Inoue Ken-ichiro, Takano Hirohisa, Kaewamatawong Theerayuth, Shimada Akinori, Suzuki Junko, Yanagisawa Rie, Tasaka Sadatomo, Ishizaka Akitoshi, Satoh Masahiko
Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba, Japan.
Free Radic Biol Med. 2008 Dec 15;45(12):1714-22. doi: 10.1016/j.freeradbiomed.2008.09.008. Epub 2008 Sep 20.
Metallothionein (MT) is a free radical scavenger induced by inflammatory stimuli; however, its roles in inflammation have not been fully investigated. In the present study, we genetically determined the role of MT in ozone (O(3))-induced lung inflammation using MT-I/II null (-/-) mice. Subacute (65 h) exposure to O(3) (0.3 ppm) induced lung inflammation and enhanced vascular permeability, which was significantly greater in MT(-/-) than in corresponding wild-type mice. Electron microscopically, O(3) exposure induced vacuolar degeneration of pulmonary endothelial and epithelial cells, and interstitial edema with focal loss of the basement membrane, which was more prominent in MT(-/-) than in wild-type mice. O(3) -induced lung expression of interleukin-6 was significantly greater in MT(-/-) than in wild-type mice; however, lung expression of the chemokines examined was comparable in both genotypes of mice in the presence of O(3). Following O(3) exposure, the formation of oxidative stress-related molecules/adducts, such as heme oxidase-1, inducible nitric oxide synthase, 8-hydroxy-2'-deoxyguanosine, and nitrotyrosine, in the lung was significantly greater in MT(-/-) than in wild-type mice. Collectively, MT protects against O(3)-induced lung inflammation, at least partly, via the regulation of pulmonary endothelial and epithelial integrity and its antioxidative property.
金属硫蛋白（MT）是一种由炎症刺激诱导产生的自由基清除剂；然而，其在炎症中的作用尚未得到充分研究。在本研究中，我们利用MT-I/II基因敲除（-/-）小鼠从基因层面确定了MT在臭氧（O₃）诱导的肺部炎症中的作用。亚急性（65小时）暴露于O₃（0.3 ppm）会诱导肺部炎症并增强血管通透性，MT（-/-）小鼠的这种情况比相应的野生型小鼠更为显著。电子显微镜观察显示，O₃暴露会诱导肺内皮细胞和上皮细胞空泡变性，以及间质水肿并伴有基底膜局灶性缺失，MT（-/-）小鼠的这些变化比野生型小鼠更为突出。MT（-/-）小鼠中O₃诱导的白细胞介素-6肺表达显著高于野生型小鼠；然而，在存在O₃的情况下，两种基因型小鼠中所检测的趋化因子的肺表达相当。O₃暴露后，MT（-/-）小鼠肺中氧化应激相关分子/加合物的形成，如血红素加氧酶-1、诱导型一氧化氮合酶、8-羟基-2'-脱氧鸟苷和硝基酪氨酸，比野生型小鼠显著增加。总体而言，MT至少部分地通过调节肺内皮和上皮的完整性及其抗氧化特性来预防O₃诱导的肺部炎症。
