Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis.

The desmosomal cadherin desmoglein-1 (DSG1) is an essential intercellular adhesion molecule that is altered in various human cutaneous disorders; however, its regulation and function in allergic disease remains unexplored. Herein, we demonstrate a specific reduction in DSG1 in esophageal biopsies from patients with eosinophilic esophagitis (EoE), an emerging allergic disorder characterized by chronic inflammation within the esophageal mucosa. Further, we show that DSG1 gene silencing weakens esophageal epithelial integrity, and induces cell separation and impaired barrier function (IBF) despite high levels of desmoglein-3. Moreover, DSG1 deficiency induces transcriptional changes that partially overlap with the transcriptome of inflamed esophageal mucosa; notably, periostin (POSTN), a multipotent pro-inflammatory extracellular matrix molecule, is the top induced overlapping gene. We further demonstrate that IBF is a pathological feature in EoE, which can be partially induced through the downregulation of DSG1 by interleukin-13 (IL-13). Taken together, these data identify a functional role for DSG1 and its dysregulation by IL-13 in the pathophysiology of EoE and suggest that the loss of DSG1 may potentiate allergic inflammation through the induction of pro-inflammatory mediators such as POSTN.

Markers of tyrosine kinase activity in eosinophilic esophagitis: a pilot study of the FIP1L1-PDGFRα fusion gene, pERK 1/2, and pSTAT5.

The pathogenesis of eosinophilic esophagitis (EoE) is incompletely understood. In certain eosinophilic diseases, activation of tyrosine kinase after fusion of the Fip1-like-1 and platelet-derived growth factor receptor-α genes (F-P fusion gene) mediates eosinophilia via downstream effectors such as extracellular-regulated kinase (ERK1/2) and signal transducers and activators of transcription (STAT5). This mechanism has not been examined in EoE. Our aim was to detect the F-P fusion gene, pERK1/2, and pSTAT5 in esophageal tissue from patients with EoE, gastroesophageal reflux disease (GERD), and normal controls. We performed a cross-sectional pilot study comparing patients with steroid-responsive and steroid-refractory EoE, to GERD patients and normal controls. EoE cases were defined by consensus guidelines. Fluorescence in situ hybridization (FISH) was performed to detect the F-P fusion gene and immunohistochemistry (IHC) was performed to detect pERK1/2 and pSTAT5 in esophageal biopsies. Twenty-nine subjects (median age 30 years [range 1-59]; 16 males; 24 Caucasians) were included: eight normal, six GERD, and 15 EoE (five steroid-refractory). On FISH, 98%, 99%, and 99% of the nuclei in the normal, GERD, and EoE groups, respectively, were normal (P= 0.42). On IHC, a median of 250, 277, and 479 nuclei/mm(2) stained for pERK 1/2 in the normal, GERD, and EoE groups, respectively (P= 0.07); the refractory EoE patients had the highest degree pERK 1/2 staining (846 nuclei/mm(2); P= 0.07). No trend was seen for pSTAT5. In conclusion, the F-P fusion gene was not detected with increased frequency in EoE. Patients with EoE had a trend toward higher levels of pERK 1/2, but not STAT5, in the esophageal epithelium, with highest levels in steroid-refractory EoE patients.

