FREE RADICAL INDUCED SURFACTANT DYSFUNCTION IN ACUTE LUNG INJURY

急性肺损伤中自由基引起的表面活性剂功能障碍

• 批准号: 6109755
• 负责人: EDWARD P INGENITO
• 金额: $ 27.43万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6109755
• 关键词: adult respiratory distress syndrome; apolipoproteins; biochemistry; biological transport; biophysics; blood proteins; disease /disorder model; free radicals; inflammation; laboratory rat; lung alveolus; lung injury; mathematical model; pathology; peptides; phosphatidylcholines; pulmonary surfactants; respiratory airway volume

Surfactant is essential for normal lung function. By lowering surface tension at the alveolar air-liquid interface, it stabilizes alveoli which might otherwise collapse at lung volumes near functional residual capacity. In adult respiratory distress syndrome (ARDS), the interfacial properties of lung surfactant are markedly abnormal, resulting in alveolar collapse, decreased lung compliance, and intrapulmonary shunt with hypoxemia. The processes responsible for surfactant dysfunction in this setting have not been established. The goal of this project is to characterize the biochemical and biophysical changes in alveolar surfactant resulting from acute inflammation. Our interests are not only at the alveolar level, where changes in the surface tension forces in ARDS lead to parenchymal instability and collapse of these spaces, but also at the level of the molecules controlling the biophysics and mechanics of the interfacial layer. We propose to examine the hypothesis that surfactant dysfunction in ARDS is due to generation of novel chemical species which inhibit surfactant function by affecting its interfacial properties. Our preliminary results suggest that these compounds are the products of reactions involving native surfactant components, plasma proteins, and free radical species generated and released from inflammatory cells in the alveolar space during acute inflammation. Our analysis further demonstrates that "surfactant dysfunction" resulting from acute inflammation can be manifest in several different ways including an isolated increase in minimum surface tension during film compression, an isolated decrease in surface film elastance during dynamic cycling, or a combination of both. By using a recently developed analytical model of surface film behavior during dynamic oscillation, we have demonstrated that these distinct profiles of dysfunction can be explained by specific changes in surfactant dynamic biophysical properties (e.g. adsorption, desorption, squeeze out/film collapse kinetics). The experiments we propose will identify l) which chemical products generated by free radical reactions involving lung surfactant and serum proteins inhibit surfactant function, 2) what biophysical phenomena are involved with surfactant dysfunction, 3) how various changes in interfacial properties of surfactant identified in vitro affect lung function in vivo, and 4) the native lung's response to application of PEEP, changes in tidal volume, and exogenous surfactant administration as approaches to reversing dysfunction. By accomplishing these objectives, we will provide new information regarding which chemical components are most important for imparting adsorption, desorption, and film stability to native surfactant, how free radical-derived inhibitors affect each of these properties of surfactant and impact on overall interfacial properties, what the chemical source and composition of these inhibitor are, and how these inhibitors affect function in the intact lung. Potentially, these studies will suggest strategies for developing effective strategies for treatment of ARDS.

表面活性剂对于正常的肺功能至关重要。通过降低 肺泡空气界面处的表面张力，稳定 肺泡可能会在附近的肺部塌陷 功能残留能力。在成人呼吸窘迫中 综合征（ARDS），肺表面活性剂的界面特性是 明显异常，导致肺泡塌陷，肺减少 依从性和肺内分流与低氧血症。过程 在这种情况下负责表面活性剂功能障碍 已建立。该项目的目的是表征 肺泡表面活性剂的生化和生物物理变化 由急性炎症引起。我们的兴趣不仅在 牙槽水平，其中表面张力的变化 ARDS导致实质不稳定和这些空间的崩溃， 而且还处于控制生物物理学的分子水平 和界面层的力学。 我们提出了以下假设 ARDS是由于抑制新型化学物种的产生 表面活性剂功能通过影响其界面特性。我们的 初步结果表明这些化合物是产品 涉及天然表面活性剂成分，血浆的反应 蛋白质，以及产生并从中释放的自由基物种 急性炎症期间肺泡空间中的炎症细胞。 我们的分析进一步表明“表面活性剂功能障碍” 急性炎症导致的几个 不同的方式，包括最小表面的孤立增加 膜压缩期间的张力，表面孤立的减少 动态循环期间的膜弹性或两者的组合。经过 使用最近开发的表面膜分析模型 动态振荡期间的行为，我们证明了 这些独特的功能障碍概况可以通过特定 表面活性剂动态生物物理特性的变化（例如 吸附，解吸，挤出/膜塌陷动力学）。 我们提出的实验将确定l）哪种化学产品 由涉及肺表面活性剂和的自由基反应产生 血清蛋白抑制表面活性剂功能，2）什么生物物理 现象涉及表面活性剂功能障碍，3）多种多样 表面活性剂的界面特性的变化已在体外鉴定 影响体内肺功能，4）本地肺对 窥视的应用，潮汐体积的变化和外源性 表面活性剂给药是逆转功能障碍的方法。 通过实现这些目标，我们将提供新的信息 关于哪些化学组件对于 将吸附，解吸和膜稳定性赋予天然 表面活性剂，自由基衍生的抑制剂如何影响每一个 表面活性剂的这些特性和对整体界面的影响 属性，这些化学源和这些的组成 抑制剂是，这些抑制剂如何影响 完整的肺。这些研究可能会提出 制定有效治疗ARD的策略。