title: Suplatast tosilate protects the lung against hyperoxic lung injury by scavenging hydroxyl radicals.
abstract: Prolonged exposure to hyperoxia produces extraordinary amounts of reactive oxygen species (ROS) in the lung and causes hyperoxic lung injury. Although supraphysiological oxygen is routinely administered for the management of respiratory failure, there is no effective strategy to prevent hyperoxic lung injury. In our previous study, we showed that suplatast tosilate, an asthma drug that inhibits T helper 2 (Th2) cytokines, ameliorated bleomycin-induced lung injury and fibrosis through Th2-independent mechanisms. Because bleomycin also generates ROS, we hypothesized that suplatast tosilate might have antioxidant activity and protect the lung against hyperoxic lung injury. To test this hypothesis, mice exposed to hyperoxia were given suplatast tosilate through drinking water. Treatment with suplatast tosilate significantly prolonged mouse survival, reduced the increases in the numbers of inflammatory cells, levels of the pro-inflammatory cytokines/chemokines IL-6 and MCP-1, and protein in bronchoalveolar lavage fluid, and ameliorated lung injury in histological assessment. Suplatast tosilate treatment also significantly inhibited hyperoxia-induced elevations in the levels of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, in bronchoalveolar lavage fluid and 8-isoprostane, a marker of lipid peroxidation, in lung tissue. This finding suggests that suplatast tosilate exerts an antioxidant activity in vivo. In addition, we investigated whether suplatast tosilate has a scavenging effect on hydroxyl radical, the most reactive and harmful ROS, using electron paramagnetic resonance spin-trapping. Suplatast tosilate was shown to scavenge hydroxyl radicals in a dose-dependent manner, and its reaction rate constant with hydroxyl radical was calculated as 2.6×1011M-1S-1, which is faster than that of several well-established antioxidants, such as ascorbate, glutathione, and cysteine. These results suggest that suplatast tosilate protects the lung against hyperoxic lung injury by decreasing the degree of oxidative stress induced by ROS, particularly by scavenging hydroxyl radicals. Suplatast tosilate might become a potential therapeutic for hyperoxic lung injury.
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8551, Japan. Electronic address: respikf127@gmail.com.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Fukuhara
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8551, Japan. Electronic address: tnaka@hiroshima-u.ac.jp.
authors.forename: Taku
authors.initials: T
authors.lastname: Nakashima
authors.affiliation: Department of Chemistry Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan. Electronic address: mabe@hiroshima-u.ac.jp.
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8551, Japan. Electronic address: ta-masuda@hiroshima-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8551, Japan. Electronic address: hirohamada@hiroshima-u.ac.jp.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hamada
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8551, Japan. Electronic address: hir@hiroshima-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8551, Japan. Electronic address: fujikazu@hiroshima-u.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujitaka
authors.affiliation: Hiroshima Cosmopolitan University, 5-13-18 Ujinanishi, Minami-ku, Hiroshima, Hiroshima 734-0014, Japan. Electronic address: nokohno@hcu.ac.jp.
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8551, Japan. Electronic address: nhattori@hiroshima-u.ac.jp.
authors.forename: Noboru
authors.initials: N
authors.lastname: Hattori
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001190:Arylsulfonates / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001761:Bleomycin / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid; D018932:Chemokine CCL2 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000633:toxicity; D015850:Interleukin-6 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013452:Sulfonium Compounds / Q000008:administration & dosage*; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D001190:Arylsulfonates; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D013452:Sulfonium Compounds; D001761:Bleomycin; D017665:Hydroxyl Radical; D000080242:8-Hydroxy-2'-Deoxyguanosine; C073028:suplatast tosilate; D003849:Deoxyguanosine
keywords: 8-OHdG; 8-isoprostane; Antioxidant activity; Electron paramagnetic resonance assay; Hydroxyl radical; Hyperoxic lung injury; MPO; Oxidative stress; Suplatast tosilate