Ding Jie, Zhang Quanyi, Luo Qipeng, Ying Yongquan, Liu Yiwei, Li Yinan, Wei Wei, Yan Fuxia, Zhang Hao
1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 2Department of Anesthesiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 3Department of Surgery and Center for Pediatric Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Crit Care Med. 2016 Jul;44(7):e544-52. doi: 10.1097/CCM.0000000000001563.
Excessive oxidative stress is a main cause of lung ischemia-reperfusion injury, which often results in respiratory insufficiency after open-heart surgery for a cardiopulmonary bypass. Previous studies demonstrate that the activation of aldehyde dehydrogenase-2 could significantly reduce the oxidative stress mediated by toxic aldehydes and attenuate cardiac and cerebral ischemia-reperfusion injury. However, both the involvement of aldehydes and the protective effect of the aldehyde dehydrogenase-2 agonist, Alda-1, in lung ischemia-reperfusion injury remain unknown.
Prospective laboratory and animal investigation were conducted.
State Key Laboratory of Cardiovascular Disease.
Primary human pulmonary alveolar epithelial cells, human pulmonary microvascular endothelial cells, and Sprague-Dawley rats.
A hypoxia/reoxygenation cell-culture model of human pulmonary alveolar epithelial cell, human pulmonary microvascular endothelial cell, and an isolated-perfused lung model were applied to mimic lung ischemia-reperfusion injury. We evaluated the effects of Alda-1 on aldehyde dehydrogenase-2 quantity and activity, on aldehyde levels and pulmonary protection.
We have demonstrated that ischemia-reperfusion-induced pulmonary injury concomitantly induced aldehydes accumulation in human pulmonary alveolar epithelial cells and lung tissues, but not in human pulmonary microvascular endothelial cells. Moreover, Alda-1 pretreatment significantly elevated aldehyde dehydrogenase-2 activity, increased surfactant-associated protein C, and attenuated elevation of 4-hydroxy-2-nonenal, apoptosis, intercellular adhesion molecule-1, inflammatory response, and the permeability of pulmonary alveolar capillary barrier, thus alleviated injury.
Our study indicates that the accumulation of 4-hydroxy-2-nonenal plays an important role in lung ischemia-reperfusion injury. Alda-1 pretreatment can attenuate lung ischemia-reperfusion injury, possibly through the activation of aldehyde dehydrogenase-2, which in turn removes 4-hydroxy-2-nonenal in human pulmonary alveolar epithelial cells. Alda-1 pretreatment has clinical implications to protect lungs during cardiopulmonary bypass.
氧化应激过度是肺缺血再灌注损伤的主要原因，这常导致体外循环心脏直视手术后出现呼吸功能不全。既往研究表明，醛脱氢酶-2的激活可显著降低有毒醛类介导的氧化应激，并减轻心脏和脑缺血再灌注损伤。然而，醛类的参与情况以及醛脱氢酶-2激动剂Alda-1在肺缺血再灌注损伤中的保护作用仍不清楚。
进行前瞻性实验室和动物研究。
心血管疾病国家重点实验室。
原代人肺泡上皮细胞、人肺微血管内皮细胞和Sprague-Dawley大鼠。
应用人肺泡上皮细胞、人肺微血管内皮细胞的缺氧/复氧细胞培养模型以及离体灌注肺模型来模拟肺缺血再灌注损伤。我们评估了Alda-1对醛脱氢酶-2数量和活性、醛水平及肺保护的影响。
我们已证明，缺血再灌注诱导的肺损伤会伴随人肺泡上皮细胞和肺组织中醛类的积累，但在人肺微血管内皮细胞中则不会。此外，Alda-1预处理可显著提高醛脱氢酶-2活性，增加表面活性物质相关蛋白C，并减轻4-羟基-2-壬烯醛的升高、细胞凋亡、细胞间黏附分子-1、炎症反应以及肺泡毛细血管屏障的通透性，从而减轻损伤。
我们的研究表明，4-羟基-2-壬烯醛的积累在肺缺血再灌注损伤中起重要作用。Alda-1预处理可减轻肺缺血再灌注损伤，可能是通过激活醛脱氢酶-2，进而清除人肺泡上皮细胞中的4-羟基-2-壬烯醛。Alda-1预处理对体外循环期间保护肺脏具有临床意义。
