The addition of pyloroplasty as a new surgical approach to enhance effectiveness of gastric electrical stimulation therapy in patients with gastroparesis.

BACKGROUND: Improvement of gastroparesis (GP) symptoms has been documented in patients treated with gastric electrical stimulation (GES), but acceleration of gastric emptying (GET) is unpredictable. The aim of our study was to evaluate the advantage of adding surgical pyloroplasty (PP) to GES for improvement of GET and control of symptoms in diabetes mellitus (DM), idiopathic (ID), and postvagotomy (P-V) GP. METHODS: A total of 49 (17 - DM, 9 - ID, 23 - P-V) consecutive GP patients: 38 female; mean age 42 (21-73 years); mean weight 158 lbs (102-245), underwent GES implantation, and 26 (53%) additionally received PP. Total Symptoms Score, 4-h GET, adverse events (AEs), and days of hospitalizations were captured at baseline and at the last visit. KEY RESULTS: The mean follow-up was 7 months. Total Symptoms Score in patients who received Enterra and PP or GES alone significantly improved compared to their baseline scores (P < 0.001). GET improved by 64% at 4 h (P < 0.001) in patients with Enterra and PP, compared to 7% observed after GES therapy alone (ns). The most impressive acceleration of GET was seen in the P-V group, who received both therapies (P = 0.004) and 8 (60%) of them normalized GET. No AEs accompanied the addition of PP to the Enterra surgery. CONCLUSIONS & INFERENCES: (i) In drug-refractory GP the addition of PP to GES substantially accelerated GET; (ii) The GET response in P-V group was the most impressive; (iii) Significant symptom reductions were achieved by both procedures; and (iv) PP added to GES may sustain better long-term symptoms control particularly in the P-V setting.

The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology.

BACKGROUND: Wireless pH and pressure motility capsule (wireless motility capsule) technology provides a method to assess regional gastrointestinal transit times. AIMS: To analyse data from a multi-centre study of gastroparetic patients and healthy controls and to compare regional transit times measured by wireless motility capsule in healthy controls and gastroparetics (GP). METHODS: A total of 66 healthy controls and 34 patients with GP (15 diabetic and 19 idiopathic) swallowed wireless motility capsule together with standardized meal (255 kcal). Gastric emptying time (GET), small bowel transit time (SBTT), colon transit time (CTT) and whole gut transit time (WGTT) were calculated using the wireless motility capsule. RESULTS: Gastric emptying time, CTT and WGTT but not SBTT were significantly longer in GP than in controls. Eighteen percent of gastroparetic patients had delayed WGTT. Both diabetic and idiopathic aetiologies of gastroparetics had significantly slower WGTT (P < 0.0001) in addition to significantly slower GET than healthy controls. Diabetic gastroparetics additionally had significantly slower CTT than healthy controls (P = 0.0054). CONCLUSIONS: In addition to assessing gastric emptying, regional transit times can be measured using wireless motility capsule. The prolongation of CTT in gastroparetic patients indicates that dysmotility beyond the stomach in GP is present, and it could be contributing to symptom presentation.

Role of bile acids, prostaglandins and COX inhibitors in chronic esophagitis in a mouse model.

AIM: To develop a new experimental model of esophagitis that serves a complementary tool to clinical investigation in an insight into the mechanism of the damage to the esophagus mucosa by aggressive factors, and role of COX inhibitors in this process. METHODS: The study was conducted in 56 male mice. Animals were divided into seven groups: (1) perfused with HCl, (2) perfused with HCl and physiologic concentration of pepsin (HCl/P), (3) perfused with similar HCl/P solution enriched with conjugated bile acids (glycho- and tauro-sodium salts) designated esophageal infusion catheter under the general anesthesia, (4) perfused as in group 2 treated with indometacin, (5) perfused as in group 2 treated with NS-398, (6) perfused as in group 3 treated with indometacin, and (7) perfused as in group 3 treated with NS-398. The esophagus was divided into 3 parts: upper, middle and lower. The PGE2 concentration was measured in all parts of esophagus using RIA method. Esophagus of sacrificed animals was macroscopically evaluated using a low power dissecting microscope (20x). Specimens, representing the most frequently seen changes were fixed, stained with H&E and assessed microscopically using the damage score, and inflammatory score. RESULTS: The macroscopic changes were significantly severer in HCl/P than those in HCl animals (77%) and in HCl/P/BA group (43%). In HCl/P NS-398 group we noticed significantly less changes than those in not treated group (42%) and in analogical group treated with indometacin (45%). In HCl/P/BA INDO group we observed significantly severer changes than that in not treated group (52%). We noticed less changes in HCl/P NS-398 than that in group with indometacin (46%). In HCl/P/BA NS-398 group we had less changes than that in indometacin group (34%). The microscopic changes observed in HCl/P/BA INDO group were severer than that in not treated group (48%). Esophagitis index in HCl group was significantly lower than in HCl/P and also HCl/P/BA group (32% and 33%). In HCl/P/BA/INDO group the esophagitis surface was larger than that in not treated group (33%). In HCL/P group the surface of esophagus with ulceration was significantly larger (10-fold) than that in HCl/P/BA group. The PGE2 concentration was significantly higher in HCl/P group than in HCl/P/BA group. The PGE2 concentration in lower part of esophagus was also significantly higher in middle than those in HCl and HCl/P/BA groups. In upper part of esophagus the PGE2 concentration was significantly higher in HCl/P/BA group than that in group treated with indometacin (46%). We also observed higher PGE2 concentration in middle part of esophagus in HCl/P/BA group than those in group treated with indometacin and in group treated with indometacin and NS-398 (by 52% and 43% respectively). CONCLUSION: Pepsin is the pivotal factor in the development of chronic esophageal injury. Bile acids diminish chronic esophageal injury induced by HCl/P, indicating its potential negative impact on pepsin proteolytic potential, pivotal for mucosal injury in low pH. The role of selective COX inhibitors is still unclear, and needs more investigations. This novel chronic experimental esophagitis is an excellent model for further study on the role of cytokines in genetically modified animals.

