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Influenza A viruses represent a major global healthcare challenge with imminent pandemics, emerging anti-viral resistance and long lag times for vaccine development raising a pressing need for novel pharmacological strategies that ideally target the pathology irrespective of the infecting strain. Reactive oxygen species (ROS) pervade all facets of cell biology with both detrimental and protective properties. Indeed there is compelling evidence that activation of the nicotinamide adenine dinucleotide phosphate-oxidase NADPH oxidase 2 (NOX2) isoform of the NADPH oxidase family of ROS-producing enzymes promotes lung oxidative stress, inflammation, injury and dysfunction to influenza A viruses of low to high pathogenicity, as well as impeding virus clearance. By contrast the NOX1 and DUOX isoforms produce ROS that provide vital protective antiviral effects for the host. In this review, we propose the concept that inhibitors of NOX2 are better alternatives than broad-spectrum antioxidant approaches for treatment of influenza pathologies, for which clinical efficacy may have been limited owing to poor bioavailability and inadvertent removal of beneficial ROS. Finally, we briefly describe the current suite of NADPH oxidase inhibitors and the molecular features of the NADPH oxidase enzymes that could be exploited by drug discovery for development of more specific and novel inhibitors to prevent or treat disease caused by influenza.
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