Lung Surfactant Activity, Inhibition and Replacement

描述（由申请人提供）：本研究研究了生物和合成肺表面活性剂的组分特异性分子生物物理学和生理活性。 一个主要的目标是开发新的高活性的磷脂酶抗性的合成外源性表面活性剂，含有新的脂质和肽用于新生儿和急性呼吸窘迫综合征（RDS和ARDS）。 该研究还旨在提高对表面活性剂活性和功能障碍的基本理解。 目的1和2检查含有新型抗磷脂酶磷脂类似物加合成肽或纯化脱辅基蛋白的合成外源性表面活性剂在灌洗切除的大鼠肺中的表面活性、抑制抗性和P-V机械效应。 灌洗小牛肺表面活性剂和目前的动物源性临床表面活性剂是比较标准。 使用补充生物物理方法来全面评估表面活性行为（Wilhelmy平衡、脉动气泡、吸附、布鲁斯特角显微镜、差示扫描量热法、FTIR光谱）。 研究的材料包括合成二醚和醚硫代膦酰基脂质和磷脂，合成区域人类序列SP-B，SP-C和SP-A肽，合成甘油磷脂，和特定的脂质和脱辅基蛋白从天然表面活性剂色谱纯化。 目的1、2中的生物物理学和切除肺研究在目的3中得到扩展，以确定最具活性的外源性表面活性剂在体内逆转表面活性剂功能障碍、改善气体交换和减少ARDS相关革兰氏阴性肺炎大鼠肺损伤方面的疗效。 还研究了具有低剪切粘度的表面活性剂分散体的制剂，以增强其在气管滴注后的肺部递送和分布。 这种生物物理和生理研究的综合层次将推进有关表面活性剂活性和功能障碍的基础知识，并定义具有最大活性、抑制抗性和肺部递送的新的外源性表面活性剂用于治疗应用。

DESCRIPTION (provided by applicant): This research studies the component-specific molecular biophysics and physiological activity of biological and synthetic pulmonary surfactants. A major goal is to develop new highly active phospholipase-resistant synthetic exogenous surfactants containing novel lipids and peptides for use in the neonatal and acute respiratory distress syndromes (RDS and ARDS). The research also seeks to improve fundamental understanding about surfactant activity and dysfunction. Aims 1 and 2 examine the surface activity, resistance to inhibition, and P-V mechanical effects in lavaged excised rat lungs of synthetic exogenous surfactants containing novel phospholipase-resistant phospholipid analogs plus synthetic peptides or purified apoproteins. Lavaged calf lung surfactant and current animal-derived clinical surfactants are comparative standards. Complementary biophysical methods are used to fully assess surface-active behavior (Wilhelmy balance, pulsating bubble, adsorption, Brewster-angle microscopy, differential scanning calorimetry, FTIR spectroscopy). Materials studied include synthetic di-ether and ether-thio-phosphonolipids and phospholipids, synthetic regional human-sequence SP-B, SP-C, and SP-A peptides, synthetic glycerophospholipids, and specific lipids and apoproteins purified chromatographically from natural surfactant. Biophysical and excised lung studies in Aims 1, 2 are extended in Aim 3, to define the efficacy of the most active exogenous surfactants in reversing surfactant dysfunction, improving gas exchange, and reducing lung injury in rats with ARDS-related gram negative pneumonitis in vivo. Also studied is the formulation of surfactant dispersions with low shear viscosity to enhance their pulmonary delivery and distribution following tracheal instillation. This integrated hierarchy of biophysical and physiological research will advance basic knowledge about surfactant activity and dysfunction, and define new exogenous surfactants with maximal activity, inhibition resistance, and pulmonary delivery for therapeutic applications.