Restorative impact of rabeprazole on gastric mucus and mucin production impairment during naproxen administration: its potential clinical significance.

Rabeprazole augments gastric mucus and mucin production in humans. However, its potential restorative impact on gastric mucus and mucin production impairment, resulting from administration of naproxen, remained to be explored. Therefore, we measured the content of mucus and mucin in gastric juice (GJ) before and after administration of naproxen with rabeprazole or placebo. The study was approved by HSC at KUMC and conducted in 21 asymptomatic, H. pylori-negative volunteers in a double-blind, placebo-controlled, crossover design. The content of gastric mucus in GJ, after exhaustive dialysis and complete lyophilization, was assessed gravimetrically, whereas the content of mucin was measured after its purification with equilibrium density-gradient ultracentrifugation in CsC1. Gastric mucus secretion during administration of naproxen with placebo declined significantly both in basal (by 44%; P < 0.001) and in pentagastrin-stimulated (by 35%; P < 0.001) conditions. Coadministration of rabeprazole significantly restored the naproxen-induced impairment in mucus production in basal conditions (by 47%; P < 0.01) and by 22% during stimulation with pentagastrin. Gastric mucin secretion during naproxen/placebo administration also declined significantly in both basal (by 39%; P < 0.01) and stimulated (by 49%; P = 0.003) conditions. Rabeprazole also significantly restored the naproxen-induced decline of gastric mucin output during pentagastrin-stimulated conditions (by 67%; P = 0.003) and by 40% in basal conditions (P = 0.05). The restorative capacity of rabeprazole on the quantitative impairment of gastric mucus and mucin during administration of naproxen may translate into a clinical benefit of protection of the upper alimentary tract from NSAID-related mucosal injury.

Secretory function of the esophageal mucosa in opossum: the role of cholinergic, peptidergic and histaminergic pathways.

PURPOSE: Esophageal histology in the opossum reveals numerous submucosal mucous glands closely resembling those commonly found in humans. The aim of the study was to examine the secretion of these glands using the commonest secretagogues. MATERIAL AND METHODS: The esophageal lumen in 5 male opossums was continuously perfused with saline during sixteen consecutive 5 min perfusion periods. After four initial equilibrating periods, each animal was injected (s.c.) with pentagastrin (6 microg/kg), bethanechol chloride (100 microg/kg) or histamine dihydrochloride (0.5 mg/kg). All sixteen (5 min) perfusates were assayed for protein by Lowry, mucin by PAS and viscosity using a cone/plate digital viscometer. Results were expressed as mean +/- SE. Statistical analysis was performed using paired Student's t-test. RESULTS: Administration of bethanechol resulted in a significant increase in esophageal mucin release from 2.4 +/- 0.4 to 8.0 +/- 1.2 microg/cm2/min (p < 0.01); enhancement of protein output from 8.9 +/- 2.0 to 20.4 +/- 2.9 microg/cm2/min (p < 0.01) and potentiation of specific viscosity from 7.5 +/- 0.6 to 14.4 +/- 0.8 (p < 0.01). Pentagastrin-induced release of mucin reached the maximal value of 5.5 +/- 0.7 microg/cm2/min (p < 0.01), protein output increased to 20.0 +/- 2.7 (p < 0.01) and viscosity expanded to 11.7 +/- 0.9 (p < 0.05). Histamine evoked an increase in mucin release to 3.9 +/- 0.4 microg/cm2/min (p < 0.01), protein output to 24.1 +/- 3.3 microg/cm2/min (p < 0.01) and viscosity to 12.8 +/- 1.1 (p < 0.05). CONCLUSIONS: The significant influence of cholinergic, histaminergic and peptidergic stimulation on physical and chemical properties of the esophageal secretion provides evidence for the role of these pathways in the pathophysiology of the esophageal mucosa.

