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.

The effect of esophageal mechanical and chemical stimuli on salivary mucin secretion in healthy individuals.

Because of a newly developed model of esophageal perfusion in humans, the authors could study the role of esophago-salivary reflex in salivary neutral and acidic mucin output. The basal rate of neutral mucin output was 0.24 +/- 0.06 mg per minute. Placement of intraesophageal tubing and inflation of balloons resulted in a highly significant increase in salivary mucin output (2.10 +/- 0.22 mg per minute; p < 0.00001). However, implementation of esophageal perfusion with saline resulted in a significant decline of salivary mucin output (1.28 +/- 0.10 mg/mL NaCl4 versus 2.08 +/- 0.24 mg/mL NaCl1; p < 0.001). Esophageal perfusion with hydrochloric acid prevented the decline of salivary mucin output observed during perfusion with saline, whereas infusion of hydrochloric acid/pepsin resulted in a significant enhancement of salivary mucin output (2.89 +/- 0.31 mg per minute; p < 0.01). Therefore, mechanical and chemical stimulations resulted in an overall 9-fold and 12-fold increase in the rate of salivary mucin output over the basal value, respectively. The basal rate of acidic mucin secretion was 0.26 +/- 0.06 mg per minute. After placement of intraesophageal tubing, inflation of balloons, perfusion hydrochloric acid, or hydrochloric acid-pepsin solution, a significant enhancement in the rate of salivary acidic mucin output, similar to that observed during measurement of neutral mucin, was observed. Therefore, during mechanical and chemical stimulation, the rate of salivary acidic mucin output increased 7.3-fold and 11.1-fold over the basal value, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Interrelationship between esophageal challenge with mechanical and chemical stimuli and salivary protective mechanisms.

Using our newly developed model of esophageal perfusion in humans, we were able to study the esophagosalivary reflex in 20 healthy volunteers (12M, 8F; mean age 40 yr). The placement of the intraesophageal catheter resulted in a 6.3-fold increase in the salivation rate over the baseline value (2.27 +/- 0.28 vs. 0.36 +/- 0.06 ml/min; p = 0.02), whereas inflation of the catheter balloons evoked a 6.9-fold increase (2.52 +/- 0.21; p < 0.001) in the rate of salivation. A stepwise and significant decline of salivation (p = 0.02), observed during subsequent perfusion with NaCl was prevented when perfusion with HCl and HCl/pepsin solutions was implemented. The placement of the intraesophageal catheter resulted in a significant increase of salivary pH over its basal value (7.77 +/- 0.05 vs. 6.89 +/- 0.11; p < 0.001). A gradual decline of salivary pH during subsequent perfusion with NaCl was eliminated when saline was replaced with HCl or HCl/pepsin (7.76 +/- 0.04 vs. 7.46 +/- 0.09; p < 0.01). Intraesophageal tubing enormously potentiated the viscosity of saliva (44.50 +/- 9.0 vs. 9.3 +/- 1.0 mPa.s; p < 0.001). A subsequent decline of viscosity during continuous perfusion with saline was also prevented when HCl was substituted for NaCl (29.95 +/- 4.5 vs. 19.50 +/- 3.30; p < 0.05). A significant potentiation of salivary volume, viscosity, and pH during esophageal stimulation of mechano- and chemoreceptors may suggest a contributing role of the esophagosalivary reflex in the maintenance of the esophageal mucosal integrity under the impact gastroesophageal reflux.

Impact of acid and pepsin on human esophageal prostaglandins.

