Giuseppe
Emeritus
Inhibition of Nox2 Oxidase Activity Ameliorates Influenza A Virus-Induced Lung Inflammation (PLoS Pathogens, abstract, edited)
[Source: PLoS Pathogens, full page: <cite cite="http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001271?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+plospathogens%2FNewArticles+%28Ambra+-+Pathogens+New+Articles%29">PLoS Pathogens: Inhibition of Nox2 Oxidase Activity Ameliorates Influenza A Virus-Induced Lung Inflammation</cite>. Abstract, edited.]
Inhibition of Nox2 Oxidase Activity Ameliorates Influenza A Virus-Induced Lung Inflammation
Ross Vlahos 1#, John Stambas 2#, Steven Bozinovski 1, Brad R. S. Broughton 3, Grant R. Drummond 3, Stavros Selemidis 3*
1 Department of Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia,
2 School of Medicine, Deakin University, Geelong, Victoria, Australia,
3 Department of Pharmacology, Monash University, Melbourne, Victoria, Australia
Abstract
Influenza A virus pandemics and emerging anti-viral resistance highlight the urgent need for novel generic pharmacological strategies that reduce both viral replication and lung inflammation. We investigated whether the primary enzymatic source of inflammatory cell ROS (reactive oxygen species), Nox2-containing NADPH oxidase, is a novel pharmacological target against the lung inflammation caused by influenza A viruses. Male WT (C57BL/6) and Nox2−/y mice were infected intranasally with low pathogenicity (X-31, H3N2) or higher pathogenicity (PR8, H1N1) influenza A virus. Viral titer, airways inflammation, superoxide and peroxynitrite production, lung histopathology, pro-inflammatory (MCP-1) and antiviral (IL-1β) cytokines/chemokines, CD8+ T cell effector function and alveolar epithelial cell apoptosis were assessed. Infection of Nox2−/y mice with X-31 virus resulted in a significant reduction in viral titers, BALF macrophages, peri-bronchial inflammation, BALF inflammatory cell superoxide and lung tissue peroxynitrite production, MCP-1 levels and alveolar epithelial cell apoptosis when compared to WT control mice. Lung levels of IL-1β were ~3-fold higher in Nox2−/y mice. The numbers of influenza-specific CD8+DbNP366+ and DbPA224+ T cells in the BALF and spleen were comparable in WT and Nox2−/y mice. In vivo administration of the Nox2 inhibitor apocynin significantly suppressed viral titer, airways inflammation and inflammatory cell superoxide production following infection with X-31 or PR8. In conclusion, these findings indicate that Nox2 inhibitors have therapeutic potential for control of lung inflammation and damage in an influenza strain-independent manner.
Author Summary
Influenza A virus pandemics are imminent and with emerging anti-viral resistance highlight an ongoing, urgent need for novel generic pharmacological strategies. Ideally these strategies should reduce both viral replication and lung inflammation, irrespective of the infecting strain by modulating the host immune response. An important paradigm strongly suggests that the lung damage arising from not only influenza A viruses but other pathogens including, but not restricted to, SARS, parainfluenza viruses, human respiratory syncytial virus and Streptococcus pneumoniae consists of an excessive host response characterised by a rapid, influx of inflammatory cells into the lungs leading to excessive reactive oxygen species (ROS) production. Our study demonstrates that the primary enzymatic source of inflammatory cell ROS, Nox2-containing NADPH oxidase, promotes airways inflammation to low and high pathogenicity influenza A virus infection and impedes with the host's ability to clear the virus. Thus, Nox2 inhibitors could be considered individually or in combination with current antiviral strategies for control of future influenza A virus pandemics.
Citation: Vlahos R, Stambas J, Bozinovski S, Broughton BRS, Drummond GR, et al. (2011) Inhibition of Nox2 Oxidase Activity Ameliorates Influenza A Virus-Induced Lung Inflammation. PLoS Pathog 7(2): e1001271. doi:10.1371/journal.ppat.1001271
Editor: Stacey Schultz-Cherry, St Jude Children's Research Hospital, United States of America
Received: June 11, 2010; Accepted: January 5, 2011; Published: February 3, 2011
Copyright: ? 2011 Vlahos et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The National Health and Medical Research Council of Australia (NHMRC) financially supported this study (Project grant I.D. 509226). The funders played no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: Stavros.Selemidis@monash.edu
# These authors contributed equally to this work.
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[Source: PLoS Pathogens, full page: <cite cite="http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001271?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+plospathogens%2FNewArticles+%28Ambra+-+Pathogens+New+Articles%29">PLoS Pathogens: Inhibition of Nox2 Oxidase Activity Ameliorates Influenza A Virus-Induced Lung Inflammation</cite>. Abstract, edited.]
