Substance P released by TRPV1-expressing neurons produces reactive oxygen species that mediate ethanol-induced gastric injury.
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.
Gazzieri
David
D
Center of Excellence for the Study of Inflammation, University of Ferrara, Viale Pieraccini 6, 50139 Florence, Italy.
Trevisani
Marcello
M
Springer
Jochen
J
Harrison
Selena
S
Cottrell
Graeme S
GS
Andre
Eunice
E
Nicoletti
Paola
P
Massi
Daniela
D
Zecchi
Sandra
S
Nosi
Daniele
D
Santucci
Marco
M
Gerard
Norma P
NP
Lucattelli
Monica
M
Lungarella
Giuseppe
G
Fischer
Axel
A
Grady
Eileen F
EF
Bunnett
Nigel W
NW
Geppetti
Pierangelo
P
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*
D002492:Central Nervous System Depressants; D017382:Reactive Oxygen Species; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; D013373:Substance P; D000431:Ethanol