Reflux Injury Research Articles

Correlation Between Traditional Barrett's Esophagus Risk Factors and Gastroesophageal Acid Reflux and Esophageal Mucosal Injury

Introduction: Repeated mucosal injury from gastroesophageal reflux (GER) causes Barrett’s esophagus (BE). We studied correlation between traditional BE risk factors and the degree of gastroesophageal acid reflux and mucosal injury. Methods: Consecutive adults who underwent pH-impedance monitoring off therapy between Oct 2013-March 2020 were included. Patients with major motility disorders were excluded. Acid exposure time (AET) was used to determine the degree of gastroesophageal acid reflux. Mucosal injury was assessed using distal mean nocturnal basal impedance (dMNBI) which measures increased mucosal permeability from reflux injury. The correlations were assessed on univariable and multivariable linear regression models. Results: After excluding 33 for major motility disorder, 219 patients were included. On multivariate model, older age (p=0.038), White race (p=0.005), and higher BMI (p=0.015) had positive correlation with AET, while sex (p=0.154) and smoking (p=0.193) were not. Non-white patients averaged 50% (95%CI, 20-70%) lower AET, AET increased with age up to 60 years and with BMI up to 33 kg/m 2 . Inverse correlation observed between dMNBI and all the risk factors and AET. On multivariate analysis, only AET (p<.001) had significant correlation with dMNBI, male sex had borderline correlation (p=0.052) and none with age (p=0.140), race (p=0.117), smoking status (p=0.461), and BMI (p=0.109). Conclusion: Differential mucosal injury from GER noted between different BE risk factors; age, obesity, and White race increase degree of acid reflux, while male sex likely has higher degree of injury from acid reflux. These observations are insightful in developing a strategy to mitigate BE risk. Funding Statement: None. Declaration of Interests: None. Ethics Approval Statement: This study was approved by the Creighton University Institutional Review Board.

Activin A-mediated epithelial de-differentiation contributes to injury repair in an in vitro gastrointestinal reflux model

Reflux esophagitis is a result of esophageal exposure to acid and bile during episodes of gastroesophageal reflux. Aside from chemical injury to the esophageal epithelium, it has been shown that acid and bile induce cytokine-mediated injury by stimulating the release of pro-inflammatory cytokines. During the repair and healing process following reflux injury, the squamous esophageal cells are replaced with a columnar epithelium causing Barrett’s metaplasia, which predisposes patients to esophageal adenocarcinoma. We identified a novel player in gastroesophageal reflux injury, the TGFβ family member Activin A (ActA), which is a known regulator of inflammation and tissue repair. In this study, we show that in response to bile salt and acidified media (pH 4) exposure, emulating the milieu to which the distal esophagus is exposed during gastroesophageal reflux, long-term treated, tolerant esophageal keratinocytes exhibit increased ActA secretion and a pro-inflammatory cytokine signature. Furthermore, we noted increased motility and expression of the stem cell markers SOX9, LGR5 and DCLK1 supporting the notion that repair mechanisms were activated in the bile salt/acid-tolerant keratinocytes. Additionally, these experiments demonstrated that de-differentiation as characterized by the induction of YAP1, FOXO3 and KRT17 was altered by ActA/TGFβ signaling. Collectively, our results suggest a pivotal role for ActA in the inflammatory GERD environment by modulating esophageal tissue repair and de-differentiation.

Role of Kruppel-Like Factor 5 in Deoxycholic Acid-Mediated Intestinal Transdifferentiation of Esophageal Squamous Epithelium.

