title: Allergen challenge sensitizes TRPA1 in vagal sensory neurons and afferent C-fiber subtypes in guinea pig esophagus.
abstract: Transient receptor potential A1 (TRPA1) is a newly defined cationic ion channel, which selectively expresses in primary sensory afferent nerve, and is essential in mediating inflammatory nociception. Our previous study demonstrated that TRPA1 plays an important role in tissue mast cell activation-induced increase in the excitability of esophageal vagal nodose C fibers. The present study aims to determine whether prolonged antigen exposure in vivo sensitizes TRPA1 in a guinea pig model of eosinophilic esophagitis (EoE). Antigen challenge-induced responses in esophageal mucosa were first assessed by histological stains and Ussing chamber studies. TRPA1 function in vagal sensory neurons was then studied by calcium imaging and by whole cell patch-clamp recordings in 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal vagal nodose and jugular neurons. Extracellular single-unit recordings were performed in vagal nodose and jugular C-fiber neuron subtypes using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Antigen challenge significantly increased infiltrations of eosinophils and mast cells in the esophagus. TRPA1 agonist allyl isothiocyanate (AITC)-induced calcium influx in nodose and jugular neurons was significantly increased, and current densities in esophageal DiI-labeled nodose and jugular neurons were also significantly increased in antigen-challenged animals. Prolonged antigen challenge decreased esophageal epithelial barrier resistance, which allowed intraesophageal-infused AITC-activating nodose and jugular C fibers at their nerve endings. Collectively, these results demonstrated that prolonged antigen challenge sensitized TRPA1 in esophageal sensory neurons and afferent C fibers. This novel finding will help us to better understand the molecular mechanism underlying esophageal sensory and motor dysfunctions in EoE.
authors.affiliation: Division of Gastroenterology, Peking University Shenzhen Hospital, Shenzhen, China; 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: Youtian
authors.initials: Y
authors.lastname: Hu
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 Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Jiefeng
authors.initials: J
authors.lastname: Xi
authors.affiliation: Division of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Tse
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Allen C
authors.initials: AC
authors.lastname: Myers
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 Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Xingde
authors.initials: X
authors.lastname: Li
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: D000200:Action Potentials; D000485:Allergens; D000818:Animals; D020013:Calcium Signaling; D004195:Disease Models, Animal; D057765:Eosinophilic Esophagitis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D004947:Esophagus / Q000294:innervation*; D006168:Guinea Pigs; D017879:Isothiocyanates / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009620:Nodose Ganglion / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin; D012677:Sensation; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D014630:Vagus Nerve / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000485:Allergens; D017879:Isothiocyanates; D050051:Transient Receptor Potential Channels; D010047:Ovalbumin; C004471:allyl isothiocyanate
keywords: dysphagia; eosinophilic esophagitis; heartburn; jugular; nodose