Review article: reflux and its consequences--the laryngeal, pulmonary and oesophageal manifestations. Conference held in conjunction with the 9th International Symposium on Human Pepsin (ISHP) Kingston-upon-Hull, UK, 21-23 April 2010.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is one of the commonest diseases of Western populations, affecting 20 to 30% of adults. GERD is multifaceted and the classical oesophageal symptoms such as heartburn and regurgitation often overlap with atypical symptoms that impact upon the respiratory system and airways. This is referred to as extra-oesophageal reflux disease (EERD), or laryngopharyngeal reflux (LPR), which manifests as chronic cough, laryngitis, hoarseness, voice disorders and asthma. AIM: The 'Reflux and its consequences' conference was held in Hull in 2010 and brought together a multidisciplinary group of experts all with a common interest in the many manifestations of reflux disease to present recent research and clinical progress in GERD and EERD. In particular new techniques for diagnosing reflux were showcased at the conference. METHODS: Both clinical and non-clinical key opinion leaders were invited to write a review on key areas presented at the `Reflux and its consequences' conference for inclusion in this supplement. RESULTS AND CONCLUSION: Eleven chapters contained in this supplement reflected the sessions of the conference and included discussion of the nature of the refluxate (acid, pepsin, bile acids and non-acid reflux); mechanisms of tissue damage and protection in the oesophagus, laryngopharynx and airways. Clinical conditions with a reflux aetiology including asthma, chronic cough, airway disease, LPR, and paediatric EERD were reviewed. In addition methods for diagnosis of reflux disease and treatment strategies, especially with reference to non-acid reflux, were considered.

Physicochemical basis for dilated intercellular spaces in non-erosive acid-damaged rabbit esophageal epithelium.

Dilated intercellular spaces (DIS) within esophageal epithelium (EE) is a histopathologic feature of non-erosive reflux disease and early lesion in acid-damaged rabbit EE associated with increased paracellular permeability. Its cause remains unknown, but the lesion's morphology suggests a significant fluid shift into the intercellular spaces (ICS). Since water follows osmotic forces and consequently ion movements, we explored the role of active (ion) transport and ion gradients in its pathogenesis. This was done by quantifying the effect of inhibited active transport and altered ion gradients on electrical resistance (R(T)) and ICS diameter in acid-exposed Ussing-chambered rabbit EE. Compared with normal Ringer, pH 7.5, 30 minutes of luminal HCl (100 mmol/L), pH 1.1, increased permeability (R(T): +5 +/- 4% vs-52 +/- 4%) and ICS diameter (0.25 +/- 0.01 microm vs 0.42 +/- 0.02 microm), but had no effect on cell morphology or diameter. Ouabain pretreatment significantly reduced active transport but had no effect on the acid-induced changes. However, negating the chloride gradient created by luminal HCl either by adding choline chloride, 100 mmol/L, serosally or by replacing luminal HCl, pH 1.1, with luminal H(2)SO(4), pH 1.1, prevented the development of DIS while maintaining the increase in permeability. DIS was also prevented in the presence of a 100 mmol/L (choline) chloride gradient by luminal exposure at neutral pH. DIS in HCl-damaged EE is caused by an H(+)-induced increase in epithelial permeability; this enables Cl(-) to diffuse along its gradient into the ICS, creating an osmotic force for water movement into and (hydrostatic) dilation of the ICS.

Nonerosive reflux disease.

Nonerosive reflux disease (NERD) is the most common phenotype of gastroesophageal reflux disease. By definition, patients with NERD have typical reflux symptoms caused by the intraesophageal reflux of gastric contents but have no visible esophageal mucosal injury. This is in contrast to patients with erosive reflux disease (ERD) or Barrett's esophagus (BE) who have obvious esophageal mucosal injury on endosco-py. Only 50% of patients with NERD have pathologic esophageal acid exposure as detected on 24-h pH monitoring. NERD patients with physiologic esophageal acid exposure and good temporal correlation of symptoms with reflux events are considered to have esophageal hypersensitivity, while patients with no symptom-reflux correlation are considered to have functional heartburn. It is possible yet uncommon for NERD to progress to severe ERD (i.e. LA Grade C or D) or BE. Patients with NERD and pathologic esophageal acid exposure have motor dysfunction and acid reflux abnormalities that are similar to patients with ERD and BE, whereas NERD patients with physiologic esophageal acid exposure have minimal abnormalities and are not much different than healthy controls. The pathological feature most indicative of NERD is the presence of dilated intercellular spaces within squamous epithelium, an ultrastructural abnormality readily identified on transmission electron microscopy but also on light microscopy. A symptomatic response to an empiric trial of high-dose proton pump inhibitor (PPI) therapy is a simple and useful strategy to establish the diagnosis of NERD, although histology and pH monitoring may be useful in confirming the diagnosis. Patients with NERD suffer similar decrements in quality of life as do patients with erosive esophagitis. Therapy is aimed at eliminating or reducing symptoms and improving quality of life. PPIs are the most effective agents for the treatment of NERD although they are less effective in providing symptom relief than in patients with erosive esophagitis. Laparoscopic antireflux surgery is an effective therapy for selected patients with NERD and outcomes are better when performed in high volume centers.

