Alda-1 Attenuates Lung Ischemia-Reperfusion Injury by Reducing 4-Hydroxy-2-Nonenal in Alveolar Epithelial Cells
Alda-1 Attenuates Lung Ischemia-Reperfusion Injury by Reducing 4-Hydroxy-2-Nonenal in Alveolar Epithelial Cells
复制标题
Alda-1 通过减少肺泡上皮细胞中的 4-Hydroxy-2-Nonenal 减轻肺缺血再灌注损伤
DOI：
10.1097/ccm.0000000000001563
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发表时间：
2016-07-01
影响因子：
8.8
通讯作者：
Zhang, Hao
中科院分区：
文献类型：
--
作者：
Ding, Jie;Zhang, Quanyi;Zhang, Hao
目的：过度的氧化应激是导致肺缺血再灌注损伤的主要原因，常导致体外循环心内直视手术后呼吸功能不全。以往的研究表明，醛脱氢酶-2的激活可以显著降低有毒醛类介导的氧化应激，减轻心脑缺血再灌注损伤。然而，醛的参与和醛脱氢酶-2激动剂Alda-1在肺缺血再灌注损伤中的保护作用仍然未知。设计：进行前瞻性实验室和动物研究。单位：心血管疾病国家重点实验室。受试者：原代人肺泡上皮细胞、人肺微血管内皮细胞和Sprague-Dawley大鼠。干预措施：采用人肺泡上皮细胞、人肺微血管内皮细胞缺氧/复氧细胞培养模型和离体肺灌流模型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、醛水平和肺保护的影响。测量和主要结果：我们已经证明，缺血-再灌注诱导的肺损伤伴随诱导醛类积累在人肺泡上皮细胞和肺组织，但不是在人肺微血管内皮细胞。此外，Alda-1预处理显著升高醛脱氢酶-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，细胞凋亡，细胞间粘附分子-1，炎症反应和肺泡毛细血管屏障通透性的升高，从而减轻损伤。结论：4-羟基-2-壬烯醛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预处理对心肺转流期间保护肺部具有临床意义。
Objectives: 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. Design: Prospective laboratory and animal investigation were conducted. Setting: State Key Laboratory of Cardiovascular Disease. Subjects: Primary human pulmonary alveolar epithelial cells, human pulmonary microvascular endothelial cells, and Sprague-Dawley rats. Interventions: 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. Measurements and Main Results: 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. Conclusions: 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.