RESUMEN
INTRODUCTION: Epithelial-mesenchymal plasticity (EMP), the process through which epithelial cells acquire mesenchymal features, is needed for wound repair but also might contribute to cancer initiation. Earlier, in vitro studies showed that Barrett's cells exposed to acidic bile salt solutions (ABS) develop EMP. Now, we have (1) induced reflux oesophagitis in Barrett's oesophagus (BO) patients by stopping proton pump inhibitors (PPIs), (2) assessed their biopsies for EMP and (3) explored molecular pathways underlying reflux-induced EMP in BO cells and spheroids. METHODS: 15 BO patients had endoscopy with biopsies of Barrett's metaplasia while on PPIs, and 1 and 2 weeks after stopping PPIs; RNA-seq data were assessed for enrichments in hypoxia-inducible factors (HIFs), angiogenesis and EMP pathways. In BO biopsies, cell lines and spheroids, EMP features (motility) and markers (vascular endothelial growth factor (VEGF), ZEB1, miR-200a&b) were evaluated by morphology, migration assays, immunostaining and qPCR; HIF-1α was knocked down with siRNA or shRNA. RESULTS: At 1 and/or 2 weeks off PPIs, BO biopsies exhibited EMP features and markers, with significant enrichment for HIF-1α, angiogenesis and EMP pathways. In BO cells, ABS induced HIF-1α activation, which decreased miR-200a&b while increasing VEGF, ZEB1 and motility; HIF-1α knockdown blocked these effects. After ABS treatment, BO spheroids exhibited migratory protrusions showing nuclear HIF-1α, increased VEGF and decreased miR-200a&b. CONCLUSIONS: In BO patients, reflux oesophagitis induces EMP changes associated with increased HIF-1α signalling in Barrett's metaplasia. In Barrett's cells, ABS trigger EMP via HIF-1α signalling. Thus, HIF-1α appears to play a key role in mediating reflux-induced EMP that might contribute to cancer in BO. TRIAL REGISTRATION NUMBER: NCT02579460.
Asunto(s)
Esófago de Barrett , Transición Epitelial-Mesenquimal , Subunidad alfa del Factor 1 Inducible por Hipoxia , Inhibidores de la Bomba de Protones , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esófago de Barrett/patología , Esófago de Barrett/metabolismo , Esófago de Barrett/genética , Movimiento Celular , Esofagitis Péptica/patología , Esofagitis Péptica/metabolismo , Esofagitis Péptica/etiología , Reflujo Gastroesofágico/metabolismo , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genéticaRESUMEN
BACKGROUND AND AIMS: The diagnosis of achalasia is associated with an average delay of 2 years. Endoscopic features may prompt an earlier diagnosis. We aimed to develop and test a novel endoscopic score, CARS, for the prediction of achalasia. METHODS: Part 1: Twenty endoscopic videos were taken from patients undergoing endoscopy for dysphagia or reflux. A survey with videos and endoscopic criteria options was distributed to 6 esophagologists and 6 general gastroenterologists. Inter-rater reliability (IRR) was measured and logistic regression was used to evaluate predictive performance. Three rounds of review were conducted to select the final score of 4 components. Part 2: A retrospective review was conducted for consecutive patients who had comprehensive esophageal testing. Each patient had a CARS endoscopic score calculated based on findings reported at endoscopy. RESULTS: From a video review and analysis of score components, IRR ranged from 0.23 to 0.57 for score components. The final CARS score was selected based on the following 4 components: Contents, Anatomy, Resistance, and Stasis. In a mixed-effects model, the mean score across raters was higher for achalasia compared with nonachalasia subjects (4.44 vs 0.87; P < .01). In part 2 of the study, achalasia patients had a higher mean CARS score compared with those with no or ineffective motility disorder (mean 4.1 vs 1.3; P < .01). CONCLUSIONS: We developed a CARS score based on reliability performance in a video-based survey and tested the score in a clinical setting. The CARS score performed well in predicting achalasia.
