Wang Na, Li Yuhua, Wang Xiaofeng, Ma Zhongliang, Wang Yunwen, Zhang Chen, Yuan Yuan, Zhao Min
Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China; Occupational Disease and Occupational Health Prevention and Control Institute, Liaoning Center for Disease Control and Prevention, Shenyang, Liaoning, China.
Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
Toxicology. 2020 Oct;443:152555. doi: 10.1016/j.tox.2020.152555. Epub 2020 Aug 5.
The specific mechanism of paraquat (PQ)-induced acute lung injury (ALI) is unclear, though inflammation is a likely contributor. Amlexanox, a TANK binding kinase 1 (TBK1) inhibitor, is a strong anti-inflammatory drug. We investigated the role of TBK1 and the potential therapeutic effect of amlexanox in the pathogenesis of PQ-induced ALI. After 30 mg/kg PQ treatment for 72 h, mouse lung pathological injury occurred, and the protein concentration in alveolar lavage fluid was increased. Next, RAW264.7 mouse macrophages were treated with 100 μM PQ for 24 h, which decreased cell viability. PQ induced oxidative damage and increased IL-1β, IFNβ, NF-κBp65, IRF3, and pTBK1/TBK1 levels in mouse lungs and RAW264.7 cells. Inhibiting the activation of TBK1 with amlexanox (100 mg/kg in mice and 50 μM in RAW264.7 cells) attenuated mouse lung injury and decreased the protein concentration in alveolar lavage fluid. Further, amlexanox relieved the oxidative damage in mouse lungs and RAW264.7 cells, reduced the levels of inflammatory factors such as IL-1β and IFNβ, and inhibited the activation of NF-κBp65 and IRF3. These results suggest that TBK1 plays a key role in the pathogenesis of PQ-induced ALI. Further, amlexanox treatment alleviates PQ-induced ALI by inhibiting the TBK1-NF-κB/IRF3 signalling pathway. Our study provides evidence that TBK1 inhibition by amlexanox alleviates PQ-induced ALI and may be a new therapeutic strategy.
百草枯（PQ）诱导急性肺损伤（ALI）的具体机制尚不清楚，不过炎症可能是一个促成因素。氨来呫诺是一种 Tank 结合激酶 1（TBK1）抑制剂，是一种强效抗炎药物。我们研究了 TBK1 的作用以及氨来呫诺在 PQ 诱导的 ALI 发病机制中的潜在治疗效果。用 30 mg/kg 的 PQ 处理 72 小时后，小鼠出现肺病理损伤，肺泡灌洗液中的蛋白质浓度升高。接下来，用 100 μM 的 PQ 处理 RAW264.7 小鼠巨噬细胞 24 小时，细胞活力降低。PQ 诱导小鼠肺组织和 RAW264.7 细胞发生氧化损伤，并使白细胞介素-1β（IL-1β）、干扰素β（IFNβ）、核因子κB p65（NF-κBp65）、干扰素调节因子 3（IRF3）以及磷酸化 TBK1/TBK1 的水平升高。用氨来呫诺（小鼠为 100 mg/kg，RAW264.7 细胞为 50 μM）抑制 TBK1 的激活可减轻小鼠肺损伤，并降低肺泡灌洗液中的蛋白质浓度。此外，氨来呫诺减轻了小鼠肺组织和 RAW264.7 细胞的氧化损伤，降低了 IL-1β 和 IFNβ 等炎症因子的水平，并抑制了 NF-κBp65 和 IRF3 的激活。这些结果表明，TBK1 在 PQ 诱导的 ALI 发病机制中起关键作用。此外，氨来呫诺治疗通过抑制 TBK1-NF-κB/IRF3 信号通路减轻了 PQ 诱导的 ALI。我们的研究提供了证据，表明氨来呫诺抑制 TBK1 可减轻 PQ 诱导的 ALI，可能是一种新的治疗策略。
