FUNDAMENTALS OF LUNG SURFACTANT ACTIVITY AND INHIBITION

这项建议侧重于天然物质的表面活性和抑制作用 和合成的肺表面活性物质。重点强调了生物物理作用和 磷脂和载脂蛋白成分在功能上的重要性 内源性肺表面活性物质(LS)随着活性的发展而发展 合成外源性替代品未来在新生儿治疗中的应用 呼吸窘迫综合征(RDS)与临床肺损伤 表现为急性或成人RDS(ARDS)。该提案各有四个目标 涉及互补的生物物理测量和肺压力 体积(P-V)力学研究。目标1研究的组件基础 整体的表面活性函数和提取纯化的LS 其疏水成分的亚组分(例如，LS的完全混合物 不含阴离子的两性离子LS磷脂 磷脂、LS中性脂、磷脂加疏水性 载脂蛋白等)。目标2和目标3涉及与模型相关的研究 表面活性剂，包括二棕榈酰磷脂酰胆碱(DPPC)和其他 合成磷脂与疏水表面活性蛋白或 合成肽(AIM 2)及新型磷脂和磷脂 用特定结构变化合成的类似物(目标3)。研究 AIMS 1-3中的正常活动由AIMS 4实验补充 生理活性物质对LS和外源表面活性物质的钝化作用 通过几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、胎粪、脂肪酸、裂解酶)。 在所有的目标中，表面活性剂被用多种界面技术研究。 (威廉米天平、振荡气泡、吸收装置)来澄清 全系列的表面张力降低、再展开、滞后和 与LS相关的吸收行为。布鲁斯特角显微镜、X射线 衍射法、差示扫描量热法和傅立叶变换 红外光谱分析也被用来加强解释 分子和膜的结构水平。为了确保生理相关性， 表面活性和缓蚀剂的P-V力学关联式为 在四个拟议目标中的每一个内在切除的大鼠肺中确定。

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.