Fukuhara Kazuhide, Nakashima Taku, Abe Manabu, Masuda Takeshi, Hamada Hironobu, Iwamoto Hiroshi, Fujitaka Kazunori, Kohno Nobuoki, Hattori Noboru
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.
Department of Chemistry Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
Free Radic Biol Med. 2017 May;106:1-9. doi: 10.1016/j.freeradbiomed.2017.02.014. Epub 2017 Feb 7.
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 2.6×10MS, 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.
长时间暴露于高氧环境会在肺部产生大量活性氧（ROS），并导致高氧性肺损伤。尽管在呼吸衰竭的治疗中常规给予超生理水平的氧气，但尚无有效的策略来预防高氧性肺损伤。在我们之前的研究中，我们发现色甘酸托西拉酯，一种抑制辅助性T细胞2（Th2）细胞因子的哮喘药物，通过不依赖Th2的机制改善了博来霉素诱导的肺损伤和纤维化。由于博来霉素也会产生活性氧，我们推测色甘酸托西拉酯可能具有抗氧化活性，并能保护肺部免受高氧性肺损伤。为了验证这一假设，给暴露于高氧环境的小鼠通过饮用水给予色甘酸托西拉酯。色甘酸托西拉酯治疗显著延长了小鼠的存活时间，减少了炎症细胞数量的增加、促炎细胞因子/趋化因子白细胞介素-6（IL-6）和单核细胞趋化蛋白-1（MCP-1）的水平以及支气管肺泡灌洗液中的蛋白质含量，并在组织学评估中改善了肺损伤。色甘酸托西拉酯治疗还显著抑制了高氧诱导的支气管肺泡灌洗液中8-羟基脱氧鸟苷（氧化DNA损伤的标志物）水平升高以及肺组织中8-异前列腺素（脂质过氧化的标志物）水平升高。这一发现表明色甘酸托西拉酯在体内发挥抗氧化活性。此外，我们使用电子顺磁共振自旋捕获技术研究了色甘酸托西拉酯对最具反应性和危害性的活性氧——羟基自由基是否具有清除作用。结果表明色甘酸托西拉酯以剂量依赖的方式清除羟基自由基，其与羟基自由基的反应速率常数经计算为2.6×10M⁻¹S⁻¹，这比几种成熟的抗氧化剂如抗坏血酸、谷胱甘肽和半胱氨酸的反应速率常数要快。这些结果表明色甘酸托西拉酯通过降低活性氧诱导的氧化应激程度，特别是通过清除羟基自由基来保护肺部免受高氧性肺损伤。色甘酸托西拉酯可能成为治疗高氧性肺损伤的一种潜在药物。
