title: Increased acid responsiveness in vagal sensory neurons in a guinea pig model of eosinophilic esophagitis.
abstract: Eosinophilic esophagitis (EoE) is characterized with eosinophils and mast cells predominated allergic inflammation in the esophagus and present with esophageal dysfunctions such as dysphagia, food impaction, and heartburn. However, the underlying mechanism of esophageal dysfunctions is unclear. This study aims to determine whether neurons in the vagal sensory ganglia are modulated in a guinea pig model of EoE. Animals were actively sensitized by ovalbumin (OVA) and then challenged with aerosol OVA inhalation for 2 wk. This results in a mild esophagitis with increases in mast cells and eosinophils in the esophageal wall. Vagal nodose and jugular neurons were disassociated, and their responses to acid, capsaicin, and transient receptor potential vanilloid type 1 (TRPV1) antagonist AMG-9810 were studied by calcium imaging and whole cell patch-clamp recording. Compared with naïve animals, antigen challenge significantly increased acid responsiveness in both nodose and jugular neurons. Their responses to capsaicin were also increased after antigen challenge. AMG-9810, at a concentration that blocked capsaicin-evoked calcium influx, abolished the increase in acid-induced activation in both nodose and jugular neurons. Vagotomy strongly attenuated those increased responses of nodose and jugular neurons to both acid and capsaicin induced by antigen challenge. These data for the first time demonstrated that prolonged antigen challenge significantly increases acid responsiveness in vagal nodose and jugular ganglia neurons. This sensitization effect is mediated largely through TRPV1 and initiated at sensory nerve endings in the peripheral tissues. Allergen-induced enhancement of responsiveness to noxious stimulation by acid in sensory nerve may contribute to the development of esophageal dysfunctions such as heartburn in EoE.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Youtian
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Pankaj J
authors.initials: PJ
authors.lastname: Pasricha
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Undem
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland syyu@jhmi.edu.
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Yu
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D057765:Eosinophilic Esophagitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D004947:Esophagus / Q000294:innervation*; D006168:Guinea Pigs; D006356:Heartburn / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D006863:Hydrogen-Ion Concentration; D008297:Male; D008564:Membrane Potentials; D009620:Nodose Ganglion / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D010047:Ovalbumin; D050916:TRPV Cation Channels / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery
chemical_list: C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; D000178:Acrylamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050916:TRPV Cation Channels; D010047:Ovalbumin; D002211:Capsaicin
keywords: antigen; transient receptor potential vanilloid type 1