Ahsen Ustaoglu1, Anh Nguyen2, Stuart Spechler2, Daniel Sifrim1, Rhonda Souza2, Philip Woodland1. 1. Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 2. Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, USA.
Abstract
BACKGROUND: Despite gastro-esophageal reflux disease affecting up to 20% of Western populations, relatively little is known about the molecular mechanisms underlying its most troublesome symptom: heartburn. Recent findings have unveiled the role of components of the esophageal mucosa in the pathogenesis of GERD including sensory nociceptive nerves and inflammatory mediators. Erosive esophagitis was long believed to develop as a result of acid injury at the esophageal lumen, but novel concepts suggest the generation of reflux-induced esophageal injury as a result of cytokine-mediated inflammation. Moreover, the localization and characterization of mucosal afferent nerves vary between GERD phenotypes and could explain the heterogeneity of symptom perception between patients who experience similar levels of acid reflux. PURPOSE: The purpose of this review is to consider the crosstalk of different factors of the esophageal mucosa in the pathogenesis of GERD, with a particular focus on mucosal innervation and molecular basis of acid-induced cytokine response. We discuss the current understanding of the mucosal response to acid injury, the nociceptive role of acid-sensitive receptors expressed in the esophageal mucosa, and the role of esophageal epithelial cells in initiating the onset of erosive esophagitis.
BACKGROUND: Despite gastro-esophageal reflux disease affecting up to 20% of Western populations, relatively little is known about the molecular mechanisms underlying its most troublesome symptom: heartburn. Recent findings have unveiled the role of components of the esophageal mucosa in the pathogenesis of GERD including sensory nociceptive nerves and inflammatory mediators. Erosive esophagitis was long believed to develop as a result of acid injury at the esophageal lumen, but novel concepts suggest the generation of reflux-induced esophageal injury as a result of cytokine-mediated inflammation. Moreover, the localization and characterization of mucosal afferent nerves vary between GERD phenotypes and could explain the heterogeneity of symptom perception between patients who experience similar levels of acid reflux. PURPOSE: The purpose of this review is to consider the crosstalk of different factors of the esophageal mucosa in the pathogenesis of GERD, with a particular focus on mucosal innervation and molecular basis of acid-induced cytokine response. We discuss the current understanding of the mucosal response to acid injury, the nociceptive role of acid-sensitive receptors expressed in the esophageal mucosa, and the role of esophageal epithelial cells in initiating the onset of erosive esophagitis.
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