title: Transient receptor potential vanilloid 4 activation constricts the human bronchus via the release of cysteinyl leukotrienes.
abstract: Prior studies have demonstrated that the ion channel transient receptor potential vanilloid 4 (TRPV4) is functionally expressed in airway smooth muscle cells and that TRPV4 single nucleotide polymorphisms are associated with airflow obstruction in patients with chronic obstructive pulmonary disease. We sought to use isometric tension measurements in ex vivo airways to determine whether short-term pharmacological activation of TRPV4 with the potent agonist GSK1016790 [N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide] would constrict human bronchial tissue. As predicted, transient receptor potential vanilloid 4 activation in the human airway produces contractions that are blocked by the nonselective transient receptor potential channel blocker ruthenium red. Moreover, the novel TRPV4-selective blocker GSK2334775 [(R)-6-(methylsulfonyl)-3-((4-(pyrrolidin-1-yl)piperindin-1-yl)methyl)-N-(2,2,2,-trifluoro-1-phenylethyl)-2-(3-(trifluoromethyl)phenyl)quinoline-4-carboxamide] inhibited these contractions over a concentration range consistent with its in vitro potency against recombinant and native TRPV4-containing channels. Surprisingly, TRPV4-dependent contractions were also blocked by a 5-lipoxygenase inhibitor and two structurally distinct cysteinyl leukotriene 1 receptor antagonists. In aggregate, our results fail to support the hypothesis that TRPV4 in airway smooth muscle cells regulates airway contractility short term. Rather, we provide pharmacological evidence that TRPV4 activation causes human airway constriction that is entirely dependent upon the production of cysteinyl leukotrienes. Together, these data identify a novel mechanism by which TRPV4 activation may contribute to pathologic remodeling and inflammation, in addition to airflow obstruction, in the diseased human respiratory tract.
authors: Respiratory Therapy Area, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania (M.A.M., M.A.L., G.E.H.); and Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, Maryland (B.J.U.).
authors: M Allen
authors: MA
authors: McAlexander
authors: Mark A
authors: MA
authors: Luttmann
authors: Gerald E
authors: GE
authors: Hunsberger
authors: Bradley J
authors: BJ
authors: Undem
mesh_terms: D000328:Adult; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018077:Receptors, Leukotriene / Q000378:metabolism; D012430:Ruthenium Red / Q000494:pharmacology; D013045:Species Specificity; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists* / Q000037:antagonists & inhibitors
chemical_list: C588264:6-(methylsulfonyl)-3-((4-(pyrrolidin-1-yl)piperindin-1-yl)methyl)-N-(2,2,2,-trifluoro-1-phenylethyl)-2-(3-(trifluoromethyl)phenyl)quinoline-4-carboxamide; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D011804:Quinolines; D018077:Receptors, Leukotriene; D013449:Sulfonamides; D013450:Sulfones; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C112381:cysteinyl-leukotriene; D012430:Ruthenium Red; D001094:Arachidonate 5-Lipoxygenase; D007930:Leucine; D003545:Cysteine; C083169:leukotriene D4 receptor; D002118:Calcium