Transient receptor potential ankyrin-1 causes rapid bronchodilation via nonepithelial PGE2

Am J Physiol Lung Cell Mol Physiol. 2020 May 1;318(5):L943-L952. doi: 10.1152/ajplung.00277.2019. Epub 2020 Apr 1.


Transient receptor potential ankyrin-1 (TRPA1) is a ligand-gated cation channel that responds to endogenous and exogenous irritants. TRPA1 is expressed on multiple cell types throughout the lungs, but previous studies have primarily focused on TRPA1 stimulation of airway sensory nerves. We sought to understand the integrated physiological airway response to TRPA1 stimulation. The TRPA1 agonists allyl isothiocyanate (AITC) and cinnamaldehyde (CINN) were tested in sedated, mechanically ventilated guinea pigs in vivo. Reproducible bronchoconstrictions were induced by electrical stimulation of the vagus nerves. Animals were then treated with intravenous AITC or CINN. AITC and CINN were also tested on isolated guinea pig and mouse tracheas and postmortem human trachealis muscle strips in an organ bath. Tissues were contracted with methacholine, histamine, or potassium chloride and then treated with AITC or CINN. Some airways were pretreated with TRPA1 antagonists, the cyclooxygenase inhibitor indomethacin, the EP2 receptor antagonist PF 04418948, or tetrodotoxin. AITC and CINN blocked vagally mediated bronchoconstriction in guinea pigs. Pretreatment with indomethacin completely abolished the airway response to TRPA1 agonists. Similarly, AITC and CINN dose-dependently relaxed precontracted guinea pig, mouse, and human airways in the organ bath. AITC- and CINN-induced airway relaxation required TRPA1, prostaglandins, and PGE2 receptor activation. TRPA1-induced airway relaxation did not require epithelium or tetrodotoxin-sensitive nerves. Finally, AITC blocked airway hyperreactivity in two animal models of allergic asthma. These data demonstrate that stimulation of TRPA1 causes bronchodilation of intact airways and suggest that the TRPA1 pathway is a potential pharmacological target for bronchodilation.

Keywords: TRPA1; allyl isothiocyanate; bronchodilation; cinnamaldehyde.

Publication types

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

MeSH terms

  • Acrolein / analogs & derivatives
  • Acrolein / pharmacology
  • Animals
  • Bronchoconstriction / drug effects
  • Dinoprostone / metabolism*
  • Electric Stimulation
  • Gene Expression Regulation
  • Guinea Pigs
  • Histamine / pharmacology
  • Humans
  • Indomethacin / pharmacology
  • Isothiocyanates / pharmacology
  • Male
  • Methacholine Chloride / pharmacology
  • Mice
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism*
  • Organ Culture Techniques
  • Potassium Chloride / pharmacology
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Respiration, Artificial
  • Signal Transduction
  • TRPA1 Cation Channel / agonists
  • TRPA1 Cation Channel / antagonists & inhibitors
  • TRPA1 Cation Channel / genetics*
  • TRPA1 Cation Channel / metabolism
  • Tetrodotoxin / pharmacology
  • Trachea / drug effects
  • Trachea / metabolism*
  • Vagus Nerve / physiology


  • Isothiocyanates
  • TRPA1 Cation Channel
  • Methacholine Chloride
  • Tetrodotoxin
  • Potassium Chloride
  • Acrolein
  • Histamine
  • allyl isothiocyanate
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone
  • cinnamaldehyde
  • Indomethacin