Geoff V. Smith

Modulation of host antimicrobial peptide (beta-defensins 1 and 2) expression during gastritis

Background: β-Defensins are a newly identified family of antimicrobial peptides that are expressed by epithelia on mucosal surfaces where their production is augmented by infection or inflammation. Helicobacter pylori colonises the gastric epithelium causing persistent gastric inflammation leading to antral and corpus gastritis, and peptic ulcer disease. Aims: To evaluate the role of β-defensins in the innate immune response of the gastric epithelium to infection and inflammation, we have assessed mRNA expression and regulation of human β-defensins 1 and 2 (hBD1, hBD2) by H pylori and proinflammatory stimuli. We have also compared gene and peptide expression of these bactericidal agents in H pylori induced gastritis with that in normal gastric mucosa. Methods: Modulation of expression of hBD1 and hBD2 by various stimuli was studied in three (AGS, MKN7, MKN45) gastric epithelial cell lines by quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR). Defensin mRNA expression was measured by semiquantitative RT-PCR in gastritis tissue and compared with controls. Peptide localisation was assessed by immunohistochemistry. Results: Cytotoxic H pylori and interleukin 1β (IL-1β) markedly upregulated expression of hBD2 in a dose and time dependent manner in both AGS and MKN7 cell lines. A modest increase in hBD1 expression was also noted during infection. Interestingly, induction of hBD1 gene expression by IL-1β was only observed in MKN7 cells. The magnitude of this response was delayed and reduced compared with hBD2 expression. In gastric biopsies, hBD2 was undetectable in normal gastric antrum but a marked increase was observed in H pylori positive gastritis compared with control tissue (p<0.001). Constitutive expression of hBD1 was observed in normal gastric mucosa and there was a significant increase in gastritis (p<0.05). Immunohistochemistry revealed a parallel increase in hBD1 and hBD2 peptide expression in gastritis tissue with positive staining confined to the surface epithelium of the gastric glands. Conclusions: Modulation of β-defensin expression by pathogenic and/or inflammatory stimuli and their cellular localisation places these antimicrobial peptides in the front line of innate host defence in the human stomach.

COX-2 inhibitors vs. NSAIDs in gastrointestinal damage and prevention

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit production of protective gastric mucosal prostaglandins and also have a direct topical irritant effect. In some patients this results in dyspepsia and development of gastroduodenal erosions and ulceration. The risk of ulcer complications, such as bleeding, perforation and death is increased approximately 4-fold in NSAID users. Patients at high risk of ulcer complications include the elderly, those taking anticoagulants, steroids and aspirin, those with a previous history of peptic ulceration and patients with concomitant serious medical problems. The interaction of NSAIDs with Helicobacter pylori (the major cause of peptic ulceration in non-NSAID users) is controversial and some studies suggest that H. pylori infection may even protect against NSAID-induced ulceration. Selective inhibitors of the inducible cyclooxygenase-2 (COX-2) enzyme spare COX-1 in the gastric mucosa and, hence, do not inhibit production of mucosal prostaglandins. COX-2-selective inhibitors are associated with a significant reduction in gastroduodenal damage compared with traditional NSAIDs. Proton pump inhibitors (PPI) are probably the best agents for healing and prevention of NSAID-induced ulcers. Preliminary studies suggest that COX-2 selective inhibitors, like traditional NSAIDs, may prevent lower gastrointestinal cancer. Further studies are needed but they may be useful in individuals at high risk of certain types of lower gastrointestinal malignancy with increased gastrointestinal tolerability and safety.

Induction of Cyclooxygenase 2 by Escherichia coli but not Helicobacter pylori lipopolysaccharide in gastric epithelial cells in vitro

Background.  Cyclooxygenase 2 (COX‐2) is an inducible enzyme that plays a key role in the synthesis of prostaglandins in response to inflammatory stimuli. It is expressed in the gastric mucosa as part of the response to infection with Helicobacter pylori. The specific interaction between H. pylori and the gastric epithelium that results in COX‐2 expression has not been identified.

Cyclooxygenase 2, p53, beta-catenin, and APC protein expression in gastric adenomatous polyps.

Gastric adenomatous polyps are rare findings in upper gastrointestinal endoscopy; however, they are associated strongly with malignant transformation. Few series describe the oncogenic characteristics of gastric adenomas. In the present study, we immunohisto-chemically assessed the expression of cyclooxygenase (COX)-2, beta-catenin, p53, and adenomatous polyposis coli (APC) in paraffin-embedded specimens of 14 gastric adenomas. Control samples of normal gastric tissue and gastric adenocarcinoma also were analyzed. Of the adenomas, 7 demonstrated overexpression of COX-2, and all demonstrated nuclear p53 accumulation. Accumulation of beta-catenin in the nucleus and cytoplasm was detected in 38% (3/8) of specimens. Loss of APC staining was observed in 50% (4/8). Similar alterations in oncoprotein expression were seen in gastric cancers but not in normal control sections. Gastric adenomas display alterations in the expression of COX-2, beta-catenin, and APC similar to those seen in adenocarcinomas; however, accumulation of p53 was significantly more common in adenomas than in cancers.

The Effect of Ascorbic Acid on Helicobacter pylori Induced Cyclooxygenase 2 Expression and Prostaglandin E2 Production by Gastric Epithelial Cells in vitro

Background.  Cyclooxygenase 2 (COX‐2) is induced by the presence of Helicobacter pylori (H. pylori) on the gastric mucosa as part of the inflammatory response; this results in the synthesis of prostaglandins that amplify the local inflammatory response. The presence of H. pylori inhibits the secretion of ascorbate into the gastric lumen. Interestingly, ascorbate inhibits the growth of H. pylori and low dietary levels are associated with an increased risk of gastric adenocarcinoma. We therefore investigated the effect of ascorbate on H. pylori mediated COX‐2 induction and prostaglandin production in vitro.

780 The value of colonoscopic and ileoscopic biopsies in the investigation of chronic diarrhoea

Introduction Colonoscopy is advocated in the investigation of chronic diarrhoea. Previous studies have supported the use of routine colonoscopic biopsy in those with normal endoscopic appearances. We assessed the additional value of colonic and ileal biopsies compared with endoscopy alone in the investigation of a cohort of patients with chronic diarrhoea attending a tertiary referral centre. Methods A retrospective search of the endoscopy database was carried out, amongst patients that underwent colonoscopy, ileoscopy, colonic and ileal biopsies in the investigation of chronic diarrhoea. The histological reports from all biopsies were then retrieved, and the data examined. Results 40 endoscopy and histology reports were reviewed and compared. There were 23 males and 17 females in the group, the age range was 6-77 years. 31 had normal endoscopic appearances. Discussion Seven out of 40 (17.5%) had abnormal colonic or ileal histology with normal endoscopic appearances. These data support the use of routine colonic and ileal biopsy in the investigation of patients with chronic diarrhoea and normal colonoscopy.