title: Defining an olfactory receptor function in airway smooth muscle cells.
abstract: Pathways that control, or can be exploited to alter, the increase in airway smooth muscle (ASM) mass and cellular remodeling that occur in asthma are not well defined. Here we report the expression of odorant receptors (ORs) belonging to the superfamily of G-protein coupled receptors (GPCRs), as well as the canonical olfaction machinery (Golfand AC3) in the smooth muscle of human bronchi. In primary cultures of isolated human ASM, we identified mRNA expression for multiple ORs. Strikingly, OR51E2 was the most highly enriched OR transcript mapped to the human olfactome in lung-resident cells. In a heterologous expression system, OR51E2 trafficked readily to the cell surface and showed ligand selectivity and sensitivity to the short chain fatty acids (SCFAs) acetate and propionate. These endogenous metabolic byproducts of the gut microbiota slowed the rate of cytoskeletal remodeling, as well as the proliferation of human ASM cells. These cellular responses in vitro were found in ASM from non-asthmatics and asthmatics, and were absent in OR51E2-deleted primary human ASM. These results demonstrate a novel chemo-mechanical signaling network in the ASM and serve as a proof-of-concept that a specific receptor of the gut-lung axis can be targeted to treat airflow obstruction in asthma.
authors.affiliation: Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Aisenberg
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Wanqu
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Premraj
authors.initials: P
authors.lastname: Rajkumar
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Cruz
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
authors.affiliation: Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Niranjana
authors.initials: N
authors.lastname: Natarajan
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Hwan Mee
authors.initials: HM
authors.lastname: Yong
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Breann
authors.initials: B
authors.lastname: De Santiago
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Oh
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: A-Rum
authors.initials: AR
authors.lastname: Yoon
authors.affiliation: Institute for Translational Medicine and Science, Rutgers University, New Brunswick, NJ 08901, USA.
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.affiliation: Genome Analysis Unit, Amgen Inc., South San Francisco, CA 94080, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Homann
authors.affiliation: Department of Inflammation, Amgen Inc., Thousand Oaks, CA 91320, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Sullivan
authors.affiliation: Department of Internal Medicine and Molecular Pharmacology and Physiology, and the Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.affiliation: Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Pluznick
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.|Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.|Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea.
authors.forename: Steven S
authors.initials: SS
authors.lastname: An
mesh_terms: D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D040542:Mechanotransduction, Cellular; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D018035:Receptors, Odorant / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; C417566:OR51E2 protein, human; D018035:Receptors, Odorant