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1.
J Pediatr Gastroenterol Nutr ; 73(2): e30-e34, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-33938522

RESUMEN

OBJECTIVES: Esophagitis dissecans superficialis (EDS) is a desquamative disorder of the superficial esophageal epithelium with variable clinical characteristics. Endoscopically, there is an appearance of superficial peeling of sheets of epithelium. Histologically there is 2-toned epithelium with coagulative necrosis of the superficial epithelium. Currently, there is paucity of data regarding this condition in children. METHODS: A 10-year retrospective search of the pathology information system was performed for cases with a pathologic diagnosis of EDS in a tertiary care pediatric center. Demographic data, clinical history, endoscopic findings, and histopathologic reports were reviewed. RESULTS: Thirteen patients (9 girls; ages 3-18 years), were identified with histologic findings of EDS. Esophageal food impaction, dysphagia, vomiting, and abdominal pain were the most common presenting symptoms. Sixty-nine percentage of the patients had underlying comorbidities and 76% were on at least 1 medication chronically. Eosinophilic esophagitis (23%), inflammatory bowel disease (23%), and gastroesophageal reflux disease (GERD) (15%) were the most common associated diagnoses. Of the 13 patients, 5 had repeat endoscopies showing complete resolution of EDS with no complications. CONCLUSIONS: EDS is an under-recognized entity that endoscopists should be familiar with. In our series, the most prevalent associations were with food impaction and eosinophilic esophagitis (EoE). Contact injury and/or inflammation may precede the development of EDS. Pediatric EDS appears to be an incidental finding without significant morbidity or mortality.


Asunto(s)
Trastornos de Deglución , Esofagitis Eosinofílica , Esofagitis , Reflujo Gastroesofágico , Adolescente , Niño , Preescolar , Trastornos de Deglución/epidemiología , Trastornos de Deglución/etiología , Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/epidemiología , Mucosa Esofágica , Esofagitis/diagnóstico , Esofagitis/epidemiología , Femenino , Humanos , Estudios Retrospectivos
2.
J Pediatr Gastroenterol Nutr ; 72(3): 392-397, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33230074

RESUMEN

OBJECTIVES: Eosinophilic esophagitis (EoE), the most common eosinophilic gastrointestinal disease (EGID), is associated with lamina propria (LP) fibrosis. The relationship of EoE to other EGIDs is still unclear. We frequently observe cases of concurrent esophageal eosinophilia and extra-esophageal mucosal eosinophilia. The purpose of this study was to compare clinical, endoscopic, and histologic features, as well as the prevalence of esophageal LP fibrosis in children with EGID and concurrent esophageal eosinophilia to children with EoE. We also examine the current practices of pathologists in evaluating fibrosis. METHODS: We reviewed esophageal biopsies from index cases of EoE (N = 38), EGID with significant esophageal eosinophilia (≥15 eos/hpf) (EGID-SEE, N = 38), EGID with mild esophageal eosinophilia (1-14 eos/hpf) (EGID-MEE, N = 12), and EGID with no esophageal eosinophilia (EGID-NEE, N = 12) for LP presence, adequacy, and fibrosis. RESULTS: EoE and EGID-SEE cases share similar demographics, esophageal endoscopic features, and symptoms. A majority of EGID-SEE cases (71%) had adequate LP for the evaluation of fibrosis, similar to EoE cases (87%). The prevalence of esophageal fibrosis in EoE (79%) and EGID-SEE (55%) cases were similar, whereas no fibrosis was detected in the EGID-MEE and EGID-NEE cases. The fibrosis was patchy and often detected in the distal esophagus. Fourteen cases were reclassified from their original clinical diagnosis as having fibrosis by the study pathologists. CONCLUSIONS: Cases of EGID-SEE have overlapping features with EoE, suggesting that all EGIDs are part of a disease continuum. A consensus for the evaluation of LP fibrosis is needed.


Asunto(s)
Enteritis , Esofagitis Eosinofílica , Gastritis , Niño , Esofagitis Eosinofílica/complicaciones , Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/epidemiología , Fibrosis , Humanos
3.
Gastroenterology ; 155(4): 1022-1033.e10, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30009819

RESUMEN

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.


Asunto(s)
Técnicas de Diagnóstico del Sistema Digestivo/normas , Esofagitis Eosinofílica/diagnóstico , Gastroenterología/normas , Inhibidores de la Bomba de Protones/administración & dosificación , Algoritmos , Consenso , Esofagitis Eosinofílica/tratamiento farmacológico , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Inhibidores de la Bomba de Protones/efectos adversos
4.
J Allergy Clin Immunol ; 142(1): 48-53, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29803797

RESUMEN

The Consortium of Eosinophilic Gastrointestinal Diseases and the International Gastrointestinal Eosinophil Researchers organized a day-long symposium at the recent 2018 Annual Meeting of the American Academy of Allergy, Asthma & Immunology, which was coupled for the first time with the World Allergy Organization meeting to create an international platform. The symposium featured experts in many facets of eosinophilic gastrointestinal diseases, including allergy, immunology, gastroenterology, pathology, and nutrition, and was a well-attended event. The basic science, genetics, cellular immunology, and clinical features of the diseases, with a focus on epithelial, eosinophil, and mast cell responses, as well as current and emerging treatment options, were reviewed. Here we briefly review some of the highlights of the material presented at the meeting.


