Lung Surfactant Activity, Inhibition and Replacement

肺表面活性剂的活性、抑制和替代

• 批准号: 6579778
• 负责人: ROBERT H NOTTER
• 金额: $ 33.86万
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579778
• 关键词: adsorption; apolipoproteins; biomechanics; biomimetics; biophysics; chromatography; drug design /synthesis /production; infrared spectrometry; inhibitor /antagonist; interferometry; laboratory rat; lung injury; nonhuman therapy evaluation; phospholipids; pneumonia; pulmonary surfactants; respiratory gas transport; surface property; synthetic peptide; viscosity

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.

描述（由申请人提供）：本研究研究生物和合成肺表面活性剂的成分特异性分子生物物理学和生理活性。 主要目标是开发含有新型脂质和肽的新型高活性抗磷脂酶合成外源表面活性剂，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了解。 目标 1 和 2 检查含有新型磷脂酶抗性磷脂类似物以及合成肽或纯化脱辅基蛋白的合成外源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当前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（威廉天平、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的二醚和醚硫代磷脂和磷脂、合成的区域人类序列 SP-B、SP-C 和 SP-A 肽、合成的甘油磷脂以及从天然表面活性剂中通过色谱纯化的特定脂质和脱辅基蛋白。 目标 1、2 中的生物物理学和离体肺研究在目标 3 中得到扩展，以确定最活跃的外源性表面活性剂在逆转表面活性剂功能障碍、改善气体交换和减少患有 ARDS 相关革兰氏阴性肺炎的大鼠体内肺损伤方面的功效。 还研究了具有低剪切粘度的表面活性剂分散体的配方，以增强其气管滴注后的肺部输送和分布。 这种生物物理和生理学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​​部递送的新型外源表面活性剂用于治疗应用。