Kawaguchi Tomonobu, Yanagihara Toyoshi, Yokoyama Tetsuya, Suetsugu-Ogata Saiko, Hamada Naoki, Harada-Ikeda Chika, Suzuki Kunihiro, Maeyama Takashige, Kuwano Kazuyoshi, Nakanishi Yoichi
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
PLoS One. 2017 Apr 6;12(4):e0175129. doi: 10.1371/journal.pone.0175129. eCollection 2017.
Hyperoxic lung injury is pathologically characterized by alveolar edema, interlobular septal edema, hyaline membrane disease, lung inflammation, and alveolar hemorrhage. Although the precise mechanism by which hyperoxia causes lung injury is not well defined, oxidative stress, epithelial cell death, and proinflammatory cytokines are thought to be involved. Probucol-a commercially available drug for treating hypercholesterolemia-has been suggested to have antioxidant and antiapoptotic effects. This study aimed to assess whether probucol could attenuate hyperoxic lung injury in mice. Mice were exposed to 95% O2 for 72 h, with or without pre-treatment with 130 μg/kg probucol intratracheally. Probucol treatment significantly decreased both the number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung injury in hyperoxia-exposed mice. Probucol treatment reduced the number of cells positive for 8-hydroxyl-2'-deoxyguanosine or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and suppressed NF-κB activation, Bax expression, and caspase-9 activation in lung tissues from hyperoxia-exposed mice. These results suggest that probucol can reduce oxidative DNA damage, apoptotic cell death, and inflammation in lung tissues. Intratracheal administration of probucol may be a novel treatment for lung diseases induced by oxidative stress, such as hyperoxic lung injury and acute respiratory distress syndrome.
高氧性肺损伤的病理特征为肺泡水肿、小叶间隔水肿、透明膜病、肺部炎症和肺泡出血。尽管高氧导致肺损伤的确切机制尚不清楚，但氧化应激、上皮细胞死亡和促炎细胞因子被认为与之有关。普罗布考——一种用于治疗高胆固醇血症的市售药物——已被认为具有抗氧化和抗凋亡作用。本研究旨在评估普罗布考是否能减轻小鼠的高氧性肺损伤。将小鼠暴露于95%氧气中72小时，气管内给予或不给予130μg/kg普罗布考预处理。普罗布考治疗显著降低了高氧暴露小鼠支气管肺泡灌洗液中的炎症细胞数量和肺损伤程度。普罗布考治疗减少了高氧暴露小鼠肺组织中8-羟基-2'-脱氧鸟苷或末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）阳性细胞的数量，并抑制了核因子κB（NF-κB）激活、Bax表达和半胱天冬酶-9激活。这些结果表明，普罗布考可以减少肺组织中的氧化性DNA损伤、凋亡细胞死亡和炎症。气管内给予普罗布考可能是治疗由氧化应激引起的肺部疾病（如高氧性肺损伤和急性呼吸窘迫综合征）的一种新方法。