Barrett's esophagus (BE) is an acquired condition in which normal squamous epithelium is replaced with metaplastic columnar epithelium as a consequence of gastroesophageal reflux disease. BE is known as a precursor of esophageal adenocarcinoma. Currently, the molecular mechanism underlying epithelial metaplasia in BE patients remains unknown. Therefore, we investigated the role of Krüppel-like factor 5 (KLF5) signaling in the initiation of BE-associated metaplasia. Sprague-Dawley (SD) rats were used to create a surgical model of bile reflux injury. Immunohistochemistry was performed to analyze human and mouse esophageal specimens. Human esophageal squamous epithelial (HET-1A) cells were treated with bile acid and used in transfection experiments. Quantitative real-time PCR and western blot analysis were performed to detect the expression of KLF5, CDX2, MUC2 and villin.Epithelial tissue from both the rat BE model and human BE patients strongly expressed KLF5, CDX2, MUC2, and villin. Bile acid treatment also increased the expression of KLF5, CDX2, MUC2 and villin in esophageal epithelial cells in a time-dependent manner. Moreover, siRNA-mediated knockdown of KLF5 blocked the expression of CDX2, MUC2 and villin, but transfection of a KLF5 expression vector into esophageal epithelial cells promoted their transdifferentiation into columnar-like cells, as demonstrated by increased expression of the intestinal markers CDX2, MUC2 and villin. Thus, in addition to its function as a transcription factor, KLF5 may be linked to an increased risk of BE development.

The Endothelin-A Receptor Antagonist Zibotentan Induces Damage to the Nasal Olfactory Epithelium Possibly Mediated in Part through Type 2 Innate Lymphoid Cells.

Zibotentan, an endothelin-A receptor antagonist, has been used in the treatment of various cardiovascular disorders and neoplasia. Castrated athymic nude mice receiving zibotentan for a preclinical xenograft efficacy study experienced weight loss, gastrointestinal bloat, and the presence of an audible respiratory click. Human side effects have been reported in the nasal cavity, so we hypothesized that the nasal cavity is a target for toxicity in mice receiving zibotentan. Lesions in the nasal cavity predominantly targeted olfactory epithelium in treated mice and were more pronounced in castrated animals. Minimal lesions were present in vehicle control animals, which suggested possible gavage-related reflux injury. The incidence, distribution, and morphology of lesions suggested direct exposure to the nasal mucosa and a possible systemic effect targeting the olfactory epithelium, driven by a type 2 immune response, with group 2 innate lymphoid cell involvement. Severe nasal lesions may have resulted in recurrent upper airway obstruction, leading to aerophagia and associated clinical morbidity. These data show the nasal cavity is a target of zibotentan when given by gavage in athymic nude mice, and such unanticipated and off-target effects could impact interpretation of research results and animal health in preclinical studies.

Longitudinal study of esophageal mucosal damage after esophagectomy and gastric interposition: relationship between reflux-related mucosal injury and Notch signaling.

Esophagectomy with gastric interposition could serve as a good human reflux model to study the molecular pathogenesis of esophageal mucosal damage induced by gastroesophageal reflux. This study was to investigate the role of Notch signaling in reflux injury of esophageal mucosa. Patients undergoing Ivor-Lewis esophagectomy for early stage esophageal squamous cell carcinoma were included. Follow-ups were scheduled at 6, 18, 36 and 48 months postoperatively, including reflux symptom assessment, endoscopic and histological evaluation of esophageal mucosal damage. The expressions of Notch1 and its downstream target gene Hes1 were evaluated by real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC). Forty-four out of 48 patients completed four follow-ups. Injuries of esophageal remnant confirmed by endoscopical and histological examinations were both more often with a longer postoperative period (P<0.05). The mRNA expression levels of Notch1 and Hes1 were decreased in a time-dependent manner after operation (P<0.001). Notch1 and Hes1 mRNA levels were significantly higher in normal squamous mucosa than in esophagitis, and higher in esophagitis than in metaplasia (P<0.05). Immunohistochemical study also demonstrated a similar protein expression pattern. Samples with endoscopic evidence of mucosal damage exhibited lower expression of Notch1 mRNA levels as compared to biopsies without visualized damage (P=0.035). This is the first longitudinal study on Notch signaling in human esophagectomy model, our preliminary findings suggest decreased Notch signaling might be involved in the development of mucosa damage caused by gastroesophageal reflux.

Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress.

