FUNDAMENTALS OF LUNG SURFACTANT ACTIVITY AND INHIBITION

肺表面活性剂活性和抑制的基础知识

• 批准号: 2857876
• 负责人: ROBERT H NOTTER
• 金额: $ 23.96万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2857876
• 关键词: X ray crystallography; biomechanics; calorimetry; chemical structure function; hydropathy; infrared spectrometry; laboratory rat; molecular film; phospholipids; physical chemical interaction; proteolipids; pulmonary surfactants; surface property; synthetic peptide

This proposal focuses on the surface activity and inhibition of natural and synthetic lung surfactants. Emphasized are the biophysical roles and functional importance of the phospholid and apoprotein constituents of endogenous lung surfactant (LS), along with the development of active synthetic exogenous substitutes for future therapeutic use in the neonatal respiratory distress syndrome (RDS) and in clinical lung injuries manifesting as acute or adult RDS (ARDS). The proposal has four Aims, each involving complementary biophysical measurements and pulmonary pressure volume (P-V) mechanical studies. Aim 1 investigates the component basis of surface and active function in whole and extracted LS and purified subfractions of its hydrophobic constituents (e.g., the complete mix of LS phospholipids, zwitterionic LS phospholipids without anionic phospholipids, LS neutral lipids, phospholipids plus hydrophobic apoproteins, etc). Aims 2 and 3 involved related studies with model surfactants, including dipalmitoyl phosphatidylcholine (DPPC) and other synthetic phospholipids combined with hydrophobic surfactant proteins or synthetic peptides (Aim 2) and novel phosphonolipids and phospholipid analogs synthesized with specific structural variations (Aim 3). Studies of normal activity in Aims 1-3 are supplemented by Aim 4 experiments on the inactivation of LS and exogenous surfactants by physiologically- relevant inhibitors that act by several mechanisms (e.g., plasma proteins, lyso-PC and other membrane lipids, meconium, fatty acids, lytic enzymes). In all Aims, surfactants are studied by multiple interfacial techniques (Wilhelmy balance, oscillating bubble, absorption apparatus) to elucidate the full range of surface tension lowering, respreading, hysteresis , and absorption behaviors relevant for LS. Brewster-angle microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy are also used to enhance interpretations at the molecular and film structural levels. To ensure physiological relevance, P-V mechanical correlates of surface activity and inhibition are determined in excised rat lungs within each of the four proposed Aims.

该提案着重于表面活动和自然抑制 和合成肺表面活性剂。强调的是生物物理角色和 磷脂和载蛋白成分的功能重要性 内源性肺表面活性剂（LS），并发展活性 合成外源替代品，用于新生儿的未来治疗用途 呼吸窘迫综合征（RDS）和临床肺损伤 表现为急性或成人RD（ARDS）。该提议有四个目标，每个目标 涉及互补的生物物理测量和肺压 体积（P-V）机械研究。 AIM 1调查了组件基础 整体和提取的LS表面和主动功能并纯化 其疏水成分的亚元素（例如，LS的完整混合物 磷脂，无阴离子的磷脂LS磷脂 磷脂，LS中性脂质，磷脂和疏水性 载蛋白等）。目标2和3涉及与模型的相关研究 表面活性剂，包括二硫酰磷脂酰胆碱（DPPC）和其他 合成磷脂结合疏水表面活性剂蛋白或 合成肽（AIM 2）和新型磷酸磷脂和磷脂 与特定结构变化合成的类似物（AIM 3）。研究 AIM 1-3中正常活动的AIM 4实验补充了 生理学上的LS和外源表面活性剂失活 通过多种机制起作用的相关抑制剂（例如，血浆蛋白， Lyso-PC和其他膜脂质，胎粪，脂肪酸，裂解酶）。 总的来说，通过多种界面技术研究表面活性剂 （Wilhelmy平衡，振荡气泡，吸收设备）以阐明 降低表面张力的全范围，重塑，滞后和 与LS相关的吸收行为。 BREWSTER-角度显微镜，X射线 衍射，差扫描量热法和傅立叶变换 红外光谱也用于增强解释 分子和膜结构水平。为了确保生理相关性， p-V表面活性和抑制的机械相关性是 在提出的四个目标中的每一个中，在切除的大鼠肺中确定。