Significant enhancement of gastric mucin content after rabeprazole administration: its potential clinical significance in acid-related disorders.

Rabeprazole is the only proton pump inhibitor that enhances the content of gastric mucin in experimental animals. We have studied, therefore, the effect of rabeprazole on the content of gastric mucin, mucus, and its viscosity in 21 asymptomatic volunteers in a double-blind study. The mucus content during rabeprazole administration significantly increased both in pentagastrin-stimulated (3.36 +/- 0.39 vs 1.50 +/- 0.32 mg/ml, P < 0.001) and basal (3.31 +/- 0.38 vs 2.28 +/- 0.36 mg/ml, P < 0.01) conditions. The content of mucin during rabeprazole was 2.6-fold (0.96 +/- 0.08 vs 0.36 +/- 0.06 mg/ml, P < 0.0001) and 41% (0.82 +/- 0.09 vs 0.58 +/- 0.09 mg/ml, P < 0.05) higher in stimulated and basal conditions, respectively. The viscosity of gastric juice during rabeprazole administration was also significantly higher both in stimulated (P < 0.01) and basal (P < 0.05) conditions. In conclusion, the unique pharmacological property of rabeprazole, significantly augmenting production of gastric mucus and mucin, may translate to additional clinical benefits in protecting the upper alimentary tract mucosa during the acid-related challenge.

The role of mucus and its components in protection and repair within the alimentary tract mucosa: Polish experience.

The Gastroenterology Research Laboratory at New York Medical College, New York City, NY, directed by Prof. Dr. George B. Jerzy Glass and after his retirement by Prof. Dr. Bronislaw L. Slomiany and Prof. Dr. Amalia Slomiany served as a launching pad for successful careers in exploration of mucus for Dr. Andrzej Gindzienski and Dr. Krzysztof Zwierz and Janusz Badurski at the Medical School in Bialystok, Poland as well as Dr. Jerzy Sarosiek at Gastroenterology Research Laboratory, University of Virginia Health Sciences Center, Charlottesville, VA and currently, Gastroenterology Research Laboratory, Kansas University Medical Center, Kansas City, KS, USA. The dynamic and insightful research endeavors implemented at the Medical School of Bialystok revealed new information regarding enzymatic pathways of mucin synthesis especially its carbohydrate components such as hexosamines. These discoveries become instrumental in our understanding of the alimentary tract mucin synthesis and function in health and disease. Similarly innovative mucus research conducted across the Atlantic Ocean uncovered the novelty of mucin elaborated within the esophageal submucosal mucous glands in humans by demonstration that its chemical characteristics are different both from human salivary and gastric mucins. In addition, a novel method for the measurement of the thickness of the gastric mucus layer ex vivo in humans has also been developed. These pioneering works are continued at both mucus exploration centers attracting younger generation of investigators enticed by the mystery of the structure and function of the mucus barrier and its leading role in mucosal protection against injury as well as immediate and unequivocal contribution to mucosal repair and reconstitution process.

Mechanisms of oesophageal mucosal defence.

The integrity of the oesophageal mucosa depends upon an equilibrium between aggressive factors, predominantly acid and pepsin, and protective mechanisms. Protective mechanisms operate within the oesophageal mucosa as pre-epithelial, epithelial and post-epithelial defences. Only the protective components of the oesophageal pre-epithelial defence can be tested in vivo in humans. It has been recently demonstrated that human oesophageal submucosal glands elaborate mucous secretion rich in bicarbonate and non-bicarbonate buffers, mucin, prostaglandin E(2), epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha). This oesophageal secretion, accompanied by similarly protective factors within the swallowed saliva, defines the protective potential of the oesophageal pre-epithelial defence that exists in the form of a mucus-buffer layer covering the oesophageal mucosa and which retards the back-diffusion of hydrogen ions. It has also been demonstrated that patients with severe erosive reflux oesophagitis exhibit qualitative impairment in both the salivary and oesophageal components of the oesophageal pre-epithelial defence. Furthermore, patients with endoscopically negative gastro-oesophageal reflux disease have a significantly stronger oesophageal pre-epithelial defence than patients with erosive reflux oesophagitis. On the other hand, African-Americans, who are less likely to develop erosive reflux oesophagitis, have a stronger oesophageal pre-epithelial defence than do Caucasians. The salivary component of the oesophageal pre-epithelial defence can be enhanced by mastication and the administration of cisapride, whereas oesophageal secretion can only be significantly augmented by cisapride.

The potential role of the esophageal pre-epithelial barrier components in the maintenance of integrity of the esophageal mucosa in patients with endoscopically negative gastroesophageal reflux disease.

