title: Antioxidant mimetics modulate oxidative stress and cellular signaling in airway epithelial cells infected with respiratory syncytial virus.
abstract: Respiratory syncytial virus (RSV) is one of the most common causes of bronchiolitis and pneumonia among infants and young children worldwide. In previous investigations, we have shown that RSV infection induces rapid generation of reactive oxygen species (ROS), which modulate viral-induced cellular signaling, and downregulation of antioxidant enzyme (AOE) expression, resulting in oxidative stress in vitro and in vivo, which plays a pathogenetic role in RSV-induced lung disease. In this study, we determined whether pharmacological intervention with synthetic catalytic scavengers could reduce RSV-induced proinflammatory gene expression and oxidative cell damage in an in vitro model of infection. Treatment of airway epithelial cells (AECs) with the salen-manganese complexes EUK-8 or EUK-189, which possess superoxide dismutase, catalase, and glutathione peroxidase activity, strongly reduced RSV-induced ROS formation by increasing cellular AOE enzymatic activity and levels of the lipid peroxidation products F(2)-8-isoprostane and malondialdehyde, which are markers of oxidative stress. Treatment of AECs with AOE mimetics also significantly inhibited RSV-induced cytokine and chemokine secretion and activation of the transcription factors nuclear factor-κB and interferon regulatory factor-3, which orchestrate proinflammatory gene expression. Both EUKs were able to reduce viral replication, when used at high doses. These results suggest that increasing antioxidant cellular capacities can significantly impact RSV-associated oxidative cell damage and cellular signaling and could represent a novel therapeutic approach in modulating virus-induced lung disease.
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Yashoda M
authors.initials: YM
authors.lastname: Hosakote
authors.forename: Narayana
authors.initials: N
authors.lastname: Komaravelli
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mautemps
authors.forename: Tianshuang
authors.initials: T
authors.lastname: Liu
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Garofalo
authors.forename: Antonella
authors.initials: A
authors.lastname: Casola
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D005029:Ethylenediamines / Q000494:pharmacology*; D028441:F2-Isoprostanes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D015227:Lipid Peroxidation; D008315:Malondialdehyde / Q000378:metabolism; D018716:Molecular Mimicry; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000473:pathology; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D012459:Salicylates / Q000494:pharmacology*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014779:Virus Replication / Q000187:drug effects; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D002374:Catalase; D016207:Cytokines; D005029:Ethylenediamines; D028441:F2-Isoprostanes; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D008315:Malondialdehyde; D050984:NF-E2 Transcription Factor, p45 Subunit; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D012459:Salicylates; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C436526:EUK-189; C494692:NFE2 protein, human; C000606290:SOD1 protein, human; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); C441642:SOD3 protein, human