Inhibition of Nox2 oxidase activity ameliorates influenza A virus-induced lung inflammation

PLoS Pathog. 2011 Feb 3;7(2):e1001271. doi: 10.1371/journal.ppat.1001271.


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+D(b)NP(366)+ and D(b)PA(224)+ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / virology
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Influenza A virus / pathogenicity
  • Influenza A virus / physiology*
  • Lung / enzymology
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Macrophages / drug effects
  • Macrophages / pathology
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NADPH Oxidase 2
  • NADPH Oxidases / antagonists & inhibitors*
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • NADPH Oxidases / physiology
  • Orthomyxoviridae Infections / complications*
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / pathology
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Oxidoreductases / physiology
  • Pneumonia / etiology*
  • Pneumonia / genetics
  • Pneumonia / pathology
  • Pneumonia / prevention & control*
  • Reactive Oxygen Species / metabolism


  • Enzyme Inhibitors
  • Membrane Glycoproteins
  • Reactive Oxygen Species
  • Oxidoreductases
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases