Inhibition of Nox2 oxidase activity ameliorates influenza A virus-induced lung inflammation.
Inhibition of Nox2 oxidase activity ameliorates influenza A virus-induced lung inflammation.
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DOI：
10.1371/journal.ppat.1001271
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发表时间：
2011-02-03
期刊：
影响因子：
6.7
通讯作者：
Selemidis S
中科院分区：
文献类型：
--
作者：
Vlahos R;Stambas J;Bozinovski S;Broughton BR;Drummond GR;Selemidis S
甲型流感病毒大流行和新出现的抗病毒耐药性突显了迫切需要新的仿制药策略，以减少病毒复制和肺部炎症。我们研究了炎症细胞ROS(活性氧物种)的主要酶来源-含NOX2的NADPH氧化酶-是否是对抗甲型流感病毒引起的肺部炎症的新的药理靶点。雄性WT(C57BL/6)和NOX2−/y小鼠分别用低致病力(X-31、H3N 2)或高致病性(PR8、H1N1)甲型流感病毒鼻腔感染。观察指标包括病毒滴度、呼吸道炎症、超氧化物和过氧亚硝酸盐生成、肺组织病理学、促炎症(MCP-1)和抗病毒(IL-1)细胞因子/趋化因子(β)、CD8+T细胞效应分子功能和肺泡上皮细胞凋亡。−/y小鼠感染X-31病毒后，肺泡灌洗液中病毒滴度、肺泡灌洗液巨噬细胞、支气管周围炎症、肺组织过氧化亚硝酸盐生成、单核细胞趋化蛋白-1水平及肺泡上皮细胞凋亡率均显著低于对照组。肺组织IL-1β水平在NOX2∼/y小鼠中是−小鼠的3倍。WT和NOX2−/y小鼠BALF和脾组织中流感特异性CD8+DbNP366+和DbPA224+T细胞数量相当。体内注射NOX2抑制剂apocynin可显著抑制X-31或PR8感染后的病毒滴度、呼吸道炎症和炎症细胞超氧化物的产生。综上所述，这些发现表明NOX2抑制剂在控制肺部炎症和损伤方面具有治疗潜力，且不依赖于流感病毒株。甲型流感病毒大流行迫在眉睫，新出现的抗病毒耐药性突显了对新的仿制药策略的持续、迫切的需要。理想情况下，这些策略应该通过调节宿主免疫反应来减少病毒复制和肺部炎症，而不考虑感染菌株。一个重要的范例有力地表明，不仅是甲型流感病毒，而且包括但不限于SARS、副流感病毒、人类呼吸道合胞病毒和肺炎链球菌在内的其他病原体引起的肺损伤包括过度的宿主反应，其特征是炎症细胞迅速涌入肺部，导致过量的活性氧(ROS)产生。我们的研究表明，炎症细胞ROS的主要酶来源，含NOX2的NADPH氧化酶，促进了对低致病性和高致病性甲型流感病毒感染的呼吸道炎症，并阻碍了宿主清除病毒的能力。因此，可以单独考虑NOX2抑制剂，也可以将其与当前的抗病毒策略结合使用，以控制未来的甲型流感病毒大流行。
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. Influenza A virus pandemics are imminent and with emerging anti-viral resistance highlight an ongoing, urgent need for novel generic pharmacological strategies. Ideally these strategies should reduce both viral replication and lung inflammation, irrespective of the infecting strain by modulating the host immune response. An important paradigm strongly suggests that the lung damage arising from not only influenza A viruses but other pathogens including, but not restricted to, SARS, parainfluenza viruses, human respiratory syncytial virus and Streptococcus pneumoniae consists of an excessive host response characterised by a rapid, influx of inflammatory cells into the lungs leading to excessive reactive oxygen species (ROS) production. Our study demonstrates that the primary enzymatic source of inflammatory cell ROS, Nox2-containing NADPH oxidase, promotes airways inflammation to low and high pathogenicity influenza A virus infection and impedes with the host's ability to clear the virus. Thus, Nox2 inhibitors could be considered individually or in combination with current antiviral strategies for control of future influenza A virus pandemics.
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