Esophageal physiology-an overview of esophageal disorders from a pathophysiological point of view.

The esophagus serves the principal purpose of transporting food from the pharynx into the stomach. A complex interplay between nerves and muscle fibers ensures that swallowing takes place as a finely coordinated event. Esophageal function can be tested by a variety of methods, endoscopy, manometry, and reflux monitoring being some of the most important. Regarding pathophysiology, motor disorders, such as achalasia, often cause dysphagia and/or chest pain. Functional esophageal disorders are a heterogeneous group with hypersensitivity as a dominant pathophysiological factor. Gastroesophageal reflux disease often causes symptoms, such as heartburn and regurgitation, and a spectrum of disease, ranging from minimal mucosal damage visible only in the microscope to esophageal ulcers and strictures in the most severe cases. Eosinophilic esophagitis is an immune-mediated condition that can result in significant dysphagia and associated luminal narrowing. In the following, we will provide an overview of the most common esophageal disorders from a combined pathophysiological and clinical view.

Curcumin: A Potent Protectant against Esophageal and Gastric Disorders.

Turmeric obtained from the rhizomes of Curcuma longa has been used in the prevention and treatment of many diseases since the ancient times. Curcumin is the principal polyphenol isolated from turmeric, which exhibits anti-inflammatory, antioxidant, antiapoptotic, antitumor, and antimetastatic activities. The existing evidence indicates that curcumin can exert a wide range of beneficial pleiotropic properties in the gastrointestinal tract, such as protection against reflux esophagitis, Barrett's esophagus, and gastric mucosal damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs) and necrotizing agents. The role of curcumin as an adjuvant in the treatment of a Helicobacter pylori infection in experimental animals and humans has recently been proposed. The evidence that this turmeric derivative inhibits the invasion and proliferation of gastric cancer cells is encouraging and warrants further experimental and clinical studies with newer formulations to support the inclusion of curcumin in cancer therapy regimens. This review was designed to analyze the existing data from in vitro and in vivo animal and human studies in order to highlight the mechanisms of therapeutic efficacy of curcumin in the protection and ulcer healing of the upper gastrointestinal tract, with a major focus on addressing the protection of the esophagus and stomach by this emerging compound.

A potential contribution of decreased galectin-7 expression in stratified epithelia to the development of cutaneous and oesophageal manifestations in systemic sclerosis.

BACKGROUNDS: Stratified epithelia have caught much attention as potential contributors to the development of dermal and oesophageal fibrosis in systemic sclerosis (SSc). Galectin-7 is a marker of all types of stratified epithelia, which is involved in the maintenance of epidermal homeostasis. So far, the role of galectin-7 has not been studied in SSc. OBJECTIVES: To investigate the potential contribution of galectin-7 to the development of clinical manifestations in SSc. METHODS: Galectin-7 expression was examined in skin samples and cultured keratinocytes by immunostaining and/or quantitative reverse transcription PCR. Serum galectin-7 levels were determined by enzyme-linked immunosorbent assay in 63 SSc and 20 healthy subjects. RESULTS: Galectin-7 expression was markedly decreased in the epidermis of SSc lesional skin compared with that of healthy control skin. Serum galectin-7 levels were significantly lower in SSc patients than in healthy controls and inversely correlated with skin score. In addition, SSc patients with diffuse pigmentation and those with oesophageal dysfunction had significantly decreased serum galectin-7 levels as compared to those without each symptom. Importantly, endothelin-1 stimulation suppressed galectin-7 expression in normal human keratinocytes, and bosentan, a dual endothelin receptor antagonist, reversed circulating galectin-7 levels and epidermal galectin-7 expression in SSc patients. CONCLUSIONS: Galectin-7 downregulation in stratified epithelia, which is mediated at least partially by autocrine endothelin stimulation, may contribute to the development of cutaneous manifestations and oesophageal dysfunction in SSc patients.

Esophageal Organoids from Human Pluripotent Stem Cells Delineate Sox2 Functions during Esophageal Specification.

