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慢性阻塞性肺病2016:药理和遗传方法确定蛋白酶和氧化应激加剧因素在小鼠模型的阻塞性肺diseases_Tsuyoshi Shuto_Kumamoto大学、日本

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Protease-antiprotease失衡和氧化应激反应被认为是严重的肺部疾病的主要病理生理特征,包括慢性阻塞性肺疾病(COPD)和囊性纤维化(CF),但他们的作用在调节阻塞性粘液表型,包括肺气肿和障碍我²ENaC——转基因小鼠(Tg),慢性阻塞性肺病的老鼠模型/ CF,是未知的。在这里,DNA芯片的分析显示,protease-dependent和氧化应激通路被激活我的肺组织²ENaC-Tg老鼠。治疗我²ENaC-Tg老鼠ONO3403丝氨酸蛋白酶抑制剂和抗氧化剂防治作用显著改善肺气肿和功能障碍。此外,损耗的小鼠内源性抗氧化剂维生素C (VC),合成的酶的基因干扰衰老标记protein-30 (SMP30)我²ENaC-Tg老鼠,增加了炎症状态。在肺组织和夸张的肺气肿和肺功能明显下降,可能是由于氧化应激增加。我们的结果定义蛋白酶和氧化应激的因素加剧阻塞性粘液表型小鼠模型的慢性阻塞性肺病/ CF。肺气肿和功能障碍是严重的阻塞性肺疾病的病理生理特征,包括慢性阻塞性肺疾病(COPD)和囊性纤维化(CF)。在这些障碍,缺陷清除粘液,过度的炎症,protease-antiprotease失衡和氧化应激反应被认为是影响严重。鉴于慢性阻塞性肺病是全世界发病率和死亡率的主要原因之一,囊性纤维化在白种人是最常见的致命的遗传疾病,关键分子的识别和路径潜在疾病的发病机制一直是多年来广泛研究的主题。理想实验,小鼠模型,展示关键COPD / CF肺表型,如粘液阻塞,杯状细胞化生,中性粒细胞炎症,和穷人细菌间隙,被诱导特定的超表达独特的建立在呼吸道上皮Na +我²亚基的通道在老鼠(我²ENaC-Tg老鼠)。最重要的是,同一组进一步揭示了组织学和形态学分析,我²ENaC-Tg老鼠不仅表现出气性表型也是肺功能障碍,而这些肺异常密切相关,这些通常观察到病人患有慢性阻塞性肺病和囊性纤维化。 ENaC is a sodium ion channel that is expressed in the apical membrane of polarized epithelial cells, especially in the lung, kidney (mainly in the collecting tubules) and the colon. An over-activation of ENaC by a targeted overexpression of βENaC on the respiratory tract leads to the generation of a concentration gradient of sodium ions (for example, sodium ions going from outside to inside the cell) followed overabsorption of water in the cells, which leads to deregulation of mucus production and clearance of the respiratory tract.Based on evidence showing that expression and function of ENaC were inversely associated with lung function in patients with cystic fibrosis and could be increased in patients with COPD, βENaC-Tg mice could be tools valuable for exploring the obstructive phenotypes of COPD mucus and cystic fibrosis in vivo. However, the mortality of βENaC-Tg mice with a mixed C3H / HeN: C57 / BL6N background was extremely high5, which limits the use of the original βENaC-Tg line as an animal model of acute and fulminant respiratory diseases . It is important to note that Livraghi-Butrico et al. Have shown that the genetic background of βENaC-Tg mice strongly affects the survival and severity of the disease in mice. Because Johannesson et al. Also clearly demonstrated that C57 / BL6 backcrossing improved survival, βENaC-Tg mice with a C57 / BL6 background could be considered as an ideal animal model which represents the phenotypes of obstructive human respiratory diseases. However, despite growing evidence of their usefulness in COPD and cystic fibrosis research, the importance of C57 / BL6-βENaC-Tg mice has only been demonstrated by a few groups around the world, suggesting that a comprehensive analysis to determine the specific molecules and pathways which could contribute to the pathogenesis of C57 / BL6-βENaC-Tg mice are also necessary. Tsuyoshi Shuto_Kumamoto

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