Autophagy is a highly conserved mechanism that is activated during cellular stress. We hypothesized that autophagy may be induced by acid reflux, which causes injury, and inflammation, and therefore, contributes to the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Currently, the role of autophagy in BE and EAC is poorly studied. We quantitatively define autophagy levels in human BE cell lines, a transgenic mouse model of BE, and human BE, and EAC biopsies. Human non-dysplastic BE had the highest basal number of autophagic vesicles (AVs), while AVs were reduced in normal squamous cells and dysplastic BE cells, and nearly absent in EAC. To demonstrate a functional role for autophagy in BE pathogenesis, normal squamous (STR), non-dysplastic BE (CPA), dysplastic BE (CPD), and EAC (OE19) cell lines were exposed to an acid pulse (pH 3.5) followed by incubation in the presence or absence of chloroquine, an autophagy inhibitor. Acid exposure increased reactive oxygen species (ROS) levels in STR and CPA cells. Chloroquine alone had a small impact on intracellular ROS or cell survival. However, combination of chloroquine with the acid pulse resulted in a significant increase in ROS levels at 6 h in STR and CPA cells, and increased cell death in all cell lines. These findings establish increased numbers of AVs in human BE compared to normal squamous or EAC, and suggest that autophagy functions to improve cell survival after acid reflux injury. Autophagy may thus play a critical role in BE pathogenesis and progression. © 2015 Wiley Periodicals, Inc.

From reflux esophagitis to Barrett's esophagus and esophageal adenocarcinoma.

The occurrence of gastroesophageal reflux disease is common in the human population. Almost all cases of esophageal adenocarcinoma are derived from Barrett's esophagus, which is a complication of esophageal adenocarcinoma precancerous lesions. Chronic exposure of the esophagus to gastroduodenal intestinal fluid is an important determinant factor in the development of Barrett's esophagus. The replacement of normal squamous epithelium with specific columnar epithelium in the lower esophagus induced by the chronic exposure to gastroduodenal fluid could lead to intestinal metaplasia, which is closely associated with the development of esophageal adenocarcinoma. However, the exact mechanism of injury is not completely understood. Various animal models of the developmental mechanisms of disease, and theoretical and clinical effects of drug treatment have been widely used in research. Recently, animal models employed in studies on gastroesophageal reflux injury have allowed significant progress. The advantage of using animal models lies in the ability to accurately control the experimental conditions for better evaluation of results. In this article, various modeling methods are reviewed, with discussion of the major findings on the developmental mechanism of Barrett's esophagus, which should help to develop better prevention and treatment strategies for Barrett's esophagus.

Ischemic Esophageal Ulceration That Developed After an Early Endoscopic Surveillance in a Patient Receiving Catheter Ablation for Atrial Fibrillation

An atrioesophageal fistula is a rare but lethal complication that develops a week to several weeks after the pulmonary vein isolation for atrial fibrillation.1 Because the thermal injury resulting from radiofrequency energy application peaks within a few days,2 the ischemic or gastric reflux injury that progresses during the following weeks was assumed to play a pivotal role in the delayed development of this complication.1 However, no report has ever precisely described the nature of the ischemic injury. Here, we report a case of an esophageal ulceration that developed after an early endoscopic surveillance that was assumed to be the result of the ischemic injury observed in patients receiving extensive pulmonary vein isolation for atrial fibrillation. A 55-year-old man with a symptomatic paroxysmal atrial fibrillation underwent extensive pulmonary vein isolation under conscious sedation. After a simultaneous pulmonary vein angiogram and esophagogram (Figure 1A), the extensive pulmonary vein isolation was carried out with an open-irrigation-tip catheter (ThermoCool, Biosense, Webster, Diamond Bar, CA). A maximum of 15 to 20 W with a duration of 20 …

Abstract PR-03: Aspirin mediated downregulation of Warburg kinase AKT1 in patients with Barrett's esophagus: Implications in neoplastic transformation