Tracheal and esophageal disorders are prevalent in humans and difficult to accurately model in mice. We therefore established a three-dimensional organoid model of esophageal development through directed differentiation of human pluripotent stem cells. Sequential manipulation of bone morphogenic protein (BMP), Wnt, and RA signaling pathways was required to pattern definitive endoderm into foregut, anterior foregut (AFG), and dorsal AFG spheroids. Dorsal AFG spheroids grown in a 3D matrix formed human esophageal organoids (HEOs), and HEO cells could be transitioned into two-dimensional cultures and grown as esophageal organotypic rafts. In both configurations, esophageal tissues had proliferative basal progenitors and a differentiated stratified squamous epithelium. Using HEO cultures to model human esophageal birth defects, we identified that Sox2 promotes esophageal specification in part through repressing Wnt signaling in dorsal AFG and promoting survival. Consistently, Sox2 ablation in mice causes esophageal agenesis. Thus, HEOs present a powerful platform for modeling human pathologies and tissue engineering.

Impairment of Nitric Oxide Pathway by Intravascular Hemolysis Plays a Major Role in Mice Esophageal Hypercontractility: Reversion by Soluble Guanylyl Cyclase Stimulator.

Paroxysmal nocturnal hemoglobinuria (PNH) patients display exaggerated intravascular hemolysis and esophageal disorders. Since excess hemoglobin in the plasma causes reduced nitric oxide (NO) bioavailability and oxidative stress, we hypothesized that esophageal contraction may be impaired by intravascular hemolysis. This study aimed to analyze the alterations of the esophagus contractile mechanisms in a murine model of exaggerated intravascular hemolysis induced by phenylhydrazine (PHZ). For comparative purposes, sickle cell disease (SCD) mice were also studied, a less severe intravascular hemolysis model. Esophagus rings were dissected free and placed in organ baths. Plasma hemoglobin was higher in PHZ compared with SCD mice, as expected. The contractile responses produced by carbachol (CCh), KCl, and electrical-field stimulation (EFS) were superior in PHZ esophagi compared with control but remained unchanged in SCD mice. Preincubation with the NO-independent soluble guanylate cyclase stimulator 3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (BAY 41-2272; 1 µM) completely reversed the increased contractile responses to CCh, KCl, and EFS in PHZ mice, but responses remained unchanged with prior treatment with NO donor sodium nitroprusside (300 µM). Protein expression of 3-nitrotyrosine and 4-hydroxynonenal increased in esophagi from PHZ mice, suggesting a state of oxidative stress. In endothelial nitric oxide synthase gene-deficient mice, the contractile responses elicited by KCl and CCh were increased in the esophagus but remained unchanged with the intravascular hemolysis induced by PHZ. In conclusion, our results show that esophagus hypercontractile state occurs in association with lower NO bioavailability due to exaggerated hemolysis intravascular and oxidative stress. Moreover, our study supports the hypothesis that esophageal disorders in PNH patients are secondary to intravascular hemolysis affecting the NO-cGMP pathway.

Esophageal tissue engineering: from bench to bedside.

For various esophageal diseases, the search for alternative techniques for tissue repair has led to significant developments in basic and translational research in the field of tissue engineering. Applied to the esophagus, this concept is based on the in vitro combination of elements judged necessary for in vivo implantation to promote esophageal tissue remodeling. Different methods are currently being explored to develop substitutes using cells, scaffolds, or a combination of both, according to the severity of lesions to be treated. In this review, we discuss recent advances in (1) cell sheet technology for preventing stricture after extended esophageal mucosectomy and (2) full-thickness circumferential esophageal replacement using tissue-engineered substitutes.

The effect of platelet-rich plasma on motility changes in experimental caustic esophageal burn.

