Abstract
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.
Highlights
Recent evidence derived from both basic and clinical studies suggest that a pleiotropic effect, i.e., an effect other than that for which the agent was intended, may be of value in the treatment of a variety of diseases
It is well known that such infections often induce a lethal acute lung injury, which largely contributes to the overproduction of reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS) induced by complicated interactions that occur between the virus and host, including immunologic effects of the host [7]
Similar to LVFX, four other FQs, LFLX, CPFX, PZFX, NFLX, showed scavenging activity against OH radicals (Fig 1C), suggesting that the OH radical scavenging ability of FQs might be dependent on the presence of a 4-quinolone ring in the molecule, the basic chemical structural unit of FQ
Summary
Recent evidence derived from both basic and clinical studies suggest that a pleiotropic effect, i.e., an effect other than that for which the agent was intended, may be of value in the treatment of a variety of diseases. Erythromycin, a macrolide antibiotic, has been reported to be effective for the treatment of chronic airway diseases, such as diffuse bronchiolitis, bronchial asthma, and chronic sinusitis. These therapeutic benefits of erythromycin extend beyond its antibiotic properties and the mechanism responsible for such pleiotropic effects includes the inhibition of neutrophil migration [1, 2], the suppression of IL-8 production [3] and Cl-secretion inhibitory action [4]. It has been proposed that scavengers of ROS or RNOS could represent a potentially new therapeutic strategy for the treatment of influenza virus-induced pneumonia [9,10,11]. Since the pulmonary damage induced by an influenza virus infection increases the risk of a secondary infection by bacteria, such as a pneumococcus, an anti-oxidant therapy is important from the point of view of suppressing secondary bacterial infections [14]
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