Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia 26505, USA.
J Pharmacol Exp Ther. 2012 Jul;342(1):81-90. doi: 10.1124/jpet.112.194142. Epub 2012 Apr 4.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an antioxidant-activated transcription factor that recently emerged as a critical regulator of cellular defense against oxidative and inflammatory lesions. Resveratrol (Res) is a natural phytoalexin that exhibits multiple therapeutic potentials, including antioxidative and anti-inflammatory effects in animals. Paraquat (PQ) is the second most widely used herbicide worldwide, but it selectively accumulates in human lungs to cause oxidative injury and fibrosis with high mortality. Here, we analyzed the molecular mechanism of the fibrogenic response to PQ and its inhibition by Res and Nrf2. PQ dose-dependently caused toxicity in normal human bronchial epithelial cells (BEAS-2B), resulting in mitochondrial damage, oxidative stress, and cell death. Res at 10 μM markedly inhibited PQ toxicity. PQ at 10 μM stimulated production of inflammatory and profibrogenic factors (tumor necrosis factor α, interleukin 6, and transforming growth factor β1) and induced the transformation of normal human lung fibroblasts (WI38-VA13) to myofibroblasts; both effects were inhibited by Res. Res strongly activated the Nrf2 signaling pathway and induced antioxidant response element-dependent cytoprotective genes. On the other hand, knockout or knockdown of Nrf2 markedly increased PQ-induced cytotoxicity, cytokine production, and myofibroblast transformation and abolished protection by Res. The findings demonstrate that Res attenuates PQ-induced reactive oxygen species production, inflammation, and fibrotic reactions by activating Nrf2 signaling. The study reveals a new pathway for molecular intervention against pulmonary oxidative injury and fibrosis.
核因子红细胞 2 相关因子 2（Nrf2）是一种抗氧化剂激活的转录因子，最近被认为是细胞抵抗氧化和炎症损伤的关键调节剂。白藜芦醇（Res）是一种天然植物抗毒素，具有多种治疗潜力，包括在动物中具有抗氧化和抗炎作用。百草枯（PQ）是世界上第二大广泛使用的除草剂，但它选择性地在人肺中积累，导致高死亡率的氧化损伤和纤维化。在这里，我们分析了 PQ 引起的纤维化反应的分子机制及其与 Res 和 Nrf2 的抑制作用。PQ 剂量依赖性地引起正常人类支气管上皮细胞（BEAS-2B）的毒性，导致线粒体损伤、氧化应激和细胞死亡。Res 在 10 μM 时显著抑制 PQ 毒性。PQ 在 10 μM 时刺激炎症和促纤维化因子（肿瘤坏死因子 α、白细胞介素 6 和转化生长因子 β1）的产生，并诱导正常人类肺成纤维细胞（WI38-VA13）向肌成纤维细胞转化；这两种作用都被 Res 抑制。Res 强烈激活 Nrf2 信号通路并诱导抗氧化反应元件依赖性细胞保护基因。另一方面，Nrf2 的敲除或敲低显著增加了 PQ 诱导的细胞毒性、细胞因子产生和肌成纤维细胞转化，并消除了 Res 的保护作用。这些发现表明，Res 通过激活 Nrf2 信号通路来减轻 PQ 诱导的活性氧产生、炎症和纤维化反应。该研究揭示了一种针对肺氧化损伤和纤维化的分子干预新途径。
