Reduction of Interleukin 8 Gene Expression in Reflux Esophagitis and Barrett's Esophagus With Antireflux Surgery

Abstract

Hypothesis: Chronic inflammation of esophageal mucosa secondary to refluxed gastric juice increases gene expression of interleukin 8 (IL-8). Antireflux surgery can reduce this overexpression. Design: Prospective analysis of archival paraffinembedded tissue. Setting: Academic tertiary medical center. Patients and Methods: One hundred eight patients with reflux symptoms were classified according to pH monitoring and endoscopic and histologic findings. Twenty patients did not have reflux or mucosal injury; 47 had reflux disease (16 esophagitis and 31 Barrett's esophagus), 20 had dysplasia, and 21 had adenocarcinoma. Microdissection was performed to exclude inflammatory cells and stromal tissue. After RNA isolation and reverse transcription, IL-8 messenger RNA expression was measured using quantitative real-time polymerase chain reaction. All patients with reflux disease had Nissen fundoplication with biopsies at matched levels within the esophagus preoperation and postoperation. Results: Expression of IL-8 was increased in patients with reflux compared with those without reflux. Patients with the highest IL-8 expression were those with Barrett's dysplasia and adenocarcinoma (PϽ.001). In patients with reflux, Nissen fundoplication led to significantly decreased IL-8 expression compared with preoperative levels in esophagitis (P=.01) and Barrett's esophagus (P=.03). Conclusions: Interleukin 8 messenger RNA expression increases during the progression of reflux disease from normalsquamousmucosatoesophagealadenocarcinoma.Elimination of reflux with Nissen fundoplication significantly reduces IL-8 expression in both squamous and Barrett's mucosa. These results demonstrate that effective antireflux surgery can modulate the gene expression of esophageal mucosa and may impact the natural history of reflux disease.

Inflammatory mediators in gastroesophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis

“…In a Japanese study of patients with nonerosive reflux disease (NERD) with minimal mucosal involvement, as determined by endoscopy, IL-8 mRNA levels were increased compared with NERD patients with no mucosal involvement and with controls (63). After successful treatment with PPIs or Nissen fundoplication, IL-8 levels declined (55,83,138). High mucosal IL-8 levels predicted an increased relapse rate for GERD within 3 years, indicating a potential prognostic role for this cytokine (53).…”

“…IL-8 has been extensively studied in GERD and is expressed in high amounts in the affected mucosa of GERD patients (36,55,56,83,138). IL-8 is a powerful chemoattractant and activator of leukocytes and other nonimmune cells.…”

The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer

“…The latter can be seen as an adaptive response to gastro-esophageal reflux exposure. In contrast, other studies implicate a stepwise increase in the expression of IL-8 from esophageal reflux disease through Barrett's esophagus to esophageal adenocarcinoma [40,41]. The IL-8 receptors, CXCR1 and CXCR2, are constitutively expressed in esophageal mucosa, especially by epithelial cells and infiltrated leukocytes [42,43].…”

“…Indeed, proton pump inhibitors (e.g. lansoprazole) and surgery reduce the levels of acids and consequently of IL-8, which results in reduced inflammatory response and tissue damage [36,41,[45][46][47]. Also the anti-inflammatory compound curcumin, which is a polyphenolic pigment isolated from the plant Curcuma longa, was found to inhibit esophageal activation and IL-8 release in response to acid [48].…”

Chemokines, chemokine receptors and the gastrointestinal system

“…Amongst these, CXCL8 is reported as a molecular marker indicative of response to therapeutic procedures. For example, Oh et al [113] compared the expression level of CXCL8 between pre-and postoperation of Nissen fundoplication in reflux esophagitis. They found that CXCL8 expression was significantly reduced postoperatively, as measured by quantitative real-time polymerase chain reaction (qRT-PCR).…”