Department of Pharmacology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Am J Physiol Lung Cell Mol Physiol. 2010 Sep;299(3):L425-33. doi: 10.1152/ajplung.00038.2010. Epub 2010 May 28.
Reactive oxygen species (ROS) produced from cigarette smoke cause oxidative lung damage including protein denaturation, lipid peroxidation, and DNA damage. Glutathione peroxidase-1 (gpx-1) is a detoxifying enzyme that may protect lungs from such damage. The aim of this study was to determine whether gpx-1 protects the lung against oxidative stress-induced lung inflammation in vivo. Male wild-type (WT) or gpx-1(-/-) mice were exposed to cigarette smoke generated from nine cigarettes per day for 4 days to induce oxidative stress and lung inflammation. The effect of the gpx mimetic ebselen on cigarette smoke-induced lung inflammation was evaluated when given prophylactically and therapeutically, i.e., during established inflammation. Mice were killed, and the lungs were lavaged with PBS and then harvested for genomic and proteomic analysis. Gpx-1(-/-) mice exposed to cigarette smoke had enhanced BALF neutrophils, macrophages, proteolytic burden, whole lung IL-17A, and MIP1alpha mRNA compared with WT mice. The gpx mimetic ebselen (10 and 100 microM) inhibited cigarette smoke extract-induced oxidation of MH-S cells in vitro and inhibited cigarette smoke-induced increases in BALF macrophages, neutrophils, proteolytic burden, and macrophage and neutrophil chemotactic factor gene expression when administered prophylactically. In addition, ebselen inhibited established BALF inflammation when administered therapeutically. These data show that gpx-1 protects against cigarette smoke-induced lung inflammation, and agents that mimic the actions of gpx-1 may have therapeutic utility in inflammatory lung diseases where cigarette smoke plays a role.
活性氧（ROS）由香烟烟雾产生，引起氧化肺损伤，包括蛋白质变性、脂质过氧化和 DNA 损伤。谷胱甘肽过氧化物酶-1（gpx-1）是一种解毒酶，可能保护肺部免受这种损伤。本研究的目的是确定 gpx-1 是否能保护肺免受体内氧化应激诱导的肺炎症。雄性野生型（WT）或 gpx-1（-/-）小鼠每天暴露于 9 支香烟的香烟烟雾中 4 天，以诱导氧化应激和肺炎症。评价 gpx 模拟物 ebselen 在预防性和治疗性给药（即在已建立的炎症期间）对香烟烟雾诱导的肺炎症的影响。处死小鼠，用 PBS 灌洗肺，然后收获用于基因组和蛋白质组分析。与 WT 小鼠相比，暴露于香烟烟雾的 gpx-1（-/-）小鼠的 BALF 中性粒细胞、巨噬细胞、蛋白水解负担、全肺 IL-17A 和 MIP1alpha mRNA 增加。gpx 模拟物 ebselen（10 和 100 microM）抑制 MH-S 细胞在体外香烟烟雾提取物诱导的氧化，并且在预防性给药时抑制 BALF 巨噬细胞、中性粒细胞、蛋白水解负担和巨噬细胞和中性粒细胞趋化因子基因表达的增加。此外，ebselen 在治疗性给药时抑制已建立的 BALF 炎症。这些数据表明 gpx-1 可防止香烟烟雾诱导的肺炎症，并且模拟 gpx-1 作用的药物在香烟烟雾起作用的炎症性肺疾病中可能具有治疗作用。
