TY - JOUR
T1 - Substance P released by TRPV1-expressing neurons produces reactive oxygen species that mediate ethanol-induced gastric injury
AU - Gazzieri, David
AU - Trevisani, Marcello
AU - Springer, Jochen
AU - Harrison, Selena
AU - Cottrell, Graeme S.
AU - Andre, Eunice
AU - Nicoletti, Paola
AU - Massi, Daniela
AU - Zecchi, Sandra
AU - Nosi, Daniele
AU - Santucci, Marco
AU - Gerard, Norma P.
AU - Lucattelli, Monica
AU - Lungarella, Giuseppe
AU - Fischer, Axel
AU - Grady, Eileen F.
AU - Bunnett, Nigel W.
AU - Geppetti, Pierangelo
N1 - Funding Information:
This work was supported by MIUR, Rome (PRIN 2003054380), and NIH (DK39957, DK43207, DK57840, DK52388).
PY - 2007/8/15
Y1 - 2007/8/15
N2 - 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.
AB - 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.
KW - Ethanol
KW - Gastric lesions
KW - Reactive oxygen species
KW - Substance P
KW - TRPV1
UR - http://www.scopus.com/inward/record.url?scp=34447308497&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2007.05.018
DO - 10.1016/j.freeradbiomed.2007.05.018
M3 - Article
C2 - 17640568
AN - SCOPUS:34447308497
SN - 0891-5849
VL - 43
SP - 581
EP - 589
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 4
ER -