title: Allergic sensitization enhances anion current responsiveness of murine trachea to PAR-2 activation.
abstract: Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor possibly involved in the pathogenesis of asthma. PAR-2 also modulates ion transport in cultured epithelial cells, but these effects in native airways are controversial. The influence of allergic inflammation on PAR-2-induced changes in ion transport has received little attention. Here, we studied immediate changes in transepithelial short circuit current (I                         (sc)) induced by PAR-2 activation in the tracheas of naive and allergic mice. Activation of PAR-2 with an apically added activation peptide (AP) induced a small increase in I                         (sc), while a much larger increase was observed following basolateral AP addition. In ovalbumin-sensitized and -challenged animals used as a model of allergic airway inflammation, the effect of basolateral AP addition was enhanced. Responses to basolateral AP in both naive and allergic mice were not decreased by blocking sodium absorption with amiloride or CFTR function with CFTR(inh)172 but were reduced by the cyclooxygenase inhibitor indomethacin and largely blocked (>80%) by niflumic acid, a calcium-activated chloride channels' (CaCC) blocker. Allergic mice also showed an enhanced response to ATP and thapsigargin. There was no change in mRNA expression of Par-2 or of the chloride channels Ano1 (Tmem16a) and Bestrophin 2 in tracheas from allergic mice, while mRNA levels of Bestrophin 1 were increased. In conclusion, basolateral PAR-2 activation in the mouse airways led to increased anion secretion through apical CaCC, which was more pronounced in allergic animals. This could be a protective mechanism aimed at clearing allergens and defending against mucus plugging.
authors.affiliation: Pulmonary Research Group, Department of Medicine, University of Alberta, 550 Heritage Medical Research Center, Edmonton, Alberta, Canada.
authors.forename: Juraj
authors.initials: J
authors.lastname: Rievaj
authors.forename: Courtney
authors.initials: C
authors.lastname: Davidson
authors.forename: Ahmed
authors.initials: A
authors.lastname: Nadeem
authors.forename: Morley
authors.initials: M
authors.lastname: Hollenberg
authors.forename: Marek
authors.initials: M
authors.lastname: Duszyk
authors.forename: Harissios
authors.initials: H
authors.lastname: Vliagoftis
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000503:physiopathology; D001565:Benzoates / Q000494:pharmacology; D000075002:Bestrophins; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D005136:Eye Proteins / Q000096:biosynthesis; D006967:Hypersensitivity / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D007473:Ion Channels / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009544:Niflumic Acid / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010047:Ovalbumin; D044464:Receptor, PAR-2 / Q000187:drug effects / Q000502:physiology*; D053778:Thiazolidines / Q000494:pharmacology; D014136:Tracheitis / Q000503:physiopathology*
chemical_list: C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001565:Benzoates; C491856:Best1 protein, mouse; D000075002:Bestrophins; D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D005136:Eye Proteins; D007473:Ion Channels; D009842:Oligopeptides; D044464:Receptor, PAR-2; D053778:Thiazolidines; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; D009544:Niflumic Acid; D000584:Amiloride; D010047:Ovalbumin; D007213:Indomethacin