Higher Blood Uric Acid in Female Humans and Mice as a Protective Factor against Pathophysiological Decline of Lung Function
Higher Blood Uric Acid in Female Humans and Mice as a Protective Factor against Pathophysiological Decline of Lung Function
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DOI：
10.3390/antiox9050387
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发表时间：
2020-05-01
期刊：
影响因子：
7
通讯作者：
Shuto, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Fujikawa, Haruka;Sakamoto, Yuki;Shuto, Tsuyoshi
氧化剂/抗氧化剂失衡在肺中起着关键作用。尿酸（UA）是一种内源性抗氧化剂，大量存在于肺组织中，但其在病理生理条件下对肺功能的影响尚不清楚。在这项工作中，药理学和遗传学抑制UA代谢的实验小鼠模型的急性和慢性阻塞性肺疾病（COPD）显示，增加血浆UA水平改善肺气肿的表型和肺功能障碍，根据减少氧化应激，特别是在女性，但不是在男性小鼠，尽管没有影响的血浆UA诱导肺表型在未患病的小鼠。体外实验表明，UA显着抑制过氧化氢（H2 O2）诱导的氧化应激在女性供体来源的原代人支气管上皮（NHBE）细胞在雌激素的情况下，这意味着UA的好处是有限的女性气道绝经后的条件。因此，我们的临床观察分析证实，较高的血液UA水平以及SLC 2A 9/GLUT 9 rs 11722228 T/T基因型与老年女性较高的肺功能相关。总之，我们的研究结果提供了第一个独特的证据，即较高的血液UA是对抗雌性小鼠肺功能病理性下降的保护因素，并且可能对抗人类女性与衰老相关的生理性下降。
The oxidant/antioxidant imbalance plays a pivotal role in the lung. Uric acid (UA), an endogenous antioxidant, is highly present in lung tissue, however, its impact on lung function under pathophysiological conditions remains unknown. In this work, pharmacological and genetic inhibition of UA metabolism in experimental mouse models of acute and chronic obstructive pulmonary disease (COPD) revealed that increased plasma UA levels improved emphysematous phenotype and lung dysfunction in accordance with reduced oxidative stress specifically in female but not in male mice, despite no impact of plasma UA induction on the pulmonary phenotypes in nondiseased mice. In vitro experiments determined that UA significantly suppressed hydrogen peroxide (H2O2)-induced oxidative stress in female donor-derived primary human bronchial epithelial (NHBE) cells in the absence of estrogen, implying that the benefit of UA is limited to the female airway in postmenopausal conditions. Consistently, our clinical observational analyses confirmed that higher blood UA levels, as well as the SLC2A9/GLUT9 rs11722228 T/T genotype, were associated with higher lung function in elderly human females. Together, our findings provide the first unique evidence that higher blood UA is a protective factor against the pathological decline of lung function in female mice, and possibly against aging-associated physiological decline in human females.