Lung Surfactant Activity, Inhibition and Replacement

肺表面活性剂的活性、抑制和替代

• 批准号: 6725491
• 负责人: ROBERT H NOTTER
• 金额: $ 30.98万
• 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/6725491
• 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）：本研究研究了生物学和合成肺表面活性剂的成分特异性分子生物物理学以及生理活性。 一个主要目标是开发新的高度活性磷脂酶耐药的合成外源表面活性剂，其中含有新型脂质和肽用于新生儿和急性呼吸遇险综合征（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。 目标1和2检查表面活性，对抑制的抗性以及P-V机械作用在含有新型磷脂酶耐药的磷脂类似物以及合成肽或合成肽或纯化的垂体蛋白的合成外源性表面活性剂中的切开大鼠肺中的P-V机械作用。 流放的小腿肺表面活性剂和当前动物衍生的临床表面活性剂是比较标准。 互补的生物物理方法用于完全评估表面活性行为（Wilhelmy平衡，脉动气泡，吸附，Brewster-gyle-gyle显微镜，差异扫描量热法，FTIR光谱法）。 所研究的材料包括合成二醚和硫硫代磷脂以及磷脂，合成区域人类序列SP SP-B，SP-C和SP-A肽，合成甘油磷脂，特定的脂质以及从天然表面抗素的脂肪素纯化的脂蛋白。 AIM 1、2中的生物物理和切除的肺研究在AIM 3中扩展，以定义最活跃的外源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与ARDS ARDS相关的Gram阴性肺炎的大鼠中的肺损伤的功效。 还研究了具有低剪切粘度的表面活性剂分散剂的制剂，以增强气管滴注后的肺部递送和分布。 生物物理和生理研究的综合层次结构将提高有关表面活性剂活性和功能障碍的基本知识，并定义具有最大活性，抑制性耐药性和用于治疗应用的肺部递送的新外源表面活性剂。