Lung Surfactant Activity, Inhibition and Replacement

描述(申请人提供)：本研究研究生物和合成肺表面活性物质的特定成分的分子生物物理和生理活性。一个主要目标是开发新的高活性、抗磷脂酶的合成外源表面活性物质，含有新的脂类和多肽，用于新生儿和急性呼吸窘迫综合征(RDS和ARDS)。这项研究还试图提高对表面活性物质活性和功能障碍的基本理解。目标1和目标2检测含有新型磷脂抗磷脂类似物和合成肽或纯化的载脂蛋白的合成外源表面活性剂对灌洗后的大鼠肺的表面活性、抑制能力和P-V机械效应。灌洗小牛肺表面活性物质和目前动物来源的临床表面活性物质是比较标准。使用互补的生物物理方法来全面评估表面活性行为(Wilhelmy平衡法、脉动气泡、吸附、布鲁斯特角显微镜、差示扫描量热法、FTIR光谱)。所研究的材料包括合成的二醚和乙醚硫代磷脂和磷脂，合成的区域人序列SP-B、SP-C和SP-A肽，合成的甘油磷脂，以及从天然表面活性物质中层析纯化的特定脂类和载脂蛋白。AIMS 1、2中的生物物理和肺切除研究在AIMS 3中得到扩展，以确定最活跃的外源性表面活性物质在体内逆转ARDS相关革兰氏阴性肺炎大鼠的表面活性物质功能障碍、改善气体交换和减少肺损伤方面的有效性。还研究了具有低剪切粘度的表面活性物质分散体的配方，以增强其在气管滴注后的肺转运和分布。这一生物物理和生理学研究的综合层次将促进关于表面活性物质活性和功能障碍的基础知识，并定义具有最大活性、抑制阻力和肺递送的新的外源性表面活性物质用于治疗应用。

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.