Oxaloacetate acid ameliorates paraquat-induced acute lung injury by alleviating oxidative stress and mitochondrial dysfunction.
Oxaloacetate acid ameliorates paraquat-induced acute lung injury by alleviating oxidative stress and mitochondrial dysfunction.
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草酰乙酸通过减轻氧化应激和线粒体功能障碍改善百草枯诱导的急性肺损伤
DOI：
10.3389/fphar.2022.1029775
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
急性肺损伤（acute lung injury，ALI）是急性百草枯（paraquat，PQ）中毒患者死亡的主要原因，过氧化损伤是PQ所致肺损伤的重要机制。PQ中毒患者缺乏有效的干预药物。草酰乙酸（OAA）参与多种体内代谢过程，从而促进活性氧（ROS）的清除并改善线粒体功能。本研究旨在探讨花生四烯酸对PQ诱导的急性肺损伤的保护作用及其分子机制。我们的数据表明，OAA治疗显着减轻PQ诱导的ALI和提高PQ中毒小鼠的存活率，并减轻PQ诱导的细胞氧化应激和线粒体功能障碍。OAA对PQ诱导的线粒体功能障碍的缓解作用可能与以下机制有关：1）OAA能有效清除细胞内ROS，抑制ROS积聚，抑制线粒体去极化; 2）OAA抑制PQ引起的L-OPA 1和MFN 2表达下调，促进线粒体融合与分裂的动态平衡; 3）PGC-1α、TFAM、COX 2、和COX 4 I1在OAA干预后显著增加，改善了线粒体呼吸功能，促进了受损细胞的生物合成和能量代谢。OAA能有效清除ROS，改善线粒体功能障碍，从而显著改善PQ中毒所致的ALI，提高动物存活率。因此，OAA可能是治疗PQ中毒的潜在药物。
Acute lung injury (ALI) is the primary cause of death among patients with acute paraquat (PQ) poisoning, whereby peroxidative damage is an important mechanism underlying PQ-induced lung injury. There is a lack of effective interventional drugs for patients with PQ poisoning. Oxaloacetic acid (OAA) participates in multiple in vivo metabolic processes, whereby it facilitates the clearance of reactive oxygen species (ROS) and improves mitochondrial function. The study aimed to assess the protective effects of OAA on PQ-induced ALI and elucidate the underlying molecular mechanism. Our data demonstrated that OAA treatment significantly alleviated PQ-induced ALI and improved the survival rate of PQ-poisoned mice, and also alleviated PQ-induced cellular oxidative stress and mitochondrial dysfunction. OAA-mediated alleviation of PQ-induced mitochondrial dysfunction depends on the following mechanisms which may explain the above findings: 1) OAA effectively cleared intracellular ROS, inhibited ROS accumulation, and mitochondrial depolarization; 2) OAA inhibited the downregulation of L-OPA1 and MFN2 caused by PQ and promoted a dynamic balance of mitochondrial fusion and fission, and 3) the expression of PGC-1α, TFAM, COX2, and COX4I1, increased significantly following OAA intervention which improved mitochondrial respiratory functions and promoted its biogenesis and energy metabolism in damaged cells. In conclusion, OAA effectively cleared ROS and improved mitochondrial dysfunction, thereby significantly improving ALI caused by PQ poisoning and the animal survival rate. Therefore, OAA may be a potential drug for the treatment of PQ poisoning.
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