RESUMO
BACKGROUND AIMS: Esophageal eosinophilia (EE) can be caused by gastroesophageal reflux disease (GERD), proton-pump inhibitor-responsive EE (PPI-REE) or eosinophilic esophagitis (EoE). This study quantified protein expression and S-nitrosylation (SNO) post-translational modifications in EE to elucidate potential disease biomarkers. METHODS: Proximal and distal esophageal (DE) biopsy proteins in patients with EE and in controls were assayed for protein content and fluorescence-labeled with and without ascorbate treatment. Protein SNO was determined, and selected protein spots were identified by matrix-assisted laser desorption ionization time-of-flight/mass spectrometry. Western blot and ingenuity pathway analysis were performed. RESULTS: Ninety-one of 648 proteins showed differential expression. There were significantly altered levels of abundance for 11 proximal and 14 DE proteins. Hierarchal clustering revealed differential SNO in inflamed tissues, indicating reactive nitrogen/oxygen species involvement. Galectin-3 was upregulated in both proximal (p < 0.04) and distal (p < 0.004) esophageal EE biopsies compared to controls. In distal EE samples, galectin-3 was significantly S-nitrosylated (p < 0.004). Principal component analysis revealed sample group discrimination distally. CONCLUSION: Proteomic analysis in EE esophageal mucosa revealed a distinct abundance and nitrosylation profile, most prominently in distal biopsies. Galectin-3 was upregulated in expression and SNO, which may indicate its potential role in mucosal inflammation. These results call for more studies to be performed to investigate the role of galectin-3 in GERD, PPI-REE and EoE.
Assuntos
Eosinofilia/metabolismo , Esofagite Eosinofílica/metabolismo , Mucosa Esofágica/metabolismo , Galectina 3/metabolismo , Refluxo Gastroesofágico/metabolismo , Processamento de Proteína Pós-Traducional , Adolescente , Biomarcadores/metabolismo , Biópsia , Proteínas Sanguíneas , Criança , Pré-Escolar , Eosinofilia/patologia , Esofagite Eosinofílica/tratamento farmacológico , Esofagite Eosinofílica/patologia , Mucosa Esofágica/patologia , Galectinas , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/patologia , Humanos , Óxido Nítrico/metabolismo , Nitrosação , Proteômica , Inibidores da Bomba de Prótons/uso terapêutico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em TandemAssuntos
Enterite/imunologia , Eosinofilia/imunologia , Eosinófilos/imunologia , Gastrite/imunologia , Gastroenteropatias/imunologia , Intestinos/patologia , Mastócitos/imunologia , Adolescente , Biópsia , Contagem de Células , Criança , Pré-Escolar , Endoscopia , Enterite/patologia , Eosinofilia/patologia , Feminino , Gastrite/patologia , Gastroenteropatias/patologia , Humanos , Imunidade nas Mucosas , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVE: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory condition with a paucity of information on health-related quality of life (HRQOL). The objective of the study was to report on the measurement properties of the PedsQL EoE Module. METHODS: The PedsQL EoE Module was completed in a multisite study by 196 pediatric patients with EoE and 262 parents of patients with EoE. RESULTS: The PedsQL EoE Module scales evidenced excellent feasibility (0.6%-3.1% missing), excellent group comparison reliability across total scale scores (patient α 0.93; parent proxy α 0.94), good reliability for the 7 individual scales (patient α 0.75-0.87; parent proxy α 0.81-0.92), excellent test-retest reliability (patient intraclass correlation coefficient 0.88; parent intraclass correlation coefficient 0.82), demonstrated no floor effects and low ceiling effects, and demonstrated a high percentage of scaling success for most scales. Intercorrelations with the PedsQL Generic Core Scales were in the medium (0.30) to large (0.50) range. PedsQL EoE Module scores were worse among patients with active histologic disease (≥ 5 eos/hpf) compared with those in remission (patient self-report: 63.3 vs 69.9 [P < 0.05]; parent proxy report: 65.1 vs 72.3 [P < 0.01]), and those treated with dietary restrictions compared with those with no restrictions (patient self-report: 61.6 vs 74.3 [P < 0.01]; parent proxy report: 65.5 vs 74.7 [P < 0.01]). CONCLUSIONS: The results demonstrate excellent measurement properties of the PedsQL EoE Module. Patients with active histologic disease and those treated with dietary restrictions demonstrated worse PedsQL scores. The PedsQL EoE Module may be used in the evaluation of pediatric EoE disease-specific HRQOL in clinical research and practice.
Assuntos
Efeitos Psicossociais da Doença , Esofagite Eosinofílica/terapia , Indicadores Básicos de Saúde , Qualidade de Vida , Adolescente , Biópsia , Criança , Pré-Escolar , Esofagite Eosinofílica/dietoterapia , Esofagite Eosinofílica/patologia , Esofagite Eosinofílica/fisiopatologia , Esôfago/patologia , Família , Estudos de Viabilidade , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Reprodutibilidade dos Testes , Autorrelato , Índice de Gravidade de Doença , Estados UnidosRESUMO
SMAD4 is a common mediator of the TGF-beta signaling pathway. One of the members of this pathway, TGF-beta 1, has an important role in controlling gut inflammation in relation to the continuous stimulation of the intestinal microbiota. SMAD4 haploinsufficiency in humans has been linked to juvenile polyposis hereditary hemorrhagic telangiectasia syndrome (JP/HHT; OMIM#17505). Hematochezia and colonic mucosal inflammation suggestive of inflammatory bowel diseases (IBD) have been reported in JP/HHT. Stimulated by recent experience with two affected pediatric patients presented here, we explored the potential role of Smad4 haploinsufficiency in a murine model of colonic inflammation. Smad4(+/-) mice were maintained on a mixed C57/129SvEv background. Chronic colitis was induced with repeated administration of dextran sulfate sodium (DSS) in drinking water. The colonic mucosal microbiota was interrogated by massively parallel pyrosequencing of the bacterial 16S rRNA gene. 66.7% of Smad4(+/-) mice were sensitive to DSS colitis compared to 14.3% of wild type (Chi-Square p=0.036). The augmented colitis was associated with microbiota separation in the Smad4(+/-) mice. Enterococcus and Enterococcus faecalis specifically was increased in abundance in the colitis-prone animals. Smad4 haploinsufficiency can associate with increased susceptibility to large bowel inflammation in mammals with variable penetrance in association with the colonic mucosal microbiota. These findings may reveal implications not only towards colonic inflammation in the setting of SMAD4 haploinsufficiency, but for colorectal cancer as well.