Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents.
Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 alpha,beta-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.
Andrè
Eunice
E
Center of Excellence for the Study of Inflammation, University of Ferrara, Ferrara, Italy.
Campi
Barbara
B
Materazzi
Serena
S
Trevisani
Marcello
M
Amadesi
Silvia
S
Massi
Daniela
D
Creminon
Christophe
C
Vaksman
Natalya
N
Nassini
Romina
R
Civelli
Maurizio
M
Baraldi
Pier Giovanni
PG
Poole
Daniel P
DP
Bunnett
Nigel W
NW
Geppetti
Pierangelo
P
Patacchini
Riccardo
R
D000171:Acrolein / Q000031:analogs & derivatives / Q000494:pharmacology*; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D017487:Ankyrins; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D005727:Ganglia, Spinal / Q000166:cytology; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012906:Smoke; D013373:Substance P / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D014026:Nicotiana / Q000737:chemistry*; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000447:Aldehydes; D017487:Ankyrins; D015220:Calcium Channels; D012906:Smoke; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C480976:Trpa1 protein, rat; D013373:Substance P; D000171:Acrolein; C012796:2-butenal; D015740:Calcitonin Gene-Related Peptide; C012843:cinnamaldehyde