Lung surfactant adsorption and inhibition

肺表面活性物质的吸附和抑制

• 批准号: 7061294
• 负责人: JONATHAN G FERNSLER
• 金额: $ 2.37万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2006-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061294
• 关键词: adsorption; blood proteins; fluorescence microscopy; fluorescence resonance energy transfer; hydropathy; intermolecular interaction; lipid solubility; low angle X ray diffraction analysis; molecular film; osmotic pressure; phase change; phospholipids; physical chemical interaction; polyethylene glycols; polymers; postdoctoral investigator; pulmonary surfactants; respiratory function; respiratory gas level; serum albumin; surface property; synthetic peptide

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a molecular-level understanding of lung surfactant inhibition by blood serum proteins, to see if this understanding can be generalized to include other inhibitors such as lysolipids and meconium, and to provide simple rules for choosing an optimal polymer and determining its concentration to reverse inhibition. Inhibition, the impediment of lung surfactant adsorption from the alveolar fluid to the air-water interface, prevents the low surface tensions necessary for proper lung function. This is an important effect in diseases associated with a lack of lung surfactant including neonatal respiratory distress syndrome (NRDS), often due to premature delivery, and acute respiratory distress syndrome (ARDS). The common features of inhibitors are (1) they are not normally present in the alveolar fluid; (2) they are water soluble, and (3) they are surface active. We hypothesize that small, soluble inhibitors (such as albumin, lysolipids, etc.) adsorb faster to an interface than the larger surfactant aggregates; hence the surfactant has to displace inhibitor from the interface in order to adsorb. This leads to an energy barrier to surfactant adsorption, and hence, less surfactant at the interface. As a result, the interface must be compressed further to reach the low surface tensions necessary for lung function. Adding hydrophilic polymers to the surfactant solution has recently been shown in animal models to reverse inhibition; however, the mechanism and method of determining the optimal polymer concentration, molecular weight and chemistry is still unknown. We have proposed that the inhibition reversal is due to the "depletion effect", caused by the increase in free volume of the solution when the surfactant is forced to the interface, which increases the polymer entropy. The depletion force helps overcome the barrier to surfactant adsorption and the theory makes specific predictions regarding polymer molecular weight, chemistry and molecular weight which will be tested under this proposal.

描述（由申请人提供）：该提案的目的是对血清蛋白抑制肺表面活性剂抑制的分子水平的理解，以查看是否可以将这种理解概括为包括其他抑制剂，例如溶血脂质和meconium，以及为选择最佳的浓度和确定浓度的简单规则。抑制作用，肺表面活性剂吸附从肺泡液到空气水界面的障碍可防止适当的肺功能所需的低表面张力。这是与缺乏包括新生儿呼吸窘迫综合征（NRDS）有关的疾病的重要作用，通常是由于过早递送和急性呼吸遇险综合征（ARDS）。抑制剂的共同特征是（1）它们通常不存在于肺泡液中； （2）它们是水溶性的，（3）它们表面活跃。我们假设比较大的表面活性剂聚集体更快地吸附到界面上的小，可溶性抑制剂（例如白蛋白，溶血脂等）。因此，表面活性剂必须从界面中置换抑制剂，以使其对吸附。这导致表面活性剂吸附的能屏障，因此在界面处的表面活性剂较少。结果，必须将界面进一步压缩，以达到肺功能所需的低表面张力。最近在动物模型中显示了在表面活性剂溶液中添加亲水性聚合物以逆转抑制作用。但是，确定最佳聚合物浓度，分子量和化学的机制和方法仍然未知。我们已经提出，抑制作用逆转是由于“耗尽效应”引起的，这是由于强迫表面活性剂被迫到界面时溶液的自由体积增加，这增加了聚合物熵。耗尽力有助于克服表面活性剂吸附的障碍，该理论对聚合物分子量，化学和分子量进行了具体预测，该预测将根据该提案进行测试。