BACKGROUND: Besides stricture formation, diminished esophageal motility after caustic esophageal burns also plays a role in the deterioration of the clinical course. In this study, we aimed to investigate the effect of caustic burn on the esophageal contractions and the effect of platelet-rich plasma (PRP) on these changes. METHODS: Twenty-one Wistar albino rats were divided into three groups [Sham operation (n = 8), caustic esophageal burn with NaOH (n = 6), PRP treatment after caustic burn (n = 7)]. After 3 weeks, esophagectomy was performed and contractions and EFS responses were evaluated in the organ bath. RESULTS: KCl- and acetylcholine-induced responses were reduced in the Burn group, but increased in Sham and PRP groups (p < 0.05). EFS responses were higher in Burn group compared to the other groups. Response with L-arginine was increased in Burn group, but decreased in PRP group. There was more decrease in the contraction in Sham and PRP groups compared to the Burn group after SNP (sodium nitroprusside) incubation (p < 0.05). L-NAME (Nω-Nitro-L-arginine methyl ester) did not change the EFS responses in the Burn group, but EFS responses were decreased significantly in Sham and PRP groups (p < 0.05). EFS responses were decreased in all groups, but more in the Sham and PRP groups after Y-27632 (Rho-kinase inhibitor) incubation (p < 0.05). CONCLUSIONS: For the first time, we demonstrated that both cholinergic and non-adrenergic non-cholinergic mechanisms are responsible for the altered motility in corrosive esophageal injury. Our results suggest that PRP treatment may be helpful in regulating the esophageal motility and decreasing altered contractions in corrosive burns. This effect may also contribute to the reduction of stricture formation, especially by reducing inappropriate contractions of the esophageal wall during the post-burn healing phase.

Esophageal multimodal stimulation and sensation.

Esophageal mechanosensation describes the relationship between a mechanical stimulation of the esophageal wall, such as bag distension, and the reaction to the stimulation perceived or unperceived. When studying mechanosensation in esophageal disease, it is important to recognize that symptoms might be due to alterations at different levels of the neuromuscular system, such as alterations at the mechanoreceptor level or in the afferent mechanosensory pathways, or irregularities in the homeostatic state. One might ask if it is possible to provoke, record, and describe the multidimensional responses behind a mechanosensory experience? It is a complex system and, at a minimum, a multidisciplinary approach is needed to avoid erroneous conclusions. The multimodal study design, taking the mode, location, and parameters of stimulation into consideration, together with controlled recording of assessment parameters, is an approach that seems rational and valid. Gastrointestinal (GI) physicians of the 21th century need to have knowledge of advances in the evaluation of GI mechanical function and what provokes symptoms. Hereby, it is possible to fully appreciate the slowly emerging awareness of how GI pain symptoms should be explored and explained to patients.

Esophageal Mucosal Calcinosis: A Rare Site of Gastrointestinal Mucosal Calcinosis.

BACKGROUND Gastrointestinal tract mucosal calcinosis (MC) tends to affect the gastric mucosa, while esophageal involvement is rare. Gastric MC may be seen with solid organ transplantation, use of aluminum-containing antacids or sucralfate, malignancy, and chronic renal failure. While the incidence of gastric MC in renal transplant patients undergoing gastric biopsy is common (between 15-29%), to our knowledge esophageal MC has only been previously reported 3 times. CASE REPORT A 68-year-old male dialysis-dependent end stage renal disease status-post deceased donor kidney transplant underwent an esophagogastroduodenoscopy (EGD) for dysphagia and diffuse esophageal wall thickening seen on imaging studies. EGD demonstrated diffuse, circumferential thick white esophageal plaques and mucosal friability. Esophageal biopsies demonstrated erosive esophagitis with basophilic calcium deposits within the fibrinopurulent exudate and squamous mucosa. Stains for fungal organisms and viruses were negative. A diagnosis of esophageal MC was made. Although the patient had a protracted postoperative course after transplantation, he had improvement of the esophageal wall thickening on imaging after transplantation. CONCLUSIONS Esophageal MC is a rare phenomenon and all of the previously reported cases of esophageal MC, including our case, have been in patients with end stage renal disease who were on dialysis. Although prolonged hypercalcemia and hyperphosphatemia, an elevated calcium-phosphorus product, and associated underlying inflammation are likely key etiologic factors, the pathogenesis of esophageal MC is not fully understood and is likely due to multiple collective etiologies. Likewise, more reported cases are likely to increase our understanding of the clinical significance and management of this rare disorder.

