title: Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury.
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.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Enoki
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishima
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Clinical Biochemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Yoshino-Machi, Nobeoka, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Sato
authors.affiliation: The Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN), 1-6-1 Okubo, Kita-ku, Kumamoto-shi, Kumamoto, 860-8568, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kimachi
authors.affiliation: The Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN), 1-6-1 Okubo, Kita-ku, Kumamoto-shi, Kumamoto, 860-8568, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Shirai
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, GPO Box U1987, Perth, 6845, Western Australia.
authors.forename: Victor T G
authors.initials: VT
authors.lastname: Chuang
authors.affiliation: Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, 1-22-4 Ikeda, Nishi-ku, Kumamoto, 860-0082, Japan; DDS Research Institute, Sojo University, 1-22-4 Ikeda, Nishi-ku, Kumamoto, 860-0082, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000821:virology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D024841:Fluoroquinolones / Q000737:chemistry / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D007371:Interferon-gamma / Q000378:metabolism; D064704:Levofloxacin / Q000737:chemistry / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008297:Male; D008813:Mice, Inbred ICR; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D064704:Levofloxacin; D007371:Interferon-gamma