BASIC MECHANISMS OF RE-EXPANSION PULMONARY EDEMA

再扩张性肺水肿的基本机制

• 批准号: 3471585
• 负责人: Robert M Jackson
• 金额: $ 7.44万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3471585
• 关键词: antioxidants; biological fluid transport; diagnostic respiratory lavage; disease /disorder model; free radicals; laboratory rabbit; model design /development; neutrophil; pulmonary edema; superoxide dismutase

The overall goal of this application is to fully characterize the basic biochemical mechanisms which account for the unilateral, permeability form of pulmonary edema which occurs in re- expanded lungs. Re-expansion pulmonary edema (RPE) has traditionally been attributed to forces during expansion which decrease lung interstitial pressure and lead to transudation of fluid. Our preliminary data support the hypothesis that the mechanism of RPE involves oxygen free radical-mediated injury to alveolar-capillary lining cells during rapid re-expansion and re-oxygenation of previously collapsed and hypoperfused lungs. In order to clarify this mechanism, we plan to accomplish the following specific aims: 1) assessment of the pro-inflammatory role of 02 metabolites (including superoxide and H2O2) in RPE, 2) study enzymatic and mitochondrial sources of O2 metabolites along with intracellular antioxidants, 3) investigate the contribution of neutrophils to the unilateral lung injury, and 4) isolate and characterize neutrophil chemoattractants produced during collapse/re-expansion. These experiments will be accomplished using a rabbit model of re-expansion edema in which the effects of free radical probes can be tested. Intracellular antioxidant defenses, especially mitochondrial SOD, will be assessed before and after re-expansion. The effects of extracellular superoxide dismutase (SOD) and catalase (CAT) on edema formation will be tested by intravenous enzyme pretreatment, and liposome-encapsulated SOD and CAT will be used to test the effects of augmented intracellular antioxidant enzymes on edema formation. Additional experiments will be conducted to determine whether aldehyde oxidase is an important source of superoxide or H2O2 in this model. Cyanide- insensitive tissue respiration will be measured as an index of lung free radical formation. Lung lavage fluid will be assayed for chemotactic activity and its cellular composition characterized at various time points before and after re-expansion. The degree of cytotoxic O2 metabolite production, effects of antioxidants, and generation of chemoattractants will also be measured in re- expanded lungs of neutropenic rabbits, to further specify the contribution of neutrophils. This form of unilateral lung injury resembles, in many ways, adult respiratory distress syndrome. It will serve as a model for testing experimental interventions in acute lung injury, since the internal control lung will greatly minimize consumption of experimental animals and no exogenous toxicant need be administered.

此应用程序的总体目标是充分表征 基本的生化机制， 肺水肿的渗透性形式，发生在再 扩张的肺 再膨胀性肺水肿（RPE） 传统上归因于膨胀期间的力， 降低肺间质压，导致 液 我们的初步数据支持这一假设， RPE的发生机制与氧自由基介导的损伤有关 肺泡毛细血管衬里细胞在快速再扩张， 对之前塌陷和灌注不足的肺进行再氧合。 为了阐明这一机制，我们计划完成 以下具体目的：1）评估促炎性 O2代谢物（包括超氧化物和H2 O2）在RPE中的作用， 2)研究O2代谢物的酶和线粒体来源 沿着细胞内抗氧化剂，3）研究 中性粒细胞对单侧肺损伤的贡献，以及4） 分离和表征产生中性粒细胞化学引诱物 在崩溃/再膨胀期间。 这些实验将 使用兔再扩张水肿模型完成， 从而可以测试自由基探针的效果。 细胞内抗氧化防御，特别是线粒体SOD， 将在重新扩展之前和之后进行评估。 的影响 细胞外超氧化物歧化酶（SOD）和过氧化氢酶（CAT）对 将通过静脉内酶试验水肿形成 预处理，脂质体包封的SOD和CAT将 用于测试增强的细胞内抗氧化剂的效果 酶对水肿形成的影响。 其他实验将 以确定醛氧化酶是否是一种 超氧化物或H2 O2的重要来源。 氰化物- 不敏感组织呼吸将被测量为肺部指数 自由基形成。 将对肺灌洗液进行分析， 趋化活性及其表征的细胞组成 在再扩张之前和之后的不同时间点。 程度 细胞毒性O2代谢产物的产生，抗氧化剂的作用， 和化学引诱物的产生也将在重新测量中测量， 扩张的肺，以进一步说明 中性粒细胞的贡献。 这种单侧肺损伤 在很多方面类似于成人呼吸窘迫综合征。 它 将作为测试实验干预的模型， 急性肺损伤，自内控肺将大大 尽量减少实验动物的消耗， 必须使用有毒物质。