Long-term regeneration and remodeling of the pig esophagus after circumferential resection using a retrievable synthetic scaffold carrying autologous cells.

Treatment of esophageal disease can necessitate resection and reconstruction of the esophagus. Current reconstruction approaches are limited to utilization of an autologous conduit such as stomach, small bowel, or colon. A tissue engineered construct providing an alternative for esophageal replacement in circumferential, full thickness resection would have significant clinical applications. In the current study, we demonstrate that regeneration of esophageal tissue is feasible and reproducible in a large animal model using synthetic polyurethane electro-spun grafts seeded with autologous adipose-derived mesenchymal stem cells (aMSCs) and a disposable bioreactor. The scaffolds were not incorporated into the regrown esophageal tissue and were retrieved endoscopically. Animals underwent adipose tissue biopsy to harvest and expand autologous aMSCs for seeding on electro-spun polyurethane conduits in a bioreactor. Anesthetized pigs underwent full thickness circumferential resection of the mid-lower thoracic esophagus followed by implantation of the cell seeded scaffold. Results from these animals showed gradual structural regrowth of endogenous esophageal tissue, including squamous esophageal mucosa, submucosa, and smooth muscle layers with blood vessel formation. Scaffolds carrying autologous adipose-derived mesenchymal stem cells may provide an alternative to the use of a gastro-intestinal conduit for some patients following resection of the esophagus.

Is glycogenic acanthosis a predictor of insulin resistance and metabolic syndrome?

BACKGROUND/AIMS: To evaluate the incidence of insulin resistance and metabolic syndrome (MetS) in patients with glycogenic acanthosis (GA). MATERIALS AND METHODS: Thirty patients with GA, detected upon endoscopy, and 30 age- and sex-matched control patients without GA were included in this case-control study. Patients with GA were considered group 1 and control group was considered group 2. Anthropometric measurements [height, weight, and waist circumference (WC)], biochemical parameters [fasting plasma glucose (FPG), triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)], and serum fasting insulin levels were evaluated. Insulin resistance (IR) was estimated by the homeostatic model assessment of IR. MetS was diagnosed using the criteria of the National Cholesterol Education Program Adult Treatment Panel III. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to evaluate associations with GA. RESULTS: There were no differences in terms of FPG, triglyceride, HDL, and LDL between groups (p-values 0.118, 0.114, 0.192, 0.086, respectively). WC was significantly higher in group 1 than in group 2 (103.77 vs 97.03, p=0.032). The number of patients with IR and MetS were significantly higher in group 1 than in group 2 (53.3% vs 13.3%, p=0.003 and 53.3% vs 23.3%, p=0.034). ORs [95% CI] of WC, IR, and MetS for GA were 0.68 [0.17-2.62], 7.12 [1.89-26.72], and 4.11 [1.04-16.21], respectively. CONCLUSION: These findings showed that IR and MetS were significantly associated with the presence of GA.

Case report: a case of eruptive collagenoma occurring in esophagus and intestine.

BACKGROUND: Eruptive collagenoma is a rare disease. All of the previously reported cases were located on the skin. Here we report such a case occurring in esophagus and intestine. CASE PRESENTATION: Our patient is a Chinese woman. Two years ago, hundreds of small nodules were identified in her esophagus and intestine. The lesions were characterized by thickened hyalinized collagen fibers and haphazard neoplastic stellate cells. The tumor cells showed generally positive for vimentin and negative for h-CALD, CD34, desmin, CD163, AE1/AE3, CK7 and CK20. The nodules were blue with Masson Trichrome stain. The clinicopathological, immunohistochemical and histochemical features of the tumor were consistent with eruptive collagenoma. The patient was not given specific treatment after diagnosis, and a routine examination indicated that there was no progress for 2 years. CONCLUSION: Hitherto, this is the first case of eruptive collagenoma to have been reported occurring in esophagus and intestine.