Electrical parameters and ion species for active transport in human esophageal stratified squamous epithelium and Barrett's specialized columnar epithelium.

The human esophagus is lined by stratified squamous epithelium (ESSE), and in some subjects with reflux disease the distal esophagus becomes lined by Barrett's specialized columnar epithelium (BSCE). ESSE and BSCE differ both histologically and functionally, the latter evident by differences in their in vivo transmural electrical potential difference (PD), ESSE averaging -15 mV and BSCE being greater than -25 mV. In this report we examine the basis for this difference in PD. This is done by mounting endoscopic biopsies of ESSE from 25 subjects without esophageal disease and BSCE from 19 with Barrett's esophagus in mini-Ussing chambers for electrical recordings basally and after bathing solution ion replacement. The results show that the PD of human ESSE reflects a low level of active ion transport (5.1 +/- 0.8 muA/cm(2)) combined with a high level of tissue (electrical) resistance (344 +/- 34 Omega.cm(2)) and that of BSCE reflects a high level of active transport (43.6 +/- 11.6 muA/cm(2)) combined with a low level of resistance (69 +/- 8 Omega.cm(2)). Furthermore, active transport in ESSE was principally due to sodium absorption whereas in BSCE it was equally divided between sodium absorption and anion (chloride/bicarbonate) secretion, the latter through an apical membrane, 4-acetamido4'-isothiocyano-2,2'-stilbenedisulfonic acid-sensitive anion channel. As an anion-secreting tissue with bicarbonate secretory capacity more than fivefold greater than ESSE, BSCE is better suited than ESSE for defense of the esophagus against reflux disease.

Effect of luminal acidity on the apical cation channel in rabbit esophageal epithelium.

Esophageal epithelial cells contain an apical cation channel that actively absorbs sodium ions (Na(+)). Since these channels are exposed in vivo to acid reflux, we sought the impact of high acidity on Na(+) channel function in Ussing-chambered rabbit epithelium. Serosal nystatin abolished short-circuit current (I(sc)) and luminal pH titrated from pH 7.0 to pH > or = 2.0 had no effect on I(sc). Circuit analysis at pH 2.0 showed small, but significant, increases in apical and shunt resistances. At pH < 2.0, I(sc) increased whereas resistance (R(T)) decreased along with an increase in fluorescein flux. The change in I(sc), but not R(T), was reversible at pH 7.4. Reducing pH from 7.0 to 1.1 with H(2)SO(4) gave a similar pattern but higher I(sc) values, suggesting shunt permselectivity. A 10:1 Na(+) gradient after nystatin increased I(sc) by approximately 4 muAmps/cm(2) and this declined at pH < or = 3.5 until it reached approximately 0.0 at pH 2.0. Impedance analysis on acid-exposed (non-nystatin treated) tissues showed compensatory changes in apical (increase) and basolateral (decrease) resistance at modest luminal acidity that were poorly reversible at pH 2.0 and associated with declines in capacitance, a reflection of lower apical membrane area. In esophageal epithelium apical cation channels transport Na(+) at gradients as low as 10:1 but do not transport H(+) at gradients of 100,000:1 (luminal pH 2.0). Luminal acid also inhibits Na(+) transport via the channels and abolishes it at pH 2.0. These effects on the channel may serve as a protective function for esophageal epithelium exposed to acid reflux.

