated glomerular filtration rate, thyroid, or liver function, suggesting that delayed-release, twice-daily EC-cysteamine is an effective long-term treatment alternative to immediate-release cysteamine given at 6-h intervals.


Assuntos
Cisteamina/administração & dosagem , Cistinose/tratamento farmacológico , Síndrome de Fanconi/tratamento farmacológico , Rim/efeitos dos fármacos , Síndrome Nefrótica/tratamento farmacológico , Adolescente , Biomarcadores/sangue , Química Farmacêutica , Creatinina/sangue , Cisteamina/efeitos adversos , Cisteamina/química , Cistinose/sangue , Cistinose/diagnóstico , Cistinose/fisiopatologia , Preparações de Ação Retardada , Esquema de Medicação , Síndrome de Fanconi/sangue , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/fisiopatologia , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Rim/metabolismo , Rim/fisiopatologia , Contagem de Leucócitos , Masculino , Síndrome Nefrótica/sangue , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
18.
J Pediatr ; 161(3): 531-535.e1, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22513268

RESUMO

OBJECTIVES: To evaluate intestinal mucosal cystine crystal (CC) load as a way to estimate tissue cystine content in children with cystinosis. STUDY DESIGN: Intestinal mucosal biopsies were obtained endoscopically from children (ages 2-18 years) with cystinosis. Using a special processing technique, CC within histiocytes were easily visible and enumerable in the mucosal tissue. Mean CC counts, calculated from stomach and duodenum combined (CC-GD), were correlated with duration of cysteamine treatment, estimated glomerular filtration rate (eGFR), and mean white blood cells (WBC) cystine levels. RESULTS: Seventeen subjects (6 male) were enrolled in 2 studies from 2001 and 2003. The CC-GD count (mean 12.5 ± 1.41 crystals/histiocyte) was lower than the colonic crystal count (mean 23.6 ± 3.38, P = .0031). Nine of 17 subjects underwent repeated endoscopy 2 years later and the trend for CC-GD was to decrease over time (P = .065). Biopsies, however, were never completely depleted of CC. In subjects who were diagnosed before age 18 months, the percent change from baseline of both eGFR and CC-GD were inversely correlated (P = .026). Mean WBC cystine levels were positively correlated with CC-GD (P = .023). CONCLUSIONS: CC are easily visible in the intestinal mucosa. CC-GD counts appear to correlate with eGFR and may help monitor response to treatment. Even when mean WBC cystine levels are low, the mucosal CC are not depleted suggesting that tissue cysteamine levels may not achieve therapeutic efficacy.


Assuntos
Cistina/metabolismo , Cistinose/metabolismo , Síndrome de Fanconi/metabolismo , Mucosa Intestinal/metabolismo , Síndrome Nefrótica/metabolismo , Adolescente , Criança , Pré-Escolar , Cristalização , Endoscopia Gastrointestinal , Feminino , Taxa de Filtração Glomerular , Histiócitos/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Sigmoidoscopia
19.
J Pediatr ; 161(4): 639-45.e1, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22633783

RESUMO

OBJECTIVE: To determine the effects of cysteamine on adiponectin multimerization in sera of patients with nonalcoholic fatty liver disease (NAFLD). STUDY DESIGN: Sera from 10 children with biopsy-proven NAFLD treated with cysteamine were assayed for adiponectin multimers at baseline, after 24 weeks of treatment, and again 16 weeks after discontinuing treatment. Pretreatment sera from subjects with NAFLD and from adult controls without NAFLD controls (n = 8) were incubated in cysteamine and multimers were measured 1 hour later. A cysteamine/adiponectin multimer dose-response curve was created. RESULTS: Following 24 weeks of cysteamine therapy, the mean percentage increase for high, medium (MMW), and low (LMW) molecular weight multimers and total adiponectin from baseline was 53% (P = .02), 19% (P = .02), 29.4% (P = .03), and 49.3% (P = .05), respectively. Levels returned to baseline at 16 weeks after stopping therapy, unlike hepatic transaminase levels which remained low. Sera from 0 week, incubated in cysteamine for 1 hour, showed a significant mean percent increase in LMW adiponectin levels and a mean percent reduction in MMW levels compared with baseline in adults with and without NAFLD. CONCLUSIONS: Cysteamine impacts adiponectin multimerization. Long-term cysteamine therapy increases levels of all multimers, whereas, in vitro short-term exposure causes a rapid increase in LMW and reduction in MMW multimers in NAFLD and healthy controls. Cysteamine may be a potential therapeutic agent for conditions associated with insulin-resistance, oxidative stress, and depressed adiponectin levels.


