Lung surfactant adsorption and inhibition

描述（由申请人提供）：本提案的目标是从分子水平了解血清蛋白对肺表面活性物质的抑制作用，以了解这种了解是否可以推广到包括其他抑制剂，如溶血脂和胎粪，并提供选择最佳聚合物和确定其浓度以逆转抑制作用的简单规则。抑制，肺表面活性剂从肺泡液吸附到空气-水界面的障碍，防止了正常肺功能所需的低表面张力。这在与缺乏肺表面活性物质相关的疾病中具有重要作用，包括新生儿呼吸窘迫综合征（NRDS）（通常由于早产）和急性呼吸窘迫综合征（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，以及（3）它们是表面活性的。我们假设，小的可溶性抑制剂（如白蛋白，溶血脂等），比较大的表面活性剂聚集体更快地吸附到界面;因此表面活性剂必须从界面置换抑制剂以进行吸附。这导致表面活性剂吸附的能垒，因此界面处的表面活性剂较少。因此，必须进一步压缩界面以达到肺功能所需的低表面张力。最近在动物模型中显示，向表面活性剂溶液中添加亲水性聚合物可逆转抑制;然而，确定最佳聚合物浓度、分子量和化学性质的机制和方法仍是未知的。我们已经提出，抑制逆转是由于“耗尽效应”，造成的自由体积的溶液中，当表面活性剂被迫到界面，这增加了聚合物熵的增加。消耗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，这些预测将在本提案下进行测试。

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.