title: Treatment with the reactive oxygen species scavenger EUK-207 reduces lung damage and increases survival during 1918 influenza virus infection in mice.
abstract: The 1918 influenza pandemic caused over 40 million deaths worldwide, with 675,000 deaths in the United States alone. Studies in several experimental animal models showed that 1918 influenza virus infection resulted in severe lung pathology associated with dysregulated immune and cell death responses. To determine if reactive oxygen species produced by host inflammatory responses play a central role in promoting severity of lung pathology, we treated 1918 influenza virus-infected mice with the catalytic catalase/superoxide dismutase mimetic, salen-manganese complex EUK-207 beginning 3 days postinfection. Postexposure treatment of mice infected with a lethal dose of the 1918 influenza virus with EUK-207 resulted in significantly increased survival and reduced lung pathology without a reduction in viral titers. In vitro studies also showed that EUK-207 treatment did not affect 1918 influenza viral replication. Immunohistochemical analysis showed a reduction in the detection of the apoptosis marker cleaved caspase-3 and the oxidative stress marker 8-oxo-2'-deoxyguanosine in lungs of EUK-207-treated animals compared to vehicle controls. High-throughput sequencing and RNA expression microarray analysis revealed that treatment resulted in decreased expression of inflammatory response genes and increased lung metabolic and repair responses. These results directly demonstrate that 1918 influenza virus infection leads to an immunopathogenic immune response with excessive inflammatory and cell death responses that can be limited by treatment with the catalytic antioxidant EUK-207.
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: kashj@niaid.nih.gov.
authors.forename: John C
authors.initials: JC
authors.lastname: Kash
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: A Sally
authors.initials: AS
authors.lastname: Davis
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Kathie-Anne
authors.initials: KA
authors.lastname: Walters
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Chertow
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Judith D
authors.initials: JD
authors.lastname: Easterbrook
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Dunfee
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aline
authors.initials: A
authors.lastname: Sandouk
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Brett W
authors.initials: BW
authors.lastname: Jagger
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Schwartzman
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Rolf E
authors.initials: RE
authors.lastname: Kuestner
authors.affiliation: Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Wehr
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University Medical School, Boston, MA 02118, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Huffman
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University Medical School, Boston, MA 02118, USA.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Rosenthal
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ozinsky
authors.affiliation: Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University Medical School, Boston, MA 02118, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Doctrow
authors.affiliation: Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jeffery K
authors.initials: JK
authors.lastname: Taubenberger
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004285:Dogs; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000821:virology; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity / Q000502:physiology*; D064149:Influenza Pandemic, 1918-1919; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000494:pharmacology*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000821:virology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016019:Survival Analysis; D019562:Viral Load; D014779:Virus Replication
chemical_list: D015415:Biomarkers; C476761:EUK 207; D016166:Free Radical Scavengers; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; D053148:Caspase 3; D003849:Deoxyguanosine
keywords: Antioxidants; Free radicals; Immune response; Influenza; Pathogenesis; Reactive oxygen species; Virus