Asunto(s)
Acalasia del Esófago , Acalasia del Esófago/diagnóstico , Humanos , Estudios Retrospectivos , Reproducibilidad de los Resultados , Femenino , Grabación en Video , Masculino , Esofagoscopía/métodos , Persona de Mediana Edad , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Modelos Logísticos , Reflujo Gastroesofágico/diagnóstico , Adulto , Variaciones Dependientes del Observador , AncianoAsunto(s)
Compuestos Heterocíclicos con 3 Anillos , Humanos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Células Th2/inmunología , Células Th2/efectos de los fármacos , Quimiocina CCL26/metabolismo , Quimiocina CCL26/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Esófago/efectos de los fármacos , Esófago/inmunología , Esófago/metabolismo , Citocinas/metabolismo , Contracción Muscular/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: Achalasia has been assumed to be an autoimmune disease targeting esophageal myenteric neurons. Recently, we proposed an alternative hypothesis that achalasia sometimes might be allergy-driven, caused by a form of eosinophilic esophagitis (EoE) in which activated eosinophils and/or mast cells infiltrating esophageal muscle release products that disrupt motility and damage myenteric neurons. To seek epidemiologic support for this hypothesis, we identified patients with achalasia in the Utah Population Database, and explored their frequency of having EoE and other allergic disorders. METHODS: We used International Classification of Diseases codes to identify patients with achalasia and allergic disorders including EoE, asthma, atopic dermatitis, contact dermatitis, allergic rhinitis, allergic conjunctivitis, hives/urticaria, and anaphylaxis. We calculated relative risk (RR) for each allergic disorder by comparing the number observed in patients with achalasia with the expected number in individuals matched for birthyear and sex, and we performed subanalyses for patients age ≤40 versus age >40 years. RESULTS: Among 844 patients with achalasia identified (55% female; median age at diagnosis, 58 years), 402 (47.6%) had ≥1 allergic disorder. Fifty-five patients with achalasia (6.5%) had EoE (1.67 EoE cases expected), for a RR of 32.9 (95% confidence interval, 24.8-42.8; P < .001). In 208 patients with achalasia age ≤40 years, the RR for EoE was 69.6 (95% confidence interval, 46.6-100.0; P < .001). RR also was increased significantly for all other allergic disorders evaluated (all greater than 3-fold higher than population rates). CONCLUSIONS: Achalasia is strongly associated with EoE and other allergic disorders. These data support the hypothesis that achalasia sometimes might have an allergic etiology.
Asunto(s)
Asma , Esofagitis Eosinofílica , Acalasia del Esófago , Humanos , Femenino , Persona de Mediana Edad , Adulto , Masculino , Esofagitis Eosinofílica/complicaciones , Esofagitis Eosinofílica/epidemiología , Esofagitis Eosinofílica/diagnóstico , Acalasia del Esófago/complicaciones , Acalasia del Esófago/epidemiología , Asma/complicaciones , EosinófilosRESUMEN
In esophageal epithelial cells in eosinophilic esophagitis (EoE), Th2 cytokines (IL-4, IL-13) signal through IL-4Rα, activating JAK to increase eotaxin-3 secretion, which draws eosinophils into the mucosa. We explored whether Th2 cytokines also might stimulate eotaxin-3 secretion and increase tension in esophageal smooth muscle (ESM), which might impair esophageal distensibility, and whether those events could be blocked by proton pump inhibitors (PPIs) or agents that disrupt IL-4Rα signaling. We established human ESM cell cultures from organ donors, characterizing Th2 cytokine receptor and P-type ATPase expression by qPCR. We measured Th2 cytokine-stimulated eotaxin-3 secretion by enzyme-linked immunosorbent assay (ELISA) and ESM cell tension by gel contraction assay, before and after treatment with omeprazole, ruxolitinib (JAK inhibitor), or IL-4Rα blocking antibody. CPI-17 (inhibitor of a muscle-relaxing enzyme) effects were studied with CPI-17 knockdown by siRNA or CPI-17 phospho(T38A)-mutant overexpression. ESM cells expressed IL-4Rα and IL-13Rα1 but only minimal H+-K+-ATPase mRNA. Th2 cytokines increased ESM eotaxin-3 secretion and tension, effects blocked by ruxolitinib and IL-4Rα blocking antibody but not consistently blocked by omeprazole. IL-13 increased ESM tension by increasing CPI-17 expression and phosphorylation, effects blocked by CPI-17 knockdown. Blocking IL-4Rα decreased IL-13-stimulated eotaxin-3 secretion, CPI-17 expression, and tension in ESM. Th2 cytokines increase ESM eotaxin-3 secretion and tension via IL-4Rα signaling that activates CPI-17. Omeprazole does not reliably inhibit this process, but IL-4Rα blocking antibody does. This suggests that ESM eosinophilia and impaired esophageal distensibility might persist despite elimination of mucosal eosinophils by PPIs, and IL-4Rα blocking agents might be especially useful in this circumstance.NEW & NOTEWORTHY We have found that Th2 cytokines increase eotaxin-3 secretion and tension in esophageal smooth muscle (ESM) cells via IL-4Rα signaling. Unlike esophageal epithelial cells, ESM cells do not express H+-K+-ATPase, and omeprazole does not inhibit their cytokine-stimulated eotaxin-3 secretion or tension. An IL-4Rα blocking antibody reduces both eotaxin-3 secretion and tension induced by Th2 cytokines in ESM cells, suggesting that an agent such as dupilumab might be preferred for patients with EoE with esophageal muscle involvement.
