title: Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate.
abstract: In this study, we used cre-lox techniques to generate mice selectively deficient in ORMDL3 in airway epithelium (Ormdl3Δ2-3/Δ2-3/CC10) to simulate an inhaled therapy that effectively inhibited ORMDL3 expression in the airway. In contrast to the anticipated reduction in airway hyperresponsiveness (AHR), OVA allergen-challengedOrmdl3Δ2-3/Δ2-3/CC10mice had a significant increase in AHR compared with wild-type mice. Levels of airway inflammation, mucus, fibrosis, and airway smooth muscle were no different inOrmdl3Δ2-3/Δ2-3/CC10and wild-type mice. However, levels of sphingosine-1-phosphate (S1P) were significantly increased inOrmdl3Δ2-3/Δ2-3/CC10mice as well as in airway epithelial cells in which ORMDL3 was inhibited with small interfering RNA. Incubation of S1P with airway smooth muscle cells significantly increased contractility. Overall,Ormdl3Δ2-3/Δ2-3/CC10mice exhibit increased allergen-induced AHR independent of inflammation and associated with increased S1P generation. These studies raise concerns for inhaled therapies that selectively and effectively inhibit ORMDL3 in airway epithelium in asthma.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Arvin B
authors.initials: AB
authors.lastname: Tam
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: James L
authors.initials: JL
authors.lastname: Mueller
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Andrew
authors.initials: A
authors.lastname: Beppu
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Ruth
authors.identifier: 0000-0001-6533-2493
authors.initials: R
authors.lastname: Gordillo
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McGeough
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Christine
authors.initials: C
authors.lastname: Vuong
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Doherty
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Maho
authors.initials: M
authors.lastname: Niwa
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093; dbroide@ucsd.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D008246:Lysophospholipids / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D008565:Membrane Proteins; C583840:ORMDL3 protein, mouse; C060506:sphingosine 1-phosphate; D013110:Sphingosine