Abstract Background: In patients with Barrett's esophagus, chronic reflux injury and inflammation are associated with esophageal adenocarcinoma, one of the most rapidly increasing lethal cancers. Epidemiological and preclinical studies support decreased risk of esophageal adenocarcinoma with NSAID use. Gastroesophageal refluxate contents can promote carcinogenesis in Barrett's metaplasia by activating AKT, which up regulates COX-2 expression and prostaglandin biosynthesis. We recently noted that neoplastic transformation in Barrett's esophagus is associated with increased AKT expression, particularly isoform AKT1. The AIM of this study is to investigate the effect of NSAID (Aspirin) use in patients with Barrett's esophagus on AKT1 expression using frozen tissue from the randomized, phase II trial of aspirin and esomeprazole for esophageal cancer chemoprevention in Barrett's esophagus patients and to assess the functional consequences of AKT1 expression in-vitro. Methods and Results: In a subset of patients (12 of 120 patients) with Barrett's esophagus who were randomized to placebo, lower dose (81 mg) or higher dose (325 mg) Aspirin for 4 weeks, both PCR and Western blot revealed marked reduction in AKT1 expression in patients who received 325 mg of Aspirin daily compared to patients who received placebo. Our in-vitro experiments support that AKT1 expression is functionally relevant to the process of carcinogenesis in Barrett's epithelial cells. Using adenovirus to induce AKT1 expression, we show that increased AKT1 expression increases Barrett's epithelial cell growth, facilitates RAS-mediated transformation of pre-neoplastic epithelial cells and promotes colony formation. Since AKT1 is known as Warburg kinase and regulates cellular glucose uptake to support aerobic glycolysis during growth de-regulation and neoplasia, we examined the uptake of fluorescent deoxyglucose analog (2-NBDG) in Barrett's epithelial cells transduced with AKT1 adenovirus. At 48 hrs, compared to control, AKT1 overexpression resulted in increased glucose uptake both by metaplastic and neoplastic Barrett's epithelial cells. Transcriptional repression of AKT1 abrogated the 2-NBDG uptake by these cells. Finally, we did pathway specific qPCRs and noted that use of Aspirin is associated with altered expression of chromatin remodelers that could down-regulate AKT1 expression. Conclusion: Collectively, our results demonstrate that Aspirin mediated down-regulation of Warburg kinase AKT1 in patients with Barrett?s esophagus is a novel mechanism for the regulation of Barrett?s epithelial cell growth. The in-depth characterization of molecular mechanisms is currently underway. This abstract is also presented as Poster A82. Citation Format: Navtej S. Buttar, Gary W. Falk, Cathrine J. DeMars, Sonia Chowdhury, Ahmed Elebiary, Anamay Sharma, Sidhartha Chaudhry, Nathan R. Foster, Katie L. Allen Ziegler, Yvonne Romero, Norman E. Marcon, Thomas Schnell, Douglas A. Corley, Prateek Sharma, Marcia R. Cruz-Correa, Chin Hur, David E. Fleischer, Amitabh Chak, Kenneth R. DeVault, David S. Weinberg, Gary Della’Zanna, Ellen Richmond, Thomas C. Smyrk, Sumithra Mandrekar, Paul J. Limburg. Aspirin mediated downregulation of Warburg kinase AKT1 in patients with Barrett's esophagus: Implications in neoplastic transformation. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PR-03.

Radial esophageal acid exposure and the dilated distal esophagus

With interest we read the article by Ohara et al. [1] published in the recent issue of the Journal of Gastroenterology. Using a novel catheter-mounted multiprobe uni-level pH monitoring system, the authors compared radial acid exposure 2 cm above the manometric lower esophageal sphincter in asymptomatic controls (n = 4), patients with non-erosive reflux disease (NERD, n = 5), and persons with reflux esophagitis (n = 10). Patients with NERD and those with esophagitis showed significantly prolonged acid exposure times on the right side of the distal esophagus (in continuation of the small curvature of the stomach), when compared with findings on the left side (great curvature side of the stomach). Furthermore, this and other recent studies have shown increased severity of endoscopically visible reflux-induced changes on the right versus the left side of the distal esophagus [2]. In addition, three-dimensional (3D) high-resolution manometry has revealed decreased competency within the right-sided portion of the lower esophageal sphincter pressure zone, when compared with the left side [3]. Taken together, the above data and the study by Ohara et al. indicate that the right side of the lower portion of the esophagus is prone to acid/reflux-exposure and reflux injury, when compared with the left side. Recent anatomical, histopathological, and physiological studies have examined the pathogenesis of gastroesophageal reflux disease (GERD) [4]. Repeated overeatinginduced gastric dilatations extend into the distal esophagus. As a consequence, the lower portion of the distal esophagus dilates and is exposed to the gastric contents. Reflux inflames the esophagus (esophagitis), weakens the lower esophageal sphincter, and stimulates the replacement of the normal mucosa by columnar lined esophagus (CLE): this is the dilated distal esophagus (DDE) [4]. Combination of the data obtained by the above investigations [2–4] and the study by Ohara et al. [1] justifies the suggestion that the development of the DDE predominantly commences within the right-side portion of the distal esophagus. These important findings should serve as the basis for future endoscopic and histopathological studies and should help to further elucidate the pathogenesis of GERD [5, 6]. In addition, biopsies directed to the right-side portion of the distal esophagus and the squamocolumnar junction (SCJ) could contribute to increasing the yield for the assessment of premalignant reflux-induced lesions, i.e., Barrett’s esophagus (±dysplasia) [2]. Finally, novel understanding gained from such studies could help to improve anti-reflux surgery, i.e., the placement of a fundic wrap with the inclusion of the ‘‘weak’’ right-side portion of the suprajunctional distal esophagus [7]. The authors are kindly asked to comment on the above suggestions.

