Overproduction of nitric oxide by endothelial cells and macrophages contributes to mitochondrial oxidative stress in adrenocortical cells and adrenal insufficiency during endotoxemia.
Overproduction of nitric oxide by endothelial cells and macrophages contributes to mitochondrial oxidative stress in adrenocortical cells and adrenal insufficiency during endotoxemia.
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DOI：
10.1016/j.freeradbiomed.2015.02.024
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发表时间：
2015-06
影响因子：
7.4
通讯作者：
Changnan Wang;Guo-Li Duan;Yu-Jian Liu;Qing Yu;Xiao-lu Tang;Wei Zhao;Xiao-Han Li;Xiaoyan Zhu;X. Ni
中科院分区：
文献类型：
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作者：
Changnan Wang;Guo-Li Duan;Yu-Jian Liu;Qing Yu;Xiao-lu Tang;Wei Zhao;Xiao-Han Li;Xiaoyan Zhu;X. Ni
我们最近证实，脂多糖(LPS)导致肾上腺线粒体氧化应激和功能障碍，从而导致肾上腺皮质功能不全。由于诱导型一氧化氮合酶(INOS)产生的一氧化氮(NO)可导致多种组织的线粒体损伤，本研究旨在探讨NO是否参与内毒素血症时肾上腺皮质线粒体氧化应激和肾上腺皮质功能不全的发生。全身注射脂多糖可增加小鼠肾上腺iNOS的表达和NO的产生。特异性iNOS抑制剂1400-W可显著减轻内毒素诱导的肾上腺线粒体超氧化物歧化和功能障碍，逆转内毒素诱导的肾上腺皮质对促肾上腺皮质激素(ACTH)的低反应性。相比之下，给予NO供体硝普钠(SNP)会导致肾上腺线粒体氧化应激和功能障碍，从而导致皮质酮对ACTH的反应迟钝。用血管内皮细胞标记物CD31或巨噬细胞标记物CD68对iNOS进行双重免疫荧光染色，发现内毒素血症时，iNOS在血管内皮细胞和巨噬细胞中表达增加，而肾上腺皮质细胞中iNOS表达增加。给予硫化氢(H_2S)供体GYY4137可抑制NO的产生并逆转内毒素诱导的肾上腺皮质低反应性。我们的数据表明，内毒素血症时主要由内皮细胞和巨噬细胞产生的NO过度产生，导致肾上腺皮质细胞线粒体氧化应激，从而导致肾上腺功能不全。
We have recently demonstrated that lipopolysaccharide (LPS) causes mitochondrial oxidative stress and dysfunction in adrenal glands, thereby leading to adrenocortical insufficiency. Since nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) leads to mitochondrial damage in various tissues, the present study aims to investigate whether NO contributes to mitochondrial oxidative stress in adrenal cortex and adrenocortical insufficiency during endotoxemia. Systemic administration of LPS increased iNOS expression and NO production in adrenal glands of mice. The specific iNOS inhibitor 1400 W significantly attenuated the LPS-induced mitochondrial superoxide production and dysfunction in adrenal glands, and reversed the LPS-induced adrenocortical hyporesponsiveness to adrenocorticotropic hormone (ACTH). In contrast, administration of the NO donor sodium nitroprusside (SNP) led to mitochondrial oxidative stress and dysfunction in adrenal glands, which resulted in a blunted corticosterone response to ACTH. Using double immunofluorescence staining for iNOS with the vascular endothelial cell marker CD31 or the macrophage marker CD68, we found that increased iNOS expression was found in vascular endothelial cells and macrophages, but not adrenocortical cells in the adrenal gland during endotoxemia. Administration of the hydrogen sulfide (H2S) donor GYY4137 inhibited NO production and reversed LPS-induced adrenocortical hyporesponsiveness. Our data suggest that overproduction of NO, which is mainly generated by endothelial cells and macrophages during endotoxemia, contributes to mitochondrial oxidative stress in adrenocortical cells and subsequently leads to adrenal insufficiency.