Gastroenterology

Gastroenterology

Volume 132, Issue 1, January 2007, Pages 154-165
Gastroenterology

Basic–alimentary tract
Gastroesophageal Reflux Disease–Associated Esophagitis Induces Endogenous Cytokine Production Leading to Motor Abnormalities

https://doi.org/10.1053/j.gastro.2006.10.009Get rights and content

Background & Aims: Gastroesophageal reflux disease is a condition frequently associated with esophagitis and motor abnormalities. Recent evidence suggests that proinflammatory cytokines, such as interleukin (IL)-1β and IL-6, may be implicated because they reduce esophageal muscle contractility, but these results derive from in vitro or animal models of esophagitis. This study used human esophageal cells and tissues to identify the cellular source of cytokines in human esophagitis investigate whether cytokines can be induced by gastric refluxate, and examine whether esophageal tissue– or cell-derived mediators affect muscle contractility. Methods: Endoscopic mucosal biopsy specimens were obtained from patients with and without esophagitis, organ-cultured, and undernatants were assessed for cytokine content. The cytokine profile of esophageal epithelial, fibroblast, and muscle cells was analyzed, and esophageal mucosa and cell products were tested in an esophageal circular muscle contraction assay. Results: The mucosa of esophagitis patients produced significantly greater amounts of IL-1β and IL-6 compared with those of control patients. Cultured esophageal epithelial cells produced IL-6, as did fibroblasts and muscle cells. Epithelial cells exposed to buffered, but not denatured, gastric juice produced IL-6. Undernatants of mucosal biopsy cultures from esophagitis patients reduced esophageal muscle contraction, as did supernatants from esophageal epithelial cell cultures. Conclusions: The human esophagus produces cytokines capable of reducing contractility of esophageal muscle cells. Exposure to gastric juice is sufficient to stimulate esophageal epithelial cells to produce IL-6, a cytokine able to alter esophageal contractility. These results indicate that classic cytokines are important mediators of the motor disturbances associated with human esophageal inflammation.

Section snippets

Patient Population and Procurement of Endoscopic Mucosal Biopsy Specimens

Mucosal biopsy specimens were obtained during videoendoscopy from the upper, middle, and lower thirds of the esophagus of patients with a clinical history compatible with GERD and patients with other non-GERD symptoms requiring upper endoscopic examination According to the endoscopic appearance of the esophageal mucosa, patients were divided into 2 groups (Table 1). The first group included subjects with symptoms of GERD and clear endoscopic and histologic signs of reflux esophagitis (n = 26),

Enhanced Production of IL-1β and IL-6 in Mucosal Biopsy Specimens of Esophagitis Patients

The nature of the tissue response in patients with GERD symptoms or reflux esophagitis-associated inflammation is poorly defined. By using a mucosal biopsy organ culture system, we initially investigated the production of cytokines with a broad spectrum of inflammatory activities, including IL-1β, IL-6, and TNF-α, as well as cytokines associated with tissue eosinophilia, including IL-4, IL-5, and eotaxin.34, 35 IL-1β was detected exclusively in the undernatants of mucosa obtained from patients

Discussion

Gastrointestinal inflammation can result in abnormal motility,4 but because each bowel segment displays different anatomic and functional characteristics, distinct inflammatory conditions trigger disturbances through different mechanisms. The motor disturbances seen in GERD suggest a direct cause-and-effect relationship with local inflammation, but the pathophysiologic basis for such a relationship still is unclear. The paucity of studies performed with human tissues and cells hampers progress

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    Supported by grants from the National Institutes of Health (DK30399 and DK50984 to C.F.; DK57030 to P.B.). The authors acknowledge the contribution of the Institute of Pathology of University Hospitals of Cleveland. Tissue samples were provided by the Human Tissue Procurement Facility of University Hospitals of Cleveland, Cleveland, Ohio.

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