Essential role of pepsin in pathogenesis of acid reflux esophagitis in rats

• Published in: Digestive diseases and sciences 2006-02, Vol.51 (2), p.303-309
• Main Authors: NAGAHAMA, Kenji, YAMATO, Masanori, NISHIO, Hikaru, TAKEUCHI, Koji
• Format: Article
• Language: English
• Subjects: Animals; Anti-Ulcer Agents - therapeutic use; Biological and medical sciences; Disease Models, Animal; Esophagitis, Peptic - etiology; Esophagitis, Peptic - pathology; Esophagitis, Peptic - prevention & control; Esophagus; Esophagus - drug effects; Esophagus - pathology; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Glutamine - pharmacology; Male; Medical sciences; Other diseases. Semiology; Pepsin A - physiology; Pepstatins - pharmacology; Protease Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-006-3129-8

Pepsin, a protease activated by gastric acid, is a component of the refluxate, yet the role of pepsin in the pathogenesis of reflux esophagitis has not been well studied. In the present study, we examined the effect of pepstatin, a specific inhibitor of pepsin, on acid reflux esophagitis. Acid reflux esophagitis was induced in rats by ligating both the pylorus and the forestomach for 3 or 4 hr. Pepstatin, ecabet Na (the anti-ulcer drug), and L-glutamine were administered intragastrically after the ligation. Pepstatin or ecabet Na, given intragastrically, significantly prevented esophageal lesions, even though they did not affect basal acid secretion in pylorus-ligated rats. Pepstatin significantly inhibited pepsin activity in vivo and in vitro, while ecabet Na inhibited this activity in vitro. By contrast, L-glutamine given intragastrically aggravated the lesions in a dose-dependent manner, but even in the presence of L-glutamine the development of esophageal lesions was totally prevented by coadministration of pepstatin or ecabet Na. L-Glutamine increased the pH of gastric contents to approximately 2.0, the optimal pH for the proteolytic activity of pepsin in vitro. In addition, intragastric administration of exogenous pepsin worsened the severity of esophageal damage. These results suggest that pepstatin is highly effective against acid reflux esophagitis, without influencing acid secretion, while L-glutamine aggravated these lesions by increasing the pepsin activity by shifting the intraluminal pH to the optimal pH range for proteolytic action. It is assumed that pepsin plays a major pathogenic role in the development of acid reflux esophagitis.