Review article: the pathophysiology of gastro-oesophageal reflux disease - oesophageal manifestations.

The pathogenesis of gastro-oesophageal reflux disease (GERD) is multifactorial, involving transient lower oesophageal sphincter relaxations (TLESRs) as well as other lower oesophageal sphincter (LES) pressure abnormalities. GERD is associated with a decrease in LES pressure, which can be provoked by factors such as foods (fat, chocolate, etc.), alcohol, smoking and medications. These factors have also been shown to increase TLESRs. As a result, reflux of acid, bile, pepsin and pancreatic enzymes occurs, leading to oesophageal mucosal injury, which can potentially progress to oesophageal adenocarcinoma in a minority of patients with Barrett's metaplasia. In addition, duodenogastric contents can also contribute to oesophageal injury. Other factors contributing to the pathophysiology of GERD include hiatal hernia, poor oesophageal clearance, delayed gastric emptying and impaired mucosal defensive factors. Hiatal hernia has a permissive role in the pathogenesis of reflux oesophagitis by promoting LES dysfunction. Delayed gastric emptying, resulting in gastric distension, can significantly increase the rate of TLESRs, contributing to postprandial GER. The mucosal defensive factors have an important role in GERD. When excessive acid causes a breakdown in oesophageal epithelial defenses, epithelial resistance may be reduced. Nocturnal GERD is associated with prolonged acid exposure and proximal extent of acid contact, which elevates the risk for oesophageal damage and GERD-related complications. In sum, GERD is a complex problem caused by many factors that are exacerbated when the patient is in the supine position.

Calcium-switch technique and junctional permeability in native rabbit esophageal epithelium.

The Ca(2+)-switch technique was used to investigate the nature of the barrier governing (paracellular) permeability across the junctions of "native" rabbit esophageal epithelium. This was done by mounting esophageal epithelium in Ussing chambers to monitor transepithelial electrical resistance (R(T)), a marker of junctional permeability. When exposed to Ca(2+)-free Ringer solutions containing EDTA, R(T) declined approximately 35% below baseline over 2 h, and this decline reversed within 2 h by restoration of (1.2 mM) Ca(2+)-containing, normal Ringer solution ("Ca(2+)-switch technique"). Junctional resealing, i.e., increased R(T) on Ca(2+) replacement, was assessed by the Ca(2+)-switch technique and shown to be 1) specific for Ca(2+), with only Mn(2+) among substituted divalent cations yielding partial resealing; 2) a function of extracellular Ca(2+) levels because maneuvers (BAPTA/AM or A23187 exposure) to alter intracellular Ca(2+) had no effect; 3) dose dependent, requiring as a minimum > or =0.5 mM Ca(2+) and 1.2 mM Ca(2+) for optimization; and 4) independent of protein synthesis because it was not inhibited by cycloheximide. Resealing was also inhibited by luminal antibodies or synthetic peptides to the extracellular domain of E-cadherin. Immunohistochemistry revealed E-cadherin within all layers of stratum corneum in Ca(2+)-free but not Ca(2+)-containing solution. The present investigation documents, using the Ca(2+)-switch technique, that esophageal epithelial junctions contain a major Ca(2+)-dependent component and that this component reflects adhesion between the extracellular domains of E-cadherin containing a histidine-alanine-valine recognition sequence.

Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium.

