Reflux esophagitis in patients with chronic obstructive pulmonary disease.

ABSTRACT: The relationship between chronic obstructive pulmonary disease (COPD) and reflux esophagitis (RE) was controversial. We investigated the factors influencing RE development in patients with COPD and evaluated the association between RE and AECOPD.Patients with COPD who underwent esophagogastroduodenoscopy from January 2003 to December 2013 in St. Paul's Hospital, the Catholic University of Korea (Seoul, Korea) were enrolled retrospectively. The grade of RE was based on the Los Angeles classification and minimal change esophagitis. Body mass index, smoking history, medical history, AECOPD, pulmonary function test data, endoscopic findings, and comorbidities were reviewed.Of a total of 218 patients with COPD, 111 (50.9%) were diagnosed with RE. None of age, sex, smoking history, or the severity of airflow limitation was associated with RE. AECOPD was not related to either the presence or severity of RE. There was no significant correlation between RE grade by Los Angeles classification and severity of airflow limitation (P = .625). Those who had RE used theophylline (P = .003) and long-acting muscarinic antagonists (P = .026) significantly more often than did controls. The use of theophylline (OR 2.05; 95% CI, 1.16-3.65, P = .014) was associated with an increased incidence of RE.The use of theophylline might increase the risk of RE in COPD patients. RE may not be associated with airflow limitation or AECOPD.

Destruction of the Dorsal Motor Nucleus of the Vagus Aggravates Inflammation and Injury from Acid-Induced Acute Esophagitis in a Rat Model.

BACKGROUND/AIMS: The aim of this study is to examine the protective effect of the cholinergic anti-inflammatory pathway (CAP) in experimental esophagitis in rats. METHODS: A total of 40 male Sprague-Dawley (SD) rats were randomly divided into five groups as follows: control group, sham + saline group, sham + acid group, operation + saline group, and operation + acid group. Two weeks after the dorsal motor nucleus of the vagus (DMV) destruction, hydrochloric acid with pepsin was perfused into the lower part of the esophagus for 90 min. The rats were sacrificed 60 min after perfusion. The esophagus was prepared for hematoxylin and eosin (HE) staining, and the degree of inflammation and NF-κB activation in the esophagus was measured. Inflammatory cytokines (TNF-α, IL-6, IL-1ß, and PGE2) in the esophagus were measured by ELISA. The brain was removed and processed for c-fos immunohistochemistry staining. The c-fos-positive neurons were counted and analyzed. RESULTS: The TNF-α, IL-1ß, IL-6, and PGE2 concentrations in the esophageal tissue increased after acid perfusion. The microscopic esophagitis scores and the activation of NF-κB p65 in the esophagus were significantly higher in the operation + acid group than in the operation + saline group. c-fos-positive neurons significantly increased in rats receiving acid perfusion in the amygdala (AM), the paraventricular nucleus of the hypothalamus (PVN), the parabrachial nucleus (PBN), the nucleus of the solitary tract (NTS)/DMV, the nucleus ambiguous (NA), the reticular nucleus of the medulla (RNM), and the area postrema (AP). After DMV destruction, c-fos expression was reduced in the AM, PVN, PBN, NTS/DMV, NA, RNM, and AP, especially in the AM, PVN, NTS/DMV, RNM, and AP. CONCLUSIONS: The DMV is an important nucleus of the CAP. The DMV lesion can aggravate esophageal inflammation and injury from acid-induced acute esophagitis in a rat model. The CAP has a protective effect on the acute esophagitis rat model and could be a new therapy for reflux esophagitis (RE).

Effect of CCl4 and blocking H2S biosynthesis on oesophageal mucosa rats: model of nonerosive oesophagitis.

