Ng David S W, Liao Wupeng, Tan W S Daniel, Chan Tze Khee, Loh Xin Yi, Wong W S Fred
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore; Immunology Program, Life Science Institute; National University of Singapore, Singapore, Singapore.
Phytomedicine. 2014 Oct 15;21(12):1638-44. doi: 10.1016/j.phymed.2014.07.018. Epub 2014 Sep 1.
Cigarette smoking is the primary cause of chronic obstructive pulmonary disease (COPD), which is mediated by lung infiltration with inflammatory cells, enhanced oxidative stress, and tissue destruction. Anti-malarial drug artesunate has been shown to possess anti-inflammatory and anti-oxidative actions in mouse asthma models. We hypothesized that artesunate can protect against cigarette smoke-induced acute lung injury via its anti-inflammatory and anti-oxidative properties. Artesunate was given by oral gavage to BALB/c mice daily 2h before 4% cigarette smoke exposure for 1h over five consecutive days. Bronchoalveolar lavage (BAL) fluid and lungs were collected for analyses of cytokines, oxidative damage and antioxidant activities. Bronchial epithelial cell BEAS-2B was exposed to cigarette smoke extract (CSE) and used to study the mechanisms of action of artesunate. Artesunate suppressed cigarette smoke-induced increases in BAL fluid total and differential cell counts; levels of IL-1β, MCP-1, IP-10 and KC; and levels of oxidative biomarkers 8-isoprostane, 8-OHdG and 3-nitrotyrosine in a dose-dependent manner. Artesunate promoted anti-oxidant catalase activity and reduced NADPH oxidase 2 (NOX2) protein level in the lungs from cigarette smoke-exposed mice. In BEAS-2B cells, artesunate suppressed pro-inflammatory PI3K/Akt and p44/42 MAPK signaling pathways, and increased nuclear Nrf2 accumulation in response to CSE. Artesunate possesses anti-inflammatory and anti-oxidative properties against cigarette smoke-induced lung injury, probably via inhibition of PI3K and p42/22 MAPK signaling pathways, augmentation of Nrf2 and catalase activities, and reduction of NOX2 level. Our data suggest that artesunate may have therapeutic potential for treating COPD.
吸烟是慢性阻塞性肺疾病（COPD）的主要病因，其发病机制与炎症细胞浸润肺组织、氧化应激增强及组织破坏有关。抗疟药物青蒿琥酯在小鼠哮喘模型中已显示出抗炎和抗氧化作用。我们推测青蒿琥酯可通过其抗炎和抗氧化特性预防香烟烟雾诱导的急性肺损伤。在连续五天的时间里，每天在暴露于4%香烟烟雾1小时前2小时，通过灌胃给予BALB/c小鼠青蒿琥酯。收集支气管肺泡灌洗（BAL）液和肺组织，用于分析细胞因子、氧化损伤和抗氧化活性。将支气管上皮细胞BEAS-2B暴露于香烟烟雾提取物（CSE）中，以研究青蒿琥酯的作用机制。青蒿琥酯以剂量依赖的方式抑制香烟烟雾诱导的BAL液中总细胞数和分类细胞数增加；抑制白细胞介素-1β（IL-1β）、单核细胞趋化蛋白-1（MCP-1）、干扰素诱导蛋白10（IP-10）和角质形成细胞趋化因子（KC）水平升高；抑制氧化生物标志物8-异前列腺素、8-羟基脱氧鸟苷（8-OHdG）和3-硝基酪氨酸水平升高。青蒿琥酯可促进暴露于香烟烟雾的小鼠肺组织中抗氧化酶过氧化氢酶的活性，并降低NADPH氧化酶2（NOX₂）蛋白水平。在BEAS-2B细胞中，青蒿琥酯可抑制促炎的磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）和p44/42丝裂原活化蛋白激酶（MAPK）信号通路，并在CSE刺激下增加细胞核中核因子E2相关因子2（Nrf2）的积累。青蒿琥酯对香烟烟雾诱导的肺损伤具有抗炎和抗氧化特性，可能是通过抑制PI3K和p42/22 MAPK信号通路、增强Nrf2和过氧化氢酶活性以及降低NOX₂水平来实现的。我们的数据表明，青蒿琥酯可能具有治疗COPD的潜力。
