MECHANISMS OF ISCHEMIA/REPERFUSION LUNG INJURY

缺血/再灌注肺损伤的机制

• 批准号: 3359822
• 负责人: JAMES E LOYD
• 金额: $ 14.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-30 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3359822
• 关键词: diagnostic respiratory lavage; disease /disorder model; eicosanoids; environmental stressor; enzyme linked immunosorbent assay; extracellular matrix; free radicals; glutathione; immunomodulators; inflammation; lipid peroxides; lung ischemia /hypoxia; lung transplantation; model design /development; neutrophil; oxidizing agents; oxidoreductase inhibitor; perfusion; platelet activating factor; pulmonary circulation; radioimmunoassay; respiratory oxygenation; sheep; superoxides; tumor necrosis factor alpha; vascular endothelium permeability; wakefulness; xanthine oxidase

This project will examine the mechanisms of lung ischemia/reperfusion (I/R) injury with the ultimate goal to discover therapy for I/R an important clinical problem. We will use a new model of lung I/R in awake sheep; after 12 hours of unilateral lung ischemia, reperfusion is associated with a prolonged increase in flow of protein-rich lung lymph, compatible with increased microvascular surface area, abnormal permeability or a combination of both. We propose to apply methods we developed in other models to distinguish increased permeability from surface area during I/R. Because we find no changes in hemodynamics or regional distribution of pulmonary blood flow during reperfusion, we propose that the "no-flow" phenomenon does not occur in lung reperfusion and will test this hypothesis further. Severe hypoxemia occurs in this model and is associated with increased wet/dry weights and inflammation in both lungs, despite only unilateral ischemia. Neutrophils are increased in both lungs when measured in lung biopsy or in bronchoalveolar lavage at 4 hours of reperfusion. We proposed that the neutrophil is critical to lung I/R, and will investigate this by depletion of circulating neutrophils before I/R. Our data indicated an increase in concentrations of metabolic products of arachidonate, including PGE2, 6-ketoPGF1 alpha, and TxB2; we propose to determine if these and other humoral mediators, including PGD2, LTB4, LTC4, platelet activating factor and tumor necrosis factor increase significanly during I/R. Lipid peroxidation products, including conjugated dienes and malondialdehyde, increase during reperfusion and suggest that free radical oxidant injury is contributory to the lung dysfunction. We will test the hypothesis that the oxidative component of the lung I/R is independent of xanthine oxidase (XO) in our model; we will administer inhibitors of XO before reperfusion and make measurements of XO in alveolar macrophages during both ischemia and reperfusion. Further we propose that reduced glutathione is an important protector against I/R. We will increase lung glutathione by n- acetylcysteinse administration before reperfusion, and will measure reduced and oxidized glutathione as a marker of oxidant stress as well as a marker of antioxidant reserve, in cells of lung lymph and bronchoalveolar lavage before and during I/R injury. Because adenosine provides effective prevention of I/R in heart and intestine, perhaps by inhibition of neutrophil superoxide production, we will infuse adenosine before lung reperfusion to investigate protection. Similarly, we will peform pilot investigation of agents reported to protect in other reperfusion models and which are appropriate for use in whole animals, for instance antiproteases. Finally, we propose to develop a model of lung transplantation in sheep, to complement our active clinical lung transplant program, utilizing information gained herein and applied to lung preservation.

这个项目将研究肺的机制 缺血/再灌注（I/R）损伤的最终目标是 发现I/R的治疗是一个重要的临床问题。 我们将 在清醒的绵羊中使用新的肺I/R模型; 单侧肺缺血再灌注与 富含蛋白质的肺淋巴液流量延长， 微血管表面积增加，渗透性异常 或两者的组合。 我们建议采用我们 在其他模型中开发，以区分增加的渗透性 从体表区域移除 因为我们发现 血流动力学或肺血流区域分布 在再灌注过程中，我们认为“无血流”现象 在肺再灌注中不发生， 进一步. 严重的低氧血症发生在这个模型中， 随着两个肺中湿/干重增加和炎症， 尽管只是单侧缺血。 中性粒细胞增加， 在肺活检或支气管肺泡中测量时， 再灌注4小时灌洗。 我们认为中性粒细胞 对肺I/R至关重要，并将通过消耗 I/R前循环中性粒细胞 我们的数据显示 花生四烯酸代谢产物的浓度，包括 PGE 2、6-ketoPGF 1 α和TxB 2;我们建议确定 这些和其他体液介质，包括PGD 2，LTB 4，LTC 4， 血小板活化因子和肿瘤坏死因子升高 在I/R期间， 脂质过氧化产物，包括 共轭二烯和丙二醛，增加期间 再灌注，并表明自由基氧化损伤是 导致了肺功能障碍 我们将检验这个假设 肺I/R的氧化成分与 黄嘌呤氧化酶（XO）在我们的模型;我们将管理抑制剂 再灌注前的XO，并进行测量XO在 在缺血和再灌注期间的肺泡巨噬细胞。 此外，我们认为还原型谷胱甘肽是一种重要的 I/R保护器 我们会增加肺部的谷胱甘肽- 再灌注前给予乙酰半胱氨酸， 测量还原型和氧化型谷胱甘肽作为氧化剂的标记物 压力以及抗氧化剂储备标记，在肺细胞中 在I/R损伤之前和期间进行淋巴和支气管肺泡灌洗。 由于腺苷能有效预防心脏I/R， 和肠道，可能通过抑制中性粒细胞超氧化物 生产，我们将在肺再灌注前注入腺苷， 调查保护。 同样，我们将进行试点 研究报告在其他再灌注中保护的药物 模型，并适用于整个动物， 例如抗蛋白酶。 最后，我们建议开发一个模型， 绵羊肺移植，以补充我们积极的临床 肺移植计划，利用本文获得的信息， 应用于肺保存。