Nonerosive esophagitis (NEO) - a chronic inflammatory condition with diagnostic and therapy unclear approaches. The aim of study was to develop the new models of NEO using the chemical ulcerogens: carbon tetrachloride (CCl(4)), hydrogen sulfide (H(2)S). We modified the method of NEO with cytoprotective prostaglandins (COX) and H(2)S biosynthesis carried out on rats, divided into groups: 1st - vehicle (1 ml 0.9% NaCl), CCl(4) (twice 0.3 ml/200g/body weight); the next day 2(nd) - vehicle; 3(rd) - nonselective blocker of COX (naproxen; 30 mg/kg); 4(th) - ATB-346 (H(2)S-releasing naproxen; 43.5 mg/kg, «Antibe Therapeutics¼, Canada) with per os administration. After H(2)S-biosythesis modification by intraperitoneal administration of cystathionine g-lyase (CSE) inhibitor, DL-propargylglycine (PAG, 25 mg/kg), cystathionine-b-synthetase (CBS) inhibitor, O-carboxymethyl-hydroxylamine hemihydrochloride (CHH, 50 mg/kg) or H(2)S donor NaHS (100 mlmol/kg), stress was inducted by Takagi, 1964. The lower third of EM and esophagogastric junction were estimated via histological score index, IL-17, IL-10 by ELISA. The obtained data indicated the strong cytotoxic influence of CCl(4) on EM, corneal and epithelial layers thickness increasing, muscle plate and submucosal edema disorganization vs control and ATB-346 treatment. Over-expression of IL-17 was achieved using PAG and BCA vs control. WIRS-associated EM injury with blocking CSE, CBS characterized by submucosal oedema, neutophilic infiltration, destructive lesions, HSI rising up to 6 vs control. Increased IL-17 to 65% and decreased IL-10 in 30% vs control. H(2)S plays key role in the integrity of oesophageal mucosa and modification of H(2)S synthesis and CCl(4)-related injury can be novel approach of animal model production NEO, similar to human NERD and will help in its pathogenesis identification and preventive drugs creation.

Effects of sterigmatocystin on esophageal epithelium and experimental reflux esophagitis in rats.

Patients with reflux esophagitis experience an increased incidence of esophageal cancer. In China, this may be the result of contamination of the food supply by Aspergillus fungi, which is known to harbor sterigmatocystin, a carcinogenic mycotoxin. To delineate the potential link between sterigmatocystin and esophageal cancer, an experimental model of reflux esophagitis was developed in rats that had undergone a cardiectomy and partial pylorus ligation. The rats were treated with sterigmatocystin or saline, and esophageal squamous cell hyperplasia was assessed based on the pathological evaluation. The expression of proliferating cell nuclear antigen (PCNA), transporter associated with antigen processing 1 (TAP1) and low molecular weight protein 2 (LMP2) was determined by immunohistochemistry. Intraperitoneal administration of sterigmatocystin promoted the proliferation of squamous epithelium. In addition, it also increased the expression of PCNA in esophageal epithelial cells in rats with reflux esophagitis and was correlated with the increased severity of epithelial hyperplasia. The expression levels of TAP1 and LMP2, which are located in the cytoplasm of esophageal epithelial cells, were reduced in rats with reflux esophagitis, and sterigmatocystin exposure further decreased the expression. Thus, the downregulation of TAP1 and LMP2 proteins by sterigmatocystin may directly affect tumor immunity by allowing transformed cells to escape the host immune surveillance, thereby promoting esophageal cancer.

Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) are important mediators of reflux-induced cell signalling in esophageal cells.