OBJECTIVES: It has recently been established that patients with nonerosive reflux disease have on biopsy within esophageal epithelium a lesion known as dilated intercellular spaces (DIS). METHODS: To further explore the nature and implications of this lesion, in vitro models of nonerosive acid and acid-pepsin damage were created in Ussing chamber-mounted rabbit esophageal epithelium. Using these models circuit analysis and permeability studies were carried out, the latter using dextran of varying size and human epidermal growth factor (EGF). RESULTS: Luminal HCl, pH 1.1, or HCl, pH 2.0 + pepsin, 1 mg/ml, for 30 min significantly reduced transepithelial electrical resistance (RT) but produced no gross erosions or histologic evidence of cell necrosis. Transmission electron microscopy, however, documented the presence of DIS. Circuit analysis on healthy esophageal epithelium showed that shunt resistance (RS) was much lower than apical membrane, basolateral membrane and transcellular resistances (Ra, Rb, and Rcell, respectively) and approached that of RT. Further, circuit analysis on acid and acid-pepsin damaged tissues showed that the declines in RT resulted from declines in RS. Moreover, the declines in RT (and so RS) were associated with a linear increase in permeability to 4 kD dextrans as well as an increase in permeability to 6 kD EGF and dextrans as large as 20 kD. CONCLUSIONS: In nonerosive acid-damaged esophageal epithelium DIS develop in association with and as a marker of reduced transepithelial resistance and increased shunt permeability. This change in shunt permeability upon acid or acid-pepsin exposure is substantial, permitting dextran molecules as large as 20 kD (33 A) to diffuse across the epithelium. Also, this shunt leak enables luminal EGF at 6 kD to diffuse across the acid-damaged epithelium and by so doing enables it to access its receptors on epithelial basal cells. We hypothesize that the shunt leak of EGF may in part account for the development of a reparative phenomenon on esophageal biopsy in patients with nonerosive reflux disease known as basal cell hyperplasia.

Physiological and morphological effects of alendronate on rabbit esophageal epithelium.

Alendronate, an aminobisphosphonate, produces as a side effect a topical (pill induced) esophagitis. To gain insight into this phenomenon, we assessed the effects of luminal alendronate on both esophageal epithelial structure and function. Sections of rabbit esophageal epithelium were exposed to luminal alendronate at neutral or acidic pH while mounted in Ussing chambers to monitor transmural electrical potential difference (PD), short-circuit current (I(sc)), and resistance (R). Morphological changes were sought by light microscopy in hematoxylin and eosin-stained sections. Impedance analysis was used for localization of alendronate-induced effects on ion transport. Luminal, but not serosal, alendronate (pH 6.9-7.2), increased PD and I(sc) in a dose- and time-dependent manner, with little change in R and mild edema of surface cell layers. The changes in I(sc) (and PD) were reversible with drug washout and could be prevented either by inhibition of Na,K-ATPase activity with serosal ouabain or by inhibition of apical Na channels with luminal acidification to pH 2.0 with HCl. An effect on apical Na channel activity was also supported by impedance analysis. Luminal alendronate at acidic pH was more damaging than either alendronate at neutral pH or acidic pH alone. These data suggest that alendronate stimulates net ion (Na) transport in esophageal epithelium by increasing apical membrane sodium channel activity and that this occurs with limited morphological change and no alteration in barrier function. Also alendronate is far more damaging at acidic than at neutral pH, suggesting its association with esophagitis requires gastric acid for expression. This expression may occur either by potentiation between the damaging effects of (refluxed) gastric acid and drug or by acid-induced conversion of the drug to a more toxic form.

Overview of the mechanisms of gastroesophageal reflux.

Reflux of acidic gastric contents through the esophagogastric junction into the esophageal lumen occurs in everyone nearly every day. The esophagogastric junction is composed of several structural components that contribute to its function as the primary antireflux barrier. Only when 1 or more of these components fail does reflux esophagitis develop. The initial focus of this review is on transient lower esophageal sphincter relaxations, a vagally mediated reflex arc that accounts for almost all reflux events in healthy individuals and the majority of reflux events in those with reflux esophagitis. The association of erosive esophagitis with low or absent (incompetent) lower esophageal sphincter (LES) pressure and anatomic disruptions of the esophagogastric junction, such as hiatal hernia, are also important, especially with respect to whether the LES dysfunction and hernia are the cause or the consequence of erosive disease.

