title: Distinct afferent innervation patterns within the human proximal and distal esophageal mucosa.
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.
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Woodland
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Rubina
authors.initials: R
authors.lastname: Aktar
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Engelbert
authors.initials: E
authors.lastname: Mthunzi
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Madusha
authors.initials: M
authors.lastname: Peiris
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Sean L
authors.initials: SL
authors.lastname: Preston
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: L Ashley
authors.identifier: http://orcid.org/0000-0003-1565-0850
authors.initials: LA
authors.lastname: Blackshaw
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom d.sifrim@qmul.ac.uk.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sifrim
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis; D017097:Electric Impedance; D004947:Esophagus / Q000294:innervation*; D064368:Healthy Volunteers; D006801:Humans; D009092:Mucous Membrane / Q000294:innervation*; D009475:Neurons, Afferent / Q000737:chemistry / Q000502:physiology*; D010539:Permeability; D012677:Sensation; D015398:Signal Transduction; D043222:Ubiquitin Thiolesterase / Q000032:analysis; D055815:Young Adult
chemical_list: D015415:Biomarkers; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase; D015740:Calcitonin Gene-Related Peptide
keywords: afferent neurons; gastroesophageal reflux; impedance; mucosal integrity; peripheral sensitization