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has been implicated in both DNA damage induction and aberrant cell signalling in various tissue and cell backgrounds. We investigated here the role of iNOS and NO in DNA damage induction and nuclear factor-kappa B (NF-κB) signalling in esophageal cells in vitro. As esophageal adenocarcinoma develops in a background of Barrett's esophagus secondary to reflux disease, it is possible that inflammatory mediators like NO may be important in esophageal cancer development. We show that reflux components like stomach acid and bile acids [deoxycholic acid (DCA)] can induce iNOS gene and protein expression and produce NO generation in esophageal cells, using real-time PCR, western blotting and NO sensitive fluorescent probes, respectively. This up-regulation of iNOS expression was not dependent on NF-κB activity. DCA-induced DNA damage was independent of NF-κB and only partially dependent on iNOS and NO, as measured by the micronucleus assay. These same reflux constituents also activated the oncogenic transcription factor NF-κB, as measured by transcription factor enzyme-linked immunosorbent assay and gene expression studies with NF-κB linked genes (e.g. interleukin-8). Importantly, we show here for the first time that basal levels of NF-κB activity (and possibly acid and DCA-induced NF-κB) are dependent on iNOS/NO and this may lead to a positive feedback loop whereby induced iNOS is upstream of NF-κB, hence prolonging and potentially amplifying this signalling, presumably through NO activation of NF-κB. Furthermore, we confirm increased protein levels of iNOS in esophageal adenocarcinoma and, therefore, in neoplastic development in the esophagus.

Risk of Barrett's oesophagus, oesophageal adenocarcinoma and reflux oesophagitis and the use of nitrates and asthma medications.

OBJECTIVE: To investigate the relationship between use of asthma medication and nitrates and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. MATERIAL AND METHODS: Data were collected on use of asthma medication and nitrates at least 1 year before interview from patients with reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Associations between use of asthma medications and nitrates and the risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma were estimated using multiple logistic regression. RESULTS: Nine hundred and forty-one subjects were recruited: 230 reflux oesophagitis, 224 Barrett's oesophagus, 227 oesophageal adenocarcinoma patients and 260 population controls. Barrett's oesophagus patients were more likely than controls to have had a diagnosis of asthma (odds ratio 2.15, 95% confidence interval 1.15-4.03) and to have used asthma medications (odds ratio 2.13, 95% confidence interval 1.09-4.16). No significant associations were observed between use of asthma medication or nitrates and reflux oesophagitis or oesophageal adenocarcinoma. CONCLUSIONS: Gastro-oesophageal reflux symptoms appear to confound the association between asthma medication use and Barrett's oesophagus. However, it is possible that asthma medications may increase the risk of Barrett's oesophagus by other mechanisms.

Impact of upper gastrointestinal lesions in patients on low-dose aspirin therapy: preliminary study.

BACKGROUND AND AIMS: We investigated the incidence of upper gastrointestinal lesions in the esophagus, stomach and duodenum in patients on low-dose aspirin (LDA) therapy. METHODS: The subjects were 101 consecutive outpatients who had been on LDA therapy (average age 67.2 +/- 8.3 years; male : female ratio 3.8:1). All subjects underwent endoscopy without ceasing their antiplatelet or anticoagulant therapy. We investigated the rates of endoscopic peptic ulcer, reflux esophagitis (RE) and malignant lesion. RESULTS: RE was detected in eight subjects and esophageal ulcer in one subject. The severity of RE, according to the Los Angeles classification, was grade A in one subject, B in four, C in two and D in one. All nine subjects (8.9%) with RE and esophageal ulcer were negative for Helicobacter pylori infection. Gastric ulcer was detected in 12 subjects (six H. pylori positive, six negative) and duodenal ulcer in four (one H. pylori positive, three negative). The incidence of gastroduodenal ulcer was 15.8% (16/101). The incidence of esophageal and gastric cancers was high at 5.9% (6/101). Subjects were surveyed using the gastrointestinal symptom rating scale, with no differences in scores for acid reflux, abdominal pain or indigestion according to the presence or absence of RE, gastric ulceration or duodenal ulceration. CONCLUSION: Upper gastrointestinal mucosal injuries and neoplasm were found in not only the stomach, but also the esophagus and duodenum in LDA taking subjects. These results emphasize the importance of endoscopic surveillance in patients on LDA therapy.

Esophageal mucosal injury with low-dose aspirin and its prevention by rabeprazole.

