The Effect And Mechanism Of Toxic Aldehyde And Alda-1 On Lung Ischemia-reperfusion Injury

Objective:Excessive oxidative stress is a main cause of lung ischemia-reperfusion injury(LIRI),which often results in respiratory insufficiency after open-heart surgery for a cardiopulmonary bypass(CPB).Previous studies demonstrate that activation of aldehyde dehydrogenase-2(ALDH2)could significantly reduce the oxidative stress mediated by toxic aldehydes,and attenuate cardiac and cerebral ischemia-reperfusion(I/R)injury.However,both the involvement of aldehydes and the protective effect of the ALDH2 agonist,Alda-1,in LIRI remain unknown.Method:Primary human pulmonary alveolar epithelial cells(HPAEpiC),human pulmonary microvascular endothelial cells(HPMEC),and Sprague-Dawley rats were used in this study.A hypoxia/reoxygenation(H/R)cell-culture model of HPAEpiC and HPMEC,and an isolated-perfused lung model were applied to mimic LIRI.We evaluated the effects of Alda-1 on ALDH2 quantity and activity,on aldehyde levels and pulmonary protection.Results:We have demonstrated that I/R induced pulmonary injury concomitantly induced aldehydes accumulation in HPAEpiC and lung tissues,but not in HPMEC.Moreover,Alda-1 pretreatment significantly elevated ALDH2 activity,increased surfactant associated protein C(SP-C),and attenuated elevation of 4-hydroxy-2-nonenal(4-HNE),apoptosis,intercellular adhesion molecule-1(ICAM-1),inflammatory response,and the permeability of pulmonary alveolar capillary barrier(PACB),thus alleviated injury.Conclusions:Our study indicates that the accumulation of 4-HNE plays an important role in LIRI.Alda-1 pretreatment can attenuate LIRI,possibly through the activation of ALDH2,which in turn removes 4-HNE in HPAEpiC.Alda-1 pretreatment has clinical implications to protect lungs during CPB.