醛类毒性和Alda-1对肺缺血再灌注损伤的影响及机制研究

发布时间：2018-03-04 13:01

本文选题：肺损伤　切入点：再灌注损伤　出处：《北京协和医学院》2017年博士论文　论文类型：学位论文

【摘要】：目的:肺缺血再灌注损伤(lung ischemia-reperfusion injury,LIRI)常导致体外循环(cardiopulmonary bypass,CPB)辅助下心脏手术术后呼吸功能不全,而过度氧化应激是其最主要原因。既往研究表明,激活乙醛脱氢酶2(aldehyde dehydrogenase-2,ALDH2)可以显著减少氧化应激导致的毒性醛类物质蓄积,从而减轻心脏和脑的缺血再灌注(ischemia-reperfusion,I/R)损伤。然而,在肺缺血再灌注损伤中,醛类物质毒性和ALDH2激动剂Alda-1可能发挥的保护作用均尚无研究。方法:本研究以原代人肺泡上皮细胞(human pulmonary alveolar epithelial cells,HPAEpiC),原代人肺微血管内皮细胞(human pulmonary microvascular endothelial cells,HPMEC)和Sprague-Dawley大鼠为研究对象。分别使用体外缺氧复氧(hypoxia/reoxygenation,H/R)细胞培养模型,和在体原位肺I/R模型模拟LIRI。检测和评价Alda-1对ALDH2含量活性、醛类物质含量和肺损伤程度的影响。结果:I/R导致肺损伤,伴随肺组织和HPAEpiC内醛类物质蓄积,但HPMEC内并无明显醛类物质蓄积。Alda-1预处理可以显著提高ALDH2活性,增加表面活性物质相关蛋白 C(surfactant associated protein C,SP-C)表达,减轻 4-羟基壬烯醛(4-hydroxy-2-nonenal,4-HNE)蓄积、细胞凋亡、细胞间粘附分子-1(intercellular adhesion molecule-1,ICAM-1)上调、炎症反应和肺泡毛细血管屏障(permeability of pulmonary alveolar capillary barrier,PACB)通透性增加,从而缓解肺损伤。结论:4-HNE蓄积在LIRI中发挥重要作用。Alda-1预处理可以通过激活ALDH2活性,减轻HPAEpiC内4-HNE蓄积,从而减轻LIRI。Alda-1预处理对CPB期间的肺保护有临床应用价值。
[Abstract]:Objective: lung ischemia-reperfusion injury-LIRI often leads to respiratory insufficiency after cardiopulmonary bypass (CPB-assisted cardiopulmonary bypass), and excessive oxidative stress is the main cause. Activation of aldehyde dehydrogenase-2ALDH2) can significantly reduce the accumulation of toxic aldehydes induced by oxidative stress, thereby alleviating the ischemia-reperfusion ischemia-reperfusion I / R injury in the heart and brain. However, in lung ischemia-reperfusion injury, The toxicity of aldehydes and the protective effect of ALDH2 agonist Alda-1 have not been studied. Methods: in this study, the primary human pulmonary alveolar epithelial cells, primary human pulmonary microvascular endothelial cells HPMECs and Sprague-Dawley rats were used in this study. Study subjects. In vitro hypoxia / reoxygenation / H / R cell culture model was used respectively. And in situ lung I / R model. The effects of Alda-1 on the activity of ALDH2, the content of aldehydes and the degree of lung injury were measured and evaluated. Results: 1 / I / R resulted in lung injury, accompanied by accumulation of aldehydes in lung tissue and HPAEpiC. But there was no obvious aldehydes accumulation. Alda-1 pretreatment could significantly increase the activity of ALDH2, increase the expression of surface-active protein associated protein Con SP-C, reduce the accumulation of 4-hydroxy-2-nonenale-4-HNEs and apoptosis in HPMEC. Intercellular adhesion molecule-1 (ICAM-1) upregulated, inflammatory response and alveolar capillary barrier permeability increased, thus relieving lung injury. Conclusion the accumulation of 1% 4-HNE plays an important role in LIRI. Alda-1 pretreatment can activate ALDH2 activity. Reducing the accumulation of 4-HNE in HPAEpiC and alleviating the preconditioning of LIRI.Alda-1 have clinical value for lung protection during CPB.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R614

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