Aspirin is used widely as an antithrombotic drug for the prevention of cardiovascular and cerebrovascular events. Although aspirin increases the risk for gastrointestinal mucosal injury, the effect on esophageal mucosa is unclear. This study investigates whether aspirin induces esophageal mucosal injury and whether a proton-pump inhibitor can prevent such injury in relation to CYP2C19 genotypes. Fifteen healthy Japanese volunteers are dosed for 7 days in a 5-way randomly crossover trial: placebo, aspirin 100 mg, rabeprazole 10 mg, and aspirin 100 mg plus rabeprazole 10 mg either once daily or 4 times per day. All subjects undergo endoscopy and 24-hour intragastric pH monitoring on day 7. With the aspirin regimen, esophageal mucosal disorders occur in 7 patients (46.7%) (5, grade M; 2, grade A). The median 24-hour pH differs significantly among subjects who develop grade M or A gastroesophageal reflux disease and those who do not develop gastroesophageal reflux disease; the median pH in grade A gastroesophageal reflux disease is significantly lower (1.5 [range, 1.1-1.9]) than that in patients without gastroesophageal reflux disease (5.6 [range, 0.8-8.4], P = .04). Rabeprazole significantly inhibits acid secretion irrespective of CYP2C19 genotypes and decreases the incidence of aspirin-related esophageal injury and symptoms according to increasing pH value. Aspirin induces esophageal mucosal injury in an acid-dependent manner. Concomitant proton-pump inhibitor therapy may prevent advanced effects of low-dose aspirin.

Combined use of omeprazole and a novel antioxidative cytoprotectant for the treatment of peptic ulcer. Facilitation of ulcer healing in experimental animals.

Peptic ulcer and gastroesophageal reflux are common acid-peptic related diseases. The pathophysiology of peptic ulcer disease has been centered on an imbalance between aggressive and defensive factors. This study was conducted to examine whether the combined use of omeprazole (CAS 73590-58-6), a proton pump inhibitor, and DA-9601, a novel anti-ulcer formulation of the extract of Artemisia asiatica Nakai, has synergistic effects on various peptic ulcers and gastroesophageal reflux diseases in animal models. An optimal combination ratio of omeprazole and DA-9601 was investigated in an acetic acid-induced ulcer model. In the results, oral pretreatment with omeprazole and DA-9601 (combination ratio, 1:3) significantly reduced alcohol-, indometacin-, acetic acid-, and cysteamine-induced gastrointestinal lesions in a synergistical manner in rats. The combination treatment also significantly attenuated the gross and histopathological lesions in an experimental reflux esophagitis model as compared to the single treatment of omeprazole or DA-9601. In an alcohol-induced gastritis model, the combined treatment resulted in a significant decrease in lipid peroxidation with concomitant increases in glutathione content and prostaglandin E2 level, which was proportional to the inhibitory effect of the combination therapy. These results suggest that the combined therapy with omeprazole and DA-9601, a cytoprotectant, can be beneficial for the treatment of peptic ulcer and reflux esophagitis.

Esophagitis-related esophageal shortening in opossum is associated with longitudinal muscle hyperresponsiveness.

Acute intraluminal acid perfusion induces esophageal shortening in humans and opossums. Lower esophageal sphincter (LES) hypotension and peristaltic dysfunction occur in patients and animal models of reflux esophagitis. This study examined whether similar shortening and motor dysfunction occur in anesthetized opossums after repeated esophageal acid exposure and whether this is associated with longitudinal muscle (LM) hyperresponsiveness. Manometry used before and after 3 consecutive days of 45-min perfusion with 100 mmol/l HCl or normal saline measured esophageal length and motor responses to induced swallows. LM electrical and mechanical responses were assessed using standard isometric tension and intracellular recording techniques. Compared with controls, repeated acid perfusion induced erosive esophagitis and significant esophageal shortening, associated with enhanced LM responses to carbachol, a significantly depolarized resting membrane potential, and abnormal spike patterns. LES resting pressure and swallow-induced peristalsis were unaffected. In this model of reflux esophagitis, marked persistent esophageal shortening and associated LM hyperresponsiveness occur before significant LES or peristaltic dysfunction, suggesting that esophageal shortening is the earliest motor disorder induced by acid injury.