PTU-171 Oestrogen plays a critical role in murine epithelial healing in a buccal model of reflux injury

IntroductionSevere oesophagitis, oesophageal adenocarcinoma (OAC) are more common in men and post-menopausal women. Female sex hormones may protect pre-menopausal women from gastro-oesophageal reflux mediated mucosal damage, delaying the onset of...

Su1763 Oestrogen Plays a Critical Role in Murine Epithelial Healing in a Buccal Model of Reflux Injury

Introduction Severe oesophagitis, oesophageal adenocarcinoma (OAC) are more common in men and post-menopausal women. Female sex hormones may protect pre-menopausal women from gastro-oesophageal reflux mediated mucosal damage, delaying the onset of BO and development of OAC in women. We have demonstrated more rapid mucosal healing and less inflammatory response in females in a murine buccal model of reflux injury. We have used a model comparing intact female mice with oestrogen deprived mice (by removal of their ovaries) to determine if this effect may be oestrogen driven. Methods Female mice (C57 strain) were divided into three groups of 5: ovariectomised (OVX), OVX with oestrogen replacement (OVX+E) (50 μg oestradiol per day dorsal implants) and intact females. 1.5 mm buccal ulcers were induced using a punch biopsy and treated with 1 M hydrochloric acid. Wounds were harvested at day 4. Wound planimetry and immunohistochemistry for macrophages and neutrophils were compared in a blinded fashion. Results Results: Re-epithelialisation was greatest in the intact group (mean 0.88 mm SEM ± 0.22) compared to the OVX (0.51 mm ± 0.13) or OVX+E (0.79 mm ± 0.12) groups. The difference between intact and OVX groups was statistically significant (p=0.04). Neutrophil wound infiltration (cells/wound area) was greater in the OVX group (1842±75) than the intact group (1279±169, p There was a greater number of macrophages in the OVX wounds (1556±128) than both OVX+E (984±95 (p=0.02) and the intact group (1026±91, p=0.01). Conclusion Lack of systemic oestrogen delays mucosal healing in buccal wounds. This may explain gender differences in the oesophageal epithelial response to gastro-oesophageal reflux injury. Competing interests None declared.

Su1764 Gender Differences in Murine Epithelial Healing in a Buccal Model of Reflux Injury

Su1764 Gender Differences in Murine Epithelial Healing in a Buccal Model of Reflux Injury

Influence of age and sex on endoscopic findings of gastrooesophageal reflux disease

