Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents

J Clin Invest. 2008 Jul;118(7):2574-82. doi: 10.1172/JCI34886.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrolein / analogs & derivatives
  • Acrolein / pharmacology*
  • Aldehydes / pharmacology*
  • Animals
  • Ankyrins
  • Calcitonin Gene-Related Peptide / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / physiology
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Cell Line
  • Ganglia, Spinal / cytology
  • Guinea Pigs
  • Humans
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurogenic Inflammation / chemically induced
  • Neurogenic Inflammation / metabolism
  • Neurogenic Inflammation / physiopathology*
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism
  • Rats
  • Smoke*
  • Substance P / metabolism
  • TRPA1 Cation Channel
  • TRPC Cation Channels
  • Tobacco / chemistry*
  • Transient Receptor Potential Channels / agonists
  • Transient Receptor Potential Channels / antagonists & inhibitors
  • Transient Receptor Potential Channels / deficiency
  • Transient Receptor Potential Channels / genetics
  • Transient Receptor Potential Channels / physiology*

Substances

  • Aldehydes
  • Ankyrins
  • Calcium Channels
  • Smoke
  • TRPA1 Cation Channel
  • TRPC Cation Channels
  • Transient Receptor Potential Channels
  • Trpa1 protein, mouse
  • Trpa1 protein, rat
  • Substance P
  • Acrolein
  • 2-butenal
  • Calcitonin Gene-Related Peptide
  • cinnamaldehyde