Asunto(s)
Alergia e Inmunología/tendencias , Enteritis , Eosinofilia , Gastritis , Gastroenterología/tendencias , Humanos
5.
Gut ; 67(4): 606-615, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28442495

RESUMEN

OBJECTIVE: In previous studies using oesophageal squamous cells from patients with Barrett's oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett's oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. DESIGN: We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IκB-NF-κB-PKAc complex activation, p65 NF-κB subunit function, and CDX2 expression. RESULTS: In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H2O2, which activated the IκB-NF-κB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IκB and p65 and greater NF-κB transcriptional activity than NES-G cells, indicating greater IκB-NF-κB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IκB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. CONCLUSIONS: Differences between NES-B and NES-G cells in NF-κB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett's oesophagus while others do not, and why aspirin might protect against development of Barrett's oesophagus.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Esófago de Barrett , Ácidos y Sales Biliares/metabolismo , Factor de Transcripción CDX2/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , FN-kappa B/efectos de los fármacos , Factor de Transcripción CDX2/metabolismo , Células Epiteliales/metabolismo , Humanos , FN-kappa B/metabolismo
6.
Gastrointest Endosc ; 87(5): 1207-1214.e3, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29309779

RESUMEN

BACKGROUND AND AIMS: Subepithelial fibrosis in eosinophilic esophagitis (EoE) can be detected only in esophageal biopsy specimens with adequate amounts of lamina propria (LP). We investigated how often pediatric esophageal biopsy specimens contain adequate LP, and whether esophageal eosinophilia influences the acquisition rates. METHODS: We evaluated 284 esophageal biopsy specimens from 39 patients with EoE, and 87 biopsy specimens from 32 patients without esophageal eosinophilia or other esophageal abnormalities for the presence of adequate LP and fibrosis. RESULTS: On a per biopsy specimen basis, there was no significant difference in the rate of procuring adequate amounts of LP between patients with EoE and patients without esophageal eosinophilia (43% vs 31%, P = .14). Eighty-five percent of patients with EoE had fibrosis. Fibrosis in patients with EoE was patchy and more likely to be detected in the middle or distal esophagus (odds ratio, 19.93; 95% confidence interval, 4.12-91.52). Among patients with fibrosis, the probability of its detection reached >95% with 7 middle-distal esophageal biopsy specimens. Most children with newly diagnosed EoE already had subepithelial fibrosis despite exhibiting only inflammatory endoscopic features. CONCLUSIONS: Most individual esophageal biopsy specimens in children are inadequate for assessing subepithelial fibrosis, and the rates of procuring adequate LP per biopsy specimen are similar in patients with and without EoE. To reliably detect fibrosis in patients with EoE, at least 7 biopsy specimens should be taken from the middle-distal esophagus. The finding of fibrosis in children with newly diagnosed EoE and only inflammatory endoscopic features suggests that fibrosis can occur early in this disease.


Asunto(s)
Biopsia/métodos , Esofagitis Eosinofílica/patología , Mucosa Esofágica/patología , Esofagoscopía/métodos , Esófago/patología , Adolescente , Niño , Preescolar , Femenino , Fibrosis , Humanos , Lactante , Masculino , Membrana Mucosa/patología , Estudios Retrospectivos
7.
Gut ; 66(9): 1542-1554, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-27694141

RESUMEN

OBJECTIVE: In an earlier study wherein we induced acute reflux by interrupting proton pump inhibitor (PPI) therapy in patients with reflux oesophagitis (RO) healed by PPIs, we refuted the traditional concept that RO develops as an acid burn. The present study explored our alternative hypothesis that RO results from reflux-stimulated production of pro-inflammatory molecules mediated by hypoxia-inducible factors (HIFs). DESIGN: Using oesophageal biopsies taken from patients in our earlier study at baseline and at 1 and 2 weeks off PPIs, we immunostained for HIF-1α, HIF-2α and phospho-p65, and measured pro-inflammatory molecule mRNAs. We exposed human oesophageal squamous cell lines to acidic bile salts, and evaluated effects on HIF activation, p65 function, pro-inflammatory molecule production and immune cell migration. RESULTS: In patient biopsies, increased immunostaining for HIF-2α and phospho-p65, and increased pro-inflammatory molecule mRNA levels were seen when RO redeveloped 1 or 2 weeks after stopping PPIs. In oesophageal cells, exposure to acidic bile salts increased intracellular reactive oxygen species, which decreased prolyl hydroxylase function and stabilised HIF-2α, causing a p65-dependent increase in pro-inflammatory molecules; conditioned media from these cells increased T cell migration rates. HIF-2α inhibition by small hairpin RNA or selective small molecule antagonist blocked the increases in pro-inflammatory molecule expression and T cell migration induced by acidic bile salts. CONCLUSIONS: In patients developing RO, increases in oesophageal HIF-2α correlate with increased pro-inflammatory molecule expression. In oesophageal epithelial cells, acidic bile salts stabilise HIF-2α, which mediates expression of pro-inflammatory molecules. HIF-2α appears to have a role in RO pathogenesis. TRIAL REGISTRATION NUMBER: NCT01733810; Results.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Epiteliales/metabolismo , Esofagitis Péptica/metabolismo , Reflujo Gastroesofágico/metabolismo , Hipoxia/metabolismo , Línea Celular , Movimiento Celular/fisiología , Esofagitis Péptica/etiología , Esofagitis Péptica/patología , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/patología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Estadística como Asunto
8.
Gut ; 65(3): 524-31, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26685124