Esophageal development and epithelial homeostasis.

The esophagus is a relatively simple organ that evolved to transport food and liquids through the thoracic cavity. It is the only part of the gastrointestinal tract that lacks any metabolic, digestive, or absorptive function. The mucosa of the adult esophagus is covered by a multilayered squamous epithelium with a remarkable similarity to the epithelium of the skin despite the fact that these tissues originate from two different germ layers. Here we review the developmental pathways involved in the establishment of the esophagus and the way these pathways regulate gut-airway separation. We summarize current knowledge of the mechanisms that maintain homeostasis in esophageal epithelial renewal in the adult and the molecular mechanism of the development of Barrett's metaplasia, the precursor lesion to esophageal adenocarcinoma. Finally, we examine the ongoing debate on the hierarchy of esophageal epithelial precursor cells and on the presence or absence of a specific esophageal stem cell population. Together the recent insights into esophageal development and homeostasis suggest that the pathways that establish the esophagus during development also play a role in the maintenance of the adult epithelium. We are beginning to understand how reflux of gastric content and the resulting chronic inflammation can transform the squamous esophageal epithelium to columnar intestinal type metaplasia in Barrett's esophagus.

The physiological background behind and course of development of the first proton pump inhibitor.

UNLABELLED: Gastric acid secretion and its related diseases and their treatments have generated important contributions to gastroenterology and its development as an autonomous medical specialty. The discovery of histamine receptors and the subsequent H2-receptor antagonists (1972) changed the practice of gastroenterology forever. Gastric acid was effectively inhibited and ulcers could be healed to an extent which had not previously been seen. An additional milestone along the same avenue was offered by the identification of hydrogen potassium adenosine triphosphatase (H(+)K(+)-ATPase) as the proton pump of the parietal cell. Nowadays, proton pump inhibitors (PPIs) are widely used. However, we need to reconsider the physiology and pathophysiology of acid secretion and its long-term inhibition to avoid potential negative effects on general health. PPIs are generally considered among the safest class of drugs. In the late 1960s, a research project was initiated to develop an antisecretory drug which could be used in acid hypersecretory disease states such as peptic ulcer disease based on the option to synthesize a local anesthetic drug that could be orally administered and therefore have its main action on the gastrin cells. This concept was soon found to be a blind track and further development of the basic compounds CMN131 by the synthesis of H77/67 were found to be active in the gastric acid secretion, and the benzimidazol analog of H77/67 was then synthesized a year later and was tested and found to exert powerful acid inhibitory effects. Binding studies with the substituted benzimidazoles clarified specific binding to H+/K+/ATPase in the secretory vesicles of the parietal cells. Since weak bases like aminopyrine accumulate in the acid compartment of the parietal cells, the chemists changed the substituents of the heterocyclic ring and obtained a compound with a weak base property with an optimal PkA value, thereby maximizing the accumulation of the compound at the site of action. This compound H168/68 was synthesized in 1979 and was given the generic name omeprazole. Omeprazole was soon shown to be a very potent inhibitor of the proton pump in vitro as well as in preparation from the human stomach tissue. Pharmacological studies showed long-lasting effect on acid secretion and a specific binding to the target site and soon found the compound to exert unique therapeutic effects. CONCLUSION: The development of the first PPI omeprazole represents an exceptional example of a unique and fruitful collaboration between people with in-depth knowledge of gastric physiology and pharmacology. Frontline expertise in biochemistry and applied clinical science were added to these components, resulting in one of the greatest therapeutic advances during the last decades of the former century.

ORAOV1 overexpression in esophageal squamous cell carcinoma and esophageal dysplasia: a possible biomarker of progression and poor prognosis in esophageal carcinoma.

