title: Role of xanthine oxidase activation and reduced glutathione depletion in rhinovirus induction of inflammation in respiratory epithelial cells.
abstract: Rhinoviruses are the major cause of the common cold and acute exacerbations of asthma and chronic obstructive pulmonary disease. We previously reported rapid rhinovirus induction of intracellular superoxide anion, resulting in NF-kappaB activation and pro-inflammatory molecule production. The mechanisms of rhinovirus superoxide induction are poorly understood. Here we found that the proteolytic activation of the xanthine dehydrogenase/xanthine oxidase (XD/XO) system was required because pretreatment with serine protease inhibitors abolished rhinovirus-induced superoxide generation in primary bronchial and A549 respiratory epithelial cells. These findings were confirmed by Western blotting analysis and by silencing experiments. Rhinovirus infection induced intracellular depletion of reduced glutathione (GSH) that was abolished by pretreatment with either XO inhibitor oxypurinol or serine protease inhibitors. Increasing intracellular GSH with exogenous H2S or GSH prevented both rhinovirus-mediated intracellular GSH depletion and rhinovirus-induced superoxide production. We propose that rhinovirus infection proteolytically activates XO initiating a pro-inflammatory vicious circle driven by virus-induced depletion of intracellular reducing power. Inhibition of these pathways has therapeutic potential.
authors.affiliation: Research Centre on Asthma and COPD.
authors.forename: Alberto
authors.initials: A
authors.lastname: Papi
authors.forename: Marco
authors.initials: M
authors.lastname: Contoli
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Laura
authors.initials: L
authors.lastname: Bristot
authors.forename: Michael R
authors.initials: MR
authors.lastname: Edwards
authors.forename: Milvia
authors.initials: M
authors.lastname: Chicca
authors.forename: Marilena
authors.initials: M
authors.lastname: Leis
authors.forename: Adalberto
authors.initials: A
authors.lastname: Ciaccia
authors.forename: Gaetano
authors.initials: G
authors.lastname: Caramori
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
authors.forename: Silvano
authors.initials: S
authors.lastname: Pinamonti
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D010850:Picornaviridae Infections / Q000378:metabolism; D014527:Uric Acid / Q000737:chemistry; D014968:Xanthine Dehydrogenase / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism*
chemical_list: D014527:Uric Acid; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D005978:Glutathione