Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Division of Thoracic Surgery, Mackay Memorial Hospital, Taipei, Taiwan; Department of Cosmetic Applications and Management, Mackay Medicine, Nursing and Management College, Taipei, Taiwan.
Free Radic Biol Med. 2014 Apr;69:208-18. doi: 10.1016/j.freeradbiomed.2014.01.026. Epub 2014 Jan 28.
Cigarette smoking causes persistent lung inflammation that is mainly regulated by redox-sensitive pathways. We have reported that cigarette smoke (CS) activates a NADPH oxidase-dependent reactive oxygen species (ROS)-sensitive AMP-activated protein kinase (AMPK) signaling pathway leading to induction of lung inflammation. Glucosamine, a dietary supplement used to treat osteoarthritis, has antioxidant and anti-inflammatory properties. However, whether glucosamine has similar beneficial effects against CS-induced lung inflammation remains unclear. Using a murine model we show that chronic CS exposure for 4 weeks increased lung levels of 4-hydroxynonenal (an oxidative stress biomarker), phospho-AMPK, and macrophage inflammatory protein 2 and induced lung inflammation; all of these CS-induced events were suppressed by chronic treatment with glucosamine. Using human bronchial epithelial cells, we demonstrate that cigarette smoke extract (CSE) sequentially activated NADPH oxidase; increased intracellular levels of ROS; activated AMPK, mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription proteins 3 (STAT3); and induced interleukin-8 (IL-8). Additionally, using a ROS scavenger, a siRNA that targets AMPK, and various pharmacological inhibitors, we identified the signaling cascade that leads to induction of IL-8 by CSE. All these CSE-induced events were inhibited by glucosamine pretreatment. Our findings suggest a novel role for glucosamine in alleviating the oxidative stress and lung inflammation induced by chronic CS exposure in vivo and in suppressing the CSE-induced IL-8 in vitro by inhibiting both the ROS-sensitive NADPH oxidase/AMPK/MAPK signaling pathway and the downstream transcriptional factors NF-κB and STAT3.
吸烟会引起持续的肺部炎症，主要受氧化还原敏感途径调节。我们已经报道，香烟烟雾（CS）激活依赖 NADPH 氧化酶的活性氧（ROS）敏感的 AMP 激活蛋白激酶（AMPK）信号通路，导致肺部炎症的诱导。葡萄糖胺是一种用于治疗骨关节炎的膳食补充剂，具有抗氧化和抗炎特性。然而，葡萄糖胺是否对 CS 诱导的肺部炎症具有类似的有益作用尚不清楚。使用一种鼠模型，我们发现，4 周的慢性 CS 暴露增加了肺部 4-羟基壬烯醛（氧化应激生物标志物）、磷酸化 AMPK 和巨噬细胞炎症蛋白 2 的水平，并诱导了肺部炎症；所有这些 CS 诱导的事件都被葡萄糖胺的慢性治疗所抑制。使用人支气管上皮细胞，我们证明香烟烟雾提取物（CSE）依次激活 NADPH 氧化酶；增加细胞内 ROS 水平；激活 AMPK、丝裂原活化蛋白激酶（MAPK）、核因子-κB（NF-κB）和信号转导和转录激活蛋白 3（STAT3）；并诱导白细胞介素-8（IL-8）。此外，使用 ROS 清除剂、针对 AMPK 的 siRNA 和各种药理学抑制剂，我们确定了导致 CSE 诱导 IL-8 的信号级联。所有这些 CSE 诱导的事件都被葡萄糖胺预处理所抑制。我们的研究结果表明，葡萄糖胺在减轻体内慢性 CS 暴露引起的氧化应激和肺部炎症以及抑制 CSE 诱导的体外 IL-8 方面具有新的作用，通过抑制 ROS 敏感的 NADPH 氧化酶/AMPK/MAPK 信号通路和下游转录因子 NF-κB 和 STAT3 来实现。