Oral cancer overexpressed 1 (ORAOV1) has been reported to exhibit high amplification levels in esophageal squamous cell cancer (ESCC) and in premalignant lesions. However, ORAOV1 protein expression levels in ESCC and esophageal squamous intraepithelial neoplasia (ESIN) have not yet been reported. We have explored the relationship of ORAOV1 protein expression with ESCC and ESIN by immunohistochemically analyzing tissue microarrays containing esophageal samples from patients with various clinical features and prognoses. The percentage of ESCC, high-grade ESIN (HGESIN), low-grade ESIN (LGESIN), and nontumoral control patients overexpressing ORAOV1 were 70.63% (101/143), 77.36% (41/53), 48.96% (47/96), and 5.79% (7/121), respectively. ORAOV1 overexpression also appears to be significantly higher in ESCC, HGESIN, and LGESIN than in the controls (all P < .001), and the levels observed for ESCC and HGESIN were also significantly higher than that in LGESIN (both P = .001). These results corresponded to high sensitivity and specificity values in ESCC, HGESIN, and LGESIN tissues. Furthermore, the increased expression of ORAOV1 is significantly associated with lymph node metastasis (P = .001) and an advanced TNM stage (III + IV) (P = .014), and patients with ORAOV1 overexpression experienced shorter overall survival time compared with those with lower ORAOV1 (χ(2) = 11.505, P = .001). This study provides the first evidence of ORAOV1 overexpression in ESCC and ESIN and demonstrates a potential role in tumor progression and metastasis. ORAOV1 overexpression could, therefore, be used as a novel biomarker of poor prognosis in patients with ESCC.

Excitatory and inhibitory enteric innervation of horse lower esophageal sphincter.

The lower esophageal sphincter (LES) is a specialized, thickened muscle region with a high resting tone mediated by myogenic and neurogenic mechanisms. During swallowing or belching, the LES undergoes strong inhibitory innervation. In the horse, the LES seems to be organized as a "one-way" structure, enabling only the oral-anal progression of food. We characterized the esophageal and gastric pericardial inhibitory and excitatory intramural neurons immunoreactive (IR) for the enzymes neuronal nitric oxide synthase (nNOS) and choline acetyltransferase. Large percentages of myenteric plexus (MP) and submucosal (SMP) plexus nNOS-IR neurons were observed in the esophagus (72 ± 9 and 69 ± 8 %, respectively) and stomach (57 ± 17 and 45 ± 3 %, respectively). In the esophagus, cholinergic MP and SMP neurons were 29 ± 14 and 65 ± 24 vs. 36 ± 8 and 38 ± 20 % in the stomach, respectively. The high percentage of nitrergic inhibitory motor neurons observed in the caudal esophagus reinforces the role of the enteric nervous system in the horse LES relaxation. These findings might allow an evaluation of whether selective groups of enteric neurons are involved in horse neurological disorders such as megaesophagus, equine dysautonomia, and white lethal foal syndrome.

[Changes in Wnt pathway inhibiting factors in nitrosamine-induced esophageal precancerosis lesions and effect of gexia zhuyu decoction].

OBJECTIVE: To discuss the changes in Wnt pathway inhibiting factors in esophageal precancerosis lesions induced by methyl benzyl nitrosamine (MBNA) and the effect of Gexia Zhuyu decoction. METHOD: Wistar rats were subcutaneously injected with MBNA (3.5 mg x kg(-1) for twice per week to establish the model. Since the 1st day after the model establishment, they were orally administered with Gexia Zhuyu decoction (16, 8 mg x kg(-1)). At the 10th week, esophageal tissues were collected to observe the pathological changes of esophageal mucosa, detect SFRP1, sFRP4, Axin1, Axin2 and GSK-3ß mRNA levels.by fluorescent quantitation PCR analysis and ß-catenin protein level by Western blotting. RESULT: Being induced by MBNA, rats in the model group showed slight atypical hyperplasia in the histopathological examination. Compared with the normal group, Gexia Zhuyu decoction dose high and low groups showed no significant pathomorphological and histological changes. The model group showed lower gene transcription levels of esophageal tissues sFRP1, sFRP4, Axin1 and Axin2 (P < 0.05 or P < 0.01) and higher ß-catenin protein expression level (P < 0.01) than the normal control group. The Gexia Zhuyu decoction low dose group showed higher gene transcription levels of esophageal tissues sFRP1, sFRP4, Axin1 and Axin2 (P < 0.05 or P < 0.01) and lower ß-catenin protein expression level (P < 0.01) than the normal control group. CONCLUSION: Up-regulated ß-catenin protein level and down-regulated Wnt pathway could enhance Wnt pathway activity of MBNA-induced esophageal precancerous lesions. Gexia Zhuyu decoction could down-regulate the ß-catenin protein level and up-regulate the transcription level of Wnt pathway inhibiting factors, but could not block MBNA-induced esophageal precancerosis lesions.

