Defective biosynthesis of ascorbic acid in Sod1-deficient mice results in lethal damage to lung tissue
Defective biosynthesis of ascorbic acid in Sod1-deficient mice results in lethal damage to lung tissue
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Sod1 缺陷小鼠抗坏血酸生物合成缺陷导致肺组织致命损伤
DOI：
10.1016/j.freeradbiomed.2020.10.023
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发表时间：
2021
影响因子：
7.4
通讯作者：
Fujii Junichi
中科院分区：
文献类型：
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作者：
Homma Takujiro;Takeda Yuji;Nakano Tomoyuki;Akatsuka Shinya;Kinoshita Daisuke;Kurahashi Toshihiro;Saitoh Shinichi;Yamada Ken-ichi;Miyata Satoshi;Asao Hironobu;Goto Kaoru;Watanabe Tetsu;Watanabe Masafumi;Toyokuni Shinya;Fujii Junichi
超氧化物歧化酶1（SOD 1）通过加速超氧阴离子自由基转化为过氧化氢，从而抑制随后的自由基链反应，在抗氧化中发挥关键作用。虽然Sod 1缺陷细胞在培养条件下不可避免地会死亡，但Sod 1敲除（KO）小鼠表现出相对温和的表型，寿命约为两年。我们假设，存在丰富水平的抗坏血酸（阿萨），这是自然产生的小鼠，有助于消除活性氧（ROS）在Sod 1-KO小鼠。为了验证这一假设，我们使用了对醛还原酶（Akr 1a）（一种参与阿萨A生物合成的酶）进行基因切除的小鼠，并建立了缺乏Sod 1和Akr 1a的双敲除（DKO）小鼠。补充阿萨A（1.5 mg/ml，在饮用水中）是DKO小鼠繁殖所需的，并且在终止阿萨补充后，他们在大约两周内死亡，不分年龄和性别。我们从小鼠主要器官的病理生理学角度探讨了死亡的病因。在阿萨停药后，在肺中观察到肉眼可见的损伤形式的显著变化。肺的组织学和免疫学分析表明组织的氧化损伤和激活的免疫反应。因此，发生在肺组织中的优先氧化损伤似乎是小鼠死亡的主要原因。这些集体结果表明，阿萨在体内应对ROS的关键功能主要是在暴露于高氧微环境的肺组织中。
Superoxide dismutase 1 (Sod1) plays pivotal roles in antioxidation via accelerating the conversion of superoxide anion radicals into hydrogen peroxide, thus inhibiting the subsequent radical chain reactions. While Sod1 deficient cells inevitably undergo death in culture conditions, Sod1-knockout (KO) mice show relatively mild phenotypes and live approximately two years. We hypothesized that the presence of abundant levels of ascorbic acid (AsA), which is naturally produced in mice, contributes to the elimination of reactive oxygen species (ROS) in Sod1-KO mice. To verify this hypothesis, we employed mice with a genetic ablation of aldehyde reductase (Akr1a), an enzyme that is involved in the biosynthesis of AsA, and established double knockout (DKO) mice that lack both Sod1 and Akr1a.Supplementation of AsA (1.5 mg/ml in drinking water) was required for the DKO mice to breed, and, upon terminating the AsA supplementation, they died within approximately two weeks regardless of age or gender. We explored the etiology of the death from pathophysiological standpoints in principal organs of the mice. Marked changes were observed in the lungs in the form of macroscopic damage after the AsA withdrawal. Histological and immunological analyses of the lungs indicated oxidative damage of tissue and activated immune responses. Thus, preferential oxidative injury that occurred in pulmonary tissues appeared to be primary cause of the death in the mice. These collective results suggest that the pivotal function of AsA in coping with ROSin vivo, is largely in pulmonary tissues that are exposed to a hyperoxygenic microenvironment.