The role of pepsin in acid injury to esophageal epithelium.

OBJECTIVES: The development of reflux esophagitis in humans is a process resulting from esophageal exposure to refluxed gastric contents. There is no doubt that damage to the esophageal epithelium requires exposure to gastric acid; however, the role of refluxed pepsin as contributor to this damage seems to be underappreciated. METHODS: The role of physiological concentrations of pepsin was examined in Ussing chambered rabbit esophageal epithelium and in cultured esophageal epithelial cells. RESULTS: The results of this investigation reaffirmed the ability of pepsin to increase the rate and degree of esophageal cell and tissue damage at acidic pH, although the range of activity was limited to pH < 3.0. Moreover, the increased rate of tissue damage by acidified pepsin rapidly (within 15 min) produced a lesion that was irreversible, whereas, in a similar time frame, acid alone produced a lesion that was completely reversible. This early lesion by acidified pepsin was localized by performance of mannitol fluxes in apparently undamaged esophageal epithelium on light microscopy to the intercellular junctional complex. Further acid produced similar degrees of cell killing as acidified pepsin at pH < 3.0 in rabbit esophageal epithelial cells in suspension but not when growing on coverslips or present within intact epithelium. CONCLUSIONS: These studies suggest that acidified pepsin plays a key role in the development of reflux esophagitis by producing an early irreversible lesion that results in an increase in paracellular permeability, which indirect evidence suggests is due to damage to the junctional complex. The irreversibility of the increase in paracellular permeability is likely to aid conversion of nonerosive to erosive damage to the epithelium by permitting luminal acid greater access to the basolateral membrane of esophageal epithelial cells, which is known to be acid permeable.

Gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a chronic disorder that affects millions of people worldwide and has the potential to lead to serious consequences, including cancer of the esophagus. It for this reason that there is such intense interest in the topic, this emphasized by the identification of some 341 articles published in the English language in the year 2000 alone. The present report highlights the results of a number of studies that either increase our understanding of the condition or raise important issues about its diagnosis and treatment. Included in the areas covered are (1) the role of genetics in GERD; (2) the mechanism for transient lower esophageal sphincter relaxations and their association with hiatal hernias; (3) the role of Helicobacter pylori in GERD and Barrett esophagus; (4) efficacy and safety of proton pump inhibitors in GERD; and (5) the mechanism for chronic cough in patients with GERD, among others.

Eicosanoids and the esophagus.

Eicosanoids are products of arachidonic acid metabolism. Among the products produced are the prostaglandins and leukotrienes, products which are known to play important roles in health and disease of many gastrointestinal tissues. Here, we review current knowledge about eicosanoids in the esophagus, including production in healthy and diseased tissues and potential physiologic and pathophysiologic effects in two important esophageal mucosal disorders, reflux esophagitis and esophageal cancer.

Mechanisms of reflux-induced epithelial injuries in the esophagus.

The esophagus is lined by a moist stratified squamous epithelium. In humans, this epithelium, as evidenced by the Bernstein test, has considerable capacity to resist damage even upon direct contact of high concentrations of luminal acid. This intrinsic property of the epithelium to defend itself against luminal acid is called "tissue resistance." Tissue resistance is comprised of a number of important structures and functions, the individual functions of which are described in this review. Moreover, when luminal acidity is sufficiently noxious, tissue resistance can be overcome, leading to heartburn and ultimately cell necrosis. Herein are described the mechanisms by which acid overcomes the epithelial defense to produce these typical signs and symptoms of gastroesophageal reflux disease.

A randomized, placebo-controlled, multicenter study of the safety and efficacy of a new polyethylene glycol laxative.

