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.

该提案重点关注天然物质的表面活性和抑制 和合成肺表面活性剂。强调的是生物物理作用和 磷脂和脱辅基蛋白成分的功能重要性 内源性肺表面活性物质（LS），随着活性肺表面活性物质的发展 用于未来新生儿治疗用途的合成外源替代品 呼吸窘迫综合征 (RDS) 和临床肺损伤 表现为急性或成人 RDS (ARDS)。该提案有四个目标，每个目标 涉及补充生物物理测量和肺压 体积（P-V）力学研究。目标 1 研究以下组件的基础 完整的表面和活性功能以及提取的LS和纯化的 其疏水成分的亚组分（例如 LS 的完整混合物） 磷脂，两性离子 LS 磷脂，不含阴离子 磷脂、LS中性脂质、磷脂加疏水性 脱辅基蛋白等）。目标2和3涉及模型的相关研究 表面活性剂，包括二棕榈酰磷脂酰胆碱（DPPC）和其他 合成磷脂与疏水性表面活性蛋白结合或 合成肽（目标 2）和新型磷脂和磷脂 合成具有特定结构变异的类似物（目标 3）。研究 目标 1-3 中的正常活动由目标 4 实验补充 LS 和外源性表面活性剂通过生理学失活 通过多种机制发挥作用的相关抑制剂（例如血浆蛋白、 lyso-PC 和其他膜脂、胎便、脂肪酸、裂解酶）。 在所有目标中，表面活性剂均通过多种界面技术进行研究 （威廉天平、振荡气泡、吸收仪）阐明 全方位的表面张力降低、重新铺展、滞后和 与 LS 相关的吸收行为。布鲁斯特角显微镜，X 射线 衍射、差示扫描量热法和傅里叶变换 红外光谱也用于增强对 分子和薄膜结构水平。为了确保生理相关性， 表面活性和抑制的 P-V 机械相关性为 在四个拟议目标中的每一个目标中，在切除的大鼠肺中测定。