OBJECTIVE: Patients with gastroesophageal reflux disease (GERD) accompanied by erosive reflux esophagitis (RE) exhibit an impairment within the esophageal pre-epithelial barrier protective components that may facilitate the development and/or progression of the mucosal injury. Little is known, however, whether such impairment is a general phenomenon affecting all patients with GERD or whether this is a characteristic feature only of patients with erosive RE. We therefore studied the rate of secretion of esophageal inorganic and organic protective factors in patients with endoscopically negative [E (-)] GERD and compared these results with the corresponding values in asymptomatic volunteers (CTRL). METHODS: The study was conducted on 33 white asymptomatic volunteers and 10 white patients with a long history of GERD confirmed by 24-h pH monitoring and a grossly negative upper endoscopy. Esophageal secretion was collected during mucosal exposure to NaCl, HCl, HC/pepsin and NaCl using the esophageal perfusion catheter. In collected samples all investigated parameters were measured. RESULTS: The pH of esophageal secretion and its content of bicarbonate, EGF, and PGE2 in patients with E (-) GERD and asymptomatic volunteers were similar. Unexpectedly, the rate of esophageal glycoconjugate (predominantly mucin) secretion was significantly higher in patients with E (-) GERD than in controls during perfusion with HCl (p < 0.05). Furthermore, secretion of protein in patients with E (-) GERD was significantly higher than in the control group during the mucosal exposure to HCl/Pepsin (p < 0.05). The nonbicarbonate buffer secretion during perfusion with HCl and HCl/Pepsin as well as the rate of esophageal TGFalpha output during infusion of final saline in patients with E (-) GERD were significantly lower than in CTRL group (p < 0.05). CONCLUSIONS: Our data indicate that patients with E (-) GERD have an esophageal secretory potential, in terms of glycoconjugate and protein, higher than that in asymptomatic controls. This phenomenon in patients with E (-) GERD may, by enhancing the quantity of the esophageal pre-epithelial barrier, help to prevent the development of erosive esophagitis. A significantly lower esophageal secretory response in patients with E (-) GERD in terms of nonbicarbonate buffers and TGFalpha may facilitate the development of GERD symptoms and histological changes of GERD, respectively.

Salivary and gastric epidermal growth factor in patients with Zollinger-Ellison syndrome: its protective potential.

OBJECTIVE: Evidence is accumulating that epidermal growth factor (EGF) is a major molecule contributing to the maintenance of the integrity of the upper alimentary tract mucosa before and after injury by acid and pepsin. Patients with Zollinger-Ellison Syndrome (ZES) typically have hypersecretion of acid and pepsin; however, the concentration and rate of secretion of salivary and gastric EGF that could counteract these potentially aggressive factors are unknown. Accordingly, this study was conducted to determine whether EGF affords mucosal protection in ZES patients. METHODS: The concentration and output of salivary (sEGF) and gastric epidermal growth factor (gEGF) were measured in eight patients with ZES and the results compared to those in 17 patients with nonulcer dyspepsia (NUD), serving as a control group. All patients had normal esophageal and gastric mucosa as determined by endoscopy. Total saliva was collected during 1-h parafilm- and 1-h pentagastrin/parafilm-stimulated conditions, as well as basal and pentagastrin-stimulated gastric juice. The concentration and output of EGF were determined by radioimmunoassay. RESULTS: The concentration of EGF in saliva collected from ZES patients after parafilm chewing was significantly higher compared to that in NUD patients (4.61 +/- 0.59 vs 2.75 +/- 0.50 ng/ml, p < 0.05). The concentration of EGF in saliva collected after pentagastrin stimulation in ZES patients was also significantly higher than in NUD patients (4.37 +/- 0.73 vs 2.22 +/- 0.37 ng/ml, p < 0.05). Salivary EGF output during parafilm chewing in ZES and NUD were similar (68 +/- 6.4 vs 109 +/- 25.2 ng/h). Salivary EGF output after administration of pentagastrin in ZES and NUD was also similar (66 +/- 6.1 vs 132 +/- 45.4 ng/h). Basal EGF output in the gastric juice of patients with ZES was 3-fold higher than in patients with NUD (801 +/- 73 vs 271 +/- 32 ng/h, p < 0.01). Pentagastrin-stimulated EGF output was similar in both groups (705 +/- 92 vs 675 +/- 168 ng/h). CONCLUSIONS: Patients with ZES have a significantly higher EGF concentration in saliva and EGF output in basal gastric juice. This elevated content of salivary and gastric EGF in ZES patients may play a protective role in preventing the development of reflux esophagitis and gastric ulcer under the impact of gastric acid and pepsin hypersecretion.

Esophagoprotective potential of cisapride. An additional benefit for gastroesophageal reflux disease.