Asunto(s)
Esofagitis Eosinofílica , Interleucina-13 , Humanos , Adenosina Trifosfatasas , Quimiocina CCL26 , Citocinas/metabolismo , Esofagitis Eosinofílica/metabolismo , Interleucina-13/farmacología , Músculo Liso/metabolismo , Omeprazol , Inhibidores de la Bomba de Protones/farmacología , Células Th2RESUMEN
BACKGROUND: There are frequent discrepancies among high-resolution manometry (HRM), functional lumen imaging probe (FLIP), and esophagram in identifying lower esophageal sphincter (LES)-related obstruction. We aimed to determine the frequency of those discrepancies and how they influenced clinical treatment/outcomes. METHODS: We identified patients who had all three tests (HRM, FLIP, and esophagram) and endoscopy performed for evaluation of esophageal symptoms in our Center for Esophageal Diseases. Discrepancies among the tests for the presence of LES obstruction were noted, and the performance of individual tests was compared against a consensus opinion rendered by a panel of esophagologists. Binary logistical regression was performed, and ROC curves were generated for prediction of the consensus clinical diagnosis of LES obstruction. KEY RESULTS: A total of 126 patients (mean age 57.9 ± 17.0 years; 67% female) met inclusion criteria. All three tests agreed on the presence or absence of LES obstruction in only 72 (57%) patients [no LES obstruction in 57 (45%), LES obstruction in 15 (12%)]. Thirteen patients (10%) had a change in management based on additional findings on FLIP +/- esophagram not seen on HRM with 69% having symptomatic improvement after LES-directed intervention. FLIP was the strongest predictor of a consensus diagnosis of LES obstruction by logistic regression and ROC (OR 23.36, AUC 0.796), followed by HRM (OR 15.41, AUC 0.764). CONCLUSIONS & INFERENCE: High-resolution manometry, functional lumen imaging probe, and esophagram each have considerable limitations for identifying LES obstruction, and discrepancies among these tests occur frequently. Multimodal testing is often required for adequate evaluation of LES-related obstruction.
Asunto(s)
Acalasia del Esófago , Trastornos de la Motilidad Esofágica , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , Esfínter Esofágico Inferior , Trastornos de la Motilidad Esofágica/diagnóstico , Unión Esofagogástrica , Manometría/métodos , Endoscopía Gastrointestinal , Pruebas Diagnósticas de Rutina , Acalasia del Esófago/diagnósticoRESUMEN
Autophagy of damaged mitochondria, called mitophagy, is an important organelle quality control process involved in the pathogenesis of inflammation, cancer, aging, and age-associated diseases. Many of these disorders are associated with altered expression of the inner mitochondrial membrane (IMM) protein Prohibitin 1. The mechanisms whereby dysfunction occurring internally at the IMM and matrix activate events at the outer mitochondrial membrane (OMM) to induce mitophagy are not fully elucidated. Using the gastrointestinal epithelium as a model system highly susceptible to autophagy inhibition, we reveal a specific role of Prohibitin-induced mitophagy in maintaining intestinal homeostasis. We demonstrate that Prohibitin 1 induces mitophagy in response to increased mitochondrial reactive oxygen species (ROS) through binding to mitophagy receptor Nix/Bnip3L and independently of Parkin. Prohibitin 1 is required for ROS-induced Nix localization to mitochondria and maintaining homeostasis of epithelial cells highly susceptible to mitochondrial dysfunction.
