Distinct afferent innervation patterns within the human proximal and distal esophageal mucosa.

Philip Woodland,Daniel Sifrim,Chung Lee,L Ashley Blackshaw,Engelbert Mthunzi,Sean L Preston,Rubina Aktar,Madusha Peiris

doi:10.1152/ajpgi.00175.2014

Philip Woodland, Daniel Sifrim + Show 6 more

Open Access

https://doi.org/10.1152/ajpgi.00175.2014

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Abstract

Little is known about the mucosal phenotype of the proximal human esophagus. There is evidence to suggest that the proximal esophagus is more sensitive to chemical and mechanical stimulation compared with the distal. This may have physiological relevance (e.g., in prevention of aspiration of gastroesophageal refluxate), but also pathological relevance (e.g., in reflux perception or dysphagia). Reasons for this increased sensitivity are unclear but may include impairment in mucosal barrier integrity or changes in sensory innervation. We assessed mucosal barrier integrity and afferent nerve distribution in the proximal and distal esophagus of healthy human volunteers. In 10 healthy volunteers baseline proximal and distal esophageal impedance was measured in vivo. Esophageal mucosal biopsies from the distal and proximal esophagus were taken, and baseline transepithelial electrical resistance (TER) was measured in Ussing chambers. Biopsies were examined immunohistochemically for presence and location of calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers. In a further four healthy volunteers we investigated for colocalization of CGRP and protein gene product (PGP) 9.5 immunoreactivity in nerve fibers. Baseline impedance was higher in the proximal than in the distal esophagus [2,936 Ω (SD578) vs. 2,229 Ω (SD821); P = 0.03], however, baseline TER was not significantly different between them. Mucosal CGRP-immunoreactive nerves were found in the epithelium of both proximal and distal esophagus, but were located more superficially in the proximal mucosa compared with the distal [11.5 (SD7) vs. 21.7 (SD5) cell layers from lumen, P = 0.002] 19% of proximal, and 10% of distal mucosal PGP-immunoreactive fibers colocalized with CGRP. PGP-immunoreactive fibers were also significantly closer to the luminal surface in the proximal compared with the distal esophagus (P < 0.001). We conclude that mucosal barrier integrity is similar in proximal and distal esophagus, but proximal mucosal afferent nerves are in a more superficial location. The enhanced sensitivity to reflux-evoked symptoms of the proximal esophagus most likely has an anatomical basis.

Highlights

HISTORICALLY, THE DISTAL ESOPHAGUS has been the focus of investigation into pathogenesis of esophageal sensation in disease [such as in gastroesophageal reflux disease (GERD)]
In GERD patients refractory to proton pump inhibitor (PPI), impedance-pH studies “on” therapy have indicated that a high proximal extent is the most important factor in determining whether or not a reflux episode will be perceived by the patient [28, 36]
This study provides a novel insight into the sensory contrast between the proximal and distal esophageal mucosa

Summary

Introduction

HISTORICALLY, THE DISTAL ESOPHAGUS has been the focus of investigation into pathogenesis of esophageal sensation in disease [such as in gastroesophageal reflux disease (GERD)]. In patients with GERD, reflux events reaching the proximal esophagus are more likely to be perceived than those reaching only the distal esophagus [3, 32]. It is known that differences in permeability of the distal esophageal mucosa can be important in pathogenesis of reflux disease, whereby a weaker mucosa may allow greater access of noxious intraluminal components to nociceptive afferent fibers. Such impairment of mucosal integrity can be demonstrated functionally ex vivo and in vivo [35]. Subjects who perceive an acid challenge as heartburn have a lower baseline distal esophageal impedance than those who do not [33]

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