Assuntos
Adiponectina/química , Cisteamina/farmacologia , Multimerização Proteica/efeitos dos fármacos , Adiponectina/sangue , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Criança , Cisteamina/uso terapêutico , Relação Dose-Resposta a Droga , Eletroforese em Gel Bidimensional , Fígado Gorduroso , Humanos , Hepatopatia Gordurosa não Alcoólica
20.
Dig Dis Sci ; 57(5): 1413-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22134787

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) and gastroesophageal reflux (GERD) both cause esophageal eosinophilia. Reports show that esophageal eosinophilia meeting criteria for EoE may respond to acid suppression mono-therapy. Consensus guidelines have termed this entity "PPI-responsive esophageal eosinophilia" (PPIRee) and recommend a trial with proton-pump inhibitors (PPIs) prior to a definitive EoE diagnosis. The mechanisms of PPIRee and whether this represents a sub-phenotype of GERD, a sub-phenotype of EoE, or its own distinct entity remain unclear. METHODS: A database search revealed children who had an initial histologic response to PPI monotherapy but had recurrence of esophageal eosinophilia and symptoms despite continued PPI therapy. In order to understand the patterns of esophageal inflammatory cells during PPI therapy we performed quantitative immunohistochemistry for mast cells, CD1a positive antigen presenting cells, and CD45RO memory T cells. RESULTS: Four pediatric patients (mean age 9.5 years) had a mean peak eosinophil count of 52 eos/hpf which initially resolved completely during PPI mono-therapy. However, despite continued PPI therapy, endoscopic abnormalities and pan-esophageal eosinophilia recurred (mean peak eosinophil count of 64 eos/hpf). There was no seasonal variation or lack of PPI adherence that explained the return of eosinopihlia. Similar to eosinophilia, mastocytosis and CD45RO cells were transiently decreased during PPI therapy. CONCLUSION: PPIs appear to be capable of transiently resolving multiple inflammatory cell subsets including eosinophils, mast cells, and CD45RO cells. Our data suggest that patients with PPIRee should have continued monitoring for EoE during PPI monotherapy. The numbers of patients in whom PPIRee is a transient phenomenon and whether PPIRee represents a sub-phenotype of EoE in children merits further investigation.


Assuntos
Eosinofilia , Esofagite Eosinofílica , Eosinófilos/metabolismo , Refluxo Gastroesofágico , Antígenos Comuns de Leucócito/metabolismo , Mastócitos/metabolismo , Inibidores da Bomba de Prótons/administração & dosagem , Linfócitos T/metabolismo , Adolescente , Criança , Pré-Escolar , Monitoramento de Medicamentos/métodos , Eosinofilia/sangue , Eosinofilia/etiologia , Eosinofilia/metabolismo , Esofagite Eosinofílica/complicações , Esofagite Eosinofílica/tratamento farmacológico , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/metabolismo , Esôfago/patologia , Feminino , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/imunologia , Refluxo Gastroesofágico/metabolismo , Humanos , Masculino , Mucosa/imunologia , Mucosa/metabolismo , Mucosa/patologia , Inibidores da Bomba de Prótons/efeitos adversos , Recidiva , Indução de Remissão , Resultado do Tratamento
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