Nox1 oxidase suppresses influenza a virus-induced lung inflammation and oxidative stress

• Published in: PloS one 2013-04, Vol.8 (4), p.e60792
• Main Authors: Selemidis, Stavros, Seow, Huei Jiunn, Broughton, Brad R S, Vinh, Antony, Bozinovski, Steven, Sobey, Christopher G, Drummond, Grant R, Vlahos, Ross
• Format: Article
• Language: English
• Subjects: Alveoli; Analysis; Animals; Biology; Body Weight; Bronchoalveolar Lavage Fluid - virology; CCL3 protein; CD4 antigen; CD8 antigen; Chemokines; Chemokines - metabolism; CYBB protein; Cytokines; Endothelial cells; Endothelium; Enzymes; Gene Deletion; Gene expression; Granulocyte-macrophage colony-stimulating factor; Health aspects; Histopathology; Infections; Infiltration; Inflammation; Inflammation - enzymology; Inflammation - immunology; Inflammation - metabolism; Inflammation - virology; Inflammatory response; Influenza; Influenza A; Influenza A virus - physiology; Interferon; Interleukin 10; Interleukin 6; Localization; Lung - enzymology; Lung - immunology; Lung - metabolism; Lung - virology; Lungs; Lymphocytes; Lymphocytes T; Male; Medicine; Mice; Mice, Inbred C57BL; Monocyte chemoattractant protein 1; NAD(P)H oxidase; NADH, NADPH Oxidoreductases - deficiency; NADH, NADPH Oxidoreductases - genetics; NADH, NADPH Oxidoreductases - metabolism; NADPH Oxidase 1; Neutrophilia; Nitric oxide; Oxidase; Oxidases; Oxidative Stress; Peroxynitrous Acid - biosynthesis; Peroxynitrous Acid - metabolism; Pharmacology; Phenotype; Rodents; Superoxides - metabolism; T-Lymphocyte Subsets - immunology; Tumor necrosis factor-α; Viral infections; Viral Load; Viruses; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060792

Influenza A virus infection is an ongoing clinical problem and thus, there is an urgent need to understand the mechanisms that regulate the lung inflammation in order to unravel novel generic pharmacological strategies. Evidence indicates that the Nox2-containing NADPH oxidase enzyme promotes influenza A virus-induced lung oxidative stress, inflammation and dysfunction via ROS generation. In addition, lung epithelial and endothelial cells express the Nox1 isoform of NADPH oxidase, placing this enzyme at key sites to regulate influenza A virus-induced lung inflammation. The aim of this study was to investigate whether Nox1 oxidase regulates the inflammatory response and the oxidative stress to influenza infection in vivo in mice. Male WT and Nox1-deficient (Nox1(-/y)) mice were infected with the moderately pathogenic HkX-31 (H3N2, 1×10(4) PFU) influenza A virus for analysis of bodyweight, airways inflammation, oxidative stress, viral titre, lung histopathology, and cytokine/chemokine expression at 3 and 7 days post infection. HkX-31 virus infection of Nox1(-/y) mice resulted in significantly greater: loss of bodyweight (Day 3); BALF neutrophilia, peri-bronchial, peri-vascular and alveolar inflammation; Nox2-dependent inflammatory cell ROS production and peri-bronchial, epithelial and endothelial oxidative stress. The expression of pro-inflammatory cytokines including CCL2, CCL3, CXCL2, IL-1β, IL-6, GM-CSF and TNF-α was higher in Nox1(-/y) lungs compared to WT mice at Day 3, however, the expression of CCL2, CCL3, CXCL2, IFN-γ and the anti-inflammatory cytokine IL-10 were lower in lungs of Nox1(-/y) mice vs. WT mice at Day 7. Lung viral titre, and airways infiltration of active CD8(+) and CD4(+) T lymphocytes, and of Tregs were similar between WT and Nox1(-/y) mice. In conclusion, Nox1 oxidase suppresses influenza A virus induced lung inflammation and oxidative stress in mice particularly at the early phases of the infection. Nox1 and Nox2 oxidases appear to have opposing roles in the regulation of inflammation caused by influenza A viruses.