Abstract
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, 1×104 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.
Highlights
Influenza A virus infections represent important infectious diseases that continue to inflict significant global morbidity and mortality [1]
The present study shows that Nox1 oxidase critically inhibits the early burst in lung pro-inflammatory cytokine expression, inflammation and oxidative stress caused by influenza A virus infection and as opposed to the Nox2 oxidase, Nox1 is a protective mechanism against such infections
At 7 days post infection, the levels of CCL2, CCL3, CXCL2, IFN-c and the anti-inflammatory cytokine IL-10 were significantly lower in influenza A virus-infected Nox12/y lung compared to WT control, whereas IL-b, IL-6, TNF-a, and GMCSF were similar between the two strains of mice (Figure 2)
Summary
Influenza A virus infections represent important infectious diseases that continue to inflict significant global morbidity and mortality [1]. Accumulated animal and human studies provide compelling evidence for a new paradigm whereby excessive production of reactive oxygen species (ROS), such as superoxide anion, and its derivatives hydrogen peroxide and peroxynitrite, are crucial mediators of the acute lung injury to influenza A virus infection [3,4,5]. The evidence supporting a pathogenic role for ROS in lung injury to influenza A virus is strong, little attention has been directed towards identifying the key enzymes that generate ROS. Knowledge of the culprit enzymes could give rise to novel pharmacological strategies for manipulating oxidative stress and the associated lung injury following influenza A virus infection
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