Asunto(s)
Membranas Mitocondriales , Mitofagia , Membranas Mitocondriales/metabolismo , Prohibitinas , Especies Reactivas de Oxígeno/metabolismo , Mitocondrias/metabolismo , Autofagia , Proteínas de la Membrana/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Mitocondriales/metabolismoRESUMEN
High-resolution manometry (HRM) with the Chicago Classification (CC) is the standard paradigm to define esophageal motility disorders. Functional lumen imaging probe (FLIP) panometry utilizes impedance planimetry to characterize esophageal compliance and secondary peristalsis. The aim of this study was to explore the clinical impact of FLIP panometry in addition to HRM. A retrospective chart review was performed on FLIP panometry cases utilizing the 322N catheter. Cases with prior foregut surgeries or botulinum injection within 6 months of FLIP panometry were excluded. EGJ-diameter and distensibility index (DI) and secondary contraction patterns at increasing balloon volumes were recorded. An EGJ-DI of ≥2.8 mm2/mm Hg at 60 mL was considered as a normal EGJ distensibility. CC diagnosis, Eckhardt score, Brief Esophageal Dysphagia Questionnaire, and clinical outcomes were obtained for each FLIP case. A total of 186 cases were included. Absent contractility and achalasia types 1 and 2 showed predominantly absent secondary contraction patterns, while type 3 had a variety of secondary contractile patterns on FLIP panometry. Among 77 cases with EGJ outflow obstruction (EGJOO), 60% had a low EGJ-DI. Among those with no motility disorder or ineffective esophageal motility on HRM, 27% had a low DI and 47% had sustained contractions on FLIP, raising concern for an esophageal dysmotility process along the achalasia and/or spastic spectrum. FLIP panometry often confirmed findings on HRM in achalasia and absent contractility. FLIP panometry is useful in characterizing EGJOO cases. Spastic features on FLIP panometry may raise concern for a motility disorder on the spastic spectrum not captured by HRM. Further studies are needed on FLIP panometry to determine how to proceed with discrepancy with HRM and explore diagnoses beyond the CC.
Asunto(s)
Acalasia del Esófago , Trastornos de la Motilidad Esofágica , Humanos , Acalasia del Esófago/diagnóstico , Estudios Retrospectivos , Espasticidad Muscular , Manometría/métodos , Unión EsofagogástricaRESUMEN
INTRODUCTION: Radiofrequency ablation (RFA) of Barrett's esophagus (BE) inflicts a wound spanning 3 epithelial types (stratified squamous, Barrett's metaplasia, gastric epithelium), yet the esophageal injury heals almost completely with squamous epithelium. Knowledge of how this unique wound heals might elucidate mechanisms underlying esophageal metaplasia. We aimed to prospectively and systematically characterize the early endoscopic and histologic features of RFA wound healing. METHODS: Patients with nondysplastic BE had endoscopy with systematic esophageal photographic mapping, biopsy, and volumetric laser endomicroscopy performed before and at 1, 2, and 4 weeks after RFA. RESULTS: Seven patients (6 men; mean age 56.1 ± 10.9 years) completed this study. Squamous re-epithelialization of RFA wounds did not only progress exclusively through squamous cells extending from the proximal wound edge but also progressed through islands of squamous epithelium sprouting throughout the ablated segment. Volumetric laser endomicroscopy revealed significant post-RFA increases in subepithelial glandular structures associated with the squamous islands. In 2 patients, biopsies of such islands revealed newly forming squamous epithelium contiguous with immature-appearing squamous cells arising from esophageal submucosal gland ducts. Subsquamous intestinal metaplasia (SSIM) was found in biopsies at 2 and/or 4 weeks after RFA in 6 of 7 patients. DISCUSSION: RFA wounds in BE are re-epithelialized, not just by squamous cells from the proximal wound margin but by scattered squamous islands in which esophageal submucosal gland duct cells seem to redifferentiate into the squamous progenitors that fuel squamous re-epithelialization. SSIM can be found in most patients during the healing process. We speculate that this SSIM might underlie Barrett's recurrences after apparently successful eradication.