Barrett's oesophagus (BO) and oesophageal adenocarcinoma are more common with increasing age and among men. Symptoms of gastrooesophageal reflux disease are equally common in both sexes and at all ages. We hypothesized that reduced postmenopausal female sex hormone levels may remove protection from acid reflux injury, leading to increased oesophagitis and its complications in older women. To examine the incidence of gastrooesophageal reflux disease and its complications in men and women in a large endoscopy database. Anonymized data were extracted from endoscopy databases covering an 11-year period. Patients with an endoscopic diagnosis of reflux oesophagitis (RO), BO, hiatus hernia and benign oesophageal stricture and total number and indications for endoscopies were identified. Out of 154 406 upper gastrointestinal endoscopies, 24 240 (15.7%) patients had RO {13,148 male, 11,092 female, mean age 59 [standard deviation (SD) 17] years}. The incidence of RO increased with age {odds ratio 1.029 [95% confidence interval (CI) 1.026-1.032], P<0.001} but this increase was more marked in women with increasing age [1.01 (1.01-1.02), P<0.001] compared with men. Increasing age was associated with an increased incidence of benign oesophageal stricture [1.02 (1.017-1.023)] and BO [1.02 (1.019-1.021)]. Although the increase in benign oesophageal stricture was more marked in women [1.024 (1.02-1.028) P<0.001] than in men, this was not the case in BO. RO and its complications, BO and benign oesophageal stricture increase with age. RO, BO and stricture are more common in absolute and relative terms among younger men than younger women. RO and stricture increase more rapidly in women than men so that the prevalence in elderly patients is similar in both sexes.

52-Year-Old Woman With Dysphagia

52-Year-Old Woman With Dysphagia

A review of the potential applications and controversies of non-invasive testing for biomarkers of aspiration in the lung transplant population

Despite improvements in one-yr survival following lung transplantation, five-yr survival lags significantly behind the transplantation of other solid organs. The contrast in survival persists despite advancements in anti-rejection regimens, suggesting a non-alloimmune mechanism to chronic lung transplant failure. Notably, markers of aspiration have been demonstrated in bronchoalveolar lavage (BAL) fluid concurrent with bronchiolitis obliterans syndrome (BOS). This recent evidence has underscored gastroesophageal reflux (GER) and its associated aspiration risk as a non-alloimmune mechanism of chronic lung transplant failure. Given the suggested safety and efficacy of laparoscopic anti-reflux procedures in the lung transplant population, identifying those at risk for aspiration is of prime importance, especially concerning the potential for long-term improvements in morbidity and mortality. Conventional diagnostic methods for GER and aspiration, such as pH monitoring and detecting pepsin and bile salts in BAL fluid, have gaps in their effectiveness. Therefore, we review the applications and controversies of a non-invasive method of defining reflux injury in the lung transplant population: the detection of biomarkers of aspiration in the exhaled breath condensate. Only by means of assay standardization and directed collaboration may such a non-invasive method be a realization in lung transplantation.

Aberrant Epithelial–Mesenchymal Hedgehog Signaling Characterizes Barrett's Metaplasia

The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium. Immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice. Marked up-regulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of Deleted in Malignant Brain Tumors 1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9, and columnar cytokeratins. Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype.

Surgical treatment of Gastroesophageal Reflux disease: yesterday and today

Gastroesophageal reflux disease (GERD) is a set of signs and symptoms and changes resulting from pathological backward flow of gastric or intestinal contents to the esophagus. Reflux of gastric contents occurs periodically in all people during a 24-hour period. Therefore physiological reflux of gastric contents that does not cause any complaints or histopathological changes in the esophagus should be differentiated from gastroesophageal reflux disease that results in subjective complaints or its complications confirmed by diagnostic methods. Prevalence of gastroesophageal reflux disease is difficult to estimate, however it is believed to occur in 0.35 to 2% of the whole population (1). Before a decision is taken to proceed with surgical treatment, detailed diagnostic workup of causes of pathological gastroesophageal reflux is required and the strategy of surgical treatment should be based on three basic principles: alleviation of typical subjective complaints, healing and prevention of recurrences of reflux injury of the esophageal mucosa and prevention of possible complications of the long standing disease such as bleeding, ulceration and esophageal stricture, aspiration pneumonia and intestinal metaplasia. Approach of surgeons to pathogenesis of esophageal ulcerations changed since Quincke reported for the first time three cases of this condition in 1879. Quincke concluded that similar macroscopic nature of esophageal ulcers and gastric ulcers and close anatomical proximity indicated that reflux of gastric juice into the esophagus could be the cause of “ulcer ex digestion”. In 1906 Tileston presented a similar concept, on the basis of examination of 41 cases of esophageal ulcerations, supporting his concept with Albert’s publications from 1839. In 1946 Allison presented a new disease entity – “peptic oesophagitis”. He reported it on the basis of clinical signs and symptoms and radiographic picture. He concluded that abnormal reflux of gastric juice through abnormal cardia is a pathological factor of the new disease. However Barret in 1950 suggested a new term for the disease reported by Allison – reflux esophagitis that was to reflect relationship between esophagitis and the disease etiological factor. A paper published in 1988 allowed us to understand a role of individual anatomical factors of so called anti-reflux mechanism, protecting against pathological gastroesophageal reflux. Further progress in the understanding of gastroesophageal reflux was associated with development of diagnostic methods used to diagnose gastroesophageal reflux and its consequences. In 1926 Robin and Jankelson were the first to demonstrate gastroesophageal reflux using a radiological study (2-8). Detailed assessment of gastroesophageal reflux and development of knowledge about pathogenesis of reflux esophagitis facilitated progress in implementation of new methods of surgical treatment of this disease. In 1919 Soeresi was the first to perform an operation