Cisapride is a novel prokinetic agent that releases acetylcholine at the level of the myenteric plexus. Acetylcholine also plays a role in the secretory function of salivary glands evoked by intraesophagal mechanical and chemical stimulation, mediated through the esophagosalivary reflex. The impact, however, of cisapride on salivary protective components mediated by esophagosalivary reflex remains unknown. Therefore, we have studied salivary pH, bicarbonate, nonbicarbonate, glycoconjugate, protein, EGF, TGF-alpha, and PGE2 before and after the administration of cisapride. The study was conducted in 20 asymptomatic volunteers (9 women and 11 men, mean age 36, range 26-52). Salivary secretions were collected under basal conditions and during masticatory, mechanical, and chemical stimulation before and after four days of cisapride administration (10 or 20 mg four times a day). Cisapride administration resulted in a 45% increase in salivary volume during the basal condition (P < 0.01), a 32% increase during mastication (P < 0.05), a 53% increase during mechanical (P < 0.05), and a 51% increase during chemical (P < 0.01) stimulation. Cisapride administration resulted also in a significant increase in salivary protein output (P < 0.05), salivary bicarbonate (P < 0.05), and nonbicarbonate buffers (P < 0.05), and salivary EGF (P < 0.05). Salivary glycoconjugate significantly increased only during mechanical stimulation with the catheter and at the end of the esophageal perfusion procedure (P < 0.05). Although a similar trend was also recorded during the analysis of salivary PGE2, this difference did not reach statistical significance. Salivary pH and TGF-alpha before and after cisapride administration remained unchanged. The stimulatory impact of cisapride on salivary volume and inorganic (bicarbonate and nonbicarbonate buffers) and organic (protein, glycoconjugate, and EGF) protective components would benefit patients with GERD and would also be potential therapy for xerostomia.

Role of platelet-activating factor in Chinese hamster ovary cell responses to cholera toxin.

Cholera toxin (CT)-induced intestinal secretion and Chinese hamster ovary cell (CHO) elongation involves cyclic adenosine monophosphate and protein synthesis-dependent prostaglandin formation. We previously reported inhibition of CT-induced intestinal secretion and CHO elongation by platelet-activating factor (PAF) receptor antagonists and secretion of PAF by human intestinal epithelial cells exposed to CT. Herein, we show that PAF is involved after cAMP and that PAF, like CT, mediates prostaglandin E2 synthesis in CHO cells. CT-induced CHO elongation was blocked by specific PAF receptor antagonists, BN52021 and SR27417. SR27417 blocked dibutyryl cAMP-induced CHO elongation, but did not alter CHO elongation caused by PGE2. Neither CT-stimulated cAMP accumulation nor PGE2 production was inhibited by SR27417. Both PGE2 and PAF caused significant CHO elongation, but the latter did not stimulate significant cAMP production. In addition, PAF, like CT and dibutyryl cAMP, stimulated significant PGE2 production. Finally, the protein synthesis inhibitor cycloheximide, which completely blocks the effect of CT on prostaglandin synthesis, also blocked that of PAF, suggesting that PAF also mediates protein synthesis-dependent prostaglandin formation. We conclude that PAF is involved in CHO cytoskeletal responses to CT after the accumulation of cAMP and, like CT, PAF stimulates protein synthesis-dependent prostaglandin accumulation.

Modulatory effect of esophageal intraluminal mechanical and chemical stressors on salivary prostaglandin E2 in humans.

As has been demonstrated, infusion of hydrochloric acid (HCl) and pepsin into the human esophageal lumen, which mimics the natural gastroesophageal reflux, results in a significant increase in salivary volume, salivary bicarbonate and epidermal growth factor. However, the impact of intraluminal acid/pepsin solution on salivary prostaglandin E2 (sPGE2), the major protective factor of the upper alimentary tract, has never been explored. Therefore, using the newly developed esophageal perfusion model, the impact of both mechanical and chemical stimuli of the esophagus on sPGE2 secretion in humans was studied. Salivary PGE2 was assessed in saliva collected during basal conditions, chewing of parafilm, placement of intraesophageal tubing, inflation of intraesophageal balloons, and perfusion with sodium chloride, HCl, or HCl/pepsin solutions. The concentration of sPGE2 was measured using the RIA kit from Amersham (Arlington Heights, IL) after the solid-phase extraction and derivatization. The concentration of sPGE2 in the basal saliva was (mean +/- standard error of mean) 186 +/- 31 pg/mL and was similar during the chewing of parafilm (171 +/- 32 pg/mL). The placement of intraesophageal tubing, however, resulted in a significant decline of sPGE2 concentration to the value of 91 +/- 22 pg/mL (P < 0.01). This decline was maintained when intraesophageal balloons, which compartmentalized a 7.5 cm perfused segment of the esophagus, were inflated (86 +/- 17 pg/mL; P < 0.01). This decline was potentiated further when subsequent perfusion with saline was implemented to reach the lowest value of 46 +/- 17 pg/mL (P < 0.001 versus basal and P < 0.05 versus tubing and balloon evoked values) at the end of the perfusing procedure. Esophageal perfusion with acid and acid/pepsin solution, however, partly restored the significant decline in sPGE2 concentration observed during prolonged perfusion with saline. The sPGE2 output during basal conditions was 89 +/- 13 pg/min and increased dramatically during stimulation by placement of intraesophageal tubing (241 +/- 48 pg/min; P < 0.01) and inflation of intraesophageal balloons (244 +/- 48 pg/min; P < 0.01). Subsequent esophageal perfusion with saline resulted in a gradual decline of sPGE2 output evoked by mechanical stimuli that reached the final value of 178 +/- 39, which was not significantly different from that observed in the basal condition (P < 0.1 versus basal value). Introduction of HCl and pepsin into the perfusing solution significantly prevented the decline of sPGE2 output observed during perfusion with saline (252 +/- 36 pg/min; P < 0.01 versus basal). The modulatory impact of mechanical and chemical stimulation on sPGE2, demonstrated for the first time in humans, may suggest the potential contribution of salivary prostanoids to the maintenance of the integrity of the esophageal mucosa.