RESUMEN

Consensus diagnostic recommendations to distinguish GORD from eosinophilic oesophagitis (EoE) by response to a trial of proton pump inhibitors (PPIs) unexpectedly uncovered an entity called 'PPI-responsive oesophageal eosinophilia' (PPI-REE). PPI-REE refers to patients with clinical and histological features of EoE that remit with PPI treatment. Recent and evolving evidence, mostly from adults, shows that patients with PPI-REE and patients with EoE at baseline are clinically, endoscopically and histologically indistinguishable and have a significant overlap in terms of features of Th2 immune-mediated inflammation and gene expression. Furthermore, PPI therapy restores oesophageal mucosal integrity, reduces Th2 inflammation and reverses the abnormal gene expression signature in patients with PPI-REE, similar to the effects of topical steroids in patients with EoE. Additionally, recent series have reported that patients with EoE responsive to diet/topical steroids may also achieve remission on PPI therapy. This mounting evidence supports the concept that PPI-REE represents a continuum of the same immunological mechanisms that underlie EoE. Accordingly, it seems counterintuitive to differentiate PPI-REE from EoE based on a differential response to PPI therapy when their phenotypic, molecular, mechanistic and therapeutic features cannot be reliably distinguished. For patients with symptoms and histological features of EoE, it is reasonable to consider PPI therapy not as a diagnostic test, but as a therapeutic agent. Due to its safety profile, ease of administration and high response rates (up to 50%), PPI can be considered a first-line treatment before diet and topical steroids. The reasons why some patients with EoE respond to PPI, while others do not, remain to be elucidated.


Asunto(s)
Esofagitis Eosinofílica/diagnóstico , Reflujo Gastroesofágico/diagnóstico , Inhibidores de la Bomba de Protones/uso terapéutico , Diagnóstico Diferencial , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/inmunología , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/inmunología , Humanos
9.
Gut ; 65(9): 1416-26, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-25986942

RESUMEN

OBJECTIVE: Barrett's metaplasia might develop if GORD causes oesophageal squamous cells to convert into columnar cells. Acid and bile exposures upregulate columnar differentiation genes like CDX2 in oesophageal squamous cells, but it is not known if such exposures downregulate squamous differentiation genes like SOX2. In addition to acid and bile, patients with GORD also have high oesophageal concentrations of nitric oxide (NO). This study aims to determine how acid, bile salts and NO affect genes that influence oesophageal cell phenotype. DESIGN: Oesophageal squamous cells from patients with Barrett's oesophagus were exposed to acidic bile salts or NOC-9 (an NO donor). SOX2, p63 (squamous transcription factor) and CDX2 mRNAs were measured by quantitative RT-PCR. SOX2 and its regulatory Akt pathway proteins were evaluated by western blotting. S-nitrosylation by NO was blocked by dithiothreitol. Immunohistochemistry for SOX2 was performed on the oesophagus of rats with surgically induced GORD which were fed diets with and without nitrite supplementation. RESULTS: In oesophageal squamous cells, NO profoundly decreased SOX2 protein and caused a significantly greater decrease in SOX2 mRNA than did acidic bile salts. NO also decreased p63 and increased CDX2 expression. NO caused S-nitrosylation of Akt, blocking its phosphorylation. Akt pathway inhibition by LY294002 or Akt siRNA reduced SOX2 mRNA. Rats fed with nitrite-supplemented diets exhibited weaker SOX2 oesophageal staining than rats fed with normal diets. CONCLUSIONS: In oesophageal squamous cells, NO blocks SOX2 expression through Akt S-nitrosylation. NO also increases CDX2 and decreases p63 expression. By triggering molecular events preventing squamous differentiation while promoting intestinal differentiation, NO might contribute to Barrett's pathogenesis.


Asunto(s)
Esófago de Barrett , Factor de Transcripción CDX2/metabolismo , Células Epiteliales , Reflujo Gastroesofágico , Óxido Nítrico/metabolismo , Factores de Transcripción SOXB1/metabolismo , Triazenos/metabolismo , Animales , Esófago de Barrett/etiología , Esófago de Barrett/metabolismo , Esófago de Barrett/patología , Ácidos y Sales Biliares/metabolismo , Diferenciación Celular , Línea Celular , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Esófago/patología , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/metabolismo , Reflujo Gastroesofágico/patología , Humanos , Masculino , ARN Mensajero/metabolismo , Ratas , Transducción de Señal/fisiología
10.
Am J Physiol Gastrointest Liver Physiol ; 309(3): G146-61, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-26045618

