Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury

Reactive oxygen species (ROS) and nitric oxide (NO) are major pathogenic molecules produced during viral lung infections, including influenza. While fluoroquinolones are widely used as antimicrobial agents for treating a variety of bacterial infections, including secondary infections associated with the influenza virus, it has been reported that they also function as anti-oxidants against ROS and as a NO regulator. Therefore, we hypothesized that levofloxacin (LVFX), one of the most frequently used fluoroquinolone derivatives, may attenuate pulmonary injuries associated with influenza virus infections by inhibiting the production of ROS species such as hydroxyl radicals and neutrophil-derived NO that is produced during an influenza viral infection. The therapeutic impact of LVFX was examined in a PR8 (H1N1) influenza virus-induced lung injury mouse model. ESR spin-trapping experiments indicated that LVFX showed scavenging activity against neutrophil-derived hydroxyl radicals. LVFX markedly improved the survival rate of mice that were infected with the influenza virus in a dose-dependent manner. In addition, the LVFX treatment resulted in a dose-dependent decrease in the level of 8-hydroxy-2’-deoxyguanosine (a marker of oxidative stress) and nitrotyrosine (a nitrative marker) in the lungs of virus-infected mice, and the nitrite/nitrate ratio (NO metabolites) and IFN-γ in BALF. These results indicate that LVFX may be of substantial benefit in the treatment of various acute inflammatory disorders such as influenza virus-induced pneumonia, by inhibiting inflammatory cell responses and suppressing the overproduction of NO in the lungs.

活性氧簇（Reactive oxygen species, ROS）与一氧化氮（nitric oxide, NO）是包括流感在内的病毒性肺部感染过程中产生的主要致病分子。氟喹诺酮类药物作为抗菌剂，被广泛用于治疗多种细菌感染，其中也包括流感病毒继发的细菌感染；已有研究证实，此类药物同时具备清除ROS的抗氧化活性及调节NO的功能。因此，本研究提出假说：临床常用氟喹诺酮类衍生物之一的左氧氟沙星（levofloxacin, LVFX），可通过抑制流感病毒感染过程中产生的羟自由基等ROS以及中性粒细胞源性NO的生成，缓解流感病毒感染引发的肺损伤。
本研究在PR8（H1N1）型流感病毒诱导的肺损伤小鼠模型中，评估了LVFX的治疗效果。电子自旋共振（Electron Spin Resonance, ESR）自旋捕获实验结果显示，LVFX可有效清除中性粒细胞源性羟自由基。LVFX可呈剂量依赖性显著提高流感病毒感染小鼠的存活率。此外，LVFX治疗可呈剂量依赖性降低病毒感染小鼠肺组织内8-羟基-2’-脱氧鸟苷（氧化应激标志物）与硝基酪氨酸（硝化应激标志物）的水平，同时降低支气管肺泡灌洗液（Bronchoalveolar Lavage Fluid, BALF）中亚硝酸盐/硝酸盐比值（NO代谢物指标）及干扰素-γ（Interferon-γ, IFN-γ）的含量。
上述结果表明，LVFX可通过抑制炎症细胞应答、减少肺部NO的过量生成，在治疗流感病毒诱导性肺炎等多种急性炎症性疾病中发挥显著临床价值。