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，看看这种理解是否可以推广到包括溶菌脂和胎粪等其他抑制物，并为选择最佳聚合物和确定其浓度以逆转抑制提供简单的规则。抑制是肺表面活性物质从肺泡液吸附到空气-水界面的障碍，阻止了正常肺功能所需的低表面张力。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)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；(3)它们是表面活性的。我们假设小的、可溶的抑制剂(如白蛋白、溶菌脂等)。与较大的表面活性剂聚集体相比，表面活性剂吸附到界面上的速度更快；因此，表面活性剂必须将缓蚀剂从界面上置换出来才能吸附。这导致了表面活性剂吸附的能量障碍，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。最近在动物模型中发现，在表面活性剂溶液中加入亲水性聚合物可以逆转抑制作用；然而，确定最佳聚合物浓度、相对分子质量和化学成分的机制和方法仍不清楚。我们提出，这种抑制逆转是由于“耗竭效应”引起的，即当表面活性剂被强迫到界面时，溶液的自由体积增加，从而增加了聚合物的熵。耗尽力有助于克服表面活性剂吸附的障碍，该理论对聚合物的相对分子质量、化学成分和相对分子质量做出了具体的预测，这些都将在这一提议下进行测试。

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.