Novel mechanisms and signaling pathways of esophageal ulcer healing: the role of prostaglandin EP2 receptors, cAMP, and pCREB.

Clinical studies indicate that prostaglandins of E class (PGEs) may promote healing of tissue injury e.g., gastroduodenal and dermal ulcers. However, the precise roles of PGEs, their E-prostanoid (EP) receptors, signaling pathways including cAMP and cAMP response element-binding protein (CREB), and their relation to VEGF and angiogenesis in the tissue injury healing process remain unknown, forming the rationale for this study. Using an esophageal ulcer model in rats, we demonstrated that esophageal mucosa expresses predominantly EP2 receptors and that esophageal ulceration triggers an increase in expression of the EP2 receptor, activation of CREB (the downstream target of the cAMP signaling), and enhanced VEGF gene expression. Treatment of rats with misoprostol, a PGE1 analog capable of activating EP receptors, enhanced phosphorylation of CREB, stimulated VEGF expression and angiogenesis, and accelerated esophageal ulcer healing. In cultured human esophageal epithelial (HET-1A) cells, misoprostol increased intracellular cAMP levels (by 163-fold), induced phosphorylation of CREB, and stimulated VEGF expression. A cAMP analog (Sp-cAMP) mimicked, whereas an inhibitor of cAMP-dependent protein kinase A (Rp-cAMP) blocked, these effects of misoprostol. These results indicate that the EP2/cAMP/protein kinase A pathway mediates the stimulatory effect of PGEs on angiogenesis essential for tissue injury healing via the induction of CREB activity and VEGF expression.

Benign glycogenic acanthosis lesions of the esophagus.

BACKGROUND/AIMS: Glycogenic acanthosis is described as benign thickening of the esophageal squamous epithelium of unknown etiology. Although its etiology is unknown, it has been reported that glycogenic acanthosis may be related to gastroesophageal reflux and hiatal hernia. The aim of the present study was to review the patients who were diagnosed with glycogenic acanthosis on upper gastrointestinal endoscopy and to determine whether there is any association between glycogenic acanthosis and gastroesophageal reflux and hiatal hernia. MATERIAL AND METHODS: A total of 504 patients who underwent upper gastrointestinal endoscopy for evaluation of non-ulcer dyspepsia were reviewed retrospectively. RESULTS: Glycogenic acanthosis was detected in 143 (28.3%) of those 504 patients. Of the 143 patients, 82 (57.3%) were male and 61 (42.7%) were female. Patients with glycogenic acanthosis were aged 20-83 years. Gastroesophageal reflux was detected in 50 (34.9%) cases with glycogenic acanthosis, while hiatal hernia was detected in 30 (20.9%) cases. Gastroesophageal reflux was detected in 102 (28.2%) control subjects, while hiatal hernia was detected in 50 (13.8%). Hiatal hernia was significantly higher in glycogenic acanthosis patients than in controls subjects (p<0.05). Glycogenic acanthosis patients had higher gastroesophageal reflux than seen in controls subjects, but the difference between groups was not statistically significant (p>0.05). CONCLUSIONS: Our results suggest that glycogenic acanthosis is primarily an age-related disease. We demonstrated that glycogenic acanthosis may be associated with gastroesophageal reflux and hiatal hernia. Further studies are necessary to confirm these findings.