RESUMEN

Metaplastic epithelial cells of Barrett's esophagus transformed by the combination of p53-knockdown and oncogenic Ras expression are known to activate signal transducer and activator of transcription 3 (STAT3). When phosphorylated at tyrosine 705 (Tyr705), STAT3 functions as a nuclear transcription factor that can contribute to oncogenesis. STAT3 phosphorylated at serine 727 (Ser727) localizes in mitochondria, but little is known about mitochondrial STAT3's contribution to carcinogenesis in Barrett's esophagus, which is the focus of this study. We introduced a constitutively active variant of human STAT3 (STAT3CA) into the following: 1) non-neoplastic Barrett's (BAR-T) cells; 2) BAR-T cells with p53 knockdown; and 3) BAR-T cells that express oncogenic H-Ras(G12V). STAT3CA transformed only the H-Ras(G12V)-expressing BAR-T cells (evidenced by loss of contact inhibition, formation of colonies in soft agar, and generation of tumors in immunodeficient mice), and did so in a p53-independent fashion. The transformed cells had elevated levels of both mitochondrial (Ser727) and nuclear (Tyr705) phospho-STAT3. Introduction of a STAT3CA construct with a mutated tyrosine phosphorylation site into H-Ras(G12V)-expressing Barrett's cells resulted in high levels of mitochondrial phospho-STAT3 (Ser727) with little or no nuclear phospho-STAT3 (Tyr705), and the cells still formed tumors in immunodeficient mice. Thus tyrosine phosphorylation of STAT3 is not required for tumor formation in Ras-expressing Barrett's cells. We conclude that mitochondrial STAT3 (Ser727) can contribute to oncogenesis in Barrett's cells that express oncogenic Ras. These findings suggest that agents targeting STAT3 might be useful for chemoprevention in patients with Barrett's esophagus.


Asunto(s)
Esófago de Barrett , Mitocondrias/metabolismo , Proteína Oncogénica p21(ras)/metabolismo , Factor de Transcripción STAT3/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Esófago de Barrett/metabolismo , Esófago de Barrett/patología , Línea Celular Transformada , Transformación Celular Neoplásica/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Transducción de Señal/fisiología
11.
Gastroenterology ; 146(2): 461-72.e6, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24120473

RESUMEN

BACKGROUND & AIMS: Tumor cells express vascular endothelial growth factor (VEGF), which induces angiogenesis. VEGF also activates VEGF receptors (VEGFRs) on or within tumor cells to promote their proliferation in an autocrine fashion. We studied the mechanisms of autocrine VEGF signaling in Barrett's esophagus cells. METHODS: Using Barrett's epithelial cell lines, we measured VEGF and VEGFR messenger RNA and protein, and studied the effects of VEGF signaling on cell proliferation and VEGF secretion. We studied the effects of inhibiting factors in this pathway on levels of phosphorylated phospholipase Cγ1 (PLCG1), protein kinase C, and extracellular signal-regulated kinases (ERK)1/2. We performed immunohistochemical analysis of phosphorylated VEGFR2 on esophageal adenocarcinoma tissues. We studied effects of sunitinib, a VEGFR2 inhibitor, on proliferation of neoplastic cells and growth of xenograft tumors in mice. RESULTS: Neoplastic and non-neoplastic Barrett's cells expressed VEGF and VEGFR2 messenger RNA and protein, with higher levels in neoplastic cells. Incubation with recombinant human VEGF significantly increased secretion of VEGF protein and cell number; knockdown of PLCG1 markedly reduced the recombinant human VEGF-stimulated increase in levels of phosphorylated PLCG1 and phosphorylated ERK1/2 in neoplastic cells. Esophageal adenocarcinoma tissues showed immunostaining for phosphorylated VEGFR2. Sunitinib inhibited VEGF signaling in neoplastic cells and reduced weight and volume of xenograft tumors in mice. CONCLUSIONS: Neoplastic and non-neoplastic Barrett's epithelial cells have autocrine VEGF signaling. In neoplastic Barrett's cells, VEGF activation of VEGFR2 initiates a PLCG1-protein kinase C-ERK pathway that promotes proliferation and is self-sustaining (by causing more VEGF production). Strategies to reduce autocrine VEGF signaling (eg, with sunitinib) might be used to prevent or treat cancer in patients with Barrett's esophagus.


Asunto(s)
Adenocarcinoma/metabolismo , Esófago de Barrett/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Esofágicas/metabolismo , Lesiones Precancerosas/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Animales , Antineoplásicos/uso terapéutico , Comunicación Autocrina , Esófago de Barrett/patología , Biomarcadores/metabolismo , Línea Celular , Proliferación Celular , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Femenino , Humanos , Inmunohistoquímica , Indoles/uso terapéutico , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Fosfolipasa C gamma/metabolismo , Fosforilación , Lesiones Precancerosas/patología , Proteína Quinasa C/metabolismo , Pirroles/uso terapéutico , Reacción en Cadena en Tiempo Real de la Polimerasa , Sunitinib , Resultado del Tratamiento
12.
Gut ; 63(7): 1042-52, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24048734