P2X purinoceptor-induced sensitization of ferret vagal mechanoreceptors in oesophageal inflammation.

1. Using an in vitro single unit recording technique we studied the changes in mechanical and chemical sensitivity of vagal afferent fibres in acute oesophagitis, with particular attention to inflammatory products such as purines. 2. Histologically verified oesophagitis was induced by oesophageal perfusion of 1 mg ml-1 pepsin in 150 mM HCl in anaesthetized ferrets for 30 min on two consecutive days. Controls were infused with 154 mM NaCl. 3. The number of action potentials evoked in oesophageal mucosal afferents by mucosal stroking with calibrated von Frey hairs (10-1000 mg) was stimulus dependent. In oesophagitis responsiveness was reduced across the range of stimuli compared with controls. 4. Topical application of the P2X purinoceptor agonist alphabeta-methylene ATP had no direct excitatory effect on afferents. In oesophagitis, but not in controls, there was a significant increase in responses to stroking with von Frey hairs during superfusion with alphabeta-methylene ATP (1 microM). 5. Mucosal afferents responded directly to one or more chemical stimuli: 26 % (5/19 afferents) responded in controls, and 47 % (7/15 afferents) in oesophagitis. There were no differences in responsiveness to bradykinin (1 microM), prostaglandin E2 (100 microM), 5-hydroxytryptamine (100 microM), capsaicin (1 mM) or hydrochloric acid (150 mM) between control and oesophagitis groups. 6. We conclude that a sensitizing effect of a P2X purinoceptor agonist on mechanosensory function is induced in oesophagitis. This effect is offset by a decrease in basal mechanosensitivity.

Experimental esophagitis induced by acid and pepsin in rabbits mimicking human reflux esophagitis.

BACKGROUND & AIMS: The lack of appropriate animal models might explain the paucity of information on the mechanisms of mucosal damage and defense in reflux esophagitis. The aim of this study was to develop a model of esophagitis in rabbits mimicking human reflux esophagitis. METHODS: New Zealand white rabbits underwent surgery for placement of a plastic tube into the cervical esophagus. Acidified pepsin (AP) was intermittently perfused for different periods. Esophageal injury was assessed by macroscopic and microscopic examination, including the cell proliferation immunohistochemical parameter mib1. RESULTS: Rabbit losses (20%) were attributable mostly to postsurgical mortality and tube displacement. Perfusion of AP for 60 min/12 h or 45 min/12 h induced high-grade esophagitis by days 3 and 5, respectively, characterized by diffuse erosion/ulceration, inflammation, bleeding, and reactive epithelial changes. Perfusion of acidified pepsin for 60 min/day, especially at 30 min/12 h, induced low-grade esophagitis characterized by superficial epithelial loss, mild/absent inflammation, and epithelial reactive changes including increased cell proliferation, basal hyperplasia, and papillomatosis, which reached maximal expression by day 7. This perfusion regimen induced mucosal adaptation to damage. CONCLUSIONS: Different and highly reproducible esophageal mucosal lesions mimicking human reflux esophagitis can be induced in rabbits with repetitive acid and pepsin exposure.

Adaptation of esophageal mucosa to acid- and pepsin-induced damage: role of nitric oxide and epidermal growth factor.

To study whether the esophageal mucosa was able to elicit mucosal adaptation, we induced esophageal damage by perfusing acidified pepsin in rabbits. Mucosal adaptation was induced by preexposing the esophageal mucosa to a mild irritant (acidified saline) for 60 min prior to acidified pepsin (strong irritant). Macroscopic and microscopic esophageal injury, cell proliferation, and mucosal barrier function (H+, K+, hemoglobin flux rates) were studied. Preexposure of the esophageal mucosa to acidified saline significantly decreased both the mucosal damage and the mucosal barrier dysfunction induced by acidified pepsin. The development of this phenomenon was nondependent on cell proliferation. Concomitant treatment with either the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine, or the perfusion of immunospecific EGF-receptor antibodies or tyrphostin-25, an inhibitor of the tyrosine kinase activities ligated to the intracytoplasmatic domain of the EGF receptor, during the preexposure period completely reversed the protection induced by acid. We conclude that the rabbit esophageal mucosa shows mucosal adaptation to acid and pepsin. The development of this phenomenon is fast, not dependent on cell proliferation, and dependent, at least in part, on nitric oxide and EGF-receptor-mediated mechanisms.

