Gastroenterology

Gastroenterology

Volume 137, Issue 5, November 2009, Pages 1776-1784
Gastroenterology

Basic—Alimentary Tract
Gastroesophageal Reflux Might Cause Esophagitis Through a Cytokine-Mediated Mechanism Rather Than Caustic Acid Injury

https://doi.org/10.1053/j.gastro.2009.07.055Get rights and content

Background & Aims

Reflux esophagitis is believed to be caused by the caustic effects of refluxed gastric acid on esophageal epithelial cells. However, caustic chemical injuries develop rapidly whereas esophagitis might not appear until weeks after the induction of reflux in animal models. We studied early histologic events in the development of reflux esophagitis in a rat model and performed in vitro experiments to determine whether exposure to acidified bile salts causes esophageal epithelial cells to secrete chemokines that might contribute to inflammation.

Methods

At various time points after esophagoduodenostomy, the rat esophagus was removed and inflammatory changes were analyzed by histologic analyses. Human esophageal squamous cell lines were exposed to acidified bile salts to evaluate their effects on cytokine production and immune-cell migration.

Results

Reflux esophagitis started at postoperative day 3 with lymphocytic infiltration of the submucosa that progressed to the epithelial surface—these findings contradicted those expected from a caustic chemical injury. Basal cell and papillary hyperplasia preceded the development of surface erosions. Exposure of squamous cells to acidified bile salts significantly increased the secretion of interleukin-8 and interleukin-1β; conditioned media from these cells caused significant increases in the migration rates of T cells and neutrophils.

Conclusions

These findings support, but do not prove, an alternative concept for the development of reflux esophagitis in which refluxed gastric juice does not directly damage the esophagus, but rather stimulates esophageal epithelial cells to secrete chemokines that mediate damage of esophageal tissue.

Section snippets

Rat model of reflux esophagitis (esophagoduodenostomy)

This study was approved by the animal care committee of the Dallas VA Medical Center. Six-week-old male Sprague–Dawley rats (Charles River Laboratories, Wilmington, MA) were housed 2 per cage under standard laboratory conditions.

Esophagoduodenostomy was performed in 34 animals using a modification of the esophagojejunostomy technique described by Buttar et al.11 This surgery left the vagally innervated stomach in place so that both gastric and duodenal contents could reflux into the esophagus.

Time course and distribution of tissue inflammation in the distal esophagus

In the sham-operated control animals, no inflammation was observed in any tissue layer of the distal esophagus (Figure 1). In animals that had an esophagoduodenostomy, in contrast, esophageal inflammation was observed at day 3, which was most prominent in the submucosa (Figure 2). Inflammation increased to first reach significantly increased levels in the lamina propria by week 1 and in the epithelial layer by week 3 (Figure 2). From weeks 3 to 8, the overall degree of inflammation remained

Discussion

The development of reflux esophagitis that we have observed in our systematic histologic study of the rat esophagus after esophagoduodenostomy is not consistent with the prevailing concept of reflux esophagitis as a caustic chemical injury. An esophageal injury caused by the direct toxic effects of refluxed gastric acid would be expected to start with the death of surface epithelial cells, which would evoke an acute inflammatory response with epithelial infiltration by polymorphonuclear cells.

References (36)

  • W.K. Kauer et al.

    Composition and concentration of bile acid reflux into the esophagus of patients with gastroesophageal reflux disease

    Surgery

    (1997)
  • S.A. Zargar et al.

    Ingestion of corrosive acidsSpectrum of injury to upper gastrointestinal tract and natural history

    Gastroenterology

    (1989)
  • H.I. Goldberg et al.

    Role of acid and pepsin in acute experimental esophagitis

    Gastroenterology

    (1969)
  • H. Isomoto et al.

    Elevated levels of chemokines in esophageal mucosa of patients with reflux esophagitis

    Am J Gastroenterol

    (2003)
  • D.O. Castell et al.

    Review article: the pathophysiology of gastrooesophageal reflux disease—oesophageal manifestations

    Aliment Pharmacol Ther

    (2004)
  • H. Thangarajah et al.

    Gastric H-K-ATPase and acid-resistant surface proteins

    Am J Physiol Gastrointest Liver Physiol

    (2002)
  • R.C. Orlando

    Pathophysiology of gastroesophageal reflux disease

    J Clin Gastroenterol

    (2008)
  • P. Zentilin et al.

    Reassessment of the diagnostic value of histology in patients with GERD, using multiple biopsy sites and an appropriate control group

    Am J Gastroenterol

    (2005)
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      Citation Excerpt :

      A clinical study of the RE pathogenesis explored the hypothesis that the development of RE is cytokine-mediated injury rather than acid burn (Dunbar et al., 2016). Refluxed gastric juice stimulated esophageal epithelial cells to secrete cytokines that induce epithelial proliferative changes, attract the T lymphocytes and other inflammatory cells that eventually destroy the mucosa instead of killing esophageal epithelial cells directly (Souza et al., 2009). Overdosed and continuous gastroesophageal reflux may activate inflammatory pathways, trigger more release of cytokines and chemokines from injured cells and impair mucosal barrier function (Orlando, 2010; Woodland et al., 2013).

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the Office of Medical Research, Department of Veterans Affairs (R.F.S. and S.J.S.), and the National Institutes of Health (DK63621 to R.F.S. and CA134571 to R.F.S. and S.J.S.).

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