RESUMEN

OBJECTIVE: Oesophagitis might result from the effects of chemokines produced by oesophageal cells in response to gastro-oesophageal reflux, and not solely from the direct, caustic effects of refluxed gastric juice. Proton pump inhibitors (PPI) can block chemokine production through mechanisms independent of their antisecretory effects. We studied omeprazole effects on chemokine production by oesophageal epithelial cells exposed to acidic bile salts. DESIGN: Human primary and telomerase-immortalised oesophageal squamous cells were exposed to acidic bile salt medium with or without omeprazole pretreatment. Interleukin (IL)-8 expression was determined by RT-PCR and ELISA. IL-8 promoter activity was measured by luciferase reporter assay. Binding of NF-κB and AP-1 subunits to the IL-8 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Immune cell migration induced by conditioned medium was determined by a double-chamber migration assay system. RESULTS: Acidic bile salt medium caused oesophageal epithelial cells to express IL-8 mRNA and protein by activating the IL-8 promoter through NF-κB and AP-1 binding. Omeprazole inhibited that acidic bile salt-stimulated IL-8 expression by blocking the nuclear translocation of p65 (an NF-κB subunit), and by blocking the binding of p65, c-jun and c-fos (AP-1 subunits) to the IL-8 promoter. Omeprazole also blocked the ability of conditioned medium from cells exposed to acidic bile salts to induce immune cell migration. CONCLUSIONS: In oesophageal squamous epithelial cells, omeprazole inhibits IL-8 expression through effects on NF-κB and AP-1 that are entirely independent of effects on gastric acid secretion. These previously unrecognised PPI effects might contribute to the healing of reflux oesophagitis.


Asunto(s)
Ácidos y Sales Biliares/farmacología , Células Epiteliales/efectos de los fármacos , Esófago/efectos de los fármacos , Interleucina-8/antagonistas & inhibidores , Omeprazol/farmacología , Inhibidores de la Bomba de Protones/farmacología , Biomarcadores/metabolismo , Línea Celular , Células Cultivadas , Inmunoprecipitación de Cromatina , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/metabolismo , Esofagitis Péptica/etiología , Esófago/metabolismo , Femenino , Humanos , Interleucina-8/metabolismo , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción AP-1/metabolismo
13.
Am J Physiol Gastrointest Liver Physiol ; 307(2): G129-39, 2014 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-24852569

RESUMEN

Hydrophobic bile acids like deoxycholic acid (DCA), which cause oxidative DNA damage and activate NF-κB in Barrett's metaplasia, might contribute to carcinogenesis in Barrett's esophagus. We have explored mechanisms whereby ursodeoxycholic acid (UDCA, a hydrophilic bile acid) protects against DCA-induced injury in vivo in patients and in vitro using nonneoplastic, telomerase-immortalized Barrett's cell lines. We took biopsies of Barrett's esophagus from 21 patients before and after esophageal perfusion with DCA (250 µM) at baseline and after 8 wk of oral UDCA treatment. DNA damage was assessed by phospho-H2AX expression, neutral CometAssay, and phospho-H2AX nuclear foci formation. Quantitative PCR was performed for antioxidants including catalase and GPX1. Nrf2, catalase, and GPX1 were knocked down with siRNAs. Reporter assays were performed using a plasmid construct containing antioxidant responsive element. In patients, baseline esophageal perfusion with DCA significantly increased phospho-H2AX and phospho-p65 in Barrett's metaplasia. Oral UDCA increased GPX1 and catalase levels in Barrett's metaplasia and prevented DCA perfusion from inducing DNA damage and NF-κB activation. In cells, DCA-induced DNA damage and NF-κB activation was prevented by 24-h pretreatment with UDCA, but not by mixing UDCA with DCA. UDCA activated Nrf2 signaling to increase GPX1 and catalase expression, and protective effects of UDCA pretreatment were blocked by siRNA knockdown of these antioxidants. UDCA increases expression of antioxidants that prevent toxic bile acids from causing DNA damage and NF-κB activation in Barrett's metaplasia. Elucidation of this molecular pathway for UDCA protection provides rationale for clinical trials on UDCA for chemoprevention in Barrett's esophagus.


Asunto(s)
Anticarcinógenos/uso terapéutico , Antioxidantes/uso terapéutico , Esófago de Barrett/tratamiento farmacológico , Daño del ADN/efectos de los fármacos , Ácido Desoxicólico/toxicidad , Células Epiteliales/efectos de los fármacos , Neoplasias Esofágicas/prevención & control , Esófago/efectos de los fármacos , Ácido Ursodesoxicólico/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antioxidantes/metabolismo , Esófago de Barrett/genética , Esófago de Barrett/metabolismo , Esófago de Barrett/patología , Catalasa/genética , Catalasa/metabolismo , Línea Celular , Células Epiteliales/metabolismo , Células Epiteliales/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Esófago/metabolismo , Esófago/patología , Femenino , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Histonas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Fosforilación , Interferencia de ARN , ARN Mensajero/metabolismo , Factores de Tiempo , Factor de Transcripción ReIA/metabolismo , Transfección , Resultado del Tratamiento , Regulación hacia Arriba , Glutatión Peroxidasa GPX1
14.
Gut ; 62(6): 824-32, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22580413

