title: Acrolein relaxes mouse isolated tracheal smooth muscle via a TRPA1-dependent mechanism.
abstract: Airway sensory C-fibres express TRPA1 channels which have recently been identified as a key chemosensory receptor for acrolein, a toxic and highly prevalent component of smoke. TRPA1 likely plays an intermediary role in eliciting a range of effects induced by acrolein including cough and neurogenic inflammation. Currently, it is not known whether acrolein-induced activation of TRPA1 produces other airway effects including relaxation of mouse airway smooth muscle. The aims of this study were to examine the effects of acrolein on airway smooth muscle tone in mouse isolated trachea, and to characterise the cellular and molecular mechanisms underpinning the effects of acrolein. Isometric tension recording studies were conducted on mouse isolated tracheal segments to characterise acrolein-induced relaxation responses. Release of the relaxant PGE₂ was measured by EIA to examine its role in the response. Use of selective antagonists/inhibitors permitted pharmacological characterisation of the molecular and cellular mechanisms underlying this relaxation response. Acrolein induced dose-dependent relaxation responses in mouse isolated tracheal segments. Importantly, these relaxation responses were significantly inhibited by the TRPA1 antagonists AP-18 and HC-030031, an NK₁ receptor antagonist RP-67580, and the EP₂ receptor antagonist PF-04418948, whilst completely abolished by the non-selective COX inhibitor indomethacin. Acrolein also caused rapid PGE₂ release which was suppressed by HC-030031. In summary, acrolein induced a novel bronchodilator response in mouse airways. Pharmacologic studies indicate that acrolein-induced relaxation likely involves interplay between TRPA1-expressing airway sensory C-fibres, NK₁ receptor-expressing epithelial cells, and EP₂-receptor expressing airway smooth muscle cells.
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Perth, Western Australia 6009, Australia. Electronic address: cheahe01@student.uwa.edu.au.
authors.forename: Esther Y
authors.initials: EY
authors.lastname: Cheah
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Perth, Western Australia 6009, Australia. Electronic address: Philip.Burcham@uwa.edu.au.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Burcham
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Perth, Western Australia 6009, Australia. Electronic address: Tracy.Mann@uwa.edu.au.
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Mann
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Perth, Western Australia 6009, Australia. Electronic address: Peter.Henry@uwa.edu.au.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Henry
mesh_terms: D000171:Acrolein / Q000494:pharmacology*; D000818:Animals; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D013373:Substance P / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D014132:Trachea / Q000187:drug effects* / Q000502:physiology; D050051:Transient Receptor Potential Channels / Q000502:physiology*
chemical_list: D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D013373:Substance P; D000171:Acrolein; D015232:Dinoprostone
keywords: AP-18 (PubChem CID: CID: 16725814); Acrolein; Acrolein (PubChem CID: 7847); Allyl Isothiocyanate (PubChem CID: 5971); Cinnamaldehyde (PubChem CID: 637511); Crotonaldehyde (PubChem CID 447466); EP receptors; HC-030031 (PubChem CID: 1150897); Mouse tracheal smooth muscle; NK(1) receptors; PF-04418948 (PubChem CID: 25114442); Prostaglandin E(2) (PubChem CID: 5280360); RP-67580 (PubChem CID: 107686); Relaxation; Substance P (PubChem CID: 36511); TRPA1