Elevated Levels of Chemokines in Esophageal Mucosa of Patients With Reflux Esophagitis

Isomoto, Hajime; Wang, Aiping; Mizuta, Yohei; Akazawa, Yuko; Ohba, Kazuo; Omagari, Katsuhisa; Miyazaki, Masanobu; Murase, Kunihiko; Hayashi, Tomayoshi; Inoue, Kenichiro; Murata, Ikuo; Kohno, Shigeru

doi:10.1111/j.1572-0241.2003.07303.x

Cited by 114 publications

(99 citation statements)

References 24 publications

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“…21,22 Furthermore, an abnormal cytokine profile was observed in colonic primary fibroblast cells. 23 To support our in vitro findings of whether acid induces HB-EGF expression in fibroblast cells, we examined HB-EGF expression in biopsy specimens from the patients with reflux esophagitis as to show the in vivo evidence.…”

Section: Predominance Of Hb-egf In Subepithelial Fibroblasts Of Humanmentioning

confidence: 99%

Fibroblast-derived HB-EGF promotes Cdx2 expression in esophageal squamous cells

Rahman

Kadowaki

Ishihara

et al. 2010

Laboratory Investigation

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The molecular basis of attaining columnar phenotype in Barrett's esophagus is poorly understood. One hypothesis states that factors locally produced by cells of mesenchymal origin in chronic reflux esophagitis induce metaplastic transformation. This study was performed to elucidate the factors secreted from fibroblasts that cause columnar phenotype in adjacent squamous epithelium. Human fibroblast cells were exposed to acidified medium for 20 min, followed by medium neutralization for 2 h, and then total RNA was hybridized to Sentrix Human-6 Expression BeadChips. Furthermore, esophageal mucosal biopsy specimens from reflux esophagitis patients were examined for HB-EGF expression using immunohistochemistry. In addition, cells from the human esophageal squamous epithelial cell line HET1A were treated with recombinant HB-EGF, and changes in expressions of Cdx2 and columnar markers were analyzed. The gene expression profile revealed significant upregulation of a variety of growth factors and inflammatory chemokines in response to acid exposure. Among them, HB-EGF was upregulated more than 10-fold. Biopsy specimens from reflux esophagitis patients showed a strong expression of HB-EGF in fibroblast cells underlying the damaged epithelium. Furthermore, in vitro stimulation of HET1A cells with HB-EGF increased Cdx2 in dose-dependent manners. Functional analysis of human Cdx2 promoter also revealed its upregulation by HB-EGF stimulation, showing the role of potential responsive elements (AP-1 and NF-kB) for its transcriptional activation. Moreover, the columnar markers cytokeratin 7 and villin were also upregulated by HB-EGF stimulation. HB-EGF induces several genes characteristics of columnar phenotypes of esophageal squamous epithelium in a paracrine manner.

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Section: Predominance Of Hb-egf In Subepithelial Fibroblasts Of Humanmentioning

confidence: 99%

Fibroblast-derived HB-EGF promotes Cdx2 expression in esophageal squamous cells

Rahman

Kadowaki

Ishihara

et al. 2010

Laboratory Investigation

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“…IL-8 is a powerful chemoattractant and activator of leukocytes and other nonimmune cells. IL-8 levels in the esophagus correlate and increase with both endoscopic and histological disease severity (54,56,138). 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).…”

Section: Inflammatory Mediators In the Inflamed Esophageal Mucosamentioning

confidence: 99%

“…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.…”

Section: Inflammatory Mediators In the Inflamed Esophageal Mucosamentioning

confidence: 99%

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

Rieder

Biancani

Harnett

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

121

102

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Gastroesophageal reflux disease (GERD) is one of the most common problems in clinical practice today. It is widely believed that functional and structural abnormalities of the gastroesophageal junction as well as an abnormal exposure to gastroduodenal contents are the main contributors to its pathogenesis. Novel findings of the inflammatory process in GERD suggest a far more complex process involving multifaceted inflammatory mechanisms. This review summarizes knowledge about the expression of inflammatory mediators in GERD and their potential cellular sources and provides an integrated concept of disease pathogenesis. In addition we evaluate the contribution of inflammatory mediators to well-known complications of GERD, namely motility abnormalities, fibrosis, and carcinogenesis. Novel findings regarding the pathophysiology of esophageal inflammation should enhance our understanding of GERD and its complications and provide new treatment insights.

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“…Of note, Fitzgerald et al [7] reported significantly higher expression levels of interleukin 8 (IL-8) messenger ribonucleic acid (mRNA) in patients with reflux esophagitis (RE), assessed by competitive reverse transcriptase polymerase chain reaction (RT-PCR), compared with subjects with non-inflamed or Barrett's esophagus. Studies from our laboratories have also demonstrated high IL-8 protein levels in esophageal biopsy samples of patients with erosive esophagitis by enzyme linked immunosorbent assay (ELISA) [8] . Furthermore, we also showed significantly high mucosal IL-8 production, which paralleled the endoscopic severity of RE [8] .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, several studies have shown that mucosal immune and inflammatory responses, characterized by specific cytokine and chemokine profiles, may determine the diversity of esophageal phenotypes of GERD [7][8][9] . Of note, Fitzgerald et al [7] reported significantly higher expression levels of interleukin 8 (IL-8) messenger ribonucleic acid (mRNA) in patients with reflux esophagitis (RE), assessed by competitive reverse transcriptase polymerase chain reaction (RT-PCR), compared with subjects with non-inflamed or Barrett's esophagus.…”

Section: Introductionmentioning

confidence: 99%

Impact of endoscopically minimal involvement on IL-8 mRNA expression in esophageal mucosa of patients with non-erosive reflux disease

Kanazawa

Isomoto²,

Wen³

et al. 2003

WJG

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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.

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Elevated Levels of Chemokines in Esophageal Mucosa of Patients With Reflux Esophagitis

Abstract: Our results indicate that chemokines produced locally in the esophageal mucosa may be involved in the development and progression of RE.

Cited by 114 publications

References 24 publications

Fibroblast-derived HB-EGF promotes Cdx2 expression in esophageal squamous cells

Fibroblast-derived HB-EGF promotes Cdx2 expression in esophageal squamous cells

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

Impact of endoscopically minimal involvement on IL-8 mRNA expression in esophageal mucosa of patients with non-erosive reflux disease

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