Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Physiology, Medical College of Jishou University, Jishou, Hunan, China.
Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Int Immunopharmacol. 2019 May;70:520-529. doi: 10.1016/j.intimp.2019.03.018. Epub 2019 Mar 19.
Overactivation of the N-methyl-d-aspartate (NMDA) receptor promotes oxidative stress, aggravates the inflammatory response and induces excitotoxic lung injury. NMDA is a synthetic agonist that selectively activates the NMDA receptor. Oleanolic acid (OA) is a natural anti-inflammatory and antioxidant compound. This study investigated the effect and possible mechanism of OA on NMDA-induced acute lung injury (ALI) in mice. OA pretreatment alleviated NMDA-induced histological lung changes and ameliorated pulmonary oedema and pulmonary permeability. At the same time, OA inhibited inflammatory cell infiltration and decreased the levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in the lung and bronchoalveolar lavage fluid (BALF). OA markedly decreased malondialdehyde (MDA) production and increased the superoxide dismutase (SOD) and glutathione (GSH) contents of the lung in vivo. Meanwhile, we first found that NMDA increased LDH activity and decreased cell viability, and induced oxidative stress and apoptosis in mouse lung epithelial (MLE)-12 cells. By employing SRT1720 and sirtinol, the activator and inhibitor of sirtuin 1 (SIRT1), we found that SRT1720 partially eliminated the increase in ROS，and sirtinol further promoted the increase in ROS caused by NMDA. OA increased MLE-12 cells viability and attenuated oxidative stress after NMDA challenge in vitro. OA suppressed NMDA-induced MLE-12 cells apoptosis, while sirtinol inhibited the effect of OA. In addition, OA significantly upregulated the levels of SIRT1, nuclear-related factor 2(Nrf2) and Bcl-2 protein and downregulated the levels of acetylated nuclear factor-kappa B (NF-κB), NLRP3 and Bax protein. In conclusion, OA attenuated NMDA-induced excitotoxic lung injury, potentially through its anti-inflammatory, antioxidative stress and anti-apoptotic effects. The mechanism may be related to activating SIRT1 and reducing NF-κB acetylation.
N-甲基-D-天冬氨酸（NMDA）受体的过度激活会促进氧化应激，加重炎症反应，并诱导兴奋性毒性肺损伤。NMDA 是一种选择性激活 NMDA 受体的合成激动剂。齐墩果酸（OA）是一种天然的抗炎和抗氧化化合物。本研究探讨了 OA 对 NMDA 诱导的小鼠急性肺损伤（ALI）的作用及其可能的机制。OA 预处理减轻了 NMDA 诱导的肺组织学变化，并改善了肺水肿和肺通透性。同时，OA 抑制了炎症细胞浸润，并降低了肺和支气管肺泡灌洗液（BALF）中肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6 和 IL-1β的水平。OA 显著降低了丙二醛（MDA）的产生，并增加了体内肺的超氧化物歧化酶（SOD）和谷胱甘肽（GSH）含量。同时，我们首次发现 NMDA 增加了 LDH 活性，降低了细胞活力，并诱导了小鼠肺上皮（MLE）-12 细胞的氧化应激和凋亡。通过使用 SRT1720 和 sirtinol，即 SIRT1 的激活剂和抑制剂，我们发现 SRT1720 部分消除了 ROS 的增加，而 sirtinol 进一步促进了 NMDA 引起的 ROS 增加。OA 增加了 MLE-12 细胞在 NMDA 攻击后的活力，并减轻了体外的氧化应激。OA 抑制了 NMDA 诱导的 MLE-12 细胞凋亡，而 sirtinol 抑制了 OA 的作用。此外，OA 显著上调了 SIRT1、核相关因子 2（Nrf2）和 Bcl-2 蛋白的水平，并下调了乙酰化核因子-κB（NF-κB）、NLRP3 和 Bax 蛋白的水平。总之，OA 减轻了 NMDA 诱导的兴奋性毒性肺损伤，其潜在机制可能与其抗炎、抗氧化应激和抗凋亡作用有关。该机制可能与激活 SIRT1 和减少 NF-κB 乙酰化有关。