RESUMEN

OBJECTIVE: Eosinophilic oesophagitis (EoE) and gastro-oesophageal reflux disease (GORD) can have similar clinical and histological features. Proton pump inhibitors (PPIs) are used to distinguish the disorders, with the assumption that only GORD can respond to PPIs. Oesophageal expression of eotaxin-3 stimulated by Th2 cytokines might contribute to oesophageal eosinophilia in EoE. Th2 cytokine effects on the oesophagus in GORD are not known. The objective of the authors was to explore the molecular mechanisms of Th2 cytokines on eotaxin-3 expression by oesophageal squamous cells from patients with GORD and EoE, and the effects of omeprazole on that eotaxin-3 expression. DESIGN: Using telomerase-immortalised and primary cultures of oesophageal squamous cells from GORD and EoE patients, the authors measured eotaxin-3 protein secretion stimulated by Th2 cytokines (interleukin (IL)-4 and IL-13). Eotaxin-3 promoter constructs were used to study transcriptional regulation. Cytokine-induced eotaxin-3 mRNA and protein expression were measured in the presence or absence of omeprazole. RESULTS: There were no significant differences between EoE and GORD primary cells in cytokine-stimulated eotaxin-3 protein secretion levels. In EoE and GORD cell lines, IL-4 and IL-13 activated the eotaxin-3 promoter, and significantly increased eotaxin-3 mRNA and protein expression. Omeprazole blocked the cytokine-stimulated increase in eotaxin-3 mRNA and protein expression in EoE and GORD cell lines. CONCLUSION: Oesophageal squamous cells from GORD and EoE patients express similar levels of eotaxin-3 when stimulated by Th2 cytokines, and omeprazole blocks that eotaxin-3 expression. These findings suggest that PPIs might have eosinophil-reducing effects independent of effects on acid reflux and that response to PPIs might not distinguish EoE from GORD.


Asunto(s)
Quimiocinas CC/metabolismo , Esofagitis Eosinofílica/tratamiento farmacológico , Reflujo Gastroesofágico/tratamiento farmacológico , Omeprazol/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Adulto , Células Cultivadas , Quimiocina CCL26 , Quimiocinas CC/efectos de los fármacos , Quimiocinas CC/genética , Ensayo de Inmunoadsorción Enzimática , Esofagitis Eosinofílica/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Esófago/patología , Femenino , Reflujo Gastroesofágico/metabolismo , Regulación de la Expresión Génica , Humanos , Interleucina-13/antagonistas & inhibidores , Interleucina-13/farmacología , Interleucina-4/antagonistas & inhibidores , Interleucina-4/farmacología , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Células Th2/fisiología
15.
Curr Opin Gastroenterol ; 29(4): 416-20, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23449027

RESUMEN

PURPOSE OF REVIEW: To review the significance and plausible mechanisms underlying 'proton pump inhibitor (PPI) responsive oesophageal eosinophilia' in eosinophilic oesophagitis (EoE). RECENT FINDINGS: EoE is defined as an immune-mediated clinicopathologic condition characterized by oesophageal dysfunction and eosinophil-predominant inflammation. This new conceptual definition has been proposed partly due to a recently identified disease phenotype called 'PPI-responsive oesophageal eosinophilia'. Emerging data support the possibility that this condition represents a clinical response to anti-inflammatory properties of PPIs that are independent of effects on gastric acid. SUMMARY: Currently, the diagnosis of EoE is reserved for patients with oesophageal eosinophilia and symptoms that do not respond to PPIs. This practice may not be appropriate, however, both because gastric acid suppression by PPIs might benefit EoE patients and because PPIs have anti-inflammatory properties that also might benefit EoE patients. More studies are sorely needed to understand the mechanisms underlying PPI-responsive oesophageal eosinophilia. Currently, a favourable response to PPI therapy should not be regarded as a proof of an underlying acid peptic disorder such as gastroesophageal reflux disease (GERD) nor should it preclude a diagnosis of EoE. Furthermore, it seems prudent to recommend a trial of PPI therapy for patients with oesophageal eosinophilia and symptoms, even when the diagnosis of EoE seems clear-cut.


Asunto(s)
Esofagitis Eosinofílica/tratamiento farmacológico , Inhibidores de la Bomba de Protones/uso terapéutico , Antiinflamatorios/uso terapéutico , Esofagitis Eosinofílica/diagnóstico , Humanos , Resultado del Tratamiento
16.
Am J Physiol Gastrointest Liver Physiol ; 303(11): G1175-87, 2012 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-23019192

RESUMEN

Eosinophilic esophagitis (EoE) is a recently recognized, immune-mediated disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. The chronic esophageal eosinophilia of EoE is associated with tissue remodeling that includes epithelial hyperplasia, subepithelial fibrosis, and hypertrophy of esophageal smooth muscle. This remodeling causes the esophageal rings and strictures that frequently complicate EoE and underlies the mucosal fragility that predisposes to painful mucosal tears in the EoE esophagus. The pathogenesis of tissue remodeling in EoE is not completely understood, but emerging studies suggest that secretory products of eosinophils and mast cells, as well as cytokines produced by other inflammatory cells, epithelial cells, and stromal cells in the esophagus, all contribute to the process. Interleukin (IL)-4 and IL-13, Th2 cytokines overproduced in allergic disorders, have direct profibrotic and remodeling effects in EoE. The EoE esophagus exhibits increased expression of transforming growth factor (TGF)-ß1, which is a potent activator of fibroblasts and a strong inducer of epithelial-mesenchymal transition. In addition, IL-4, IL-13, and TGF-ß all have a role in regulating periostin, an extracellular matrix protein that might influence remodeling by acting as a ligand for integrins, by its effects on eosinophils or by activating fibrogenic genes in the esophagus. Presently, few treatments have been shown to affect the tissue remodeling that causes EoE complications. This report reviews the potential roles of fibroblasts, eosinophils, mast cells, and profibrotic cytokines in esophageal remodeling in EoE and identifies potential targets for future therapies that might prevent EoE complications.


