Fujikawa Haruka, Sakamoto Yuki, Masuda Natsuki, Oniki Kentaro, Kamei Shunsuke, Nohara Hirofumi, Nakashima Ryunosuke, Maruta Kasumi, Kawakami Taisei, Eto Yuka, Takahashi Noriki, Takeo Toru, Nakagata Naomi, Watanabe Hiroshi, Otake Koji, Ogata Yasuhiro, Tomioka Naoko H, Hosoyamada Makoto, Takada Tappei, Ueno-Shuto Keiko, Suico Mary Ann, Kai Hirofumi, Saruwatari Junji, Shuto Tsuyoshi
Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Global Oriented) Program", Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Antioxidants (Basel). 2020 May 6;9(5):387. doi: 10.3390/antiox9050387.
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 (HO)-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.
氧化还原失衡在肺部起着关键作用。尿酸（UA）作为一种内源性抗氧化剂，在肺组织中大量存在，然而，其在病理生理条件下对肺功能的影响尚不清楚。在这项研究中，在急性和慢性阻塞性肺疾病（COPD）实验小鼠模型中对UA代谢进行药理学和基因抑制，结果显示，血浆UA水平升高可改善肺气肿表型和肺功能障碍，这与氧化应激降低有关，具体表现为仅在雌性小鼠而非雄性小鼠中出现这种情况，尽管血浆UA诱导对未患病小鼠的肺部表型没有影响。体外实验表明，在没有雌激素的情况下，UA能显著抑制过氧化氢（HO）诱导的雌性供体来源的原代人支气管上皮（NHBE）细胞的氧化应激，这意味着UA的益处仅限于绝经后条件下的女性气道。同样，我们的临床观察分析证实，较高的血液UA水平以及SLC2A9/GLUT9 rs11722228 T/T基因型与老年女性的肺功能较高有关。总之，我们的研究结果首次提供了独特的证据，表明较高的血液UA是雌性小鼠肺功能病理衰退的保护因素，并且可能是人类女性衰老相关生理衰退的保护因素。
