Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants

Abstract

Background and aims: Approximately 10% of adults experience gastro-oesophageal reflux symptoms with a variable oesophageal response. A total of 60% have no endoscopic abnormality, 30% have oesophagitis, and 10% have Barrett's oesophagus. We investigated whether the inflammatory cell infiltrate and cytokine profiles of these clinical phenotypes merely vary in severity or are fundamentally different. Methods: Patients with reflux symptoms and a normal oesophagus (n=18), oesophagitis (n=26), and Barrett's oesophagus (n=22 newly diagnosed, n=28 surveillance) were recruited. Endoscopic and histopathological degrees of inflammation were scored. Cytokine expression was determined by competitive reverse transcriptase-polymerase chain reaction and immunohistochemistry. Results: In oesophagitis, endoscopic and histopathological grades of inflammation correlated highly. mRNA expression of proinflammatory interleukin (IL)-1β, IL-8, and interferon γ (IFN-γ) were increased 3-10-fold compared with non-inflamed squamous or Barrett's oesophageal samples. There was a modest increase in anti-inflammatory IL-10 but no increase in IL-4. In Barrett's oesophagus, 29/50 had no endoscopic evidence of inflammation and histopathological inflammation was mild in 17/50 and moderate in 24/50, independent of acid suppressants. Expression of IL-1β, IL-8, and IFN-γ was similar to non-inflamed squamous mucosa. IL-10 was increased 1.6-fold similar to oesophagitis. IL-4 was increased fourfold, with 100-fold increase in IL-4/T cell receptor expression, compared with squamous oesophagus or oesophagitis. Conclusions: Barrett's oesophagus is characterised by a distinct Th-2 predominant cytokine profile compared with the proinflammatory nature of oesophagitis. The specific oesophageal immune responses may influence disease development and progression.

Expression of Reactive Oxygen Species in Reflux Disease

“…The present study is also made on patients with mild esophagitis, classified to LA-A by the endoscopist (1). Several studies have looked at pro-inflammatory cytokines expression along the inflammation-metaplasia-dysplasia-adenocarcinoma sequence in the esophagus and have also found a stepwise-elevated expression correlate to grade of severity of the disease (20)(21). Such association was not made in the present study for IL-1β and IL-6 at protein level, whereas gene transcript for IL-6 was increased in ERD-patients indicating somewhat small alteration may exist beyond the detections level for protein.…”

Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers

“…Other key genes dysregulated in EAC compared with preinvasive BE samples included IL-6, Cox-2, C/EBPβ, and POSTN, which are in keeping with the inflammatory-related pathways ascertained from the ontology and KEGG analyses. The up-regulation of inflammation-related genes and associated ontologies fits with the idea that the inflammatory microenvironment is considered to be the seventh hallmark of cancer (2) and with previous work in our laboratory and others linking inflammation and TGF-β to BE carcinogenesis (24)(25)(26)(27). More work is required to understand the cross-talk and combined influences of the stroma and luminal components on epithelial cell behavior in BE.…”

The effect of sildenafil on segmental oesophageal motility and gastro‐oesophageal reflux

“…This suggests that the drop in LES pressure we saw with sildenafil -on average to about 8 mmHg -did not predispose to gastro-oesophageal reflux. A number of other factors are thought to predispose to gastro-oesophageal disease: immunological responses of the oesophageal mucosa to injury, 14 TLESR, 15 hiatus hernia, 16 and defects of acid clearing 17 are all candidates. We recorded TLESR only one time in one subject after sildenafil and none of our subjects had a hiatus hernia.…”