Inhibition of Nox2 Oxidase Activity Ameliorates Influenza A Virus-Induced Lung Inflammation

PLoS Pathogens

Stavros Selemidis¹  Brad R. S. Broughton¹  Grant R. Drummond¹  Ross Vlahos²  Steven Bozinovski²  John Stambas³ 

[1] Department of Pharmacology, Monash University, Melbourne, Victoria, Australia;Department of Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia;School of Medicine, Deakin University, Geelong, Victoria, Australia

关键词: Influenza A virus;    Inflammation;    Superoxides;    Influenza;    T cells;    Macrophages;    Cytotoxic T cells;    Infectious disease control;   

DOI  :  10.1371/journal.ppat.1001271

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY