Lung surfactant adsorption and inhibition

描述（由申请人提供）：本提案的目标是在分子水平上了解血清蛋白对肺表面活性剂的抑制作用，看看这种理解是否可以推广到其他抑制剂，如溶脂和胎粪，并提供简单的规则，以选择最佳聚合物并确定其浓度以逆转抑制作用。抑制作用阻碍了肺表面活性剂从肺泡液到空气-水界面的吸附，阻止了正常肺功能所必需的低表面张力。这在与肺表面活性物质缺乏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），通常由早产引起，以及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，(3)它们具有表面活性。我们假设小的可溶性抑制剂（如白蛋白、溶脂等）比大的表面活性剂聚集体吸附到界面上更快；因此，表面活性剂必须从界面上取代抑制剂才能吸附。这导致表面活性剂吸附的能量屏障，因此，界面上的表面活性剂较少。因此，界面必须进一步压缩，以达到肺功能所需的低表面张力。在表面活性剂溶液中加入亲水性聚合物最近在动物模型中被证明可以逆转抑制作用；然而，确定最佳聚合物浓度、分子量和化学性质的机理和方法尚不清楚。我们提出抑制逆转是由于“耗竭效应”造成的，当表面活性剂被强迫到界面时，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，该理论对聚合物的分子量、化学性质和分子量做出了具体的预测，这些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.