title: Up-regulation of endothelin-1 in gastric mucosal inflammatory responses to Helicobacter pylori Lipopolysaccharide: effect of omeprazole and sucralfate.
abstract: BACKGROUND
  Helicobacter pylori is recognized as a primary etiologic factor in the development of gastric disease and the product of particular significance to the virulent action of the bacterium is its cell wall lipopolysaccharide. We applied the animal model of H. pylori lipopolysaccharide-induced acute gastritis to study the effect of antiulcer agents, omeprazole and sucralfate, on the course of mucosal inflammatory responses by analyzing the interplay between the extent of epithelial cell apoptosis and the mucosal expression of endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha), and the activity of constitutive (cNOS) and inducible (NOS-2) nitric oxide synthase.
  
  
  METHODS
  Rats pretreated twice daily for 3 consecutive days with omeprazole at 40 mg/kg, sucralfate at 100 mg/kg or the vehicle, were subjected to intragastric application of H. pylori lipopolysaccharide at 50 microg/animal, and after 2, 4, and 10 additional days on the antiulcer drug or vehicle regimen their mucosal tissue used for histologic and biochemical assessment.
  
  
  RESULTS
  In the absence of antiulcer agents, H. pylori lipopolysaccharide elicited within 2 days a pattern of acute mucosal inflammatory responses accompanied by a massive epithelial cell apoptosis, a 2.9-fold increase in the mucosal expression of ET-1, an 11.7-fold enhancement in TNF-alpha, and a 9.3-fold increase in NOS-2, while cNOS activity showed a 5.5-fold decrease. The extent of mucosal inflammatory involvement reached a maximum by the 4th day and showed a decline by the 10th day. This was reflected in a marked reduction in epithelial cell apoptosis, decrease in the mucosal expression of ET-1, TNF-alpha and NOS-2, and the recovery in cNOS activity. Comparing to the vehicle controls, treatment with proton pump inhibitor, omeprazole, led at the end of a 10 day period to a 48.3% reduction in the extent of mucosal inflammatory involvement elicited by H. pylori lipopolysaccharide, while a 74.2% reduction in the mucosal inflammatory involvement was achieved with gastroprotective agent, sucralfate. Moreover, this advantage of sucralfate over omeprazole in countering the lipopolysaccharide-induced changes was reflected at the end of 10 day treatment period in a 20.4% greater decrease in apoptosis, a 47.5% greater reduction in TNF-alpha and a 50.7% greater reduction in ET-1. However, both agents exerted similar influence on the restoration of gastric mucosal cNOS activity and showed a comparable effect at the end of a 10 day treatment in countering the lipopolysaccharide-induced increase in the expression of NOS-2.
  
  
  CONCLUSIONS
  The findings suggest that an increase in the mucosal ET-1 level elicited by H. pylori lipopolysaccharide, combined with a decline in cNOS may be responsible for the induction of TNF-alpha and triggering the inflammatory process. We also show that sucralfate exhibits greater efficacy than omeprazole in suppressing the H. pylori-induced mucosal inflammatory responses. This property of sucralfate may well be due to its ability to suppress the mucosal rise in ET-1.
authors.affiliation: Research Center, University of Medicine and Dentistry of New Jersey, Newark 07103-2400, USA. slomiabr@umdnj.edu
authors.forename: B L
authors.initials: BL
authors.lastname: Slomiany
authors.forename: J
authors.initials: J
authors.lastname: Piotrowski
authors.forename: A
authors.initials: A
authors.lastname: Slomiany
mesh_terms: D000208:Acute Disease; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D017209:Apoptosis; D019332:Endothelin-1 / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005756:Gastritis / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D016480:Helicobacter pylori; D008070:Lipopolysaccharides; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009853:Omeprazole / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013392:Sucralfate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000897:Anti-Ulcer Agents; D019332:Endothelin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013392:Sucralfate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D009853:Omeprazole