title: Pepsin hydrolysis of the adherent mucus barrier and subsequent gastric mucosal damage in the rat: effect of diosmectite and 16,16 dimethyl prostaglandin E2.
abstract: OBJECTIVE
  The gastroduodenal mucus layer is progressively eroded at its luminal surface as a consequence of pepsin mucolysis. Diosmectite binds to gastric mucus and modifies its rheological properties. Prostaglandins are well-known mucus secretagogues. The aim of this study is to describe interactions of diosmectite and 16,16 dimethyl prostaglandin E2 on adherent gastroduodenal mucus and pepsin mucolysis in the rat.
  
  
  METHODS
  Instillation of pepsin (1 or 2 mg.mL-1 at pH1 or pH2) into the pylorus ligated stomach of anaesthetised rats resulted in progressive disruption of the adherent mucus layer and a large, significant, increase in soluble degraded mucin compared to that following instillation of HCl pH1 or pH2. Pepsin (2 mg.mL-1), instillation over 2 hours, but not HCl alone, consistently resulted in small focal, haemorrhagic mucosal lesions, significant bleeding into the lumen and histologically, localised punctate ulcers in an otherwise intact epithelium. Diosmectite (500 mg.kg-1) and 16,16 dimethyl prostaglandin E2 were given by oro-gastric intubation.
  
  
  RESULTS
  Diosmectite, given 30 minutes beforehand, inhibited breakdown of the adherent gastric mucus barrier by pepsin in vivo. When administered up to 16 hours prior to the experiment, diosmectite prevented pepsin induced gastric mucosal haemorrhage and histological epithelial damage. Substantial amounts of diosmectite (39.6 micrograms/mm2, equivalent in volume to layer 93 microns thick) were bound to the gastric mucosa 30 minutes after administration. Diosmectite (100:1 by weight to enzyme) completely inhibited pepsin hydrolysis of protein in vitro. Topical 16,16 dimethyl prostaglandin E2, 5 micrograms.kg-1 increased the thickness of the adherent mucus layer by two-fold. Both doses of the prostaglandin prevented pepsin induced gastric mucosal haemorrhage and histological epithelial damage.
  
  
  CONCLUSIONS
  These results show that both diosmectite and prostaglandin increase the effectiveness of the mucus barrier against mucosal damage by pepsin in vivo.
authors.affiliation: Department of Physiological Sciences, Medical School, Newcastle-upon-Tyne, UK.
authors.forename: A
authors.initials: A
authors.lastname: Leonard
authors.forename: M T
authors.initials: MT
authors.lastname: Droy-Lefaix
authors.forename: A
authors.initials: A
authors.lastname: Allen
mesh_terms: D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003864:Depression, Chemical; D005752:Gastric Mucins / Q000032:analysis; D005753:Gastric Mucosa / Q000737:chemistry / Q000187:drug effects*; D005765:Gastrointestinal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006471:Gastrointestinal Hemorrhage / Q000517:prevention & control*; D007501:Iron / Q000032:analysis; D008297:Male; D010434:Pepsin A / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017640:Silicates
chemical_list: D005752:Gastric Mucins; D005765:Gastrointestinal Agents; D017640:Silicates; C033214:Smectite; D007501:Iron; D010434:Pepsin A; D015064:16,16-Dimethylprostaglandin E2