Detrimental impact of acid and pepsin on the rate of luminal release of transforming growth factor alpha. Its potential pathogenetic role in the development of reflux esophagitis.

The impact of intraluminal acid and pepsin on the rate of esophageal luminal release of transforming growth factor alpha (TGF alpha), measured by RIA, in 21 asymptomatic volunteers and 26 patients with reflux esophagitis (RE) was investigated. Esophageal secretion was collected, using an esophageal perfusion catheter, during mucosal exposure to NaCl, HCl or HCl/Pepsin and final saline. The basal rate of luminal TGF alpha release in controls was steady throughout the entire four perfusion periods with saline. This rate declined by 71% during mucosal exposure to HCl (p = 0.002) and by 74% during esophageal perfusion with HCl/pepsin (p = 0.011). The basal rate of luminal TGF alpha release in patients with RE was 27% higher than the corresponding value in controls (1.076 +/- 0.140 vs. 0.850 +/- 0.180 ng/min, p = 0.050). Mucosal exposure to acid and acid/pepsin solutions in RE patients also resulted in a significant decline in the luminal release of TGF alpha by 43% (p < 0.001) and by 42% (p < 0.001) respectively. Despite this decline, TGF alpha in patients with RE was significantly higher (p < 0.001) than in controls. The decline in esophageal TGF alpha release during HCl and HCl/pepsin exposure may facilitate the development of mucosal damage. The increase in esophageal TGF alpha release in patients with RE may represent a compensatory mechanism developed by the mucosal inflammatory changes.

Impact of Helicobacter pylori colonization on immunoreactive epidermal growth factor and transforming growth factor-alpha in gastric juice. Its potential pathogenetic implications.

Epidermal growth factor (EGF), pivotal in mucosal protection, is partly degraded proteolytically at low pH in the gastric milieu; gastric acid secretion, on the other hand, remains influenced by H. pylori colonization. The aim of this study, therefore, was to evaluate the impact of low pH and H. pylori colonization status on immunoreactive EGF and the other member of EGF-family, immunoreactive transforming growth factor-alpha (TGF-alpha). Eighteen patients with nonulcer dyspepsia (NUD) colonized by H. pylori and 55 NUD patients without H. pylori colonization were investigated. Gastric juice samples were aspirated at the beginning of the endoscopy procedure and immediately placed on ice, and their pH was recorded. The measurement of immunoreactive EGF and TGF-alpha was performed using commercially available radioimmunoassays (RIAs) after adjustment of pH to neutral using an assay buffer. Statistical analysis was performed using sigma-Stat for Windows. The concentration of immunoreactive EGF in patients with NUD colonized by H. pylori was 80% lower (P < 0.02) than in those without H. pylori and in both groups immunoreactive EGF was significantly lower when the pH of gastric juice was below 4.0. The concentration of immunoreactive EGF in H. pylori(+) and H. pylori(-) patients was similar when the pH of aspirated gastric juice was above 4.0. However, with gastric juice pH < 4.0, the EGF concentration was 64% lower in H. pylori(+) patients than H. pylori(-) patients (P < 0.05). In general, the concentration of immunoreactive TGF-alpha in gastric juice was unaffected by H. pylori colonization or pH of gastric juice. It is concluded that: (1) significantly lower immunoreactive EGF concentrations in patients with pH below 4.0 indicate that immunoreactive EGF but not immunoreactive TGF-alpha is affected by an acidic gastric milieu; (2) the further reduction of gastric juice immunoreactive EGF at pH below 4.0 in patients colonized by H. pylori suggests that this microorganism may elaborate factors that accelerate its proteolytic degradation or inhibit its rate of synthesis and/or secretion; and (3) this diminished content of immunoreactive EGF at low pH, especially in patients colonized by H. pylori, may facilitate the development and/or progression of mucosal damage.