Is the etiology of eosinophilic esophagitis in adults a response to allergy or reflux injury? Study of cellular proliferation markers

Recent research suggests that allergy may be the key factor in the etiology of eosinophilic esophagitis (EE); however, historically, the condition was hypothesized as related to reflux injury to the esophageal mucosa. We studied this hypothesis by comparing markers of inflammation and cellular proliferation in EE and reflux esophagitis. Lower esophageal biopsies of adult patients with EE (n = 10), reflux esophagitis (n = 8), and normal controls (n = 13) were assessed quantitatively for the expression of the cyclooxygenase-2 (COX-2) enzyme, cellular proliferation, and oncogenic resistance to apoptosis using monoclonal antibodies for COX-2, Ki-67, and Bcl-2, respectively. Normal esophageal epithelium demonstrated weak diffuse uptake of COX-2 stain in the basal layer. No COX-2 expression was demonstrated in the EE group, significantly less than the control and reflux groups (P < 0.01 and P < 0.001, respectively). Cellular proliferation measured by Ki-67 expression was higher in EE and reflux compared with control (P < 0.001 and P < 0.01). Ki-67 expression, and thus degree of hyperplasia, appeared greater in EE than reflux, but was not statistically significant (P = 0.228). The degree of apoptosis was similar in all study groups. EE and reflux esophagitis are proliferative conditions expressing Ki-67 in higher concentrations than control. Mucosal proliferation in reflux esophagitis is COX-2 dependent. This novel research in EE has demonstrated downregulation of COX-2 expression compared with reflux esophagitis and control. We hypothesize that the allergy-related cytokine IL-13 known to inhibit COX-2 expression and found in high concentrations in EE as responsible for this. The pathogenesis of EE is likely dependent on allergy rather than reflux injury to the esophagus.

Direct Evidence of Mast Cell Participation in Acute Acid‐induced Esophageal Inflammation in Mice

Mast cells have been implicated in the pathogenesis of esophagitis resulting from gastroesophageal acid reflux, but their precise role has been difficult to define. We proposed to directly examine the contribution of mast cells to neutrophil infiltration in a mouse model of acid-induced esophageal injury. Normal and mast cell-deficient (Kit) mice underwent either a surgical procedure to induce acute acid reflux injury of the esophagus or sham surgery. Neutrophil infiltration in the esophagus was determined by morphometrical quantification. To further delineate the involvement of mast cells, acid-induced esophageal injury was elicited in mast cell-deficient mice that had undergone mast cell reconstitution by bone marrow transplantation. Normal mice exhibited significant neutrophil infiltration into the esophagus as a result of acid-induced injury. The neutrophil accumulation was significantly diminished in mast cell-deficient mice. However, the neutrophil infiltration that resulted from acid-induced injury in mast cell-reconstituted Kit mice was similar to that seen in normal mice. Our findings provide direct evidence that mast cells participate in the recruitment of neutrophils during acid-induced esophageal injury in mice.