Asunto(s)
Esófago de Barrett , Carcinoma de Células Escamosas , Ablación por Catéter , Neoplasias Esofágicas , Anciano , Esófago de Barrett/patología , Carcinoma de Células Escamosas/cirugía , Neoplasias Esofágicas/patología , Esofagoscopía , Humanos , Masculino , Metaplasia/complicaciones , Persona de Mediana Edad , Cicatrización de HeridasRESUMEN
Barrett oesophagus, in which a metaplastic columnar mucosa that can predispose individuals to cancer development lines a portion of the distal oesophagus, is the only known precursor of oesophageal adenocarcinoma, the incidence of which has increased profoundly over the past several decades. Most evidence suggests that Barrett oesophagus develops from progenitor cells at the oesophagogastric junction that proliferate and undergo epithelial-mesenchymal transition as part of a wound-healing process that replaces oesophageal squamous epithelium damaged by gastroesophageal reflux disease (GERD). GERD also seems to induce reprogramming of key transcription factors in the progenitor cells, resulting in the development of the specialized intestinal metaplasia that is characteristic of Barrett oesophagus, probably through an intermediate step of metaplasia to cardiac mucosa. Genome-wide association studies suggest that patients with GERD who develop Barrett oesophagus might have an inherited predisposition to oesophageal metaplasia and that there is a shared genetic susceptibility to Barrett oesophagus and to several of its risk factors (such as GERD, obesity and cigarette smoking). In this Review, we discuss the mechanisms, pathophysiology, genetic predisposition and cells of origin of Barrett oesophagus, and opine on the clinical implications and future research directions.
Asunto(s)
Esófago de Barrett , Neoplasias Esofágicas , Reflujo Gastroesofágico , Estudio de Asociación del Genoma Completo , Humanos , MetaplasiaRESUMEN
The pathogenesis of subsquamous intestinal metaplasia (SSIM), in which glands of Barrett's esophagus (BE) are buried under esophageal squamous epithelium, is unknown. In a rat model of reflux esophagitis, we found that columnar-lined esophagus developed via a wound-healing process involving epithelial-mesenchymal plasticity (EMP) that buried glands under ulcerated squamous epithelium. To explore a role for reflux-induced EMP in BE, we established and characterized human Barrett's organoids and sought evidence of EMP after treatment with acidic bile salts (AB). We optimized media to grow human BE organoids from immortalized human Barrett's cells and from BE biopsies from seven patients, and we characterized histological, morphological, and molecular features of organoid development. Features and markers of EMP were explored following organoid exposure to AB, with and without a collagen I (COL1) matrix to simulate a wound-healing environment. All media successfully initiated organoid growth, but advanced DMEM/F12 (aDMEM) was best at sustaining organoid viability. Using aDMEM, organoids comprising nongoblet and goblet columnar cells that expressed gastric and intestinal cell markers were generated from BE biopsies of all seven patients. After AB treatment, early-stage Barrett's organoids exhibited EMP with loss of membranous E-cadherin and increased protrusive cell migration, events significantly enhanced by COL1. Using human BE biopsies, we have established Barrett's organoids that recapitulate key histological and molecular features of BE to serve as high-fidelity BE models. Our findings suggest that reflux can induce EMP in human BE, potentially enabling Barrett's cells to migrate under adjacent squamous epithelium to form SSIM.NEW & NOTEWORTHY Using Barrett's esophagus (BE) biopsies, we established organoids recapitulating key BE features. During early stages of organoid development, a GERD-like wound environment-induced features of epithelial-mesenchymal plasticity (EMP) in Barrett's progenitor cells, suggesting that reflux-induced EMP can enable Barrett's cells to migrate underneath squamous epithelium to form subsquamous intestinal metaplasia, a condition that may underlie Barrett's cancers that escape detection by endoscopic surveillance, and recurrences of Barrett's metaplasia following endoscopic eradication therapy.
Asunto(s)
Esófago de Barrett , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Esofagitis Péptica , Reflujo Gastroesofágico , Animales , Esófago de Barrett/patología , Ácidos y Sales Biliares/farmacología , Carcinoma de Células Escamosas/complicaciones , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/patología , Reflujo Gastroesofágico/complicaciones , Humanos , Metaplasia , Organoides/patología , RatasRESUMEN
Barrett's esophagus (BE) is a common condition associated with chronic gastroesophageal reflux disease. BE is the only known precursor to esophageal adenocarcinoma, a highly lethal cancer with an increasing incidence over the last 5 decades. These revised guidelines implement Grading of Recommendations, Assessment, Development, and Evaluation methodology to propose recommendations for the definition and diagnosis of BE, screening for BE and esophageal adenocarcinoma, surveillance of patients with known BE, and the medical and endoscopic treatment of BE and its associated early neoplasia. Important changes since the previous iteration of this guideline include a broadening of acceptable screening modalities for BE to include nonendoscopic methods, liberalized intervals for surveillance of short-segment BE, and volume criteria for endoscopic therapy centers for BE. We recommend endoscopic eradication therapy for patients with BE and high-grade dysplasia and those with BE and low-grade dysplasia. We propose structured surveillance intervals for patients with dysplastic BE after successful ablation based on the baseline degree of dysplasia. We could not make recommendations regarding chemoprevention or use of biomarkers in routine practice due to insufficient data.