Prostaglandin E2 content in residual gastric juice reflects endoscopic damage to the gastric mucosa after naproxen sodium administration.

OBJECTIVES: The diagnostic potential of residual gastric juice for development of naproxen sodium-induced mucosal damage has not been explored. We studied prostaglandin E2 (PGE2) content in residual gastric juice before and after naproxen sodium administration and assessed relationships with endoscopic mucosal damage. METHODS: Thirty volunteers received the recommended over-the-counter dose (660 mg/day) of naproxen sodium or placebo in this 7-day, double-blind, endoscopically controlled, cross-over study. RESULTS: PGE2 concentration in gastric juice did not increase after placebo; naproxen significantly reduced PGE2 concentration (p < 0.001). In three subjects in whom no endoscopic changes occurred after naproxen administration, PGE2 concentration increased by 14%. In seven subjects who developed hemorrhagic changes, PGE2 concentration declined by 50% (p = 0.08). In 20 subjects who developed numerous hemorrhagic and erosive changes within the antral mucosa, PGE2 concentration declined by 70% (p < 0.001). The starting PGE2 value in subjects with severe mucosal hemorrhagic and erosive changes after naproxen was almost eightfold higher than in subjects who did not develop mucosal damage (p = 0.007) and 67% higher than in subjects with hemorrhagic changes only (p = 0.25). CONCLUSION: PGE2 measurement in residual gastric juice, aspirated before and after nonsteroidal antiinflammatory drug treatment, may be useful in monitoring mucosal damage and may identify patients who are likely to develop endoscopic mucosal changes.

Enhancement of salivary esophagoprotection: rationale for a physiological approach to gastroesophageal reflux disease.

BACKGROUND & AIMS: Secretion of salivary protective factors in patient s with gastroesophageal reflux disease is impaired. However, the impact of physiological stimulus mastication on salivary protective factors output remains largely unknown. The aim of this study was to measure salivary volume, pH, HCO3-, peptide growth factors, prostaglandin, mucin, protein, and viscosity during mastication. METHODS: In 31 asymptomatic volunteers and 36 patients with endoscopic reflux esophagitis, in basal and parafilm chewing-stimulated saliva, its volume, pH, bicarbonate, epidermal growth factor, transforming growth factor alpha, prostaglandin E2, mucin, protein, and viscosity were investigated. RESULTS: Masticatory stimulation in controls resulted in a significantly increased salivary volume by 205%, pH by 7.6%, bicarbonate by 335%, mucin by 137%, protein by 98%, epidermal growth factor by 123%, and prostaglandin E2 by 132%, accompanied by an increase in transforming growth factor alpha by 80% with 19% decline in viscosity vs. basal values. Mastication in reflux esophagitis significantly increased salivary volume by 215%, pH by 6.8%, bicarbonate by 257%, mucin by 135%, protein by 94%, epidermal growth factor by 207%, and prostaglandin E2 by 240%, whereas transforming growth factor alpha increased by 225% and viscosity by 64% when compared with corresponding basal values. CONCLUSIONS: A profound and significant increase in the secretion rate of inorganic and organic protective components in saliva during masticatory stimulation suggests its potential value as a therapeutic approach to the treatment of patients with gastroesophageal reflux disease.

The relationship between the content of aggressive and protective components in gastric juice and endoscopic findings after naproxen sodium and acetaminophen administration.

OBJECTIVES: To evaluate the diagnostic value of residual gastric juice, we assessed various secretory components before and after placebo, acetaminophen, or naproxen sodium administration. METHODS: In a double-blind, randomized, cross-over study in 30 asymptomatic volunteers, mucin, hydrophobicity, protein, pepsin, and pH were measured in residual gastric juice before and after placebo, naproxen sodium (660 mg/d), or acetaminophen (4000 mg/d) administration. Mucus layer thickness in biopsy specimens was assessed, and mucosal damage was endoscopically evaluated. RESULTS: All parameters were unchanged after 7 days of placebo. Naproxen caused a 46% (p = 0.008) increase in the rate of luminal mucin release, an 18% increase (p = 0.510) in protein release, and a 61% decrease (p = 0.001) in hydrophobicity. Antral and duodenal mucus gel thickness were compromised, and hemorrhagic and erosive endoscopic changes were noted. Acetaminophen resulted only in a significant decline of pepsin. In subjects without endoscopic damage after naproxen, a nonsignificant decrease in hydrophobicity was noted. However, in subjects with endoscopic changes, a 55% decrease (p = 0.002) in hydrophobicity and a 42% increase (p = 0.024) in the rate of luminal mucin release were demonstrated. The initial mucin of subjects who developed endoscopic mucosal changes after naproxen was 53% higher than in subjects without damage. Subjects with endoscopic changes also exhibited a 48% lower initial hydrophobicity and a 43% lower pepsin than subjects without endoscopic changes. CONCLUSIONS: Gastric mucosal damage after naproxen sodium results in profound changes within the gastric mucosal barrier, and analysis of residual gastric juice components adequately reflects these changes. In contrast, acetaminophen results in only minimal gastric juice changes. Analysis of residual gastric juice may be useful in monitoring the extent of mucosal damage and identifying patients likely to develop mucosal damage.