OBJECTIVE: This study was designed to determine the efficacy and safety of a new laxative, Braintree polyethylene glycol (PEG) laxative (Miralax, Braintree Laboratories, Braintree, MA). METHODS: This investigation was designed as a placebo-controlled, blinded, randomized, multicenter parallel trial. Study subjects were constipated but otherwise healthy outpatients who had < or =2 stools during a 7-day qualification period. Braintree PEG laxative 17 g or dextrose placebo p.o. in 8 oz of water for a 14-day treatment period. A diary recorded each bowel movement and subjective symptoms of stool consistency, ease of passage, cramps, and flatus. CBC, blood chemistries and urinalysis were performed before and after the treatment period. RESULTS: There were 151 randomized subjects, 131 female and 20 male. An increase in bowel movement frequency was observed with the PEG laxative as compared to placebo (p<0.001), with the greatest difference in efficacy in wk 2 of treatment (p<0.001). By wk 2 of treatment, on average, placebo subjects had 2.7 bowel movements/wk and PEG-treated study subjects had 4.5 movements/wk (p<0.01), or more than one bowel movement every 2 days. Investigator (p<0.005) and patient (p<0.001) subjective assessment of perception of treatment effectiveness, and patient evaluations of stool consistency and passage showed significant improvement in the active treatment group (p<0.001). There were no significant differences in laboratory changes or adverse experiences recorded between groups. CONCLUSION: Braintree PEG laxative is safe and effective in the short term for the treatment of constipation.

Lumen-to-surface pH gradients in opossum and rabbit esophagi: role of submucosal glands.

The opossum esophagus, like that of humans, contains a network of submucosal glands with the capacity to secrete bicarbonate ions into the esophageal lumen. To evaluate the role of these glands in protecting the epithelial surface from acid insult, we measured the lumen-to-surface pH gradient in opossum esophagus at different luminal pH and compared it to that of rabbit esophagus, an organ devoid of submucosal glands. Sections of opossum and rabbit esophageal epithelium were mounted luminal side up in a modified Ussing chamber. pH-sensitive microelectrodes, positioned within 5 microm of the epithelial cell surface, were used to monitor surface pH during perfusion with solutions of different pH. At luminal pH 7. 5, the pH(s) of both opossum and rabbit were similar (pH(s) = 7.5). Lowering luminal pH from 7.5 to 3.5 in opossum decreased pH(s) to 4.2+/-0.16, a value significantly higher than pH of perfusate, whereas in rabbit this maneuver decreased pH(s) to 3.69+/-0.08, a value not significantly different from pH of perfusate. In opossum but not in rabbit, addition of carbachol to the serosal solution increased basal pH(s) to 7.8+/- 0.1 and significantly blunted the decline in pH(s) on perfusion with acidic Ringer solution (pH 3.5), with pH(s) falling to 5.6+/-0.45. The effect of carbachol on surface buffering was inhibited by prior treatment with atropine. Luminal acidification to pH 2.0 in opossum (as in rabbit) abolished the lumen-to-surface pH gradient even after addition of serosal carbachol. We conclude that the presence of submucosal glands in esophagus contributes through bicarbonate secretion to creation of a lumen-to-surface pH gradient. Although this gradient can be modulated by carbachol, its capacity to buffer (and therefore to protect) the epithelial surface against back-diffusing H(+) is limited and dissipated at pH 2.0.

Gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a common chronic disorder affecting millions of people worldwide. This is a review of a number of published studies in the past year that increase current understanding or raise important issues about this disorder. Among the areas covered are the epidemiology and role of genetics in GERD; its pathogenesis with respect to duodenogastric reflux and impaired epithelial barrier function; the effects of atropine on transient lower esophageal sphincter relaxations; the role of acid suppression, heat shock proteins, and the enzyme cyclooxygenase-2 in Barrett esophagus and esophageal adenocarcinoma; the complication rates in laparoscopic fundoplication; and the results of ablation therapy for the treatment of Barrett esophagus and esophageal adenocarcinoma. These investigations reinforce a sense of the complexity of GERD and provide optimism that modern technology will continue to be used to develop more effective treatments.