OBJECTIVES: Although the prostaglandin-mediated mucosal protection within the gastric compartment has been well established, its potential role in the maintenance of integrity of the esophageal mucosa in humans has not been explored due to the lack of appropriate methodology. METHODS: We have recently developed an esophageal perfusion catheter, equipped with two balloons, compartmentalizing a 7.5-cm segment of the esophageal lumen. Using this catheter, we studied the impact of the luminal perfusion with saline, HCl (0.01 M, pH 2.1), and HCl/pepsin solutions (0.5 mg/ml) on esophageal luminal release of PGE2 in 21 asymptomatic, presumably healthy volunteers (12 M, 9F; mean age 40 yr). The content of PGE2 in its methyl oximated form was measured by RIA (Amersham, IL), using a novel iodinated label. Results are expressed as mean +/- SEM. Student's t test was used for statistical analysis. RESULTS: Perfusion of the esophageal lumen resulted in continuous release of PGE2 into the perfusate at the rate of 1880 +/- 393 pg/min during the first 8-min perfusion period. During continuation of perfusion with saline, the luminal release of PGE2 was maintained at the rate of 1820 +/- 640 pg/min during the second 8-min perfusion period. This rate declined (although in nonsignificant fashion; p < 0.2) during the third perfusion period, reaching a plateau of 1220 +/- 473 pg/min and maintained during the last (period IV) perfusion period with saline. Introduction of acid during the perfusion period II in the second group of investigated subjects resulted in a rapid and statistically significant decline of the luminal release of PGE2 to the value of 1020 +/- 167 ng/min (p < 0.01). Continuation of esophageal perfusion with acid during the next 8-min perfusion period further diminished the luminal release of PGE2 to the value of 520 +/- 73; p < 0.001. The significant decline in the rate of luminal PGE2 release was still maintained despite the replacement of acid with saline during the ending 8-min perfusion (period IV; 560 +/- 80 ng/min; p < 0.001). Esophageal perfusion with HCl/pepsin solution, in group III subjects, potentiated luminal release of PGE2, reaching the value of 1553 +/- 340 pg/min, which is 3 times higher than the value of PGE2 observed during corresponding perfusion with HCl (period III; p < 0.03). This significant impact of HCl/pepsin solution was still maintained despite the substitution of HCl/pepsin with NaCl during the last perfusion period, and was still significantly higher (1260 +/- 220 pg/min; p < 0.02) than the corresponding value during the ending perfusion with NaCl after HCl (group II). This study for the first time demonstrates that luminal release of PGE2 in humans remains under a significant impact of luminal chemical factors such as acid and pepsin. CONCLUSION: The modulatory effect of acid and pepsin on esophageal mucosal prostaglandin release may play a role in the development of reflux-related mucosal pathology.

Human esophageal secretion: mucosal response to luminal acid and pepsin.

BACKGROUND/AIMS: Although esophageal histology in humans reveals numerous submucosal mucous glands, their secretion has never been explored. Therefore, we have studied the chemical composition and physical characteristics of esophageal secretion under the impact of luminal saline, acid, and acid/pepsin solutions. METHODS: The esophageal lumen in 21 healthy volunteers was continuously perfused with saline, HCI, or HCI/pepsin. Perfusates were assayed for mucin, protein, and viscosity. In addition, analysis of amino acid and sugar composition of purified esophageal mucin was performed. RESULTS: Esophageal perfusion with saline resulted in luminal release of mucin at the rate of 0.23 +/- 0.03 mg.cm-2 x min-1. Acid/pepsin solution significantly enhanced luminal release of mucin (0.32 +/- 0.03 mg.cm-2 x min-1; P < 0.01). HCI/pepsin solution also significantly increased the luminal output of protein (P < 0.01) and significantly impaired the viscosity of the esophageal perfusate (P < 0.05). Threonine, serine, and proline were the major amino acids within the esophageal mucin, whereas galactose was the predominant carbohydrate. CONCLUSIONS: Luminally released esophageal mucin, shown for the first time in humans, contributes significantly to maintaining the high viscosity of esophageal secretions. Significant increase in the luminal release of mucin under the impact of acid and pepsin, with subsequent decline of the perfusate viscosity, may indicate that mucin is the major target for gastric acid and pepsin, absorbing the deleterious impact of the gastroesophageal refluxate.

Effect of esophageal intraluminal mechanical and chemical stressors on salivary epidermal growth factor in humans.

