title: Substance P released by TRPV1-expressing neurons produces reactive oxygen species that mediate ethanol-induced gastric injury.
abstract: Although neurokinin 1 receptor antagonists prevent ethanol (EtOH)-induced gastric lesions, the mechanisms by which EtOH releases substance P (SP) and SP damages the mucosa are unknown. We hypothesized that EtOH activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to release SP, which stimulates epithelial neurokinin 1 receptors to generate damaging reactive oxygen species (ROS). SP release was assayed in the mouse stomach, ROS were detected using dichlorofluorescein diacetate, and neurokinin 1 receptors were localized by immunofluorescence. EtOH-induced SP release was prevented by TRPV1 antagonism. High dose EtOH caused lesions, and TRPV1 or neurokinin 1 receptor antagonism and neurokinin 1 receptor deletion inhibited lesion formation. Coadministration of low, innocuous doses of EtOH and SP caused lesions by a TRPV1-independent but neurokinin 1 receptor-dependent process. EtOH, capsaicin, and SP stimulated generation of ROS by superficial gastric epithelial cells expressing neurokinin 1 receptors by a neurokinin 1 receptor-dependent mechanism. ROS scavengers prevented lesions induced by a high EtOH dose or a low EtOH dose plus SP. Gastric lesions are caused by an initial detrimental effect of EtOH, which is damaging only if associated with TRPV1 activation, SP release from sensory nerves, stimulation of neurokinin 1 receptors on epithelial cells, and ROS generation.
authors.affiliation: Center of Excellence for the Study of Inflammation, University of Ferrara, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Gazzieri
authors.forename: Marcello
authors.initials: M
authors.lastname: Trevisani
authors.forename: Jochen
authors.initials: J
authors.lastname: Springer
authors.forename: Selena
authors.initials: S
authors.lastname: Harrison
authors.forename: Graeme S
authors.initials: GS
authors.lastname: Cottrell
authors.forename: Eunice
authors.initials: E
authors.lastname: Andre
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoletti
authors.forename: Daniela
authors.initials: D
authors.lastname: Massi
authors.forename: Sandra
authors.initials: S
authors.lastname: Zecchi
authors.forename: Daniele
authors.initials: D
authors.lastname: Nosi
authors.forename: Marco
authors.initials: M
authors.lastname: Santucci
authors.forename: Norma P
authors.initials: NP
authors.lastname: Gerard
authors.forename: Monica
authors.initials: M
authors.lastname: Lucattelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lungarella
authors.forename: Axel
authors.initials: A
authors.lastname: Fischer
authors.forename: Eileen F
authors.initials: EF
authors.lastname: Grady
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000633:toxicity; D000431:Ethanol / Q000633:toxicity*; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013373:Substance P / Q000187:drug effects / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D002492:Central Nervous System Depressants; D017382:Reactive Oxygen Species; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; D013373:Substance P; D000431:Ethanol