Asunto(s)
Esofagitis Eosinofílica/patología , Eosinófilos/fisiología , Moléculas de Adhesión Celular/metabolismo , Esofagitis Eosinofílica/fisiopatología , Eosinófilos/patología , Transición Epitelial-Mesenquimal , Humanos , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Mastocitos/patología , Mastocitos/fisiología , Células Th2/inmunología , Factor de Crecimiento Transformador beta/biosíntesis
17.
Am J Physiol Gastrointest Liver Physiol ; 303(5): G561-9, 2012 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-22744336

RESUMEN

One way to link chronic inflammation with cancer is through the intrinsic inflammatory pathway, in which genetic alterations that induce malignant transformation also produce a cancer-promoting, inflammatory microenvironment. Signal transducer and activator of transcription 3 (STAT3) contributes to the intrinsic inflammatory pathway in Barrett's esophagus. In human tumors, honokiol (a polyphenol in herbal teas) has growth-inhibitory and proapoptotic effects associated with suppressed activation of STAT3. We used human Barrett's epithelial and esophageal adenocarcinoma cell lines to determine effects of honokiol on cell number, necrosis, apoptosis, and anchorage-independent growth and to explore STAT3's role in those effects. We determined Ras activity and expression of phosphorylated ERK1/2, phosphorylated Akt, and phosphorylated STAT3 in the presence or absence of honokiol. Cells were infected with constitutively active Stat3-C to assess effects of honokiol-induced STAT3 inhibition on apoptosis. Honokiol decreased cell number and increased necrosis and apoptosis in transformed Barrett's cells, but not in nontransformed cells. In adenocarcinoma cells, honokiol also increased necrosis and apoptosis and decreased anchorage-independent growth. Within 30 min of honokiol treatment, transformed Barrett's cells decreased expression of phosphorylated STAT3; decreases in Ras activity and phosphorylated ERK1/2 expression were detected at 24 h. Infection with Stat3-C significantly reduced apoptosis after honokiol treatment. Honokiol causes necrosis and apoptosis in transformed Barrett's and esophageal adenocarcinoma cells, but not in nontransformed Barrett's cells, and the proapoptotic effects of honokiol are mediated by its inhibition of STAT3 signaling. These findings suggest a potential role for targeting the intrinsic inflammatory pathways as a therapeutic strategy to prevent Barrett's carcinogenesis.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Esófago de Barrett/metabolismo , Compuestos de Bifenilo/farmacología , Lignanos/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Adenocarcinoma/prevención & control , Antineoplásicos Fitogénicos/uso terapéutico , Esófago de Barrett/tratamiento farmacológico , Esófago de Barrett/patología , Compuestos de Bifenilo/uso terapéutico , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Neoplasias Esofágicas/prevención & control , Humanos , Lignanos/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Transducción de Señal
18.
Am J Physiol Gastrointest Liver Physiol ; 300(3): G454-60, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21148399

RESUMEN

Cancer-related inflammation recently has been proposed as a major physiological hallmark of malignancy. Some genetic alterations known to promote cellular proliferation and induce malignant transformation also may participate in an intrinsic inflammatory pathway that produces a cancer-promoting inflammatory microenvironment. Little is known about this intrinsic inflammatory pathway in Barrett's esophagus. We have used a series of nontransformed and transformed human Barrett's epithelial cell lines developed in our laboratory to explore the potential contribution of interleukin (IL)-6 and signal transducer and activator of transcription (STAT3) (key molecules in the intrinsic inflammatory pathway) to Barrett's carcinogenesis. We determined IL-6 mRNA expression and protein secretion and protein expression of activated phospho-STAT3 and its downstream target myeloid cell leukemia (mcl)-1 (Mcl-1). We used an IL-6 blocking antibody and two JAK kinase inhibitors (AG490 and JAK inhibitor I) to assess whether STAT3 activation is IL-6 dependent. We also used small interfering RNAs (siRNAs) to STAT3 and Mcl-1 to assess effects of STAT3 pathway inhibition on apoptosis. Phospho-STAT3 was expressed only by transformed Barrett's cells, which also exhibited higher levels of IL-6 mRNA and of IL-6 and Mcl-1 proteins than nontransformed Barrett's cells. STAT3 phosphorylation could be blocked by IL-6 blocking antibody and by AG490 and JAK inhibitor I. In transformed Barrett's cells, rates of apoptosis following exposure to deoxycholic acid were significantly increased by transfection with siRNAs for STAT3 and Mcl-1. We conclude that activation of the IL-6/STAT3 pathway in transformed Barrett's epithelial cells enables them to resist apoptosis. These findings demonstrate a possible contribution of the intrinsic inflammatory pathway to carcinogenesis in Barrett's esophagus.


