title: Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma.
abstract: Asthma is defined by airway inflammation and hyperresponsiveness, and contributes to morbidity and mortality worldwide. Although bronchodilation is a cornerstone of treatment, current bronchodilators become ineffective with worsening asthma severity. We investigated an alternative pathway that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists BAY 41-2272 and BAY 60-2770, triggered bronchodilation in normal human lung slices and in mouse airways. Both BAY 41-2272 and BAY 60-2770 reversed airway hyperresponsiveness in mice with allergic asthma and restored normal lung function. The sGC from mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes to sGC occurred in human lung slices or in human airway smooth muscle cells when given chronic NO exposure to mimic the high NO in asthmatic lung. Our findings show how allergic inflammation in asthma may impede NO-based bronchodilation, and reveal that pharmacologic sGC agonists can achieve bronchodilation despite this loss.
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Arnab
authors.identifier: http://orcid.org/0000-0002-7498-1994
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Rutgers Institute for Translational Medicine & Science, Rutgers University, New Brunswick, NJ 08901;
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Koziol-White
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Kewal
authors.initials: K
authors.lastname: Asosingh
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Georgina
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Lisa
authors.initials: L
authors.lastname: Ruple
authors.affiliation: Institute of Vegetative Physiology, Universität Würzburg, Wuerzburg 97070, Germany;
authors.forename: Dieter
authors.initials: D
authors.lastname: Groneberg
authors.affiliation: Institute of Vegetative Physiology, Universität Würzburg, Wuerzburg 97070, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Friebe
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Suzy A A
authors.initials: SA
authors.lastname: Comhair
authors.affiliation: Pharma Research Centre, Bayer Pharma AG, D-42096 Wuppertal, Germany;
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.affiliation: Rutgers Institute for Translational Medicine & Science, Rutgers University, New Brunswick, NJ 08901;
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Aronica
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195 erzurus@ccf.org stuehrd@ccf.org.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; erzurus@ccf.org stuehrd@ccf.org.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Stuehr
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000201:enzymology; D001993:Bronchodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018920:Coculture Techniques; D006152:Cyclic GMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006162:Guanylate Cyclase / Q000187:drug effects*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D012995:Solubility; D014132:Trachea / Q000187:drug effects
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D018927:Anti-Asthmatic Agents; D001565:Benzoates; D001713:Biphenyl Compounds; D001993:Bronchodilator Agents; D006845:Hydrocarbons, Fluorinated; D011720:Pyrazoles; D011725:Pyridines; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D006152:Cyclic GMP
keywords: S-nitrosylation; bronchoconstriction; bronchodilation; heme protein; nitric oxide