Although various animal and clinical studies have demonstrated the significant effect of salivary epidermal growth factor (sEGF) on esophageal morphology and function, its secretory patterns still remain inadequately explored. Therefore, we have studied the impact of esophageal mechanical and chemical stimuli on sEGF in humans. sEGF was measured in saliva collected during basal conditions, chewing of parafilm, placement of esophageal tubing, inflation of intraesophageal balloons, and perfusion with NaCl, HCl, and HCl/pepsin solutions. The concentration of sEGF was measured with a radioimmunoassay kit from Amersham (Arlington Heights, IL). The concentration of sEGF in basal saliva was (mean +/- SEM) 2.08 +/- 0.22 ng/ml. Chewing the parafilm resulted in a significant decline of sEGF concentration to the value of 1.39 +/- 0.16 ng/ml (p < 0.0005). Similar decline in sEGF concentration also prevailed after placement of intraesophageal tubing (p < 0.03), and inflation of intraesophageal balloons (p < 0.01). This decline intensified significantly when prolonged esophageal perfusion with saline was implemented (p < 0.03 vs. tubing). Substitution of NaCl with HCl in the second and third perfusion periods prevented the decline in sEGF concentration, whereas HCl accompanied by pepsin enhanced sEGF concentration. The rate of sEGF output was 0.90 +/- 0.13 ng/min during basal conditions and increased significantly during parafilm chewing (1.53 +/- 0.25 ng/min; p < 0.05). However, sEGF secretion during both placement of esophageal tubing and inflation of balloons increased 4.1- and 4.9-fold, respectively (p < 0.002 and < 0.00005), over the basal value, and 2.4- and 2.9-fold, respectively, over the parafilm stimulated secretion. Subsequently, we observed a further significant decline of sEGF output (p < 0.05) which was sustained during perfusion of the esophagus with saline. Interestingly, esophageal perfusion with HCl prevented the decline of sEGF secretion observed during perfusion with saline. sEGF output during esophageal perfusion with HCl/pepsin exhibited a strong increase, reaching the value of 5.86 +/- 0.70 ng/ml. This value corresponds to a 58% increase over the secretory rate observed during mechanical stimulation by placement of esophageal tubing (3.71 +/- 0.47; p < 0.05). HCl/pepsin-induced potentiation of sEGF secretion was also highly significantly increased over both the value recorded during basal (p < 0.0005) and parafilm-stimulated (p < 0.002) conditions. Subsequent substitution of HCl/pepsin solution with a final saline perfusate still maintained enhanced sEGF output, compared with both basal (p < 0.02) and parafilm-stimulated conditions (p < 0.02).(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence on secretion of epidermal growth factor by the esophageal mucosa in humans.

Luminal release of esophageal epidermal growth factor (EGF) into the perfusing solutions (saline, HCl, and HCl/pepsin), aspirated with the newly developed esophageal perfusion catheter, was measured in 20 healthy volunteers (12 male, 8 female; mean age 40 yr; range 30-56 yr). A potential salivary contamination was excluded by a complete seal (with two balloons) of perfused esophageal segment and by a simultaneous, carefully monitored, collection of saliva. The concentration of EGF in each of 16 fully recovered 2-min perfusion samples was measured by RIA kit (Amersham, IL). The concentration of EGF in recovered NaCl perfusate varied between (mean +/- SEM) 1.78 +/- 0.19 and 2.14 +/- 0.14 ng/ml, whereas output varied between 9.25 +/- 0.98 and 11.14 +/- 0.82 ng/min. During perfusion with HCl, both the concentration of EGF within the esophageal perfusate and its secretion declined significantly to a value of 0.68 +/- 0.17 ng/ml (p < 0.0001) and 3.56 +/- 0.90 ng/min (p < 0.0001), respectively. Introduction of pepsin into an acidic perfusion solution (0.5 mg/ml of HCl) resulted in a significant increase in EGF concentration (1.99 +/- 0.36 ng/ml; p < 0.001) and output (10.24 +/- 1.84; p < 0.01), compared with EGF values recorded during perfusion with HCl. EGF output, calculated from a sealed 7.5-cm segment of the esophagus, was 10.39 +/- 0.89 ng/min, and was maintained at a steady state throughout an entire saline perfusion procedure. We present evidence that human esophageal mucosa has an enormous EGF secretory potential. The rapid esophageal EGF secretory response to intraluminal challenge with aggressive factors implies its role in the maintenance of the mucosal integrity.