title: S-Nitrosoglutathione Attenuates Airway Hyperresponsiveness in Murine Bronchopulmonary Dysplasia.
abstract: Bronchopulmonary dysplasia (BPD) is characterized by lifelong obstructive lung disease and profound, refractory bronchospasm. It is observed among survivors of premature birth who have been treated with prolonged supplemental oxygen. Therapeutic options are limited. Using a neonatal mouse model of BPD, we show that hyperoxia increases activity and expression of a mediator of endogenous bronchoconstriction, S-nitrosoglutathione (GSNO) reductase. MicroRNA-342-3p, predicted in silico and shown in this study in vitro to suppress expression of GSNO reductase, was decreased in hyperoxia-exposed pups. Both pretreatment with aerosolized GSNO and inhibition of GSNO reductase attenuated airway hyperresponsiveness in vivo among juvenile and adult mice exposed to neonatal hyperoxia. Our data suggest that neonatal hyperoxia exposure causes detrimental effects on airway hyperreactivity through microRNA-342-3p-mediated upregulation of GSNO reductase expression. Furthermore, our data demonstrate that this adverse effect can be overcome by supplementing its substrate, GSNO, or by inhibiting the enzyme itself. Rates of BPD have not improved over the past two decades; nor have new therapies been developed. GSNO-based therapies are a novel treatment of the respiratory problems that patients with BPD experience.
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Raffay
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Dylag
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Juliann M
authors.initials: JM
authors.lastname: Di Fiore
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Smith
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Helly J
authors.initials: HJ
authors.lastname: Einisman
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Mitchell M
authors.initials: MM
authors.lastname: Lakner
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Ahmad M
authors.initials: AM
authors.lastname: Khalil
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Peter M
authors.initials: PM
authors.lastname: MacFarlane
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.affiliation: Division of Neonatology (T.M.R., A.M.D., J.M.D.F., P.M.M., R.J.M.) and Division of Pediatric Pulmonology (L.A.S., H.J.E., Y.L., B.G.), Department of Pediatrics, Rainbow Babies and Children's Hospital, and Department of Pharmacology (M.M.L.) and Department of Genetics and Genome Sciences (A.M.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio benjamin.gaston@case.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gaston
mesh_terms: D000336:Aerosols / Q000494:pharmacology; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018496:Hyperoxia / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D026422:S-Nitrosoglutathione / Q000494:pharmacology / Q000627:therapeutic use*; D014162:Transfection
chemical_list: D000336:Aerosols; D035683:MicroRNAs; C581863:Mirn342 microRNA, mouse; D026422:S-Nitrosoglutathione; D052250:Nitric Oxide Synthase Type III; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent