FUNDAMENTALS OF LUNG SURFACTANT ACTIVITY AND INHIBITION

该建议侧重于天然产物的表面活性和抑制作用， 和合成肺表面活性剂。强调的是生物物理作用， 磷脂和载脂蛋白成分的功能重要性 内源性肺表面活性物质（LS），沿着发展活跃 未来用于新生儿治疗的合成外源性替代品 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， 包括补充的生物物理测量和肺压 体积（P-V）力学研究。目标1研究了 在整个和提取的LS和纯化的表面和活性功能 其疏水成分的亚级分（例如，LS的完全混合 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）。目的2和3涉及模型相关研究 表面活性剂，包括二棕榈酰磷脂酰胆碱（DPPC）和其他 与疏水性表面活性剂蛋白结合的合成磷脂， 合成肽（Aim 2）和新的膦酰基脂质和磷脂 合成具有特定结构变异的类似物（Aim 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的生理失活- 通过几种机制起作用的相关抑制剂（例如，血浆蛋白， 溶血PC和其他膜脂质、胎粪、脂肪酸、溶解酶）。 在所有的目标中，表面活性剂都是通过多界面技术来研究的 （威廉米天平，振荡气泡，吸收装置）来阐明 全范围的表面张力降低、再扩散、滞后， 与LS相关的吸收行为。X射线布儒斯特角显微镜检查 衍射、差示扫描量热法和傅里叶变换 红外光谱也被用来提高解释在 分子和膜结构水平。为了确保生理相关性， 表面活性和抑制的P-V机械相关性是 在所提出的四个目标中的每一个中，在离体大鼠肺中测定。

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.