Our results demonstrate enhanced mucosal expression of IL-8 in incipient GERD even without mucosal breaks. NF-kappaB activation may be implicated in the pathogenesis in GERD.
AIM:Little has been known about the pathogenesis of nonerosive reflux disease (NERD). Recent studies have implicated interleukin 8 (IL-8) in the development and progression of gastroesophgeal reflux disease (GERD). The purpose of this study was to determine IL-8 RNA expression levels in NERD patients with or without subtle mucosal changes.
METHODS:We studied 26 patients with NERD and 13 asymptomatic controls. Biopsy sample was taken from the esophagus 3 cm above the gastroesophageal junction and snap frozen for measurement of IL-8 mRNA levels by realtime quantitative polymerase chain reaction (PCR). We also examined mRNA expression of IL-8 receptors, CXCR-1 and -2 by reverse transcriptase PCR. The patients were endoscopically classified into grade M (mucosal color changes without visible mucosal break) and N (neither minimal involvement nor mucosal break) of the modified Los Angeles classification.
RESULTS:The relative IL-8 mRNA expression levels were significantly higher in esophageal mucosa of NERD patients than those of the controls. There was a significant difference in IL-8 mRNA levels between grade M and N. The CXCR-1 and -2 mRNAs were constitutively expressed in esophageal mucosa.
CONCLUSION:Our results suggest that high IL-8 levels in esophageal mucosa may be involved in the pathogenesis of NERD through interaction with its receptors. NERD seems to be composed of a heterogeneous population in terms of not only endoscopically minimal involvement but also immune and inflammatory processes.
Summary The exact pathophysiological mechanisms responsible for gastroesophageal reflux disease (GERD) remain unclear. Recent studies have shown that mucosal immune and inflammatory responses, characterized by specific cytokine and chemokine profiles, may underlie the diverse esophageal phenotypes of GERD. Interleukin 8 (IL-8), a representative chemokine, mediates neutrophil trafficking via its receptors, mainly CXCR-1. The IL-8 mRNA and protein levels are increased in the esophageal mucosa, not only in reflux esophagitis (RE), but also in endoscopy-negative GERD (NERD), through activation of nuclear factor-κB (NF-κB), which is a pivotal transcription factor. Mucosal IL-8 concentrations have been found to parallel the endoscopic severity of RE, implying that this cytokine is a key player in the development of GERD. The mucosal levels of the C-C chemokines, macrophage chemoattractant protein 1 (MCP-1) and regulated on activation normal T-cell-expressed and presumably secreted (RANTES), which primarily attract monocytes and lymphocytes to the site of inflammation, respectively, are also elevated in RE. The secreted levels of IL-8 and IL-1β, a prototype of proinflammatory cytokine, are maximal at the proximal segment within Barrett esophagus (BE) tissue. The expression of the two pleiotrophic proinflammatory cytokines, IL-6 and tumor necrosis factor α, is enhanced in the intestinal epithelium of BE, which places this epithelium at a higher risk for developing malignancy. BE is characterized by a distinct Th-2 predominant cytokine profile (IL-4 and -10), compared to the proinflammatory nature of RE (interferone-γ). Treatment with a proton pump inhibitor, lansoprazole reduces the mucosal levels of IL-8 mRNA and protein in GERD, including RE and NERD. This may occur in part through an anti-inflammatory action of proton pump inhibitors beyond gastric acid inhibition.
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