Asunto(s)
Adenocarcinoma , Esófago de Barrett , Neoplasias Esofágicas , Reflujo Gastroesofágico , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiología , Adenocarcinoma/terapia , Esófago de Barrett/complicaciones , Esófago de Barrett/diagnóstico , Esófago de Barrett/terapia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/terapia , Esofagoscopía , Reflujo Gastroesofágico/complicaciones , HumanosRESUMEN
BACKGROUND: Functional lumen imaging probe (FLIP) panometry can show spastic secondary contractile patterns of unclear significance in symptomatic patients who have no esophageal obstructive disorders, and no motility disorders on high-resolution manometry (HRM). METHODS: We retrospectively analyzed non-obstructed, symptomatic patients with HRM findings of no motility disorder or ineffective esophageal motility (IEM) for whom spastic secondary contractile patterns identified by FLIP panometry were used to guide treatment. Symptoms were scored using the Brief Esophageal Dysphagia Questionnaire (BEDQ). KEY RESULTS: We identified ten symptomatic patients treated at our medical center who met inclusion criteria (seven women; mean age 56 years; eight no motility disorder, two IEM). On FLIP panometry, seven had spastic secondary contractions at 60 ml, two at 40 ml, and one at both 40 ml and 60 ml balloon volumes. Eight patients (80%) had improvement in BEDQ scores with therapies that targeted the spastic secondary contractile patterns identified by FLIP (five botulinum toxin injection, two Esoflip dilation, and one Heller myotomy). Interestingly, review of HRM tracings revealed that all patients had a novel HRM finding of mid-vertical pressurization in at least 20% swallows, with seven exhibiting this finding in >50% of swallows. CONCLUSIONS: This case series demonstrates that treatments targeting spastic secondary contractions identified by FLIP panometry can result in symptomatic improvement in patients with no obstructive disorder and no diagnostic motility disorder on HRM. In such patients, we have identified the novel HRM finding of mid-vertical pressurization, which might be the manometric manifestation of spasm limited to the mid-esophagus.
Asunto(s)
Trastornos de la Motilidad Esofágica , Trastornos de la Motilidad Esofágica/diagnóstico , Femenino , Humanos , Manometría/métodos , Persona de Mediana Edad , Espasticidad Muscular , Estudios RetrospectivosRESUMEN
Obesity is associated with gastroesophageal reflux disease (GERD) and its complications including reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Traditionally, these associations have been attributed to the mechanical effect of abdominal fat in increasing intra-abdominal pressure, thereby promoting gastroesophageal reflux and causing disruption of antireflux mechanisms at the esophagogastric junction. However, recent studies suggest that visceral adipose tissue (VAT) produces numerous cytokines that can cause esophageal inflammation and impair esophageal mucosal barrier integrity through reflux-independent mechanisms that render the esophageal mucosa especially susceptible to GERD-induced injury. In this report, we review mechanisms of esophageal mucosal defense, the genesis and remodeling of visceral adipose tissue during obesity, and the potential role of substances produced by VAT, especially the VAT that encircles the esophagogastric junction, in the impairment of esophageal mucosal barrier integrity that leads to the development of GERD complications.
