title: Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-Cβ.
abstract: Enhanced contractility of airway smooth muscle (ASM) is a major pathophysiological characteristic of asthma. Expanding the therapeutic armamentarium beyond β-agonists that target ASM hypercontractility would substantially improve treatment options. Recent studies have identified naturally occurring phytochemicals as candidates for acute ASM relaxation. Several flavonoids were evaluated for their ability to acutely relax human and murine ASM ex vivo and murine airways in vivo and were evaluated for their ability to inhibit procontractile signaling pathways in human ASM (hASM) cells. Two members of the flavonol subfamily, galangin and fisetin, significantly relaxed acetylcholine-precontracted murine tracheal rings ex vivo (n = 4 and n = 5, respectively, P < 0.001). Galangin and fisetin also relaxed acetylcholine-precontracted hASM strips ex vivo (n = 6-8, P < 0.001). Functional respiratory in vivo murine studies demonstrated that inhaled galangin attenuated the increase in lung resistance induced by inhaled methacholine (n = 6, P < 0.01). Both flavonols, galangin and fisetin, significantly inhibited purified phosphodiesterase-4 (PDE4) (n = 7, P < 0.05; n = 7, P < 0.05, respectively), and PLCβ enzymes (n = 6, P < 0.001 and n = 6, P < 0.001, respectively) attenuated procontractile Gq agonists' increase in intracellular calcium (n = 11, P < 0.001), acetylcholine-induced increases in inositol phosphates, and CPI-17 phosphorylation (n = 9, P < 0.01) in hASM cells. The prorelaxant effect retained in these structurally similar flavonols provides a novel pharmacological method for dual inhibition of PLCβ and PDE4 and therefore may serve as a potential treatment option for acute ASM constriction.
authors.affiliation: Division of Pediatric Pulmonology, Department of Pediatrics College of Physicians and Surgeons of Columbia University, New York, New York;
authors.forename: Amy
authors.initials: A
authors.lastname: Brown
authors.affiliation: Department of Anesthesiology College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Danielsson
authors.affiliation: Department of Anesthesiology College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Townsend
authors.affiliation: Department of Anesthesiology College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, Texas.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Perez-Zoghbi
authors.affiliation: Department of Anesthesiology College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
authors.affiliation: Department of Anesthesiology College of Physicians and Surgeons of Columbia University, New York, New York; and gg2125@cumc.columbia.edu.
authors.forename: George
authors.initials: G
authors.lastname: Gallos
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001249:Asthma / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects; D020013:Calcium Signaling; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D051379:Mice; D009119:Muscle Contraction; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D054799:Phospholipase C beta / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D005419:Flavonoids; D044948:Flavonols; D058988:Phosphodiesterase 4 Inhibitors; C037032:galangin; D015544:Inositol 1,4,5-Trisphosphate; D054799:Phospholipase C beta; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C017875:fisetin
keywords: bronchodilation; flexiVent; myograph; phosphodiesterase; phytochemical