title: Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice.
abstract: Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.|Respiratory Research Group, Woolcock Institute of Medical Research and School of Life Sciences, University of Technology, Sydney, NSW, 2007, Australia.
authors.forename: Pawan
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Roslyn
authors.initials: R
authors.lastname: Yi
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Nayak
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Nadan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Respiratory Research Group, Woolcock Institute of Medical Research and School of Life Sciences, University of Technology, Sydney, NSW, 2007, Australia.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
authors.forename: Morgan J
authors.initials: MJ
authors.lastname: Knight
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Pan
authors.affiliation: Respiratory Research Group, Woolcock Institute of Medical Research and School of Life Sciences, University of Technology, Sydney, NSW, 2007, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Oliver
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Deshpande
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002633:Chemotaxis / Q000187:drug effects; D002738:Chloroquine / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D007114:Immunization; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects; D039981:Pyroglyphidae / Q000187:drug effects; D011803:Quinine / Q000627:therapeutic use*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013649:Taste
chemical_list: D000485:Allergens; D016207:Cytokines; D043562:Receptors, G-Protein-Coupled; D002738:Chloroquine; D011803:Quinine; D020782:Matrix Metalloproteinases