Rosmarinic Acid Ameliorates Pulmonary Ischemia/Reperfusion Injury by Activating the PI3K/Akt Signaling Pathway.
Rosmarinic Acid Ameliorates Pulmonary Ischemia/Reperfusion Injury by Activating the PI3K/Akt Signaling Pathway.
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迷迭香酸通过激活 PI3K/Akt 信号通路改善肺缺血/再灌注损伤
DOI：
10.3389/fphar.2022.860944
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发表时间：
2022
影响因子：
5.6
通讯作者：
Zeng, Chunyu
中科院分区：
文献类型：
--
作者：
Luo, Wenbin;Tao, Yu;Chen, Shengnan;Luo, Hao;Li, Xiaoping;Qu, Shuang;Chen, Ken;Zeng, Chunyu
肺缺血/再灌注（IR）损伤是急性肺损伤的主要原因，其机制主要是活性氧（ROS）诱导的细胞损伤和凋亡。由于迷迭香酸（RA）已被确定为抗氧化剂的天然酯，这种天然化合物可能会保护肺IR损伤。在这项研究中，小鼠在肺IR损伤之前通过管饲法每天给予RA（50、75或100 mg/kg），持续7天。结果发现，肺缺血再灌注损伤时低氧血症、肺水肿及血清炎症因子水平均明显升高。RA预处理（75和100 mg/kg）有效地逆转这些参数，而50 mg/kg RA预处理不太明显。我们的数据还表明RA预处理减轻了IR损伤后促氧化剂NADPH氧化酶（NOX 2和NOX 4）的上调和抗氧化剂超氧化物歧化酶（SOD 1和SOD 2）的下调。体外研究表明，RA对缺氧/复氧（AR）处理的人肺上皮细胞株A549细胞具有保护作用，其保护作用从5 μM开始，15 μM时达到最大，20-25 μM时逐渐减弱。此外，RA预处理（15 μM）大大降低了AR处理后乳酸脱氢酶的释放水平。此外，我们的研究结果表明，RA通过激活磷脂酰肌醇3激酶（PI 3 K）/蛋白激酶B（Akt）信号通路，抑制ROS的产生，减少肺泡上皮细胞凋亡，这一点得到了wortmannin的支持，因为wortmannin的存在阻断了RA介导的保护作用。同时，wortmannin也逆转了RA对小鼠的保护作用。总之，我们的研究结果表明，RA通过PI 3 K/Akt介导的抗氧化和抗凋亡在肺IR损伤中的有益作用，这可能是一种有希望的肺IR损伤的治疗干预。
Pulmonary ischemia/reperfusion (IR) injury is the leading cause of acute lung injury, which is mainly attributed to reactive oxygen species (ROS) induced cell injuries and apoptosis. Since rosmarinic acid (RA) has been identified as an antioxidant natural ester, this natural compound might protect against pulmonary IR injury. In this study, the mice were given RA daily (50, 75, or 100 mg/kg) by gavage for 7 days before the pulmonary IR injury. We found that hypoxemia, pulmonary edema, and serum inflammation cytokines were aggravated in pulmonary IR injury. RA pretreatment (75 and 100 mg/kg) effectively reversed these parameters, while 50 mg/kg RA pretreatment was less pronounced. Our data also indicated RA pretreatment mitigated the upregulation of pro-oxidant NADPH oxidases (NOX2 and NOX4) and the downregulation of anti-oxidant superoxide dismutases (SOD1 and SOD2) upon IR injury. In vitro studies showed RA preserved the viability of anoxia/reoxygenation (AR)-treated A549 cells (a human lung epithelial cell line), and the results showed the protective effect of RA started at 5 μM concentration, reached its maximum at 15 μM, and gradually decreased at 20–25 μM. Besides, RA pretreatment (15 μM) greatly reduced the lactate dehydrogenase release levels subjected to AR treatment. Moreover, the results of our research revealed that RA eliminated ROS production and reduced alveolar epithelial cell apoptosis through activating the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, which was supported by using wortmannin, because in the presence of wortmannin, the RA-mediated protection was blocked. Meanwhile, wortmannin also reversed the protective effects of RA in mice. Together, our results demonstrate the beneficial role of RA in pulmonary IR injury via PI3K/Akt-mediated anti-oxidation and anti-apoptosis, which could be a promising therapeutic intervention for pulmonary IR injury.
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