本文選題：肺損傷　切入點(diǎn)：再灌注損傷　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：目的:肺缺血再灌注損傷(lung ischemia-reperfusion injury,LIRI)常導(dǎo)致體外循環(huán)(cardiopulmonary bypass,CPB)輔助下心臟手術(shù)術(shù)后呼吸功能不全,而過(guò)度氧化應(yīng)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(yīng)激導(dǎo)致的毒性醛類(lèi)物質(zhì)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(lèi)物質(zhì)毒性和ALDH2激動(dòng)劑Alda-1可能發(fā)揮的保護(hù)作用均尚無(wú)研究。方法:本研究以原代人肺泡上皮細(xì)胞(human pulmonary alveolar epithelial cells,HPAEpiC),原代人肺微血管內(nèi)皮細(xì)胞(human pulmonary microvascular endothelial cells,HPMEC)和Sprague-Dawley大鼠為研究對(duì)象。分別使用體外缺氧復(fù)氧(hypoxia/reoxygenation,H/R)細(xì)胞培養(yǎng)模型,和在體原位肺I/R模型模擬LIRI。檢測(cè)和評(píng)價(jià)Alda-1對(duì)ALDH2含量活性、醛類(lèi)物質(zhì)含量和肺損傷程度的影響。結(jié)果:I/R導(dǎo)致肺損傷,伴隨肺組織和HPAEpiC內(nèi)醛類(lèi)物質(zhì)蓄積,但HPMEC內(nèi)并無(wú)明顯醛類(lèi)物質(zhì)蓄積。Alda-1預(yù)處理可以顯著提高ALDH2活性,增加表面活性物質(zhì)相關(guān)蛋白 C(surfactant associated protein C,SP-C)表達(dá),減輕 4-羥基壬烯醛(4-hydroxy-2-nonenal,4-HNE)蓄積、細(xì)胞凋亡、細(xì)胞間粘附分子-1(intercellular adhesion molecule-1,ICAM-1)上調(diào)、炎癥反應(yīng)和肺泡毛細(xì)血管屏障(permeability of pulmonary alveolar capillary barrier,PACB)通透性增加,從而緩解肺損傷。結(jié)論:4-HNE蓄積在LIRI中發(fā)揮重要作用。Alda-1預(yù)處理可以通過(guò)激活A(yù)LDH2活性,減輕HPAEpiC內(nèi)4-HNE蓄積,從而減輕LIRI。Alda-1預(yù)處理對(duì)CPB期間的肺保護(hù)有臨床應(yīng)用價(jià)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(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R614

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1 丁潔;醛類(lèi)毒性和Alda-1對(duì)肺缺血再灌注損傷的影響及機(jī)制研究[D];北京協(xié)和醫(yī)學(xué)院;2017年

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本文編號(hào)：1565740