Monophasic luminal release of prostaglandin E2 in patients with reflux esophagitis under the impact of acid and acid/pepsin solutions. Its potential pathogenetic significance.

Normal human esophageal mucosa exhibits biphasic secretory responses to intraluminal stimuli in terms of PGE2 release with a decline under the impact of HCl and an increase in PGE2 release during mucosal exposure to HCl/Pepsin. PGE2 secretory patterns in patients with reflux esophagitis (RE) remain unknown. We have studied, therefore, luminal release of PGE2 in 28 patients with nonhealed and healed RE, and compared the obtained results with corresponding values recorded in controls. The rate of luminal release of PGE2 in nonhealed RE exhibited a monophasic patterns, i.e., significantly decreased both during mucosal exposure to HCl (2,273 +/- 444, vs. 3,655 +/- 600 pg/min, p = 0.025) and HCl/pepsin (1,271 +/- 244, vs. 3,655 +/- 600 pg/min. p = 0.003) as compared to its basal value. However, the rate of luminal PGE2 release in patients with nonhealed RE in basal conditions and during mucosal exposure to HCl was significantly higher than corresponding values in controls. Luminal release of PGE2 in patients with healed endoscopic esophagitis was significantly lower as compared to corresponding values recorded in patients with nonhealed endoscopic changes and in controls. In conclusion, (a) monophasic inhibitory responses of the esophageal mucosa to intraluminal HCl and HCl/pepsin solutions in patients with RE indicate a different pattern of mucosal secretory response to intraluminal stimuli; (b) inhibition of the rate of luminal release of PGE2 under the impact of HCl/pepsin may play a role in the development and/or progression of mucosal damage; and (c) the decline in the rate of luminal PGE2 release in healed RE indicates that its elevated value in active esophageal disease should be considered as an implication of mucosal damage induced by HCl/pepsin.

Modulatory impact of acid and pepsin on esophageal hydrophobicity in humans.

OBJECTIVES: The role of hydrophobicity in the pathophysiology of the gastrointestinal tract is well established as a protective mechanism against the impact of lumenal acid and pepsin. Hydrophobic properties of esophageal secretion in humans remain largely unknown. METHODS: We have studied, therefore, hydrophobicity by using fluorescence probe in human esophageal secretion, elaborated under the impact of saline followed by HCl, HCl/pepsin, and final saline. RESULTS: Basal hydrophobicity of human esophageal secretion, elaborated during mucosal exposure to saline, was 237 +/- 32. This value, however, declined 72% during mucosal exposure to HCl (66 +/- 14 vs 237 +/- 32; p < 0.001) and 87% during mucosal exposure to acid supplemented with pepsin (30 +/- 4 vs 237 +/- 32; p < 0.001). Moreover, hydrophobicity upon perfusion with HCl/pepsin was 55% lower than after perfusion with HCl alone (30 +/- 4 vs 66 +/- 14), although the result was insignificant. Substitution of saline for HCl/pepsin solution during the last perfusion period resulted in a partial recovery of hydrophobicity in esophageal secretion (131 +/- 30 vs 30 +/- 4; p < 0.001), although this value was lower than the basal hydrophobicity value (131 +/- 30 vs 237 +/- 32; p = 0.028). In addition, we continuously observed a significant shift in the fluorescence emission maximum from 508 +/- 6.4 to 486 +/- 0.9 (p < 0.001) during perfusion with starting saline, to 492 +/- 1.6 (p < 0.001) during exposure to HCl, to 493 +/- 1.1 (p < 0.001) during perfusion with HCl/pepsin, and to 488 +/- 0.9 (p < 0.001) during infusion of final saline. The maximum emission wavelength after esophageal exposure to initial saline also was significantly lower than the maximum emission upon perfusion with HCl (492 +/- 1.6 vs 486 +/- 0.9; p < 0.05) and HCl/pepsin (493 +/- 1.1 vs 486 +/- 0.9; p < 0.05). Although basal hydrophobicity in males was similar to corresponding values recorded in females, mucosal exposure to HCl (pH 2.1) resulted in an 84% decline in females but only 60% in males. Therefore, the hydrophobicity value in females during the perfusion period with HCl was 52% lower than in males (p = 0.129). CONCLUSIONS: Esophageal secretion exhibits its hydrophobic nature presumably through the presence of mucus components such as mucin and mucin-associated phospholipids. The inhibitory impact of HCl and HCl/pepsin solutions on esophageal hydrophobicity may play a role in the pathogenesis of mucosal damage by gastroesophagel refluxate.