Chen Jing-Hsien, Lin Hui-Hsuan, Chiang Tai-An, Hsu Jeng-Dong, Ho Hsieh-Hsun, Lee Yi-Chieh, Wang Chau-Jong
Graduate Institute of Biological Science and Technology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, Tainan, Taiwan.
Toxicol Sci. 2008 Dec;106(2):364-75. doi: 10.1093/toxsci/kfn195. Epub 2008 Sep 16.
Gaseous nitrogen oxide (gNO) is an important indoor and outdoor air pollutant. Many studies have indicated gNO causes lung tissue damage by its oxidation properties and free radicals. However, there are considerably few data on the association between lung cancer and gNO exposure. The purpose of this study was to examine whether gNO could contribute to the process of malignant progression of lung cancer. The results of wound-healing assay and in vitro transwell assay revealed that gNO-induced dose and time dependently the migration and invasion of A549 cells, a human lung cancer cell line, under noncytotoxic concentrations. gNO was able to induce release of NO from A549 cells, an effect that was mediated via the activation of inducible nitric oxide synthases (iNOS), but not constitutive isoforms, during the same treatment period. An increased expression of matrix metalloproteinase (MMP) and a coincided reduction in repress tissue inhibitors of metalloprotease-2 were observed upon the treatment of gNO. The gNO-mediated MMP-2 induction appeared to be a consequence of nuclear factor kappa B and activation protein-1 activation, because that their DNA binding activity was enhanced by gNO. All these influences of gNO were efficiently repressed by the pretreatment of a NOS inhibitor (N(G)-nitro-L-arginine methyl ester). Using a mouse model, we showed that gNO promoted A549 metastasis to the lung through a mechanism involving the iNOS-dependent MMP-2 activity. Our data imply that gNO exposure, which in turn led to iNOS activation and the enhancement of MMP-mediated cellular events, was related to lung cancer development.
气态氮氧化物（gNO）是一种重要的室内外空气污染物。许多研究表明，gNO因其氧化特性和自由基会导致肺组织损伤。然而，关于肺癌与gNO暴露之间关联的数据相当少。本研究的目的是检验gNO是否会促进肺癌的恶性进展过程。伤口愈合试验和体外Transwell试验的结果显示，在无细胞毒性浓度下，gNO诱导人肺癌细胞系A549细胞的迁移和侵袭呈剂量和时间依赖性。在相同处理期间，gNO能够诱导A549细胞释放NO，这一效应是通过诱导型一氧化氮合酶（iNOS）的激活介导的，而非组成型同工型。用gNO处理后，观察到基质金属蛋白酶（MMP）表达增加，同时金属蛋白酶组织抑制剂-2表达降低。gNO介导的MMP-2诱导似乎是核因子κB和激活蛋白-1激活的结果，因为gNO增强了它们的DNA结合活性。gNO的所有这些影响都被一氧化氮合酶抑制剂（N（G）-硝基-L-精氨酸甲酯）预处理有效抑制。使用小鼠模型，我们表明gNO通过涉及iNOS依赖性MMP-2活性的机制促进A549细胞转移至肺部。我们的数据表明，gNO暴露反过来导致iNOS激活和MMP介导的细胞事件增强，这与肺癌发展有关。
