Department of Emergency Medicine, Second People's Hospital of Yunnan Province, Kunming, China.
Department of Critical Care Medicine, People's Hospital of Xishuangbanna Dai Nationality Autonomous Prefecture, Pingpong, China.
Basic Clin Pharmacol Toxicol. 2021 Feb;128(2):334-347. doi: 10.1111/bcpt.13505. Epub 2020 Oct 14.
The protective functions of thalidomide in paraquat (PQ)-induced injury have been reported. But the mechanisms remain largely unknown. In this research, a PQ-treated rat model was established and further treated with thalidomide. Oedema and pathological changes, oxidative stress, inflammation, fibrosis and cell apoptosis in rat lungs were detected. A PQ-treated RLE-6TN cell model was constructed, and the viability and apoptosis rate of cells were measured. Differentially expressed microRNAs (miRNAs) after thalidomide administration were screened out. Binding relationship between miR-141 and histone deacetylase 6 (HDAC6) was validated. Altered expression of miR-141 and HDAC6 was introduced to identify their involvements in thalidomide-mediated events. Consequently, thalidomide administration alone exerted no damage to rat lungs; in addition it reduced PQ-induced oedema. The oxidative stress, inflammation and cell apoptosis in rat lungs were reduced by thalidomide. In RLE-6TN cells, thalidomide increased cell viability and decreased apoptosis. miR-141 was responsible for thalidomide-mediated protective events by targeting HDAC6. Overexpression of HDAC6 blocked the protection of thalidomide against PQ-induced injury via activating the IkBα-NF-κB signalling pathway. Collectively, this study evidenced that thalidomide protects lung tissues from PQ-induced injury through a miR-141/HDAC6/IkBα-NF-κB axis.
沙利度胺已被报道具有对抗百草枯（PQ）诱导损伤的保护作用。但其作用机制仍知之甚少。本研究建立了 PQ 处理的大鼠模型，并进一步用沙利度胺进行处理。检测了大鼠肺组织的水肿和病理变化、氧化应激、炎症、纤维化和细胞凋亡。构建了 PQ 处理的 RLE-6TN 细胞模型，测量了细胞的活力和凋亡率。筛选出沙利度胺给药后差异表达的 microRNAs（miRNAs）。验证了 miR-141 与组蛋白去乙酰化酶 6（HDAC6）之间的结合关系。改变 miR-141 和 HDAC6 的表达，以确定它们在沙利度胺介导的事件中的作用。结果表明，沙利度胺单独给药对大鼠肺组织没有损伤，反而减轻了 PQ 诱导的水肿。沙利度胺还降低了大鼠肺组织的氧化应激、炎症和细胞凋亡。在 RLE-6TN 细胞中，沙利度胺增加了细胞活力，减少了细胞凋亡。miR-141 通过靶向 HDAC6 负责沙利度胺介导的保护事件。HDAC6 的过表达通过激活 IkBα-NF-κB 信号通路阻断了沙利度胺对 PQ 诱导损伤的保护作用。综上所述，本研究表明，沙利度胺通过 miR-141/HDAC6/IkBα-NF-κB 轴保护肺组织免受 PQ 诱导的损伤。
