PDF(Pubmed)
Abstract：
BACKGROUND: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms.
METHODS: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway.
RESULTS: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and transforming growth factor-β1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions.
CONCLUSIONS: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.
METHODS: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway.
RESULTS: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and transforming growth factor-β1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions.
CONCLUSIONS: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.
摘要：
背景：辛伐他汀（Sim），羟甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，已广泛应用于心血管疾病的预防和治疗。研究表明Sim通过干扰成纤维细胞增殖和胶原合成发挥抗纤维化作用。本研究旨在确定Sim是否可以减轻二氧化硅诱导的肺纤维化并探索其潜在机制。
方法：采用气管灌注法建立大鼠矽肺模型，并给予Sim（5或10mg/kg）治疗，AICAR（AMPK激动剂），和Apocynin（一种NOX抑制剂）28天。收集肺组织用于进一步分析，包括病理组织学，炎症反应，氧化应激，上皮间质转化(EMT),和AMPK-NOX途径。
结果：Sim在给药后28天显著降低了二氧化硅诱导的肺部炎症和纤维化。Sim可以降低白细胞介素（IL）-1β的水平，肺组织中IL-6、肿瘤坏死因子-α和转化生长因子-β1。羟脯氨酸的表达，α-SMA和波形蛋白下调，而E-cad在Sim处理的大鼠中增加。此外,NOX4,p22pox,p40phox,p-p47phox/p47phox表达和ROS水平均升高，而p-AMPK/AMPK在二氧化硅诱导的大鼠中降低。Sim或AICAR处理可以显著逆转二氧化硅诱导的AMPK活性降低和NOX活性增加。Apocynin处理表现出与Sim相似的保护作用，包括下调氧化应激和抑制EMT过程和炎症反应。
结论：Sim通过AMPK-NOX通路下调EMT和氧化应激，减轻二氧化硅诱导的肺部炎症和纤维化。
方法：采用气管灌注法建立大鼠矽肺模型，并给予Sim（5或10mg/kg）治疗，AICAR（AMPK激动剂），和Apocynin（一种NOX抑制剂）28天。收集肺组织用于进一步分析，包括病理组织学，炎症反应，氧化应激，上皮间质转化(EMT),和AMPK-NOX途径。
结果：Sim在给药后28天显著降低了二氧化硅诱导的肺部炎症和纤维化。Sim可以降低白细胞介素（IL）-1β的水平，肺组织中IL-6、肿瘤坏死因子-α和转化生长因子-β1。羟脯氨酸的表达，α-SMA和波形蛋白下调，而E-cad在Sim处理的大鼠中增加。此外,NOX4,p22pox,p40phox,p-p47phox/p47phox表达和ROS水平均升高，而p-AMPK/AMPK在二氧化硅诱导的大鼠中降低。Sim或AICAR处理可以显著逆转二氧化硅诱导的AMPK活性降低和NOX活性增加。Apocynin处理表现出与Sim相似的保护作用，包括下调氧化应激和抑制EMT过程和炎症反应。
结论：Sim通过AMPK-NOX通路下调EMT和氧化应激，减轻二氧化硅诱导的肺部炎症和纤维化。
