tetano
Editor, Senior Moderator
Free Radic Biol Med. 2013 Oct 16. pii: S0891-5849(13)00645-X. doi: 10.1016/j.freeradbiomed.2013.10.014. [Epub ahead of print]
Treatment with the reactive oxygen species scavenger EUK-207 reduces lung damage and increases survival during 1918 influenza virus infection in mice.
Kash JC, Xiao Y, Sally Davis A, Walters KA, Chertow DS, Easterbrook JD, Dunfee RL, Sandouk A, Jagger BW, Schwartzman LM, Kuestner RE, Wehr NB, Huffman K, Rosenthal RA, Ozinsky A, Levine RL, Doctrow SR, Taubenberger JK.
Source
Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. Electronic address: kashj@niaid.nih.gov.
Abstract
The 1918 influenza pandemic caused over 40 million deaths worldwide with 675,000 deaths in the US 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 post-infection. Post-exposure 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.
? 2013 Published by Elsevier Inc.
KEYWORDS:
3-NT, 3-nitrotyrosine, 8-OHdG, 8-Oxo-2′-deoxyguanosine, ANOVA: analysis of normal variance, Antioxidants, FPKM, Immune response, Influenza, LD(50), NGS, PFU, Pathogenesis, Reactive oxygen species, Used, Virus, cCASP3, cleaved caspase 3, day post-infection, dpi, fragments per kilobase of exon per million fragments mapped, lethal dose 50%, next-generation sequencing, plaque forming units
PMID:
24140866
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24140866
Treatment with the reactive oxygen species scavenger EUK-207 reduces lung damage and increases survival during 1918 influenza virus infection in mice.
Kash JC, Xiao Y, Sally Davis A, Walters KA, Chertow DS, Easterbrook JD, Dunfee RL, Sandouk A, Jagger BW, Schwartzman LM, Kuestner RE, Wehr NB, Huffman K, Rosenthal RA, Ozinsky A, Levine RL, Doctrow SR, Taubenberger JK.
Source
Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. Electronic address: kashj@niaid.nih.gov.
Abstract
The 1918 influenza pandemic caused over 40 million deaths worldwide with 675,000 deaths in the US 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 post-infection. Post-exposure 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.
? 2013 Published by Elsevier Inc.
KEYWORDS:
3-NT, 3-nitrotyrosine, 8-OHdG, 8-Oxo-2′-deoxyguanosine, ANOVA: analysis of normal variance, Antioxidants, FPKM, Immune response, Influenza, LD(50), NGS, PFU, Pathogenesis, Reactive oxygen species, Used, Virus, cCASP3, cleaved caspase 3, day post-infection, dpi, fragments per kilobase of exon per million fragments mapped, lethal dose 50%, next-generation sequencing, plaque forming units
PMID:
24140866
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24140866