Expression of protease-activated-receptor 2 (PAR-2) in human esophageal mucosa.

OBJECTIVE: The role of duodenal reflux in gastroesophageal reflux disease (GERD) containing bile salts and pancreatic enzymes (with special attention to trypsin) is still under discussion. Proteinase-activated receptors (PARs) are a novel family and PAR-2 is a unique member of this family because it is activated by trypsin. The aim of the present study was to examine the presence and the position of the PAR-2 receptor in human esophageal mucosa in different subgroups of GERD. MATERIAL AND METHODS: Distal biopsies taken from healthy controls, patients with erosive reflux disease (ERD), patients with specialized intestinal metaplasia (SIM) and adenocarcinoma were analyzed for the PAR-2 receptor with reverse-transcription polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. RESULTS: Gene transcripts for the PAR-2 receptor were found in all groups, with increased levels in SIM patients compared to controls. However, this visual pattern was not seen for the protein expression of the PAR-2 receptor showing no apparent quantitative differences between the groups. Immunohistochemistry revealed distinct staining for the PAR-2 receptor in the luminal part of the esophageal epithelium. CONCLUSIONS: The localization of the PAR-2 receptor indicates that the receptor can be cleaved and activated by trypsin in duodenogastric esophageal refluxate. The data thus suggest that the trypsin-PAR-2 pathway may be involved in the pathogenesis of GERD.

Concept of Crohn's disease being conditioned by four main components, and irritable bowel syndrome being an incomplete Crohn's disease.

Several mechanisms have been proposed for the development of Crohn's disease. Evidence in favour of a unifying 4-component concept to explain the development of Crohn's disease is presented. The four components are a genetic predisposition to an increased intestinal permeability, the key and initial triggering factor being an oral-pharyngeal bacterium that increases the mucosal permeability of the small intestine with only a minimal inflammatory reaction, an adherent-invasive strain of Escherichia coli that penetrates the mucosa and causes an acute inflammatory reaction in the intestinal wall, and finally a secondary invasion of bacteria causing the chronic inflammatory characteristics. Irritable bowel syndrome (IBS) is a functional bowel disorder with intermittent symptoms of varying intensity. Clinically, there is evidence to suggest a link between IBS patients with diarrhoea and patients with Crohn's disease. The common denominator and initial trigger for IBS with diarrhoea and Crohn's disease seems to be an increased small intestinal permeability, probably caused by an oral-pharyngeal bacterial strain. The important missing factor in IBS patients seems to be the adherent-invasive strain of E. coli in the proximal colon, causing the acute inflammatory process in patients with Crohn's disease. IBS with diarrhoea can then be looked upon as an incomplete Crohn's disease.

Strong activation of PAR-2 receptors: a common trigger for the development of gastrointestinal adenocarcinomas?

Helicobacter pylori infection is considered to be an important factor in the development of gastric cancer, while duodenogastroesophageal reflux is claimed to be the main cause of development of esophageal adenocarcinoma. A pronounced activation of PAR-2 receptors may be a common denominator in triggering the development of these cancers, and possibly pancreatic and colonic cancers as well. Evidence supporting such a concept is presented.

Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes.

OBJECTIVES: Irritable bowel syndrome (IBS) is a heterogeneous condition and defined according to symptoms. Low-grade inflammation has been associated with IBS, particularly that following infection, but whether altered intestinal permeability profiles relate to irritable bowel subtype or onset is uncertain. Our aim was to compare small and large intestinal permeability in various subtypes of IBS to healthy controls. METHODS: Intestinal permeability was measured using 1.8 MBq of 51Cr-EDTA and collecting urine over 24 h; Study 1: patients with diarrhea-predominant postinfectious IBS (N=15), constipation-predominant IBS (N=15), and healthy controls (N=15); Study 2: two groups of diarrhea-predominant IBS (D-IBS), one with a history of onset after acute gastroenteritis (postinfectious) (N=15) and the other without such a history (nonpostinfectious) (N=15) both compared with healthy controls (N=12). RESULTS: Permeability expressed as percentage of total dose excreted in urine (median [inter-quartile range]). Study 1: Proximal small intestinal permeability was increased in postinfectious IBS (0.19 [0.12-0.23]) in contrast to constipated IBS (0.085 [0.043-0.13]) and controls (0.07 [0.035-0.19]) (p=0.02). IBS patients with eczema, asthma, or hayfever had increased proximal small intestinal permeability compared with IBS patients without atopy (p=0.02). Study 2: Small intestinal permeability was greater in nonpostinfectious diarrhea-predominant IBS (0.84 [0.69-1.49]) compared with postinfectious IBS (0.43 [0.29-0.63], p=0.028) or controls (0.27 [0.2-0.39]), p=0.001). CONCLUSIONS: Small intestinal permeability is frequently abnormal in diarrhea-predominant IBS. Those without a history of infectious onset appear to have a more severe defect.