Asunto(s)
Esófago de Barrett/patología , Mucosa Esofágica/metabolismo , Reflujo Gastroesofágico/patología , Obesidad/patología , Esófago de Barrett/metabolismo , Mucosa Esofágica/patología , Esofagitis Péptica/metabolismo , Esofagitis Péptica/patología , Esófago/patología , Reflujo Gastroesofágico/metabolismo , Humanos , Obesidad/metabolismoRESUMEN
INTRODUCTION: Whether cardiac mucosa at the esophagogastric junction is normal or metaplastic is controversial. Studies attempting to resolve this issue have been limited by the use of superficial pinch biopsies, abnormal esophagi resected typically because of cancer, or autopsy specimens in which tissue autolysis in the stomach obscures histologic findings. METHODS: We performed histologic and immunohistochemical studies of the freshly fixed esophagus and stomach resected from 7 heart-beating, deceased organ donors with no history of esophageal or gastric disease and with minimal or no histologic evidence of esophagitis and gastritis. RESULTS: All subjects had cardiac mucosa, consisting of a mixture of mucous and oxyntic glands with surface foveolar epithelium, at the esophagogastric junction. All also had unique structures we termed compact mucous glands (CMG), which were histologically and immunohistochemically identical to the mucous glands of cardiac mucosa, under esophageal squamous epithelium and, hitherto undescribed, in uninflamed oxyntic mucosa throughout the gastric fundus. DISCUSSION: These findings support cardiac mucosa as a normal anatomic structure and do not support the hypothesis that cardiac mucosa is always metaplastic. However, they do support our novel hypothesis that in the setting of reflux esophagitis, reflux-induced damage to squamous epithelium exposes underlying CMG (which are likely more resistant to acid-peptic damage than squamous epithelium), and proliferation of these CMG as part of a wound-healing process to repair the acid-peptic damage could result in their expansion to the mucosal surface to be recognized as cardiac mucosa of a columnar-lined esophagus.
Asunto(s)
Mucosa Esofágica/anatomía & histología , Unión Esofagogástrica/anatomía & histología , Mucosa Gástrica/anatomía & histología , Donantes de Tejidos , Adulto , Muerte Encefálica , Cardias/anatomía & histología , Cardias/patología , Epitelio/anatomía & histología , Epitelio/patología , Mucosa Esofágica/patología , Unión Esofagogástrica/patología , Femenino , Mucosa Gástrica/patología , Técnicas de Preparación Histocitológica , Humanos , Inmunohistoquímica , Masculino , Metaplasia , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND & AIMS: In upper airway cells, T helper 2 cytokines that signal through interleukin-4 (IL-4) receptor-α have been shown to stimulate eotaxin-3 secretion via a nongastric proton pump (ngH+,K+ATPase). To seek novel targets for eosinophilic esophagitis (EoE) treatments, we evaluated ngH+,K+ATPase expression in EoE squamous cells, and explored molecular pathways involved in eotaxin-3 secretion by IL-4 receptor-α signaling. METHODS: ngH+,K+ATPase expression in EoE cells was evaluated by quantitative real-time polymerase chain reaction and Western blotting. IL-4-stimulated eotaxin-3 secretion was measured by enzyme-linked immunosorbent assay after treatment with omeprazole, SCH 28080 (potassium-competitive acid blocker), ethylene glycol-bis(ß-aminoethyl)-N,N,N',N'-tetraacetoxymethyl ester (calcium chelator), 2-aminoethoxydiphenyl borate (inhibitor of endoplasmic reticulum calcium release), verapamil, and diltiazem (L-type calcium channel inhibitors). Intracellular calcium transients were measured by Fluo-4 fluorescence. Key experiments were confirmed in EoE primary cells and in RNA sequencing datasets from mucosal biopsies of patients with EoE and controls. RESULTS: EoE cells expressed ngH+,K+ATPase messenger RNA and protein. Omeprazole and SCH 28080 decreased IL-4-stimulated eotaxin-3 secretion. IL-4 increased intracellular calcium transients, and IL-4-stimulated eotaxin-3 secretion was blocked by ethylene glycol-bis(ß-aminoethyl)-N,N,N',N'-tetraacetoxymethyl ester, 2-aminoethoxydiphenyl borate, verapamil, and diltiazem. The combination of omeprazole and verapamil suppressed IL-4-stimulated eotaxin-3 secretion more than either agent alone. EoE biopsies expressed higher ngH+,K+ATPase and exhibited more calcium signaling than controls. CONCLUSIONS: EoE cells express a nongastric proton pump that mediates T helper 2 cytokine-stimulated eotaxin-3 secretion. IL-4 induces calcium release from the endoplasmic reticulum and calcium entry via L-type calcium channels, increasing intracellular calcium that contributes to eotaxin-3 secretion by EoE cells. L-type calcium channel inhibitors block T helper 2 cytokine-stimulated eotaxin-3 secretion, suggesting a potential role for these agents in EoE treatment.