發(fā)布時間：2018-03-04 13:01

  本文選題：肺損傷　切入點：再灌注損傷　出處：《北京協(xié)和醫(yī)學院》2017年博士論文　論文類型：學位論文

【摘要】：目的:肺缺血再灌注損傷(lung ischemia-reperfusion injury,LIRI)常導致體外循環(huán)(cardiopulmonary bypass,CPB)輔助下心臟手術術后呼吸功能不全,而過度氧化應激是其最主要原因。既往研究表明,激活乙醛脫氫酶2(aldehyde dehydrogenase-2,ALDH2)可以顯著減少氧化應激導致的毒性醛類物質蓄積,從而減輕心臟和腦的缺血再灌注(ischemia-reperfusion,I/R)損傷。然而,在肺缺血再灌注損傷中,醛類物質毒性和ALDH2激動劑Alda-1可能發(fā)揮的保護作用均尚無研究。方法:本研究以原代人肺泡上皮細胞(human pulmonary alveolar epithelial cells,HPAEpiC),原代人肺微血管內皮細胞(human pulmonary microvascular endothelial cells,HPMEC)和Sprague-Dawley大鼠為研究對象。分別使用體外缺氧復氧(hypoxia/reoxygenation,H/R)細胞培養(yǎng)模型,和在體原位肺I/R模型模擬LIRI。檢測和評價Alda-1對ALDH2含量活性、醛類物質含量和肺損傷程度的影響。結果:I/R導致肺損傷,伴隨肺組織和HPAEpiC內醛類物質蓄積,但HPMEC內并無明顯醛類物質蓄積。Alda-1預處理可以顯著提高ALDH2活性,增加表面活性物質相關蛋白 C(surfactant associated protein C,SP-C)表達,減輕 4-羥基壬烯醛(4-hydroxy-2-nonenal,4-HNE)蓄積、細胞凋亡、細胞間粘附分子-1(intercellular adhesion molecule-1,ICAM-1)上調、炎癥反應和肺泡毛細血管屏障(permeability of pulmonary alveolar capillary barrier,PACB)通透性增加,從而緩解肺損傷。結論:4-HNE蓄積在LIRI中發(fā)揮重要作用。Alda-1預處理可以通過激活ALDH2活性,減輕HPAEpiC內4-HNE蓄積,從而減輕LIRI。Alda-1預處理對CPB期間的肺保護有臨床應用價值。
[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.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R614

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1 丁潔;醛類毒性和Alda-1對肺缺血再灌注損傷的影響及機制研究[D];北京協(xié)和醫(yī)學院;2017年

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本文編號：1565740