Inhibition of Nox2 Oxidase Activity Ameliorates Influenza A Virus-Induced Lung Inflammation
Ross Vlahos 1#, John Stambas 2#, Steven Bozinovski 1, Brad R. S. Broughton 3, Grant R. Drummond 3, Stavros Selemidis 3*
1 Department of Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia,
2 School of Medicine, Deakin University, Geelong, Victoria, Australia,
3 Department of Pharmacology, Monash University, Melbourne, Victoria, Australia
Abstract
Influenza A virus pandemics and emerging anti-viral resistance highlight the urgent need for novel generic pharmacological strategies that reduce both viral replication and lung inflammation. We investigated whether the primary enzymatic source of inflammatory cell ROS (reactive oxygen species), Nox2-containing NADPH oxidase, is a novel pharmacological target against the lung inflammation caused by influenza A viruses. Male WT (C57BL/6) and Nox2−/y mice were infected intranasally with low pathogenicity (X-31, H3N2) or higher pathogenicity (PR8, H1N1) influenza A virus. Viral titer, airways inflammation, superoxide and peroxynitrite production, lung histopathology, pro-inflammatory (MCP-1) and antiviral (IL-1β) cytokines/chemokines, CD8+ T cell effector function and alveolar epithelial cell apoptosis were assessed. Infection of Nox2−/y mice with X-31 virus resulted in a significant reduction in viral titers, BALF macrophages, peri-bronchial inflammation, BALF inflammatory cell superoxide and lung tissue peroxynitrite production, MCP-1 levels and alveolar epithelial cell apoptosis when compared to WT control mice. Lung levels of IL-1β were ~3-fold higher in Nox2−/y mice. The numbers of influenza-specific CD8+DbNP366+ and DbPA224+ T cells in the BALF and spleen were comparable in WT and Nox2−/y mice. In vivo administration of the Nox2 inhibitor apocynin significantly suppressed viral titer, airways inflammation and inflammatory cell superoxide production following infection with X-31 or PR8. In conclusion, these findings indicate that Nox2 inhibitors have therapeutic potential for control of lung inflammation and damage in an influenza strain-independent manner.
Author Summary
Influenza A virus pandemics are imminent and with emerging anti-viral resistance highlight an ongoing, urgent need for novel generic pharmacological strategies. Ideally these strategies should reduce both viral replication and lung inflammation, irrespective of the infecting strain by modulating the host immune response. An important paradigm strongly suggests that the lung damage arising from not only influenza A viruses but other pathogens including, but not restricted to, SARS, parainfluenza viruses, human respiratory syncytial virus and Streptococcus pneumoniae consists of an excessive host response characterised by a rapid, influx of inflammatory cells into the lungs leading to excessive reactive oxygen species (ROS) production. Our study demonstrates that the primary enzymatic source of inflammatory cell ROS, Nox2-containing NADPH oxidase, promotes airways inflammation to low and high pathogenicity influenza A virus infection and impedes with the host's ability to clear the virus. Thus, Nox2 inhibitors could be considered individually or in combination with current antiviral strategies for control of future influenza A virus pandemics.
Citation: Vlahos R, Stambas J, Bozinovski S, Broughton BRS, Drummond GR, et al. (2011) Inhibition of Nox2 Oxidase Activity Ameliorates Influenza A Virus-Induced Lung Inflammation. PLoS Pathog 7(2): e1001271. doi:10.1371/journal.ppat.1001271
Editor: Stacey Schultz-Cherry, St Jude Children's Research Hospital, United States of America
Received: June 11, 2010; Accepted: January 5, 2011; Published: February 3, 2011
Copyright: ? 2011 Vlahos et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The National Health and Medical Research Council of Australia (NHMRC) financially supported this study (Project grant I.D. 509226). The funders played no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: Stavros.Selemidis@monash.edu
# These authors contributed equally to this work.
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