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

Abstract

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.

Fig. 1.

A: multidirectional model of interactions between immune and nonimmune cells in gastroesophageal reflux disease (GERD)-induced inflammation of the esophagus. This also explains the development of complications in patients with GERD such as motility disturbances, fibrosis, and carcinogenesis. B: hematoxylin and eosin staining of GERD affected vs. control mucosa. In GERD a nonspecific infiltrate of inflammatory immune cells can be seen. Magnification ×10 and ×40.

Fig. 2.

Working model for the effect of inflammatory mediators on muscle contraction. Acid reflux in the esophagus causes formation of platelet-activating factor (PAF) by the esophageal mucosa. PAF is then released from the mucosa to activate the circular muscle, causing the sequential production of IL-6, H₂O₂, and IL-1β. H₂O₂ and IL-1β induce production of PAF and IL-6, all of which are known to depress neurogenic muscle contraction by inhibiting release of ACh.

Fig. 3.

A: working model for esophageal fibrosis. Chronic inflammation can drive fibrogenesis. This process involves essentially all cell types that can contribute to the activation of local mesenchymal cells. B: Masson trichrome staining of a peptic esophageal stricture. Collagen fibers are depicted in blue. Massive subepithelial and submucosal collagen accumulation (*) with neoangiogenesis and an inflammatory infiltrate (arrows) can be noted. Magnification ×10.

Fig. 4.

Mechanisms of inflammation induced carcinogenesis in GERD. Genetic alterations and increased cellular regeneration link an inflamed and damaged epithelium to metaplasia, dysplasia, and carcinoma. IL-1ra, IL-1 receptor antagonist.