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COPD 2016:血浆尿酸作为阻塞性肺疾病女性小鼠和人类呼吸功能障碍和肺气肿的保护因素_ Haruka fujikawa_熊本大学，日本

摘要

慢性阻塞性肺病的主要病理生理特征之一是氧化应激。我们使用COPD肺组织作为小鼠模型(βENaC转基因小鼠)的DNA微阵列分析表明，氧化剂和抗氧化剂之间存在不平衡。尿酸(UA)是嘌呤代谢的产物，是体内最强大的内源性抗氧化剂之一。有趣的是，最近的队列研究表明，低血清AU水平与较高的COPD水平相关。然而，实验证据仍然没有定论。为了阐明血清DU水平如何影响肺部COPD表型，我们用oxonate治疗βENaC-Tg小鼠，oxonate是一种尿酸酶的药理抑制剂，尿酸酶是一种氧化尿囊素中的DU的酶，可以增加小鼠血中UA的浓度。特别是，用oxenate (500 mg / kg /天，po, 4-5周)治疗βENaC-Tg小鼠显示，COPD的典型表型，如肺气肿，已经通过基于呼吸机的FlexiVent系统测定的平均线性拦截(MLI)和肺功能(FEV 0.1%)的改变被证明，雌性小鼠倾向于改善，而非雄性小鼠则用oxenate βENaC-Tg治疗。此外，一项针对日本健康筛查项目参与者的横断面研究和回顾性纵向研究也证明了血浆UA水平与女性肺功能之间的相关性。我们的研究表明，血浆UA是雌性小鼠和阻塞性肺疾病患者呼吸功能障碍和肺气肿的保护因素。呼吸功能障碍影响生活质量，并促进慢性非传染性肺病的发展，如慢性阻塞性肺病(COPD)，这种疾病的特点是空气空间平均大小增加、弹性下降和一秒钟用力呼气量/用力肺活量减少。 In general, respiratory dysfunction is associated with the accumulation of oxidative stress, a condition of imbalance between the formation of reactive oxygen species (ROS) and cellular antioxidant capacity due to the increased generation of ROS and / or dysfunction of the antioxidant system, indicating that a decrease in oxidative stress is crucial for the maintenance of pulmonary homeostasis. Consistently, some epidemiological studies have shown that dietary intake of antioxidants delays the decline in lung function in healthy adults. Among the endogenous antioxidants in the epithelial coating fluid (ELF), uric acid (UA) exists in higher concentrations and has the potential role of trapping ROS (e.g., singlet oxygen and hydroxyl radicals).Although DU is a terminal product of purine metabolism in humans and great apes, this is not the case for most mammals; great apes and great apes have lost the enzymatic activity of urate oxidase, or uricase (Uox), which converts AU to allantoin, due to a loss of function during evolution. As a result, the levels of UA in human blood are much higher than in other mammals, such as mice. UA is known as an antioxidant abundant in human blood. In fact, high levels of UA have been reported to be beneficial for central nervous system (CNS) disorders related to oxidative damage. Paradoxically, high plasma AU levels are detrimental to the host due to its ability to be pro-oxidant under certain conditions, thereby increasing not only the risk of gout, but also many diseases linked to oxidative stress. The paradox of AU in respiratory diseases, particularly in COPD, is often discussed in epidemiological studies, but the conclusions are controversial. Horsfall et al. claimed lower AU blood levels were associated with risk of COPD, while others showed higher AU blood levels correlated with exacerbation of COPD Haruka Fujikawa

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