Reflux oesophagitis and clozapine.

In a series of thirty-six patients treated with clozapine we report four cases who developed upper gastrointestinal symptoms suggestive of reflux oesophagitis within 6 weeks of starting this drug. Subsequent endoscopic examination revealed moderately severe erosive oesophagitis in three of them. Of these one had received treatment for a peptic ulcer in the past but the other two had no previous history of any upper gastrointestinal disorder. The pharmacology of clozapine in relation to gastro-oesophageal reflux is discussed.

Tetracycline-induced proximal oesophagitis.

Medication-induced oesophagitis is an unusual cause of oesophageal damage. A patient is presented who developed sudden onset of odynophagia and dysphagia while taking tetracycline. Endoscopy revealed proximal oesophagitis which was confirmed histologically. Symptoms resolved rapidly after stopping the offending drug. Drug-induced oesophagitis should be considered in patients with unexplained oesophageal symptoms. This condition is often unrecognized as symptoms usually resolve on cessation of the drug. Prevention is the best approach.

Enzymatic digestion of esophageal meat impaction. A study of Adolph's Meat Tenderizer.

While a solution of Adolph's Meat Tenderizer (AMT) is commonly used to treat esophageal meat impaction, few studies describe its clinical effects. We examined AMT with regard to (1) its papain activity; (2) its ability to digest meat cubes in vitro; and (3) its effect on rabbit esophageal mucosa. A standard papain assay was developed against which the activity of AMT was compared. Proteolytic activity was detected in AMT only when the papain activators, 0.02 M cysteine and 0.008 M EDTA, were added to the system. Meat cubes incubated in AMT solution exhibited no evidence of digestion as determined by protein release or change in sample weight. A solution of AMT had no adverse effect on normal esophageal mucosa in rabbits, but significantly increased esophagitis when infused onto previously inflamed mucosa. We conclude that AMT solution has no inherent capacity to digest or to reduce the size of an impacted meat bolus, and may, in fact, worsen existing esophagitis.

[Peptic lesions of the upper digestive tract and drugs. Prospective study]. / Atteintes peptiques du tractus digestif supérieur et médicaments. Etude prospective.

The association between drugs and diseases of the gastrointestinal tract is well known but has always been evaluated qualitatively and not quantitatively. To study the importance of this association, a prospective study was undertaken at the University of Geneva Hospital in 456 subjects. A statistically significant (p less than 0.05) correlation was found in the following associations: aspirin and multiple gastric ulcers, aspirin and severe erosive gastritis; non-steroidal antiinflammatory drugs and multiple duodenal ulcers, non-steroidal antiinflammatory drugs and mild erosive gastritis. On the other hand, no correlation was found between any of the observed gastrointestinal diseases and prednisone, alcohol or tobacco.

Oesophageal tissue reaction to different suture materials. An experimental study in the cat.

Oesophageal tissue reaction to different suture materials (chromic catgut, silk, prolene and stainless steel wire) was analysed and compared in 45 cats with and without reflux oesophagitis. Diffuse reflux oesophagitis was produced in 12 out of 21 animals subjected to oesophagocardiomyotomy (Marwedel-Wendel) combined with production of a fixed hiatal hernia of sliding type. Steel wire sutures produced minimal tissue reaction and undisturbed fibroplasia both in the intact oesophagus and in the presence of reflux oesophagitis. The steel wire sutures were found to be superior to the chromic catgut, silk, and prolene.