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J. Biol. Chem., Vol. 283, Issue 42, 28595-28606, October 17, 2008

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Role of Xanthine Oxidase Activation and Reduced Glutathione Depletion in Rhinovirus Induction of Inflammation in Respiratory Epithelial Cells^*

Alberto Papi, Marco Contoli, Pierluigi Gasparini, Laura Bristot, Michael R. Edwards^¶, Milvia Chicca, Marilena Leis, Adalberto Ciaccia, Gaetano Caramori, Sebastian L. Johnston^¶1, and Silvano Pinamonti¹²

From the Research Centre on Asthma and COPD and the Department of Biology, University of Ferrara, 44100 Ferrara, Italy and the ^¶Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection & Immunity & MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, W2 1PG United Kingdom

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-B 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.

Received for publication, July 28, 2008

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Via Savonarola 9, 44100 Ferrara, Italy. Tel.: 390532210420; Fax: 390532210297; E-mail: ppa{at}unife.it.

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