Asunto(s)
Apoptosis , Esófago de Barrett/metabolismo , Transformación Celular Neoplásica/metabolismo , Células Epiteliales/metabolismo , Neoplasias Esofágicas/metabolismo , Esofagitis/metabolismo , Esófago/metabolismo , Interleucina-6/metabolismo , Factor de Transcripción STAT3/metabolismo , Esófago de Barrett/genética , Esófago de Barrett/patología , Línea Celular Transformada , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Ácido Desoxicólico/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Esofagitis/genética , Esofagitis/patología , Esófago/efectos de los fármacos , Esófago/patología , Genes ras , Humanos , Interleucina-6/genética , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Interferencia de ARN , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/genética , Transducción de Señal , Telomerasa/genética , Telomerasa/metabolismo , Factores de Tiempo , Transfección , Microambiente Tumoral , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Tirosina
19.
Am J Physiol Gastrointest Liver Physiol ; 301(2): G278-86, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21636532

RESUMEN

Gastroesophageal reflux is associated with adenocarcinoma in Barrett's esophagus, but the incidence of this tumor is rising, despite widespread use of acid-suppressing medications. This suggests that refluxed material other than acid might contribute to carcinogenesis. We looked for potentially carcinogenetic effects of two bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on Barrett's epithelial cells in vitro and in vivo. We exposed Barrett's (BAR-T) cells to DCA or UDCA and studied the generation of reactive oxygen/nitrogen species (ROS/RNS); expression of phosphorylated H2AX (a marker of DNA damage), phosphorylated IkBα, and phosphorylated p65 (activated NF-κB pathway proteins); and apoptosis. During endoscopy in patients, we took biopsy specimens of Barrett's mucosa before and after esophageal perfusion with DCA or UDCA and assessed DNA damage and NF-κB activation. Exposure to DCA, but not UDCA, resulted in ROS/RNS production, DNA damage, and NF-κB activation but did not increase the rate of apoptosis in BAR-T cells. Pretreatment with N-acetyl-l-cysteine (a ROS scavenger) prevented DNA damage after DCA exposure, and DCA did induce apoptosis in cells treated with NF-κB inhibitors (BAY 11-7085 or AdIκB superrepressor). DNA damage and NF-κB activation were detected in biopsy specimens of Barrett's mucosa taken after esophageal perfusion with DCA, but not UDCA. These data show that, in Barrett's epithelial cells, DCA induces ROS/RNS production, which causes genotoxic injury, and simultaneously induces activation of the NF-κB pathway, which enables cells with DNA damage to resist apoptosis. We have demonstrated molecular mechanisms whereby bile reflux might contribute to carcinogenesis in Barrett's esophagus.


Asunto(s)
Esófago de Barrett/metabolismo , Ácido Desoxicólico/farmacología , Células Epiteliales/metabolismo , FN-kappa B/metabolismo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ácido Ursodesoxicólico/farmacología , Anciano , Análisis de Varianza , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Transformación Celular Neoplásica , Daño del ADN/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Histonas/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Masculino , Persona de Mediana Edad , Inhibidor NF-kappaB alfa , Ratas , Transducción de Señal/efectos de los fármacos
20.
Pediatr Transplant ; 15(8): E187-91, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20670357

RESUMEN

Post-transplant lymphoproliferative disorder is a life-threatening neoplasm that can occur after orthotopic liver transplant. We report a 14-month-old female status-post OLT with an atypical presentation of PTLD as a solitary renal mass. At eight-wk post-transplant, she presented with elevated transaminases, CMV counts (73,000 copies/mL), and EBV counts (35,000 copies/mL). CT scan revealed a solid heterogeneously enhancing right renal mass measuring 2.6 × 2.4 × 3.3 cm. The radiological diagnosis was Wilms tumor, although PTLD could not be excluded. Complete resection of a Wilms tumor is potentially curative. A needle biopsy would upstage the malignancy and result in radiochemotherapy that is deleterious to a liver graft. The mass was not amenable to partial nephrectomy. A total nephrectomy, given life-long nephrotoxic immunosuppressants, was an unfavorable option. Thus, needle biopsy was performed. Histology confirmed monoclonal, EBV-associated PTLD and diffuse large B-cell lymphoma. Her therapy included immunosuppression reduction, cyclophosphamide, steroids, and anti-CD20 monoclonal antibody. Concomitantly, she received Cytogam and gancyclovir. Complete remission was achieved three months after chemotherapy. This case illustrates that young age, CMV infection, and EBV infection are strong risk factors for PTLD. With such risk factors present, any mass or lesion in a solid organ transplant patient should be considered PTLD until proven otherwise.


Asunto(s)
Neoplasias Renales/diagnóstico , Trasplante de Hígado/efectos adversos , Trastornos Linfoproliferativos/diagnóstico , Tumor de Wilms/diagnóstico , Biopsia con Aguja , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Riñón/patología , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/patología , Nefrectomía
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