Alda-1 Attenuates Lung Ischemia-Reperfusion Injury by Reducing 4-Hydroxy-2-Nonenal in Alveolar Epithelial Cells

• Published in: Critical care medicine Vol. 44; no. 7; p. e544
• Main Authors: Ding, Jie, Zhang, Quanyi, Luo, Qipeng, Ying, Yongquan, Liu, Yiwei, Li, Yinan, Wei, Wei, Yan, Fuxia, Zhang, Hao
• Format: Journal Article
• Language: English
• Published: United States 01.07.2016
• Subjects: Aldehyde Dehydrogenase, Mitochondrial - metabolism; Aldehydes - metabolism; Alveolar Epithelial Cells - metabolism; Animals; Benzamides - pharmacology; Benzamides - therapeutic use; Benzodioxoles - pharmacology; Benzodioxoles - therapeutic use; Cells, Cultured; Humans; Rats; Rats, Sprague-Dawley; Reperfusion Injury - metabolism; Reperfusion Injury - prevention & control
• ISSN: 1530-0293
• 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.